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Michael Wang,1,* Claude Negrier,2,* Frank Driessler,3,* Clifford Goodman,4,* Mark W Skinner5,6,* 1University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 2National Reference Center for Haemophilia, Louis Pradel Cardiology Hospital, University of Lyon, Lyon, France; 3Bayer, Basel, Switzerland; 4The Lewin Group, Falls Church, VA, USA; 5Institute for Policy Advancement Ltd, Washington, DC, USA; 6McMaster University, Hamilton, ON, Canada*These authors contributed equally to this workCorrespondence: Frank Driessler, Bayer AG, Peter Merian Straße 84, Basel, CH-4052, Switzerland, Tel +41 79 422 32 18, Email frank.driessler@bayer.comPurpose: The anticipated emergence of hemophilia gene therapy will present people with hemophilia (PWH) and treating clinicians with increasingly complex treatment options. It will be critical that PWH and their families be empowered to participate fully in decision-making through transparent communication and the development of targeted educational resources.Methods: The Council of Hemophilia Community (CHC) convened across a series of roundtable meetings to define the patient journey for hemophilia gene therapy, and to develop a question-and-answer style resource to guide discussion between healthcare professionals (HCPs) and their patients. Patient groups were also consulted during the development of this tool.Results: The CHC defined 5 key stages in the hemophilia gene therapy patient journey: pre-gene therapy (information-seeking and decision-making), treatment initiation, short- and long-term post-gene therapy follow-up. PWH will have different questions and concerns at each stage of their journey, which should be discussed with their HCP to aid decision-making. The resulting patient journey infographic and Q&A resource (see Supplementary Materials) has been developed for HCPs and PWH to provide a novel and practical roadmap of key issues and considerations throughout all stages.Conclusion: These resources support a collaborative, patient-centric, shared decision-making approach to inform treatment decision discussions between HCPs and PWH. The value of such discussions will be influenced by the language adopted; health literacy is a particularly important consideration, and these discussions should be accessible and tailored to PWH. HCPs and PWH can benefit from awareness of the common questions and uncertainties as they progress together along the patient journey. While the contents of this article are specific to hemophilia gene therapy, the concepts developed here could be adapted to aid patients in other disease states.Keywords: hemophilia, patients, HCP guidance, health literacy, disease awareness, treatment landscape

Intra-articular infusion of local anaesthetic after joint arthroplasty is attractive in that it is simple and will not cause motor block. However the efficacy of the technique has yet to be established. We enrolled 66 patients scheduled for unilateral total knee arthroplasty under general anaesthesia and single-shot femoral and sciatic nerve blocks. All patients had an intra-articular Painbuster device sited at the end of the procedure. Patients were then randomised to control or one of two treatment arms - low-dose and high-dose ropivacaine. In the control group the balloon was filled with saline, in the low-dose group with 0.2% ropivacaine and in the high-dose group 0.375% ropivacaine. The catheters were infused continuously for 48 hours and then removed. Patients were followed up daily for three days to determine pain scores, opioid consumption and subjective assessment of the analgesic efficacy of the catheter Data were analysed for 30 controls and 31 in the treatment arms. Both groups were similar There were no significant differences between the control and treatment groups at all time points after adjustment for age. Patients in the high-dose group had higher pain scores and higher opioid consumption than the control groups from 24 to 48 hours. There were two cases of infection, both in the treatment groups. No positive benefit of intra-articular infusion of local anaesthetic after total knee arthroplasty could be identified. On the contrary there may be negative effects in terms of expense, pain and possibly infection risks. [ABSTRACT FROM AUTHOR]

BACKGROUND: The use of bilateral amplification is now common clinical practice for hearing aid users but not for cochlear implant recipients. In the past, most cochlear implant recipients were implanted in one ear and wore only a monaural cochlear implant processor. There has been recent interest in benefits arising from bilateral stimulation that may be present for cochlear implant recipients. One option for bilateral stimulation is the use of a cochlear implant in one ear and a hearing aid in the opposite nonimplanted ear (bimodal hearing). PURPOSE: This study evaluated the effect of wearing a cochlear implant in one ear and a digital hearing aid in the opposite ear on speech recognition and localization. RESEARCH DESIGN: A repeated-measures correlational study was completed. STUDY SAMPLE: Nineteen adult Cochlear Nucleus 24 implant recipients participated in the study. INTERVENTION: The participants were fit with a Widex Senso Vita 38 hearing aid to achieve maximum audibility and comfort within their dynamic range. DATA COLLECTION AND ANALYSIS: Soundfield thresholds, loudness growth, speech recognition, localization, and subjective questionnaires were obtained six-eight weeks after the hearing aid fitting. Testing was completed in three conditions: hearing aid only, cochlear implant only, and cochlear implant and hearing aid (bimodal). All tests were repeated four weeks after the first test session. Repeated-measures analysis of variance was used to analyze the data. Significant effects were further examined using pairwise comparison of means or in the case of continuous moderators, regression analyses. The speech-recognition and localization tasks were unique, in that a speech stimulus presented from a variety of roaming azimuths (140 degree loudspeaker array) was used. RESULTS: Performance in the bimodal condition was significantly better for speech recognition and localization compared to the cochlear implant-only and hearing aid-only conditions. Performance was also different between these conditions when the location (i.e., side of the loudspeaker array that presented the word) was analyzed. In the bimodal condition, the speech-recognition and localization tasks were equal regardless of which side of the loudspeaker array presented the word, while performance was significantly poorer for the monaural conditions (hearing aid only and cochlear implant only) when the words were presented on the side with no stimulation. Binaural loudness summation of 1-3 dB was seen in soundfield thresholds and loudness growth in the bimodal condition. Measures of the audibility of sound with the hearing aid, including unaided thresholds, soundfield thresholds, and the Speech Intelligibility Index, were significant moderators of speech recognition and localization. Based on the questionnaire responses, participants showed a strong preference for bimodal stimulation. CONCLUSIONS: These findings suggest that a well-fit digital hearing aid worn in conjunction with a cochlear implant is beneficial to speech recognition and localization. The dynamic test procedures used in this study illustrate the importance of bilateral hearing for locating, identifying, and switching attention between multiple speakers. It is recommended that unilateral cochlear implant recipients, with measurable unaided hearing thresholds, be fit with a hearing aid. [ABSTRACT FROM AUTHOR]

This paper contributes to the literature on the geographies of care and caregiving by examining the implications of weather for providing home and community care for children and older adults. Integrating research from two previous qualitative studies of formal and informal care provisioning in Ontario, Canada, the authors re-analyzed semi-structured interviews with 83 directors, managers, paid staff, volunteers and family members to examine the challenges they faced when providing care during the winter season. Similar to other settings where winter conditions like snow, ice and cold temperatures are commonplace, the studies were set within a health policy context in which there is not enough recognition of the difficulties of weather for coordinating, managing and providing care to disabled, injured, chronically ill and frail individuals. The re-analysis focused on how winter conditions translate into geographical, administrative, economic, operational, physical, social and psychological barriers within and across different 'scales of care'. The findings indicate that the problems posed by weather are crucial yet often underestimated aspects of home and community care provided by formal and informal caregivers. The analysis of weather-related challenges for care provisioning needs to be extended to other seasonal conditions (e.g., the challenges of delivering care in extreme heat), to the developing world and even to the burgeoning debates on the health implications of global environmental change. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the effect of the increased instantaneous input dynamic range (IIDR) in the Nucleus Freedom cochlear implant (CI) system on recipients' ability to perceive soft speech and speech in noise. Ten adult Freedom CI recipients participated. Two maps differing in IIDR were placed on each subject's processor at initial activation. The IIDR was set to 30 dB for one map and 40 dB for the other. Subjects used both maps for at least one month prior to speech perception testing. Results revealed significantly higher scores for words (50 dB SPL), for sentences in background babble (65 dB SPL), and significantly lower sound field threshold levels with the 40 compared to the 30 dB IIDR map. Ceiling effects may have contributed to non-significant findings for sentences in quiet (50 dB SPL). The Freedom's increased IIDR allows better perception of soft speech and speech in noise. [ABSTRACT FROM AUTHOR]

Thirty 'new' lists of monosyllabic words were created at the University of Melbourne and recorded by Australian and American English speakers. These new lists and the ten original CNC lists (Peterson and Lehiste, 1962) were used during the feasibility study of the Nucleus Research Platform 8 Cochlear Implant System (Holden et al, 2004). Performance was similar across original and new lists for six implanted Australian subjects; for four implanted U.S. subjects, mean performance was 23 percentage points lower with the new than with the original lists. To evaluate differences between original and new lists for the American English recording, 22 CI recipients were administered all 40 CNC lists (30 new and 10 original lists). The overall mean word score for the new lists was significantly lower (22.3 percentage points) than for the original lists. Acoustic analysis revealed that decreased performance was most likely due to reduced amplitudes of certain initial and final consonants. The new CNC lists can be used as more difficult test material for clinical research. [ABSTRACT FROM AUTHOR]

This paper considers how long-term care restructuring, under the rubric of managed competition, has increased pressure on voluntary sector providers of long-term care to elderly populations in small, rural places. Drawing on in-depth interviews with key-informants from non-profit organizations, we present a case study set in rural Ontario to develop a situated understanding of the impact of restructuring on voluntary sector providers of long-term care. We contend that managed competition (underway in Ontario since 1995) has constrained providers, eroded service choices, and reduced access to long-term care in rural areas leaving rural populations more disadvantaged than ever before when it comes to public service provisioning. [ABSTRACT FROM AUTHOR]

Results of studies performed in our laboratory suggest that cochlear implant recipients understand speech best if the following speech processor parameters are individually chosen for each person: minimum and maximum stimulation levels on each electrode in the speech processor program (MAP), stimulation rate, and speech coding strategy. If these and related parameters are chosen to make soft sounds (from approximately 100 to 6,000 Hz) audible at as close to 20 dB hearing level as possible and loud sounds not too loud, recipients have the opportunity to hear speech in everyday life situations that are of key importance to children who are learning language and to all recipients in terms of ease of communication. [ABSTRACT FROM AUTHOR]

The choice of frequency boundaries for the analysis channels of cochlear implants has been shown to impact the speech perception performance of adult recipients (Skinner et al, 1995; Fourakis et al, 2004). While technological limitations heretofore have limited the clinical feasibility of investigating novel frequency assignments, the SPEAR3 research processor affords the opportunity to investigate an unlimited number of possibilities. Here, four different assignments are evaluated using a variety of speech stimuli. All participants accommodated to assignment changes, and no one assignment was significantly preferred. The results suggest that better performance can be achieved using a strategy whereby (1) there are at least 7-8 electrodes allocated below 1000 Hz, (2) the majority of remaining electrodes are allocated between 1100-3000 Hz, and (3) the region above 3 kHz is represented by relatively few electrodes (i.e., 1-3). The results suggest that such frequency assignment flexibility should be made clinically available. [ABSTRACT FROM AUTHOR]

Two speech processor programs (MAPs) differing only in electrode frequency boundary assignments were created for each of eight Nucleus 24 Cochlear Implant recipients. The default MAPs used typical frequency boundaries, and the experimental MAPs reassigned one additional electrode to vowel formant regions. Four objective speech tests and a questionnaire were used to evaluate speech recognition with the two MAPs. Results for the closed-set vowel test and the formant discrimination test showed small but significant improvement in scores with the experimental MAP. Differences for the Consonant-Vowel Nucleus-Consonant word test and closed-set consonant test were nonsignificant. Feature analysis revealed no significant differences in information transmission. Seven of the eight subjects preferred the experimental MAP, reporting louder, crisper, and clearer sound. The results suggest that Nucleus 24 recipients should be given an opportunity to compare a MAP that assigns more electrodes in vowel formant regions with the default MAP to determine which provides the most benefit in everyday life. [ABSTRACT FROM AUTHOR]

Our knowledge of testis development and function mainly comes from research using mammalian model organisms, primarily the mouse. However, there are integral differences between men and other mammalian species regarding cellular composition and expression profiles during fetal and post-natal testis development and in the mature testis. Therefore, to specifically learn more about human testis development and function, there is a need to use human testis tissue for research. Human testicular tissues that have been donated for research have allowed extensive molecular and cytological assessments, as well as single-cell transcriptome and epigenome analyses. These tissues have also been used for the development of cell technologies and in vitro models that aim to improve infertility treatments and diagnostics. Biopsied material taken from patients and designated for research is usually very small in size and is unsuitable for comprehensive studies. On the other hand, research using whole testes obtained from deceased, deidentified donors has become a valuable resource to assess conservation between humans and other organisms and identify human-specific phenomena. This review discusses the acquisition of donated deidentified human testes and their use for basic science research., (© 2025 The Author(s). Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Introduction: People with haemophilia A (PwHA) experience acute and chronic pain associated with reduced quality of life (QoL)., Aims: This post hoc analysis of pooled data from the HAVEN 1 (NCT02622321), 3 (NCT02847637), 4 (NCT03020160) and STASEY (NCT0319179) studies assessed the impact of emicizumab prophylaxis on pain-related QoL in PwHA., Methods: PwHA received emicizumab during the four studies. In this analysis, pain was assessed using patient-reported responses to pain-specific questions from the Haem-A-QoL/Haemo-QoL-SF and the pain/discomfort dimension of the EQ-5D-5L. Responses were recorded at baseline and at regular intervals for up to 78 weeks following treatment initiation. Additional analyses evaluated the population with target joints at baseline, and the overall population stratified by age, factor (F)VIII inhibitor status and prior treatment., Results: At the data cut-off, 504 PwHA had been treated across the four studies; 464 and 470 completed the Haem-A-QoL/Haemo-QoL-SF and the EQ-5D-5L, respectively. Improvements in pain-related QoL were observed by Week 13 of emicizumab prophylaxis and maintained through Week 78. In the overall population, responses of 'never/rarely' for 'my swellings hurt' and 'pain in joints' increased from 37.0% and 30.0% at baseline to 84.0% and 61.0% by Week 13, suggesting reductions in acute and chronic pain, respectively. Similar improvements were seen in the target joint population, and across all strata. Greater improvements were observed in younger versus older PwHA., Conclusion: Pain-related QoL improved with emicizumab prophylaxis regardless of target joints, age, FVIII inhibitor status or prior treatment. Haemophilia-specific assessments are needed to accurately capture and characterize pain in PwHA., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Introduction: The 2024 ISTH clinical practice guideline (CPG) for treatment of congenital haemophilia, the NBDF-McMaster Guideline on Care Models for Haemophilia Management, and ASH ISTH NBDF WFH guidelines on the diagnosis and management of VWD all utilised GRADE methodology., Aim: Discuss missed opportunities and the methodological approach of the ISTH Guideline in contrast to how GRADE was previously applied in rare diseases., Methods: Critically analyse the methodology of each guideline along with best practices in the use of GRADE. Where applicable, the WFH Guidelines for the Management of Haemophilia were analysed., Results: Important differentiating features in applying GRADE were identified. Where a strong evidence base is lacking, data other than those from randomized controlled trials, which may not always be justified, need to be considered, including incorporation of outcomes important to people living with the disease. Justification and stakeholder input to prioritize questions requiring a new guideline, panel composition with necessary patient participation and content expertise were also found to be significant differentiating features., Conclusion: The puristic approach taken in the ISTH Guideline development process, without consideration of accepted adaptations to GRADE implementation, created a missed opportunity for progressing haemophilia care, leading to guideline recommendations that have been widely deemed invalid and obsolete by expert healthcare professionals and by those living with the condition, the very people who are expected to implement or bear the impact of the recommendations. Lessons learnt from this comparative analysis should guide future guideline development and encourage collaboration to further advance haemophilia., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Evidence-based clinical practice guidelines drive optimal patient care and facilitate access to high-quality treatment. Creating guidelines for rare diseases such as haemophilia, where evidence does not often come from randomized controlled trials but from non-randomized and well-designed observational studies and real-world data, is challenging. The methodology used for assessing available evidence should consider this critical fact. In formulating guidelines, it is essential to include treatment goals and patient preference., Aim: This paper comprehensively critiques, against this background, the recommendations of the ISTH clinical practice guidelines for the treatment of haemophilia., Methods: Each recommendation was critically reviewed against available evidence as well as existing guidelines and commented upon for its scientific validity, impact on clinical practice and access to care globally. The validity of the way in which the GRADE methodology was applied to existing evidence was also assessed., Results: The critique provided shows that these recommendations have major limitations: they did not state treatment goals and contradict existing guidelines; opportunities for providing access to innovation were missed when the therapeutic benefits of the products approved in the last decades were not included. A major reason for this is the inappropriate adoption of the GRADE methodology without adaptations and without considering treatment goals and patient-relevant outcomes., Conclusion: These recommendations may mislead healthcare professionals, payers and governments and therefore cannot serve the patient community well. They setback the advances made in haemophilia care because they overlook important available evidence and do not guide clinical practice to contemporary standards., (© 2024 John Wiley & Sons Ltd.)

Introduction: Treatment options are expanding for von Willebrand disease (VWD). A core outcome set (COS)-a minimum set of agreed-upon outcomes to be used in every clinical trial for a given condition-provides guidance on which outcomes are most important to measure to ensure necessary data is collected for a variety of stakeholders and enable comparison across products and trials., Aim: coreVWD aimed to develop a COS for trials for prophylaxis and perioperative treatments for VWD., Methods: A modified Delphi consensus process was used to condense/prioritize a long list of potential outcomes. Over three Delphi rounds, a multi-stakeholder panel (patients, clinicians, pharmaceutical company representatives, HTA organizations, payer, and government organization representatives) rated each outcome from 1 (not important to include in a COS) to 9 (essential to include). Outcomes were eliminated or retained based on pre-determined criteria; a special provision to elevate patient priorities was included. An in-person consensus meeting was held after Delphi round 2., Results: Thirty-nine panellists participated. The final COS for prophylaxis treatment included 18 outcomes, seven of which are part of a special subset selected for women, girls and people with the potential to menstruate. There were 11 outcomes in the final perioperative branch COS. Six outcomes overlapped both COS., Conclusions: The coreVWD COS represents a consensus list of outcomes for clinical trials for both factor and non-factor VWD therapies. These outcomes will be useful across the lifecycle of a product, from clinical development through regulatory and market access phases and into patient-provider decision-making., (© 2024 John Wiley & Sons Ltd.)

Introduction: The use of shared decision-making (SDM) in clinical settings is becoming more prevalent. The evolving and increasingly complex treatment landscape of haemophilia management has augmented the need and desire for SDM between patients and their healthcare team. SDM tools have been used in other chronic conditions and can be an effective form of education for patients and clinicians., Aim: The World Federation of Hemophilia (WFH) partnered with people with haemophilia (PWH), patient advocacy groups, and healthcare practitioners to form an expert working group to develop an educational tool for PWH and their caregivers. The primary objectives included educating PWH on the available prophylactic treatments and facilitating discussion between PWH and their healthcare team., Methods: The tool was proposed and developed by the expert working group, workshopped at conference round tables, and evaluated in two focus groups., Results: The interactive WFH SDM Tool guides users through the SDM treatment journey and provides an opportunity for reflection on current disease impact and treatment preferences, educational fact sheets and videos, and a comparison between treatment classes. Two forms of the SDM Tool are available: an online platform with a summary page that may be printed and shared and a printable workbook. All evidence in the tool is based on the prescribing information or phase III clinical trial publications. The Tool will be updated twice each year., Conclusion: The WFH SDM Tool is the first available resource that translates published guidance on SDM in haemophilia into a practical, user-friendly tool aimed at facilitating patient-centred treatment decisions., (© 2024 John Wiley & Sons Ltd.)

Introduction: Currently, no quality-of-life instrument exists that captures the full experience of the mental health outlook (MHO), a coreHEM core outcome, in people with haemophilia, including the potential transformational experience of receiving gene therapy., Aim: To describe the methods used to develop a content validated patient-reported outcome measure (PROM) that measures MHO for people with haemophilia., Methods: A conceptual framework, developed from a literature/evidence review, was used to create an interview guide and draft a questionnaire. Males aged 15 or older with severe/moderate haemophilia were eligible to participate in concept elicitation or cognitive debriefing interviews. The conceptual framework was refined based on a thematic analysis of concept elicitation interviews and PROM items were developed from the conceptual framework. Cognitive debriefing sessions that prioritised relevance and understanding of the PROM were held in two rounds; items were updated iteratively., Results: A conceptual framework with five domains (stigma, anxiety, depression, life interference and identity) was constructed from over 300 identified MHO concepts. Fifty-three participants took part in interviews. After 32 concept elicitation interviews, the framework was updated by including eight new sub-concepts and eliminating two. Updates to the questionnaire included items added or removed and improved wording. The final coreHEM MHO PROM has 26 questions in two sections (general mental health associated with haemophilia, and a gene therapy section)., Conclusions: The instrument is content-validated and can be used as an exploratory outcome. MHO scores can be measured and compared to give more insight into patient quality of life., (© 2024 John Wiley & Sons Ltd.)

Centrosomes are the canonical microtubule organizing centers (MTOCs) of most mammalian cells, including spermatocytes. Centrosomes comprise a centriole pair within a structurally ordered and dynamic pericentriolar matrix (PCM). Unlike in mitosis, where centrioles duplicate once per cycle, centrioles undergo two rounds of duplication during spermatogenesis. The first duplication is during early meiotic prophase I, and the second is during interkinesis. Using mouse mutants and chemical inhibition, we have blocked centriole duplication during spermatogenesis and determined that non-centrosomal MTOCs (ncMTOCs) can mediate chromosome segregation. This mechanism is different from the acentriolar MTOCs that form bipolar spindles in oocytes, which require PCM components, including gamma-tubulin and CEP192. From an in-depth analysis, we identified six microtubule-associated proteins, TPX2, KIF11, NuMA, and CAMSAP1-3, that localized to the non-centrosomal MTOC. These factors contribute to a mechanism that ensures bipolar MTOC formation and chromosome segregation during spermatogenesis when centriole duplication fails. However, despite the successful completion of meiosis and round spermatid formation, centriole inheritance and PLK4 function are required for normal spermiogenesis and flagella assembly, which are critical to ensure fertility., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: The Patient Reported Outcomes, Burdens, and Experiences (PROBE) questionnaire is a patient-reported outcome tool that assesses quality of life and disease burden in people with haemophilia (PWH)., Aim: To assesses the test-retest reliability of PROBE when completed using the mobile phone application., Methods: We recruited PWH, including carriers, and individuals with no bleeding disorders who attended haemophilia-related workshops or via social media. Participants completed PROBE three times (twice on the app: T1 and T2, and once on the web, T3). Test-retest reliability was analysed for T1 versus T2 (app to app, time period one) and T2 versus T3 (app to web, time period two)., Results: We enrolled 48 participants (median age = 56 [range 27-78] years). Eighteen participants (37.5%) were PWH and seven (14.6%) were carriers. On general health domain questions, we found almost perfect agreement, except for a question on the frequency of use of pain medication in the last 12 months [Kappa coefficient (κ) .72 and .37 for time period one and two, respectively] and any use of pain medications (κ .75) for time period two. For haemophilia-related questions, we found substantial to perfect agreement, except for the questions on the number of joint bleeds in the previous 6 months for time period one (κ .49) and the number of bleeds in the previous two weeks for time period two (κ .34)., Conclusions: The results demonstrate the reliability of the PROBE app. The app can be used interchangeably with the paper and web platforms for PROBE administration., (© 2024 John Wiley & Sons Ltd.)

Background: Severe hemophilia A (HA) negatively impacts health-related quality of life (HRQOL)., Objectives: We aimed to analyze HRQOL in adult men with severe HA without inhibitors after valoctocogene roxaparvovec gene transfer in the phase 3 trial GENEr8-1., Methods: Participant-reported outcomes were the hemophilia-specific quality of life questionnaire for adults (Haemo-QOL-A), the EQ-5D-5L instrument, the Hemophilia Activities List (HAL), and the Work Productivity and Activity Impairment Questionnaire: Hemophilia Specific (WPAI+CIQ:HS). Participants completed the questionnaires at baseline and through 104 weeks postinfusion with 6 × 10 13 vg/kg of valoctocogene roxaparvovec. Scores were analyzed per participant characteristics and outcomes., Results: For 132 HIV-negative participants, mean change from baseline in Haemo-QOL-A Total Score met the anchor-based clinically important difference (CID: 5.5) by week 12; the mean (SD) increase was 7.0 (12.6) at week 104. At week 104, improvement in Consequences of Bleeding, Treatment Concern, Worry, and Role Functioning domain scores exceeded the CID (6). EQ-5D-5L Utility Index scores improved above the CID at week 52, but not at week 104. EQ-5D-5L visual analog scale and HAL scores increased from baseline to week 104. Participants reported less activity and work impairment at week 104 than baseline. Participants with problem joints had lower mean baseline Haemo-QOL-A Total and domain scores than those without them, but improved over 104 weeks, except for 11 participants with ≥3 problem joints. Participants with 0 bleeds during the baseline prophylaxis period reported Haemo-QOL-A score improvements above the CID, including in the Consequences of Bleeding domain., Conclusion: Valoctocogene roxaparvovec provided clinically meaningful HRQOL improvement for men with severe HA., Competing Interests: Declaration of competing interests B.O.M. reports consulting fees from BioMarin Pharmaceutical Inc and Freeline. A.L.D. reports research funding from Sanofi, Takeda, Freeline, BioMarin Pharmaceutical Inc, and the American Thrombosis and Hemostasis Network; consulting fees from BioMarin Pharmaceutical Inc, Genentech/Roche, Kedrion, CSL Behring, and uniQure; and service on the board of the World Federation of Hemophilia USA. A.D.L. reports consulting or advisory panel fees from BioMarin Pharmaceutical Inc, Dova, CSL Behring, Merck, Catalyst, and HEME Biologics; and participation as a clinical trial investigator in trials sponsored by BioMarin Pharmaceutical Inc, Sangamo, and Pfizer. F.P. reports honoraria as a speaker for educational symposia by Grifols, Sanofi, and Takeda and as an advisory member for Sanofi and Roche. M.C.O. reports consulting fees from Bayer, BioMarin Pharmaceutical Inc, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda; research grants from Pfizer, Roche, and Takeda; service as a clinical trial investigator for BioMarin Pharmaceutical Inc, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda; speaker honoraria from Bayer, BioMarin Pharmaceutical Inc, Novo Nordisk, Roche, and Takeda; travel support from Novo Nordisk, Roche, and Takeda; and participation in grant reviewing for Grifols. J.M. reports consulting fees from Baxalta, CSL Behring, Catalyst Biosciences, Freeline, LFB, Novo Nordisk, and Spark; research grants from and service as a clinical trial investigator for BioMarin Pharmaceutical Inc, CSL Behring, Novo Nordisk, Pfizer, Sobi, Roche, Novartis, Sanofi, and Unique; and speaker fees from Novo Nordisk, Pfizer, Sanofi, Sobi, Shire, Roche, Takeda, the International Society on Thrombosis and Haemostasis, and the World Federation of Hemophilia. K.P. reports consulting fees and research grants from Sobi, Octapharma, Novo Nordisk, and Pfizer; and served as a clinical trial investigator for uniQure, BioMarin Pharmaceutical Inc, and Roche. J-D.W. reports consulting fees from Bayer, Novo Nordisk, Pfizer, Chugai, Sanofi, Takeda, and Sobi; speaker fees from Bayer, CSL Behring, Novo Nordisk, Pfizer, Chugai, Sanofi, and Takeda; and service as a clinical trial investigator for Bayer, BioMarin Pharmaceutical Inc, Novo Nordisk, Pfizer, Roche/Chugai, and Sanofi. G.L. has received honoraria for participating in educational events from Novartis, LEO, Sobi, Alexion, Takeda, Novo Nordisk, and Sanofi; and consulting fees from UCB. A.G. reports honoraria for service on advisory boards from BioMarin Pharmaceutical Inc, Genentech, Pfizer, Bayer, ATHN, Novo Nordisk, uniQure, and Sanofi Genzyme; and travel grants from BioMarin Pharmaceutical Inc. E.C. reports consulting fees from Genentech, BioMarin Pharmaceutical Inc, Novo Nordisk, Takeda, Sanofi, HEMA Biologics, and CSL Behring; and speaker fees from Genentech. D.P. reports a travel grant from Pfizer. H.C. reports consulting fees from Bayer, BioMarin Pharmaceutical Inc, Roche, and Sobi; served as a clinical trial investigator for BioMarin Pharmaceutical Inc, Bioverativ, CSL Behring, LFB, Octapharma, Roche, Pfizer, Sobi, and Takeda; reports speaker fees from BioMarin Pharmaceutical Inc, Pfizer, Roche, and Sobi; and reports travel grants from BioMarin Pharmaceutical Inc, CSL Behring, Octapharma, Roche, and Sobi. M.F.L.F. reports participation in advisory boards and receiving speaking fees from Shire/Takeda, Amgen, CSL Behring, Novo Nordisk, Bayer, LFB, Pfizer, and Sobi. E.M. reports consulting fees and travel support from BioMarin Pharmaceutical Inc and served as a clinical trial investigator for BioMarin Pharmaceutical Inc. M.W.S. reports consulting fees from Bayer, BioMarin Pharmaceutical Inc, Pfizer (DMC), Roche/Genentech, Sanofi, Spark (DMC), and Takeda; and research grants from BioMarin Pharmaceutical Inc, Freeline, Roche, Takeda, and uniQure. R.Klamroth reports consulting fees from Bayer, Biotest, BioMarin Pharmaceutical Inc, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, and Sobi; research grants from Bayer and LEO; speaker fees from Bayer, Biotest, BioMarin Pharmaceutical Inc, CSL Behring, Daiichi Sankyo, LEO, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, and Sobi; travel support from Bayer, Biotest, BioMarin Pharmaceutical Inc, CSL Behring, Daiichi Sankyo, LEO, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, and Sobi; and service as a clinical trial investigator for Bayer, BioMarin Pharmaceutical Inc, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Takeda/Shire, Sobi, and uniQure. S.W.P. reports consulting fees from Apcintex, ASC Therapeutics, Bayer, BioMarin Pharmaceutical Inc, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, Roche/Genentech, Sanofi, Spark Therapeutics, Takeda, and uniQure; and service as a clinical trial investigator for BioMarin Pharmaceutical Inc, Freeline, Genentech/Roche, Sanofi, and uniQure. J.Q. is a former employee of BioMarin Pharmaceutical and may hold stock. H.Y., T.M.R., and W.Y.W. are employees and stockholders of BioMarin Pharmaceutical Inc. C.W.T., H.T., R.Kazmi, and T-L.K. have no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Despite prior research that examines the spatial and temporal dimensions of older adult care, there is disparate research on the influence of patient flow priorities on older adult care over time and place. Drawing on a qualitative case study of rural older adult transitions in care in the Canadian context we examine how patient flow prioritization undervalues older patients' needs and the local contexts in which care is provided. Certainly, accounting for the spatial and temporal dimensions of older adult care has broader implications that will enhance future research, policy and practice. Policy makers, researchers and clinicians may then use these recommendations as a stepping stone to align the health care system with the older populations that they serve., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The introduction of adeno-associated virus-mediated, liver-directed gene therapy into the hemophilia treatment landscape brings not only great promise but also considerable uncertainty to a community that has a history punctuated by the devastating effects of HIV and hepatitis C virus. These infections were introduced into people with hemophilia through the innovation of factor concentrates in the 1970s and 1980s. Concentrates, heralded as a major advance in treatment at the time, brought devastation and death to the community already challenged by the complications of bleeding into joints, vital organs, and the brain. Over the past 5 decades, considerable advances in hemophilia treatment have improved the survival, quality of life, and participation of people with hemophilia, although challenges remain and health equity with their unaffected peers has not yet been achieved. The decision to take a gene therapy product is one in which an informed, holistic, and shared decision-making approach must be employed. Bias on the part of health care professionals and people with hemophilia must be addressed and minimized. Here, we review data leading to the regulatory authorization of valoctocogene roxaparvovec, an adeno-associated virus 5 gene therapy, in Europe to treat hemophilia A and etranacogene dezaparvovec-drlb in the United States and Europe to treat hemophilia B. We also provide an overview of the decision-making process and recommend steps that should be taken by the hemophilia community to ensure the safety of and optimal outcomes for people with hemophilia who choose to receive a gene therapy product., Competing Interests: Declaration of competing interests R.K. received research funding from Bayer. G.F.P. is a consultant for ASC Therapeutics, BioMarin, Frontera, Metagenomi, Pfizer, Regeneron, and Spark Therapeutics. M.W.S.’s institution has received research funding from BioMarin, Freeline, Spark Therapeutics, and uniQure. The other authors have no competing interests to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)