• Adherence and a Potential Trade-Off Currently Faced in Optimizing Hemophilia Treatment

      Burke, Tom; Asghar, Sohaib; Misciattelli, Natalia; Kar, Sharmila; Morgan, George; Dhillon, Harpal; O'Hara, Jamie (Elsevier, 2021-08-03)
      INTRODUCTION Severe hemophilia, i.e., <1% normal FVIII level (A) or FIX level (B), are congenital bleeding disorders characterized by uncontrolled bleeding. The clinical benefits of prophylactic FVIII/IX replacement therapy are well understood, but require adherence to a schedule of routine infusions. Optimal adherence is associated with better joint outcomes and lower rates of chronic pain. Nonetheless a lack of patient-reported data has to date limited our understanding of the patient burden associated with adherence to treatment, and the relationship between adherence and the ability to work, among people living with hemophilia in the US. Data from the Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) study reported a high proportion of adults with hemophilia B receiving routine infusions (at least one infusion per month), showing a negative impact on their ability to work, and people receiving routine infusions were more likely than people treated on-demand to report an inability to work in most situations. The ability of people living with hemophilia to participate in the labor force, without barriers to job choice or working hours, is a key outcome in the drive to achieve health equity. The objective of the analysis is to examine the relationship between adherence and the labor force participation of people with severe hemophilia in the US. METHODS This analysis draws data from a patient-reported study, the ‘Cost of Severe Hemophilia Across the US: A Socioeconomic Survey’ (CHESS US+). Conducted in 2019, the CHESS US+ study is a cross-sectional patient-centered study of adults with severe hemophilia in the US. A patient-completed questionnaire collected data on clinical, economic, and humanistic outcomes, for a 12-month retrospective period. This analysis examines labor force participation and employment status (full-time, part-time, unemployed, retired) and chronic pain categorized by ‘none’, low-level ('1-5'), and high-level ('6-10'). The analysis was stratified by adherence to treatment, self-reported on a 1-10 scale, from “not at all” to “fully”, categorized into low (1-6), moderate (7-9) and full (10) adherence. Results are presented as mean (standard deviation) or N (%). RESULTS The analysis comprised 356 people with severe hemophilia A (73%) and B (27%) who participated in CHESS US+ study. In Table 1, the baseline characteristics of the study population are stratified by full adherence (N = 119), moderate adherence (N=134) and low adherence (N=103). Having no chronic pain was most prevalent in the full adherence group (37.7%), compared to moderate (8.3%) or low (13.9%) adherence cohorts. Chronic pain, both low- and high-levels were least prevalent among people with full adherence. Moreover, people with low adherence were disproportionately more likely to have high-levels of chronic pain relative to moderate adherence or full adherence (Table 1). Unemployment, however, was highest in full adherence (21.1%), and people with full adherence were also least likely to be in full-time employment (42%). The full-time employment rate decreased as adherence declined from full to moderate (Table 1), and was comparable in people with low adherence (57.3%) or moderate adherence (54.5%). CONCLUSIONS This analysis of CHESS US+ examined the complex relationship between labor market outcomes and adherence to treatment, among adults with severe hemophilia in the US. Adherence was associated with lower rates of chronic pain, representing the importance of achieving an optimal treatment strategy. Nonetheless, patients achieving optimal adherence were less likely to be in full-time employment, and more likely to be part-time or unemployed, comparatively. Together, these data characterize a trade-off in clinical outcomes versus workforce participation, and suggest that the goal of achieving health equity may currently still be unmet. Disclosures Burke: HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Asghar: HCD Economics: Current Employment. Misciattelli: Freeline: Current Employment, Current equity holder in publicly-traded company. Kar: Freeline: Current Employment, Current equity holder in publicly-traded company. Morgan: uniQure: Consultancy; HCD Economics: Current Employment. Dhillon: HCD Economics: Current Employment; F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. . O'Hara: HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy.
    • An Insight into the Impact of Hemophilia a on Daily Life According to Disease Severity: A Preliminary Analysis of the CHESS II Study

      Noone, Declan; Nissen, Francis; Xu, Tao; Burke, Tom; Asghar, Sohaib; Dhillon, Harpal; Aizenas, Martynas; Meier, Oliver; O'Hara, Jamie; Khair, Kate (Elsevier, 2021-08-03)
      Introduction: Hemophilia A (HA) is a congenital bleeding disorder caused by a deficiency in clotting factor VIII (FVIII). There are currently limited data on the impact of HA on daily life. Here we examine the impact of HA on the daily life of adult persons with HA (PwHA) without current FVIII inhibitors according to disease severity. Methods: The Cost of Haemophilia in Europe: a Socioeconomic Survey II (CHESS II) is a retrospective, burden-of-illness study in adults with mild, moderate, and severe HA or hemophilia B (defined by endogenous FVIII/IX [IU/dL] relative to normal; mild, 5-<40%; moderate, 1-5%; severe, <1%); this analysis includes only PwHA. Male participants (aged ≥18 years) diagnosed with HA (without FVIII inhibitors) at least 12 months prior to clinical consultation were enrolled from Denmark, France, Germany, Italy, the Netherlands, Romania, Spain, and the UK. Data on clinical outcomes and healthcare resource utilization were captured via electronic case report forms disseminated to hemophilia specialists. PwHA completed a paper-based questionnaire utilizing 5-point Likert scales to assess the disease burden on their daily life. Overall, 12 months’ retrospective data were examined. Informed consent was obtained and the study was approved by the University of Chester ethical committee. Results: Of 258 PwHA completing questionnaires, 15.9% (n=41), 27.9% (n=72), and 56.2% (n=145) had mild, moderate, and severe HA, respectively. Of those with severe HA, 60.0% were currently receiving FVIII prophylaxis (standard of care for severe HA); in comparison, 4.9% and 6.9% of those with mild and moderate HA were receiving prophylaxis (Table 1). Treatment adaptation in anticipation of physical or social activity was reported by 19.5%, 23.6%, and 38.6% of those with mild, moderate, and severe HA, respectively. Over a third of participants with mild (36.6%) and moderate (44.4%) HA, and 64.8% of those with severe HA (58.6% with severe HA receiving on-demand treatment and 69.0% receiving prophylaxis) agreed or strongly agreed that HA had reduced their physical activity (Figure 1). Overall, 38.9% of those with moderate HA and 58.6% of those with severe HA (63.8% with severe HA receiving on-demand treatment and 55.2% receiving prophylaxis) agreed or strongly agreed that their HA had reduced their social activity; this was less pronounced in mild HA (9.8%). Additionally, 31.7%, 36.1%, and 64.1% of those with mild, moderate, and severe HA (62.1% with severe HA receiving on-demand treatment and 65.5% receiving prophylaxis) agreed or strongly agreed that their HA had caused them to miss opportunities. Correspondingly, frustration due to HA was felt by 19.5%, 34.7% and 57.9% (56.9% with severe HA receiving on-demand treatment and 58.6% receiving prophylaxis) of people, respectively. When asked whether they believed their daily life was compromised due to their hemophilia, 24.4%, 37.5%, and 63.4% of those with mild, moderate, and severe HA, respectively, agreed. Pain, as reported by the physician, was noted in 36.6% of people with mild HA (100% was reported as 'mild'); in people with moderate HA, pain was reported as 'mild', ‘moderate’, and ‘severe’ in 44.4%, 20.8%, and 1.4% of PwHA, respectively. In people with severe HA, pain was reported as ‘mild’, ‘moderate’, and ‘severe’ in 39.7%, 27.6%, and 8.6% for those receiving on-demand treatment, and 37.9%, 32.2%, and 8.0% for those receiving prophylaxis, respectively. Conclusions: In all disease severity groups, there was a notable group of PwHA that felt that they have had to reduce their physical and social activity, have had fewer opportunities and are frustrated due to their disease. While the impact on daily life is most pronounced in people with severe HA (including those receiving on-demand treatment and those receiving prophylaxis), it is also apparent in mild and moderate HA, indicating that there may be an unmet medical need in these groups. Disclosures Noone: Healthcare Decision Consultants: Membership on an entity's Board of Directors or advisory committees; Research Investigator PROBE: Research Funding; European Haemophilia Consortium: Membership on an entity's Board of Directors or advisory committees. Nissen: F. Hoffmann-La Roche Ltd: Current Employment; Actelion: Consultancy; Novartis: Research Funding; GSK: Research Funding. Xu: F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Burke: University of Chester: Current Employment; HCD Economics: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Asghar: HCD Economics: Current Employment. Dhillon: F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. ; HCD Economics: Current Employment. Aizenas: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. O'Hara: HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy. Khair: Biomarin: Consultancy; HCD Economics: Consultancy; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medikhair: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Haemnet: Membership on an entity's Board of Directors or advisory committees.
    • Bleeding Data across Baseline FIX Expression Levels in People with Hemophilia B: An Analysis Using the 'Factor Expression Study'

      Burke, Tom; Shaikh, Anum; Ali, Talaha; Li, Nanxin; Konkle, Barbara A; Noone, Declan; O'Mahony, Brian; Pipe, Steven W; O'Hara, Jamie (Elsevier, 2021-12-24)
      Introduction Complications such as spontaneous and trauma-related bleeding events typically experienced by people with hemophilia B (PWHB) are associated with long-term joint damage and chronic pain, and burdensome treatment with intravenous factor IX administration. Gene therapy, designed to enable the endogenous production of the missing clotting factor, has potential for curative benefit in PWHB (Dolan et al, 2018). Due to its link to risk for bleeding episodes, factor expression level (FEL) is commonly used as an endpoint in hemophilia gene therapy trials. However, little data currently exist linking FEL to bleeding risk in PWHB, most notably within the mild range. As such, the aim of this analysis was to examine the relationship between annual bleed rate (ABR) data across baseline FEL in PWHB. Methods Data from adult non-inhibitor PWHB, across Europe and the United States (US) who received clotting factor on-demand (OD), were drawn from the 'Cost of HaEmophilia in adults: a Socioeconomic Survey' (CHESS) studies. The CHESS studies are retrospective, burden-of-illness studies in people with hemophilia A or B, capturing the economic and humanistic burden associated with living with hemophilia. Additional data were collected to supplement the existing CHESS studies, particularly in people with exogenous FEL in the mild and moderate range. ABR was defined as the physician-reported number of bleed events experienced by the patient in the 12 months to study capture. A generalized linear model (GLM) was used to analyze variation in ABR data across FEL, adjusting for covariates age, body mass index (BMI), and blood-borne viruses. Following this, a multivariable restricted cubic spline (RCS) GLM regression was performed to create, model, and test for the potential non-linear relationship between FEL and ABR. The RCS regression employed 3 knots, located at baseline FEL values of 1, 5, and 10, and controlled once again for age, BMI, and blood-borne viruses. Results A total of 407 adult non-inhibitor PWHB, receiving an OD therapy regimen and with information on ABR, were profiled. The GLM provided adequate fit for the modeling of bleed data; the average marginal effect at the mean was computed from the GLM regression outputs. After controlling for the effects of all other model covariates, the regression analysis showed a significant association between FEL and ABR; for every 1% increase in FEL, the average ABR decreased by 0.08 units (p<0.001). The results of the RCS regression found a significant non-linear relationship between FEL and ABR, ceteris paribus (p<0.001). Conclusions The results of this analysis found baseline FEL to be significantly associated with ABR in PWHB; as baseline FEL increased, ABR reduced. This highlights the clinical importance of new hemophilia gene therapies potentially increasing FEL to that of the mild or non-hemophilic range in terms of reducing patient burden through the better prevention of bleeding events in PWHB. Disclosures Ali:  UniQure: Current Employment. Li:  UniQure: Current Employment. Konkle:  Pfizer, Sangamo, Sanofi, Sigilon, Spark, Takeda and Uniqure: Research Funding; BioMarin, Pfizer and Sigilon: Consultancy. O'Mahony:  BioMarin Pharmaceutical Inc.: Consultancy; Freeline: Consultancy; Uniqure: Speakers Bureau. Pipe:  Apcintex: Consultancy; ASC Therapeutics: Consultancy; Bayer: Consultancy; Biomarin: Consultancy, Other: Clinical trial investigator; Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; HEMA Biologics: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; Novo Nordisk: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy, Other; Sangamo Therapeutics: Consultancy; Sanofi: Consultancy, Other; Takeda: Consultancy; Spark Therapeutics: Consultancy; uniQure: Consultancy, Other; Regeneron/ Intellia: Consultancy; Genventiv: Consultancy; Grifols: Consultancy; Octapharma: Consultancy; Shire: Consultancy.
    • Characterization of microwave and terahertz dielectric properties of single crystal La2Ti2O7 along one single direction

      Zhang, Man; orcid: 0000-0002-1094-7279; Tang, Zhiyong; orcid: 0000-0002-1921-6034; Zhang, Hangfeng; Smith, Graham; orcid: 0000-0003-3273-7085; Jiang, Qinghui; Saunders, Theo; orcid: 0000-0003-4250-3071; Yang, Bin; Yan, Haixue; orcid: 0000-0002-4563-1100
      New generation wireless communication systems require characterisations of dielectric permittivity and loss tangent at microwave and terahertz bands. La2Ti2O7 is a candidate material for microwave application. However, all the reported microwave dielectric data are average value from different directions of a single crystal, which could not reflect its anisotropic nature due to the layered crystal structure. Its dielectric properties at the microwave and terahertz bands in a single crystallographic direction have rarely been reported. In this work, a single crystal ferroelectric La2Ti2O7 was prepared by floating zone method and its dielectric properties were characterized from 1 kHz to 1 THz along one single direction. The decrease in dielectric permittivity with increasing frequency is related to dielectric relaxation from radio frequency to microwave then to terahertz band. The capability of characterizing anisotropic dielectric properties of a single crystal in this work opens the feasibility for its microwave and terahertz applications.
    • Characterization of microwave and terahertz dielectric properties of single crystal La2Ti2O7 along one single direction

      Zhang, Man; orcid: 0000-0002-1094-7279; Tang, Zhiyong; orcid: 0000-0002-1921-6034; Zhang, Hangfeng; Smith, Graham; orcid: 0000-0003-3273-7085; Jiang, Qinghui; Saunders, Theo; orcid: 0000-0003-4250-3071; Yang, Bin; Yan, Haixue; orcid: 0000-0002-4563-1100 (Elsevier, 2021-08-27)
      New generation wireless communication systems require characterisations of dielectric permittivity and loss tangent at microwave and terahertz bands. La2Ti2O7 is a candidate material for microwave application. However, all the reported microwave dielectric data are average value from different directions of a single crystal, which could not reflect its anisotropic nature due to the layered crystal structure. Its dielectric properties at the microwave and terahertz bands in a single crystallographic direction have rarely been reported. In this work, a single crystal ferroelectric La2Ti2O7 was prepared by floating zone method and its dielectric properties were characterized from 1 kHz to 1 THz along one single direction. The decrease in dielectric permittivity with increasing frequency is related to dielectric relaxation from radio frequency to microwave then to terahertz band. The capability of characterizing anisotropic dielectric properties of a single crystal in this work opens the feasibility for its microwave and terahertz applications.
    • COVID-19 presenting as intussusception in infants: A case report with literature review

      Athamnah, Mohammad N.; Masade, Salim; Hamdallah, Hanady; Banikhaled, Nasser; Shatnawi, Wafa; Elmughrabi, Marwa; Al Azzam, Hussein S. O.
      The novel Corona virus disease 2019 (COVID-19) first presented in Wuhan, China. The virus was able to spread throughout the world, causing a global health crisis. The virus spread widely in Jordan after a wedding party held in northern Jordan. In most cases of COVID-19 infection, respiratory symptoms are predominant. However, in rare cases the disease may present with non-respiratory symptoms. The presentation of COVID-19 as a case of intussusception in children is a strange and rare phenomenon. We present here a case of a two-and-a-half month old male baby who was brought to hospital due to fever, frequent vomiting, dehydration and blood in stool. He was diagnosed as intussusception. The child was tested for corona due to the large societal spread of the virus and because he was near his mother, who was suffering from symptoms similar to corona or seasonal flu (she did not conduct a corona test). Patient was treated without surgery and recovered quickly. The COVID-19 infection was without respiratory symptoms, and there was no need for the child to remain in hospital after treatment of intussusception. The relationship between viruses, mesenteric lymphoid hyperplasia, and intussusception is a confirmed relation. ACE2 is the key receptor required for SARA-COV-2 to enter the host cells. ACE2 has been also found in the brush border of the intestinal mucosa, as well as it is a key inflammatory regulator in the intestine. This may suggest that SARSA-COV-2 could invade the respiratory tract as well as gastrointestinal tract or both. Few case reports documented the presentation of COVID-19 as intussusception in children. In the light of the wide-spread of corona virus, performing COVID-19 tests for children with intussusception can help linking the two entities. Development of gastrointestinal symptoms in COVID-19 positive children should raise concern about the development of intussusception.
    • Effect of Moderate and Severe Hemophilia a on Daily Life in Children and Their Caregivers: A CHESS Paediatrics Study Analysis

      Khair, Kate; Nissen, Francis; Silkey, Mariabeth; Burke, Tom; Shang, Aijing; Aizenas, Martynas; Meier, Oliver; O'Hara, Jamie; Noone, Declan (Elsevier, 2021-08-03)
      Introduction: Hemophilia A (HA) is a congenital bleeding disorder, caused by a deficiency in clotting factor VIII (FVIII) and characterized by uncontrolled bleeding and progressive joint damage. This analysis assesses the impact of disease burden on the daily life of children with hemophilia A (CwHA) and their caregivers, addressing a deficit of current research on this topic. Methods: The Cost of Haemophilia in Europe: a Socioeconomic Survey in a Paediatric Population (CHESS Paediatrics) is a retrospective, burden-of-illness study in children with moderate and severe HA (defined by endogenous FVIII [IU/dL] relative to normal; moderate, 1-5%; severe, <1%) across France, Germany, Italy, Spain and the UK. CwHA were recruited and stratified by both age group (0-5 years:6-11 years:12-17 years=1:1:1) and disease severity (severe:moderate=approximately 2:1, prioritizing children with severe HA [CwSHA]). Data for this analysis were captured from physicians, children, and their caregivers. Physicians completed online case report forms for treated children, and the child and/or their caregivers completed a paper-based questionnaire utilizing 5-point Likert scales. For CwHA aged 0-7, the questionnaire was completed by the caregiver, while for CwHA aged 8-17, children and caregivers completed different sections. Hours of care provided by the caregiver and work lost by the caregiver were reported as median values due to non-normal data distribution. Informed consent was obtained for all participants. Upon review, the study was approved by the University of Chester ethical committee. Results: Data from child/caregiver questionnaires were available for 196 CwHA (moderate, 25.5%; severe, 74.5%); the majority of these children, as expected, were receiving prophylaxis (72.4%), and did not have FVIII inhibitors (89.8%; Table 1). There was a direct impact of disease burden on CwHA, particularly with regard to physical and social activities (Figure 1). Overall, it was agreed or strongly agreed by the child or caregiver that 48.0% and 57.5% of children with moderate HA (CwMHA) and CwSHA respectively, have reduced physical activity due to HA, and 46.0% and 57.5%, respectively, have reduced social activity due to HA. A total of 36.0% and 61.0% of CwMHA and CwSHA, respectively, had adapted their treatment in anticipation of physical or social activity (Table 1). Furthermore, 34.0% of CwMHA and 55.4% of CwSHA were frustrated due to their disease, and many (CwMHA, 36.0%; CwSHA, 50.7%) felt that they had missed opportunities (Figure 1). For 66.0% of CwMHA and 76.0% of CwSHA, it was reported that their daily life was compromised due to their HA. Caregivers provided a median (interquartile range [IQR]) of 19.0 (10.0-59.5) and 12.0 (5.0-20.0) hours a week of care for the hemophilia-related needs of their CwMHA (n=30) or CwSHA (n=105), respectively. Of those who responded, 17.4% (n=4/23) and 25.0% (n=20/80) of caregivers to CwMHA or CwSHA, respectively, stated they have lost work due to their caregiving duty. This was more than twice as common for caregivers in families with multiple CwHA (42.9%, n=9/21 responses) compared with those in families with one CwHA (18.5%, n=15/81 responses). Median (IQR) hours of work per week estimated to be lost were 20.0 (17.0-22.0) for caregivers of CwMHA (n=4) and 12.5 (4.50-20.0) for caregivers of CwSHA (n=20). Conclusions: In conclusion, both children and caregivers make sacrifices in their daily lives due to HA; many CwHA reported reduced physical and social activities, fewer opportunities and feelings of frustration due to their HA. Caregivers reported spending a significant number of hours caring for their child and some reported losing work due to their caring responsibilities. However, some outcomes may be limited by the small number of respondents and narrow response options, particularly those regarding the caregiver burden. Responses on the hours of work lost may be subject to selection bias, as caregivers who have lost work may be more likely to respond to this question. Additionally, as this question is targeted at caregivers in employment, it is unknown if some caregivers have left employment due to their caregiving responsibilities. According to this analysis, children/caregivers are frequently required to adapt the child's treatment before the child engages in activities. Overall, the burden of disease was similar in children with moderate and severe HA. Disclosures Khair: Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Biomarin: Consultancy; HCD Economics: Consultancy; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medikhair: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Haemnet: Membership on an entity's Board of Directors or advisory committees. Nissen: GSK: Research Funding; Novartis: Research Funding; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment. Silkey: Aerotek AG: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Burke: HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Shang: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Aizenas: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. O'Hara: HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy. Noone: Research Investigator PROBE: Research Funding; Healthcare Decision Consultants: Membership on an entity's Board of Directors or advisory committees; European Haemophilia Consortium: Membership on an entity's Board of Directors or advisory committees.
    • Examination and Validation of a Patient-Centric Joint Metric: “Problem Joint”; Empirical Evidence from the CHESS US Dataset

      Burke, Tom; Rodriguez Santana, Idaira; Chowdary, Pratima; Curtis, Randall; Khair, Kate; Laffan, Michael; McLaughlin, Paul; Noone, Declan; O'Mahony, Brian; Pasi, John; et al. (Elsevier, 2021-08-03)
      Introduction Severe hemophilia (FVIII/FIX level <1%) is characterized by spontaneous hemarthrosis leading to progressive joint deterioration and chronic pain in the affected individual. Unless these recurrent hemarthroses can be prevented, e.g. with the use of prophylactic factor replacement therapy, these patients will develop chronic synovitis, pain, and eventually destruction of the joint. Current metrics such as ’Target joint’ and other clinical measures of joint morbidity are prevalent and widely accepted. Measures focused solely on bleeding activity, such as the ’Target joint’ metric, are arguably becoming less sensitive as current treatment strategies look to significantly reduce or eradicate joint bleeds, though they maintain clinically relevant and complementary to delivery of comprehensive hemophilia care. Key opinion leaders in the haemophilia field have debated the need for a more patient relevant measure of haemophilia-related joint morbidity. ‘Problem Joint’ (PJ), which is defined as having chronic joint pain and/or limited range of movement due to compromised joint integrity (chronic synovitis and/or haemophilic arthropathy), with or without persistent bleeding was derived through consensus. The objectives of this working group are to examine the usefulness and validity of the PJ metric. Initial research presented here was used to test the sensitivity of PJ as a patient relevant metric with respect to key outcomes for US haemophilia patients. Methods Data on PJs, as well as demographic, clinical and socio-economic variables was captured within the ‘Cost of Haemophilia Across Europe: A Socioeconomic Survey’ datasets (CHESS: I, II, Paediatric, and US studies). These data contain a total of 992 paediatric (age 1-17) and 2,437 adults (age 18+) with haemophilia from eight European countries and the US. Statistical analysis explored the association of PJ count and location with respect to two key outcomes: quality of life, as measured by an EQ-5D score, and overall work impairment, measured by the Work Productivity and Activity Impairment Questionnaire (WPAI). Those with current inhibitors were excluded from the analysis, and the US cohort comprised the focus of this initial research into the topic. Results The US cohort contained information on 345 people with haemophilia (PwH) and captured adults only, with a mean age of 35 years. Approximately, 43% of PwH had one or more PJs. Lower body PJs were more prevalent than upper body: 40% had one or more lower body PJs vs. 27% upper body. The majority of PJs were located in the ankles, knees and elbows. The relationship between EQ-5D and number of PJs showed a negative trend (see Figure 1): the average EQ-5D score was: 0.81 for those with zero PJs (N=197); 0.79 for those with one PJ (N=24); 0.70 for two PJs (N=29); 0.68 for three PJs (N=24) and 0.49 for those patients with four of more PJs (N=59). Similarly, an increase in number of PJs meant greater work productivity impairment versus no PJs recorded: 30.08% (N=102) vs. 19.51% (N=137), respectively. Discussion Results from the US cohort found that an increase in the number of PJs was associated with an increasing humanistic burden in PwH. The proposed Problem Joint definition takes a holistic viewpoint and provides a patient relevant perspective. Further work is planned to evaluate the appropriateness of the measure, and test the sensitivity in European and pediatric cohorts. Disclosures Burke: HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Rodriguez Santana: HCD Economics: Current Employment. Chowdary: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Shire (Baxalta): Membership on an entity's Board of Directors or advisory committees; Spark: Membership on an entity's Board of Directors or advisory committees; BioMarin: Honoraria; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Freeline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Curtis: Bayer: Consultancy; Novo Nordisk: Consultancy; Patient Reported Outcomes, Burdens and Experiences: Consultancy; USC Hemophilia Utilization Group Study (HUGS): Consultancy. Khair: Haemnet: Membership on an entity's Board of Directors or advisory committees; Biomarin: Consultancy; HCD Economics: Consultancy; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medikhair: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau. Laffan: Shire: Consultancy; LFB: Consultancy; Roche: Consultancy; Sobi: Consultancy; Pfizer: Consultancy; CSL: Consultancy; Pfizer: Speakers Bureau; Bayer: Speakers Bureau; Roche-Chugai: Speakers Bureau; Takeda: Speakers Bureau; Leo-Pharma: Speakers Bureau; Octapharma: Consultancy. McLaughlin: BioMarin: Consultancy; Novo Nordisk: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Roche/Chugai: Speakers Bureau; Takeda: Speakers Bureau. Noone: European Haemophilia Consortium: Membership on an entity's Board of Directors or advisory committees; Research Investigator PROBE: Research Funding; Healthcare Decision Consultants: Membership on an entity's Board of Directors or advisory committees. O'Mahony: Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Freeline: Honoraria; UniQure: Honoraria. Pasi: BioMarin: Consultancy, Honoraria, Other: Grants, personal fees, and nonfinancial support; honoraria as member of scientific advisory boards and symposia; uniQure: Other: Grants and nonfinancial support , Research Funding; ApcinteX: Consultancy, Other: Personal fees ; Octapharma: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia , Speakers Bureau; Novo Nordisk: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia ; Catalyst Biosciences: Consultancy, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Biotest: Consultancy, Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Alnylam (Sanofi): Other: Personal fees and nonfinancial support ; Takeda: Consultancy, Honoraria, Other: Personal fees; honoraria as member of scientific advisory boards and symposia ; Sanofi: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia, Research Funding; Sigilon: Research Funding; Tremeau: Research Funding; Sobi: Consultancy, Honoraria, Other; Roche: Honoraria, Other; Pfizer: Other. Skinner: Genentech: Consultancy, Honoraria; Spark Therapeutics: Other, Speakers Bureau; Pfizer: Other, Speakers Bureau; Takeda: Honoraria, Research Funding; uniQure: Research Funding; Biomarin: Consultancy, Research Funding; CSL Behring: Research Funding; Freeline Therapeutics: Research Funding; Novo Nordisk: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Sobi: Research Funding; Bayer: Consultancy, Research Funding. O'Hara: HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy.
    • Group LCD and group reversible LCD codes

      Dougherty, Steven T.; Gildea, Joe; Korban, Adrian; orcid: 0000-0001-5206-6480; Roberts, Adam M.; orcid: 0000-0002-0654-7096 (Elsevier, 2022-06-17)
      In this paper, we give a new method for constructing LCD codes. We employ group rings and a well known map that sends group ring elements to a subring of the n × n matrices to obtain LCD codes. Our construction method guarantees that our LCD codes are also group codes, namely, the codes are ideals in a group ring. We show that with a certain condition on the group ring element v, one can construct non-trivial group LCD codes. Moreover, we also show that by adding more constraints on the group ring element v, one can construct group LCD codes that are reversible. We present many examples of binary group LCD codes of which some are optimal and group reversible LCD codes with different parameters.
    • Housing market spillovers through the lens of transaction volume: A new spillover index approach

      Yang, Jian; Tong, Meng; Yu, Ziliang (Elsevier, 2021-10-25)
      Proposing and applying a new spillover index approach based on data-determined structural vector autoregression to measure connectedness, we examine the daily housing market information transmission via transaction volume among Chinese city-level housing markets from 2009 to 2018. We document substantial information transmission on Chinese housing markets even within one day and find that the role a city-level housing market may play in the information transmission network resembles a pattern observed on other financial markets, which can be generally classified into three distinctive groups: prime senders, exchange centers, and prime receivers. City hierarchy and some fundamental economic factors, such as GDP per capita and average wage, appear to be significant determinants of such a pattern. The findings extend the existing voluminous literature solely based on housing prices or price volatility spillovers and shed new light on the China’s government intervention strategy on the housing market.
    • Millimeter-Wave Free-Space Dielectric Characterization

      Liu, Xiaoming; Gan, Lu; Yang, Bin
      Millimeter wave technologies have widespread applications, for which dielectric permittivity is a fundamental parameter. The non-resonant free-space measurement techniques for dielectric permittivity using vector network analysis in the millimeter wave range are reviewed. An introductory look at the applications, significance, and properties of dielectric permittivity in the millimeter wave range is addressed first. The principal aspects of free-space millimeter wave measurement methods are then discussed, by assessing a variety of systems, theoretical models, extraction algorithms and calibration methods. In addition to conventional solid dielectric materials, the measurement of artificial metamaterials, liquid, and gaseous-phased samples are separately investigated. The pros of free-space material extraction methods are then compared with resonance and transmission line methods, and their future perspective is presented in the concluding part.
    • Millimeter-wave free-space dielectric characterization

      Liu, Xiaoming; Gan, Lu; Yang, Bin (Elsevier, 2021-05-12)
      Millimeter wave technologies have widespread applications, for which dielectric permittivity is a fundamental parameter. The non-resonant free-space measurement techniques for dielectric permittivity using vector network analysis in the millimeter wave range are reviewed. An introductory look at the applications, significance, and properties of dielectric permittivity in the millimeter wave range is addressed first. The principal aspects of free-space millimeter wave measurement methods are then discussed, by assessing a variety of systems, theoretical models, extraction algorithms and calibration methods. In addition to conventional solid dielectric materials, the measurement of artificial metamaterials, liquid, and gaseous-phased samples are separately investigated. The pros of free-space material extraction methods are then compared with resonance and transmission line methods, and their future perspective is presented in the concluding part.
    • New extremal binary self-dual codes from block circulant matrices and block quadratic residue circulant matrices

      Gildea, J.; Kaya, A.; Taylor, R.; orcid: 0000-0002-8563-2212; Tylyshchak, A.; orcid: 0000-0001-7828-3416; Yildiz, B.; orcid: 0000-0001-8106-3123 (Elsevier, 2021-08-20)
      In this paper, we construct self-dual codes from a construction that involves both block circulant matrices and block quadratic residue circulant matrices. We provide conditions when this construction can yield self-dual codes. We construct self-dual codes of various lengths over F 2 and F 2 + u F 2 . Using extensions, neighbours and sequences of neighbours, we construct many new self-dual codes. In particular, we construct one new self-dual code of length 66 and 51 new self-dual codes of length 68.
    • New singly and doubly even binary [72,36,12] self-dual codes from M 2(R)G - group matrix rings

      Korban, Adrian; orcid: 0000-0001-5206-6480; Şahinkaya, Serap; Ustun, Deniz; orcid: 0000-0002-5229-4018 (Elsevier, 2021-09-17)
      In this work, we present a number of generator matrices of the form [ I 2 n | τ 2 ( v ) ] , where I 2 n is the 2 n × 2 n identity matrix, v is an element in the group matrix ring M 2 ( R ) G and where R is a finite commutative Frobenius ring and G is a finite group of order 18. We employ these generator matrices and search for binary [ 72 , 36 , 12 ] self-dual codes directly over the finite field F 2 . As a result, we find 134 Type I and 1 Type II codes of this length, with parameters in their weight enumerators that were not known in the literature before. We tabulate all of our findings.
    • Opinion of the Scientific Committee on Consumer safety (SCCS) – Final Opinion on propylparaben (CAS No 94-13-3, EC No 202-307-7)

      Bodin, Laurent; Rogiers, Vera; Bernauer, Ulrike; Chaudhry, Qasim; Coenraads, Pieter Jan; orcid: 0000-0001-9458-7129; Dusinska, Maria; Ezendam, Janine; Gaffet, Eric; Galli, Corrado Ludovico; Granum, Berit; et al.
      In cosmetic products, the ingredient propylparaben (CAS No 94-13-3, EC No 202-307-7) with the chemical names Propyl 4-hydroxybenzoate and 4-Hydroxybenzoic acid propyl ester is currently regulated as a preservative in a concentration up to 0.14 % (as acid) (Annex V/12a). In addition, a safe concentration was established for mixtures of parabens, where the sum of the individual concentrations should not exceed 0.8 % (as acid). However, in such mixtures the sum of the individual concentrations of butyl- and propylparaben and their salts should not exceed 0.14 %. Propylparaben was subject to different safety evaluations in 2005 (SCCP/0874/05), 2006 (SCCP/1017/06), 2008 (SCCP/1183/08), 2010 (SCCS/1348/10), 2011 (SCCS/1446/11), 2013 (SCCS/1514/13). On the basis of the safety assessment of propylparaben, and considering the concerns related to potential endocrine disrupting properties, the SCCS has concluded that propylparaben is safe when used as a preservative in cosmetic products up to a maximum concentration of 0.14 %. The available data on propylparaben provide some indications for potential endocrine effects. However, the current level of evidence is not sufficient to regard it as an endocrine disrupting substance, or to derive a toxicological point of departure based on endocrine disrupting properties for use in human health risk assessment. The SCCS mandates do not address environmental aspects. Therefore, this assessment did not cover the safety of propylparaben for the environment.
    • Reframing how we care for people with persistent non-traumatic musculoskeletal pain. Suggestions for the rehabilitation community

      Lewis, Jeremy S.; orcid: 0000-0001-7870-9165; Stokes, Emma K.; Gojanovic, Boris; orcid: 0000-0001-5075-9371; Gellatly, Pamela; orcid: 0000-0001-7401-2096; Mbada, Chidozie; orcid: 0000-0003-3666-7432; Sharma, Saurab; orcid: 0000-0002-9817-5372; Diener, Ina; orcid: 0000-0001-7426-4840; O’Sullivan, Peter (Elsevier, 2021-06-05)
      There have been repeated calls to re-evaluate how clinicians provide care for people presenting with persistent non-traumatic musculoskeletal conditions. One suggestion is to move away from the ‘we can fix and cure you’ model to adopting an approach that is more consistent with approaches used when managing other persistent non-communicable diseases; education, advice, a major focus on self-management including lifestyle behavioural change, physical activity and medications as required. Currently the global delivery of musculoskeletal care has many of the elements of a ‘super wicked problem’, namely conflict of interest from stake-holders due to the consequences of change, prevailing expectation of a structural diagnosis and concomitant fix for musculoskeletal pain, persistent funding of high risk, more expensive care when low risk more economic viable options that don’t impact on the quality of outcome exist, and an unquestionable need to find a solution now with the failure resulting in a growing social and economic burden for future generations. To address these issues, 100 participants included clinicians, educators and researchers from low-, middle- and high-income countries, eight presenters representing the physiotherapy, sport medicine and the orthopaedic professions and the insurance industry, together with three people who shared their lived experiences of persistent musculoskeletal pain, discussed the benefits and barriers of implementing change to address this problem. This paper presents the results from the stakeholders’ contextual analysis and forms the basis for the proposed next steps from an action and advocacy perspective.
    • Reframing how we care for people with persistent non-traumatic musculoskeletal pain. Suggestions for the rehabilitation community

      Lewis, Jeremy S.; orcid: 0000-0001-7870-9165; Stokes, Emma K.; Gojanovic, Boris; orcid: 0000-0001-5075-9371; Gellatly, Pamela; orcid: 0000-0001-7401-2096; Mbada, Chidozie; orcid: 0000-0003-3666-7432; Sharma, Saurab; orcid: 0000-0002-9817-5372; Diener, Ina; orcid: 0000-0001-7426-4840; O’Sullivan, Peter
      There have been repeated calls to re-evaluate how clinicians provide care for people presenting with persistent non-traumatic musculoskeletal conditions. One suggestion is to move away from the ‘we can fix and cure you’ model to adopting an approach that is more consistent with approaches used when managing other persistent non-communicable diseases; education, advice, a major focus on self-management including lifestyle behavioural change, physical activity and medications as required. Currently the global delivery of musculoskeletal care has many of the elements of a ‘super wicked problem’, namely conflict of interest from stake-holders due to the consequences of change, prevailing expectation of a structural diagnosis and concomitant fix for musculoskeletal pain, persistent funding of high risk, more expensive care when low risk more economic viable options that don’t impact on the quality of outcome exist, and an unquestionable need to find a solution now with the failure resulting in a growing social and economic burden for future generations. To address these issues, 100 participants included clinicians, educators and researchers from low-, middle- and high-income countries, 8 presenters representing the physiotherapy, sport medicine and the orthopaedic professions and the insurance industry, together with 3 people who shared their lived experiences of persistent musculoskeletal pain, discussed the benefits and barriers of implementing change to address this problem. This paper presents the results from the stakeholders’ contextual analysis and forms the basis for the proposed next steps from an action and advocacy perspective.
    • Sexuality and the human rights of persons with dementia

      Peisah, Carmelle; Ayalon, Liat; Verbeek, Hilde; Benbow, Susan M.; Wiskerke, Esther; Rabheru, Kiran; Sorinmade, Oluwatoyin
      We explore barriers to enjoyment of human rights to sexuality of persons with dementia and remedies for addressing these. Enjoyment of sexuality is contingent upon actualisation of rights to dignity, autonomy, respect for will and preferences, abuse safeguarding and equitable access to highest standards of sexual health. Persons with dementia living at home or in care face systemic barriers to enjoyment of sexuality fuelled by ageism, apathy and ignorance, compounded by complex legal barriers in relation to consent. Such challenges can be tackled with awareness raising and education of care staff, families and physicians, including training for capacity assessment with dimensional, non-categorical conceptualisation of capacity, leaving room for supported decision-making. These measures, together with strengthened legislative and human rights frameworks to cater to the specific needs of older people, may allow people to live well with dementia and exercise their human rights to enjoy sexuality in a safe and lawful manner.
    • Simulating Topological Robustness of Fano Resonance in Rotated Honeycomb Photonic Crystals

      Hajivandi, J.; Kaya, E.; Edwards, G.; Kurt, H.
      The Fano resonance with a distinctive ultra-sharp, asymmetric line shape and high quality factor, is a widely occurring phenomena, that has a large variety of optical, plasmonic and microwave manifestations. In this paper, we explore the characteristic robustness of a Fano resonance mode, which is topologically protected by engineering a band inversion, induced by breaking the mirror symmetry of a two-dimensional honeycomb photonic crystal (HPC), associated with C 6 point group symmetry. Dark and bright topological edge modes appear in the band gap which arise when Dirac cone is opened up. Destructive and constructive interference of the dark and bright modes leads to the asymmetric line shape of the Fano resonance. The Fano resonance is very sensitive to the material changes and structural perturbations. This property can be applied to obtain new sensor designs. Here we demonstrate that the topological Fano resonance mode preserves its asymmetric, ultra-sharp line shape in the presence of the disorder, defects and cavities.The stability of the Fano resonance mode has useful optical device applications such as in low threshold lasers, and extremely precise interferometers.
    • Simulating topological robustness of Fano resonance in rotated Honeycomb photonic crystals

      Hajivandi, J.; Kaya, E.; Edwards, G.; Kurt, H. (Elsevier, 2021-07-08)
      The Fano resonance with a distinctive ultra-sharp, asymmetric line shape and high quality factor, is a widely occurring phenomena, that has a large variety of optical, plasmonic and microwave manifestations. In this paper, we explore the characteristic robustness of a Fano resonance mode, which is topologically protected by engineering a band inversion, induced by breaking the mirror symmetry of a two-dimensional honeycomb photonic crystal (HPC), associated with C 6 point group symmetry. Dark and bright topological edge modes appear in the band gap which arise when Dirac cone is opened up. Destructive and constructive interference of the dark and bright modes leads to the asymmetric line shape of the Fano resonance. The Fano resonance is very sensitive to the material changes and structural perturbations. This property can be applied to obtain new sensor designs. Here we demonstrate that the topological Fano resonance mode preserves its asymmetric, ultra-sharp line shape in the presence of the disorder, defects and cavities.The stability of the Fano resonance mode has useful optical device applications such as in low threshold lasers, and extremely precise interferometers.