Evidence‐based guidelines support integrated disease management as the optimal model of haemophilia care

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/122450/1/hae12997_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/122450/2/hae12997.pd

Evidence‐based guidelines support integrated disease management as the optimal model of haemophilia care

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/122450/1/hae12997_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/122450/2/hae12997.pd

Clinical Considerations for Capsid Choice in the Development of Liver-Targeted AAV-Based Gene Transfer

As gene transfer with adeno-associated virus (AAV) vectors is starting to enter clinical practice, this review examines the impact of vector capsid choice in liver-directed gene transfer for hemophilia. Given that there are multiple clinical trials completed and ongoing in this field, it is important to review the clinical evidence, particularly as a range of AAV-vector serotypes including AAV2, AAV5, AAV8, and AAV10 have been tested. Although there have been a number of successful trials, the development of two investigational AAV vectors for hemophilia B has been discontinued because they did not meet efficacy and/or safety expectations. Whether this difference between success and failure of gene transfer approaches reflects capsid choice, vector design, manufacturing system, or other variables is a question of great interest. Here, we examine the body of evidence across trials to determine the possible influences of serotype choice on key clinical outcomes such as safety, vector clearance, treatment eligibility, occurrence of transaminase elevations, activation of capsid-directed cytotoxic T cell responses, and clinical efficacy. In summary, gene transfer requires a balance between achieving sufficient transgene expression and minimizing destructive immune responses, which may be affected by AAV-vector serotype choice

Recognizing the need for personalization of haemophilia patient‐reported outcomes in the prophylaxis era

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134854/1/hae13066.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134854/2/hae13066_am.pd

MCFD2, a second gene defective in combined factor V/factor VIII deficiency, encodes a novel ER protein that interacts with LMAN1 (ERGIC‐53) to form a cofactor‐specific sorting receptor

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106096/1/jth03926.pd

The mutation Ser2117Leu, in the second hydrophobic spike of the factor V C2 domain, increases phospholipid affinity and specific activity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106082/1/jth05227.pd

The feasibility of implementing high-intensity interval training in cardiac rehabilitation settings: A retrospective analysis

Background: Cardiovascular disease is the leading cause of death worldwide. Notwithstanding the well-known benefits of cardiac rehabilitation (CR), adherence to CR remains low, particularly in women. High-intensity interval training (HIIT) has received specific attention as an emerging exercise-training paradigm that addresses frequently cited barriers to CR (i.e. lack of motivation/enjoyment and time, perceiving exercise regime as tiring/boring) and improves cardiovascular risk factors. Previous studies have examined the safety of HIIT in CR; there is little evidence on the feasibility of HIIT in CR. The aims of this study were to evaluate the feasibility of HIIT within a CR setting and examine the sex differences regarding the feasibility of such programming. Methods: Patients attended an on-site HIIT CR program (10-min warm-up, 25 min of interspersed high-intensity [HI - 4 min at 85–95% HRpeak] and lower intensity [LO - 3 min at 60–70% HRpeak] intervals, 10-min cool-down) twice weekly for 10 weeks. Heart rate (HR) and the Borg rating of perceived exertion (RPE) scale (6–20 points) were recorded at each session. Feasibility was assessed by: [1] attendance and compliance: the number of sessions attended and the compliance to the prescribed HI and LO HR ranges; [2] the patient experience: patients’ perceived effort, program difficulty, if the program was challenging and satisfying; and, [3] safety. Descriptive statistics were used to report the means and their variations. Mann-Whitney U tests and Chi-square analyses were performed to examine sex-differences. Results: A total of 151 patients (33% women, 57.5 ± 9.1 years) attended the HIIT program and completed 16 ± 5 classes with a low attrition rate (11.3%). Most patients met or exceeded the prescribed target HR for the HI (80%) and LO (84%) intervals, respectively. Patients reported a “somewhat hard” RPE for HI (14 ± 2 points) and “very light” for LO (10 ± 2 points) intervals. All patients were satisfied with the program and found it challenging. Most patients found HIIT to be difficult (7 ± 2 points, scale range 0–10 points), yet safe (97%). Three vasovagal episodes occurred and more women dropped-out of the program than men (p < 0.01). Conclusions: HIIT is a feasible, safe and well-received exercise paradigm in a CR setting

Biological mechanisms underlying inter‐individual variation in factor VIII clearance in haemophilia

Previous studies have highlighted marked inter‐individual variations in factor VIII (FVIII) clearance between patients with haemophilia (PWH). The half‐life of infused FVIII has been reported to vary from as little as 5.3 hours in some adult PWH, up to as long as 28.8 hours in other individuals. These differences in clearance kinetics have been consistently observed using a number of different plasma‐derived and recombinant FVIII products. Furthermore, recent studies have demonstrated that half‐life for extended half‐life (EHL‐) FVIII products also demonstrates significant inter‐patient variation. Since time spent with FVIII trough levels <1% has been shown to be associated with increased bleeding risk in PWH on prophylaxis therapy, this variability in FVIII clearance clearly has major clinical significance. Recent studies have provided significant novel insights into the cellular basis underlying FVIII clearance pathways. In addition, accumulating data have shown that endogenous plasma VWF levels, ABO blood group and age, all play important roles in regulating FVIII half‐life in PWH. Indeed, multiple regression analysis suggests that together these factors account for approximately 34% of the total inter‐individual variation in FVIII clearance observed between subjects with severe haemophilia A. In this review, we consider these and other putative modulators of FVIII half‐life, and discuss the biological mechanisms through which these factors impact upon FVIII clearance in vivo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156160/2/hae14078.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156160/1/hae14078_am.pd

Structured smoking cessation training for health professionals on cardiology wards: a prospective study.

Background: Smoking is a major cardiovascular risk factor, and smoking cessation is imperative for patients hospitalised with a cardiovascular event. This study aimed to evaluate a systems-based approach to helping hospitalised smokers quit and to identify implementation barriers. Design: Prospective intervention study followed by qualitative analysis of staff interviews Methods: The prospective intervention study assessed the effects of implementing standard operating procedures (SOPs) for the provision of counselling and pharmacotherapy to smokers admitted to cardiology wards on counselling frequency. In addition, a qualitative analysis of staff interviews was undertaken to examine determinants of physician and nurse behaviour; this sought to understand barriers in terms of motivation, capability and/or opportunity. Results: A total of 150 smoking patients were included in the study (75 before and 75 after SOP implementation). Before the implementation of SOPs, the proportion of patients reporting to have received cessation counselling from physicians and nurses was 6.7% and 1.3%, respectively. Following SOP implementation, these proportions increased to 38.7% (p < 0.001) and 2.7% (p = 0.56), respectively. Qualitative analysis revealed that lack of motivation, e.g. role incongruence, appeared to be a major barrier. Conclusions: Introduction of a set of standard operating procedures for smoking cessation advice was effective with physicians but not nurses. Analysis of barriers to implementation highlighted lack of motivation rather than capability or opportunity as a major factor that would need to be addressed