Experimental and Numerical Investigation of Wire Waveguides for Therapeutic Ultrasound Angioplasty

Therapeutic ultrasound angioplasty is an emerging minimally invasive cardiovascular procedure for disrupting atherosclerotic lesions using small diameter wire waveguides. The lesions are damaged through a combination of direct ablation, pressure waves, cavitation and acoustic streaming caused by distal-tip displacements at ultrasonic frequencies. Numerical and experimental methods are used to investigate the outputs of the wire waveguides during ultrasonic activation. A commercially available generator and acoustic horn are used in combination with Nickel-Titanium (NiTi) wire waveguides in this study. A laser sensor is used to measure the frequency and amplitude output of the distal tip of the wire waveguide, and this is compared to amplitude estimations obtained using an optical microscope. Power is observed to affect both amplitude and frequency. Clinical devices will require long, flexible waveguides with diameters small enough to access the coronary arteries. A finite element model is used to design tapered sections in long wire waveguides in order to achieve low profile distal geometry, and improve ultrasonic wave transmission. These tapered sections reduce the wire waveguide diameter in two stages, firstly from 1 to 0.35mm and then from 0.35 to 0.2, while increasing the amplitude of the ultrasonic wave by factors of 2.85 and 1.75, respectively. The numerical model also showed damping could potentially be a significant problem in long untapered wire waveguides (\u3e1.5m). Experimental ablation trials were conducted using the tapered long wire waveguides, including assessment of the effect of various combinations of bend radii and bend angles. The waveguide was found to perform well, but increased power levels were required to transmit ultrasound through tortuous waveguide configurations

Experimental and numerical investigation of wire waveguides for therapeutic ultrasound angioplasty

Therapeutic ultrasound angioplasty is an emerging minimally invasive cardiovascular procedure for disrupting atherosclerotic lesions using small diameter wire waveguides. The lesions are damaged through a combination of direct ablation, pressure waves, cavitation and acoustic streaming caused by distal-tip displacements at ultrasonic frequencies. Numerical and experimental methods are used to investigate the outputs of the wire waveguides during ultrasonic activation. A commercially available generator and acoustic horn are used in combination with Nickel-Titanium (NiTi) wire waveguides in this study. A laser sensor is used to measure the frequency and amplitude output of the distal tip of the wire waveguide, and this is compared to amplitude estimations obtained using an optical microscope. Power is observed to affect both amplitude and frequency. Clinical devices will require long, flexible waveguides with diameters small enough to access the coronary arteries. A finite element model is used to design tapered sections in long wire waveguides in order to achieve low profile distal geometry, and improve ultrasonic wave transmission. These tapered sections reduce the wire waveguide diameter in two stages, firstly from 1 to 0.35mm and then from 0.35 to 0.2, while increasing the amplitude of the ultrasonic wave by factors of 2.85 and 1.75, respectively. The numerical model also showed damping could potentially be a significant problem in long untapered wire waveguides (>l.5m). Experimental ablation trials were conducted using the tapered long wire waveguides, including assessment of the effect of various combinations of bend radii and bend angles. The waveguide was found to perform well, but increased power levels were required to transmit ultrasound through tortuous waveguide configurations

Assessing the value of orphan drugs using conventional cost-effectiveness analysis:Is it fit for purpose?

Conventional cost-effectiveness analysis-i.e., assessing pharmaceuticals through a cost per quality-adjusted life year (QALY) framework-originated from a societal commitment to maximize population health given limited resources. This "extra-welfarist" approach has produced pricing and reimbursement systems that are not well- aligned with the unique considerations of orphan drugs. This framework has been slow to evolve along with our increased understanding of the impact of rare diseases, which in turn has complicated the assessment of orphan drugs meant to treat rare diseases. Herein, we (i) discuss the limitations of conventional cost-effectiveness analysis as applied to assessing access to, as well as the pricing and reimbursement of, orphan drugs, (ii) critically appraise alternative and supplemental approaches, and (iii) offer insights on plausible steps forward

Hemophilia treatment in 2021: choosing the”optimal” treatment using an integrative, patient-oriented approach to shared decision-making between patients and clinicians

The mainstay of hemophilia treatment is to prevent bleeding through regular long-term prophylaxis and to control acute breakthrough bleeds. Various treatment options are currently available for prophylaxis, and treatment decision-making is a challenging and multifaceted process of identifying the most appropriate option for each patient. A multidisciplinary expert panel convened to develop a practical, patient-oriented algorithm to facilitate shared treatment decision-making between clinicians and patients. Key variables were identified, and an algorithm proposed based on five variables: bleeding phenotype, musculoskeletal status, treatment adherence, venous access, and lifestyle. A complementary, patient-focused preference tool was also hypothesized, with the aim of exploring individual patients' priorities, preferences, and goals. It is hoped that the proposed algorithm and the hypothesized patient preference tool will assist in selecting a treatment for each patient that is as efficient as possible in preventing bleeds while also accounting for the patient's expectations and prioritiesFunded by a grant from Novo Nordis

Association of factor expression levels with annual bleeding rate in people with haemophilia B

From Wiley via Jisc Publications RouterHistory: received 2022-01-13, rev-recd 2022-07-29, accepted 2022-08-08, pub-electronic 2022-11-04Article version: VoRPublication status: PublishedIntroduction: Gene therapy clinical trials measure steady‐state clotting factor expression levels (FELs) to evaluate the modulation of the bleeding phenotype, aiming to offer consistent protection against breakthrough bleeding events. The link between FELs and bleeding risk in people with haemophilia B (PwHB) is not well understood. Aim: We evaluated the association between FEL and ABR in PwHB. Methods: This cross‐sectional study extended the CHESS burden of illness studies in Europe and the United States. Recruitment of additional adult males with haemophilia B supplemented the existing CHESS sample size of PwHB and FELs. PwHB receiving prophylaxis were excluded, as fluctuating FELs may have confounded the analysis. Demographic and clinical characteristics were reported descriptively. Any recorded baseline FEL was reported by the haemophilia‐treating physicians according to the medical records. Generalised linear models with log link explored the association between changes in FEL and ABR. Results: The study included 407 PwHB and no inhibitors receiving on‐demand treatment. Mean age was 36.7 years; 56% from the EU, 44% from the United States. Mean baseline FEL was 9.95 IU/dl (SD, 10.47); mean ABR was 2.4 bleeds/year (SD, 2.64). After adjusting for covariates, the model showed that for every 1% increase in FEL the average ABR decreased by .08 (p < .001). Predicted number of bleeding events according to FEL showed a significant non‐linear relationship between FEL and ABR (p < .05). Conclusion: This analysis showed a significant relationship between FEL and ABR, where increases in FEL were associated with decreases in ABR among men with HB in Europe and the US

Humanistic burden of problem joints for children and adults with haemophilia

From Wiley via Jisc Publications RouterHistory: received 2022-05-10, rev-recd 2022-11-25, accepted 2022-12-14, pub-electronic 2022-12-27Article version: VoRPublication status: PublishedFunder: BioMarin and uniQureFunder: Sanofi, BioMarin and TakedaFunder: Bayer, Roche, Swedish Orphan Biovitrum AB (Sobi), Novo Nordisk and SHIREIntroduction: The “problem joint” (PJ) concept was developed to address patient‐centric needs for a more holistic assessment of joint morbidity for people with haemophilia (PwH). Aim: To quantify the humanistic burden of PJs in PwH to further support validation of the PJ outcome measure. Methods: Multivariable regression models evaluated the relationship between PJs and health‐related quality of life (HRQoL, EQ‐5D‐5L) and overall work productivity loss (WPL) using data from the ‘Cost of HaEmophilia: a Socioeconomic Survey’ population studies (adults: CHESS II, CHESS US+; children/adolescents: CHESS‐Paeds). Covariates included were haemophilia severity, age, comorbidities and education. Results: The CHESS II sample included 292 and 134 PwH for HRQoL and WPL analyses, mean age 38.6 years (39% ≥1 PJ, 61% none). CHESS US+ included 345 and 239 PwH for HRQoL and WPL, mean age 35 years (43% ≥1 PJ, 57% none). CHESS‐Paeds included 198 PwH aged 4–17 (HRQoL only), mean age 11.5 years (19% ≥1 PJ, 81% none). In CHESS II and CHESS US+, presence of PJs was associated with worse HRQoL (Both p < .001). Few CHESS‐Paeds participants had PJs, with no significant correlation with HRQoL. In CHESS II, upper body PJs were significantly correlated to WPL (p < .05). In CHESS US+, having ≥1 PJ or upper and lower body PJs were significantly correlated to WPL (vs. none; both p < .05). Conclusion: This study has shown a meaningful burden of PJs on PwH, which should be considered in clinical and health policy assessments of joint health

European principles of care for women and girls with inherited bleeding disorders

INTRODUCTION: Despite increasing awareness of issues faced by women and girls with inherited BDs (WGBD), standards of care are lacking, with disparities in diagnosis and treatment for WGBD across Europe. We aimed to develop practical principles of care (PoC) to promote standardization of care for WGBD within European Haemophilia Treatment and Comprehensive Care Centres (HTC/CCCs). METHODS: The co-creation process, supported by the European Association for Haemophilia and Allied Disorders, consisted of four multidisciplinary meetings with health care providers (HCPs) experienced in WGBD care, and European Haemophilia Consortium representatives, combined with broad patient and HCP consultations in the European haemophilia community. Relevant medical societies outside Europe were contacted for confirmation. RESULTS: We developed ten PoC for WGBD, stressing the importance and benefits of a centralized, multidisciplinary, comprehensive, family-centred approach to support and manage WGBD during all life stages. These PoC emphasise the right to equitable access and quality of care for all people with BDs, irrespective of gender. Multiple medical societies outside Europe also confirmed their support for endorsement. CONCLUSIONS: Ten PoC for WGBD evolved from an iterative process among stakeholders, supported by relevant medical societies worldwide. These PoC can serve as a benchmark for diagnosis and comprehensive multidisciplinary management of WGBD, and improve awareness of their unique challenges. They offer a framework to guide HTC/CCCs in providing equitable care for all WGBD, both in their own services and in other healthcare settings. Implementation of these principles aims to positively impact the health, wellbeing and quality of life for WGBD

Monitoring to improve quality of life in women with bleeding disorders

Systematic structures to understand the incidence and prevalence of bleeding disorders in women and girls are in place in some countries and becoming more robust, though there is still room for improvement. More co-ordinated data gathering is providing new insights into the diagnosis and treatment of girls with bleeding disorders and demonstrating clear deficits in care compared with boys that can have important implications around puberty. Recognition and recording of female symptoms such as heavy menstrual bleeding (HMB) may lag behind that of symptoms with a greater perception bias, such as joint bleeds, and affect quality of life and wellbeing. Addressing inequity of symptom recognition and recording is needed to drive appropriate and timely treatment interventions. New symptom tools can empower patients to differentiate normal from abnormal bleeding so they can seek and receive help. Greater awareness among health care professionals (HCPs) of women's bleeding disorders and the establishment of referral networks for diagnosis and treatment, with multidisciplinary assessment and follow-up, are still needed

Design Issues for Therapeutic Ultrasound Angioplasty Waveguides

Therapeutic ultrasound angioplasty is a new minimally invasive cardiovascular procedure for disrupting atherosclerotic lesions. Mechanical energy is transmitted in the form of ultrasound waves via long, flexible wire waveguides navigated to the lesion site through the vascular system. The underpinning principle of this technology is that plaque may be disrupted through a combination of direct contact ablation, pressure waves, cavitation and acoustic streaming, which all depend on the amplitude and frequency of displacements at the distal tip of the wire waveguide. This study identifies a number of key design issues for clinical devices of this type, and describes testing procedures to measure selected performance characteristics. A commercially available generator (100 W) and acoustic horn are used in combination with Nickel-Titanium (NiTi) wire waveguides. A laser sensor system was constructed to measure the frequency and amplitude output at the distal tip of the wire waveguide, and this was compared to amplitude estimations obtained using an optical microscope. Power was observed to affect both output amplitude and frequency. A finite element model has been previously developed to simulate the transmission of ultrasound waves in short wire waveguides. In this study, this methodology has been extended to the design of long, tapered wires for realistic clinical applications. Trials were conducted using these wire waveguides, demonstrating the ablation of model calcified materials accessed via long wire waveguides

Relationship between bleeding episodes, health-related quality of life and direct costs in adults with severe haemophilia A: Secondary analyses from the CHESS study.

From PubMed via Jisc Publications RouterHistory: received 2021-05-27, revised 2022-05-19, accepted 2022-06-11Publication status: aheadofprintFunder: Baxalta US, Inc., a Takeda company, Lexington, MA, US