The mechanism and clinical application of farnesyl diphosphate farnesyltransferase 1 in cancer metabolism.

Cancer poses a significant risk to human well-being. Among the crucial characteristics of cancer is metabolic reprogramming. To meet the relentless metabolic needs, cancer cells enhance cholesterol metabolism within the adverse tumor microenvironment. Reprograming cholesterol metabolism includes a series of modifications in the synthesis, absorption, esterification, and metabolites associated with cholesterol. These adjustments have a strong correlation with the proliferation, invasion, metastasis, and other characteristics of malignant tumors. FDFT1, also known as farnesyl diphosphate farnesyltransferase 1, is an enzyme crucial in the process of cholesterol biosynthesis. Its significant involvement in tumor metabolism has garnered considerable interest. The significance of FDFT1 in cancer metabolism cannot be overstated, as it actively interacts with cancer cells. This paper aims to analyze and consolidate the mechanism of FDFT1 in cancer metabolism and explore its clinical application. The goal is to contribute new strategies and targets for the prevention and treatment of cancer metabolism.

Health-Related Quality-of-Life Impacts Associated with Transfusion-Dependent ß-Thalassemia in the USA and UK: A Qualitative Assessment.

BACKGROUND: Individuals living with transfusion-dependent ß-thalassemia (TDT) experience reduced health-related quality of life due to fatigue and chronic pain, which cause disruptions to daily life. Currently, limited qualitative data exist that describe these impacts. OBJECTIVE: This study aimed to examine the ways in which symptoms and current treatments of TDT impact health-related quality of life, to holistically describe the humanistic burden of TDT, and to identify the unmet needs of individuals living with TDT. METHODS: Adults (aged ≥ 18 years) with TDT and caregivers of adolescents (aged 12‒17 years) with TDT participated in semi-structured one-on-one virtual interviews and focus group discussions. Interviews were conducted in the USA and UK and lasted approximately 60 minutes. After transcription, the interviews were analyzed thematically using a framework approach. RESULTS: A total of ten interviews/focus group discussions (six interviews and four focus group discussions) were conducted with 14 adults with TDT and two caregivers of adolescents with TDT. A framework analysis revealed five themes describing health-related quality of life (negative impacts on daily activities, social life, family life, work and education, and psychological well-being) and three themes describing the lived experience of TDT (impact of red blood cell transfusions and iron chelation therapy, treatment, and stigma). Physical, psychological, and treatment-related factors contributed to negative impacts on daily activities, social and family life, and work and education. Concerns about reduced lifespan, relationships and family planning, and financial independence were detrimental to participants' mental well-being. Participants reported having high resilience to the many physical and psychological challenges of living with TDT. A lack of TDT-specific knowledge among healthcare professionals, particularly regarding chronic pain associated with the disease, left some participants feeling ignored or undermined. Additionally, many participants experienced stigma and were reluctant to disclose their disease to others. CONCLUSIONS: Individuals living with TDT experience substantial negative impacts on health-related quality of life that disrupt their daily lives, disruptions that are intensified by inadequate healthcare interactions, demanding treatment schedules, and stigma. Our study highlights the unmet needs of individuals living with TDT, especially for alternative treatments that reduce or eliminate the need for red blood cell transfusions and iron chelation therapy.

Enhancement of dissolution rate and oral bioavailability of poorly soluble drug florfenicol by using solid dispersion and effervescent disintegration technology.

OBJECTIVE: Florfenicol(FF) is an excellent veterinary antibiotic, limited by poor solubility and poor bioavailability. SIGNIFICANCE: Here in, we aimed to explore the applicability of fast disintegrating tablets compressed from Florfenicol-loaded solid dispersions (FF-SD-FDTs) to improve the dissolution rate and oral bioavailability of Florfenicol. METHODS: Utilizing selecting appropriate preparation methods and carriers, the solid dispersions of Florfenicol (FF-SDs) were prepared by solvent evaporation and the fast disintegrating tablets (FF-SD-FDTs) were prepared by the direct compression (DC) method. RESULTS: The tablet properties including hardness, friability, disintegration time, weight variation, etc. all met the specifications of Chinese Veterinary Pharmacopeia(CVP). FF-SD-FDTs significantly improved drug dissolution and dispersion of FF in vitro compared to florfenicol conventional tablets (FF-CTs). A pharmacokinetics study in German shepherd dogs proved the AUC0-∞ and Cmax values of FF-SD-FDTs are 1.38 and 1.38 times more than FF-CTs, respectively. CONCLUSIONS: Overall, it can be concluded that FF-SD-FDTs with excellent disintegration and dissolution properties were successfully produced, which greatly improved the oral bioavailability of the poorly soluble drug FF, and the study provided a new idea for a broader role of FF in pet clinics.

Economic and clinical burden of managing transfusion-dependent ß-thalassemia in the United States.

AIMS: To describe clinical complications, treatment use, healthcare resource utilization (HCRU), and costs among patients with transfusion-dependent ß-thalassemia (TDT) in the United States. MATERIALS AND METHODS: Merative MarketScan Databases were used to identify patients with ß-thalassemia between 1 March 2010, and 1 March 2019. Patients were eligible for inclusion with ≥1 inpatient claim or ≥2 outpatient claims for ß-thalassemia and ≥8 red blood cell transfusions (RBCTs) during any 12-month period after and including the date of the first qualifying ß-thalassemia diagnosis code. Matched controls consisted of individuals without ß-thalassemia. Clinical and economic outcomes of patients were assessed during ≥12 months of follow-up, defined as the period from the index date (i.e. the first RBCT) to either the end of continuous enrollment in benefits, inpatient death, or 1 March 2020. RESULTS: Overall, 207 patients with TDT and 1035 matched controls were identified. Most patients received iron chelation therapy (ICT) (91.3%), with a mean of 12.1 (standard deviation [SD] = 10.3) ICT claims per-patient-per-year (PPPY). Many also received RBCTs, with a mean of 14.2 (SD = 4.7) RBCTs PPPY. TDT was associated with higher annual ($137,125) and lifetime ($7.1 million) healthcare costs vs. matched controls ($4183 and $235,000, respectively). Annual costs were driven by ICT (52.1%) and RBCT use (23.6%). Patients with TDT had 7-times more total outpatient visits/encounters, 3-times more prescriptions, and 33-times higher total annual costs than matched controls. LIMITATIONS: This analysis may underestimate the burden of TDT, as indirect healthcare costs (e.g. absenteeism, presenteeism, etc.) were not included. Results may not be generalizable to patients excluded from this analysis, including those with other types of insurance or without insurance. CONCLUSIONS: Patients with TDT have high HCRU and direct healthcare costs. Treatments that eliminate the need for RBCTs could reduce the clinical and economic burden of managing TDT.

Economic and Clinical Burden of Managing Sickle Cell Disease with Recurrent Vaso-Occlusive Crises in the United States.

INTRODUCTION: The aim of this study was to describe the clinical complications, treatment use, healthcare resource utilization (HCRU), and costs among patients with sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs) in the US. METHODS: Merative MarketScan Databases were used to identify patients with SCD with recurrent VOCs from March 1, 2010, to March 1, 2019. Inclusion criteria were ≥ 1 inpatient or ≥ 2 outpatient claims for SCD and ≥ 2 VOCs per year in any 2 consecutive years after the first qualifying SCD diagnosis. Individuals without SCD in these databases were used as matched controls. Patients were followed for ≥ 12 months, from their second VOC in the 2nd year (index date) to the earliest of inpatient death, end of continuous enrollment in medical/pharmacy benefits, or March 1, 2020. Outcomes were assessed during follow-up. RESULTS: In total, 3420 patients with SCD with recurrent VOCs and 16,722 matched controls were identified. Patients with SCD with recurrent VOCs had a mean of 5.0 VOCs (standard deviation [SD] = 6.0), 2.7 inpatient admissions (SD 2.9), and 5.0 emergency department visits (SD 8.0) per patient per year during follow-up. Compared to matched controls, patients with SCD with recurrent VOCs incurred higher annual ($67,282 vs. $4134) and lifetime ($3.8 million vs. $229,000 over 50 years) healthcare costs. CONCLUSION: Patients with SCD with recurrent VOCs experience substantial clinical and economic burden driven by inpatient costs and frequent VOCs. There is a major unmet need for treatments that alleviate or eliminate clinical complications, including VOCs, and reduce healthcare costs in this patient population.

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

INTRODUCTION: 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.

Levels, source apportionment, and risk assessment of polycyclic aromatic hydrocarbons in vegetable bases of northwest China.

Dietary consumption of contaminated vegetables is the main route of human exposure to polycyclic aromatic hydrocarbons (PAHs). However, there is a lack of research on PAHs in vegetables from northwest China. In this study, the concentrations, sources, and risk assessment of PAHs in the soil and vegetables of Urumqi, an urbanized city in Xinjiang, China, were investigated. The total concentrations of 16 PAHs in soil and vegetable samples ranged 10.58-77.20 and 93.7-1071.8 ng/g, with average values of 2.86 and 242.76 ng/g, respectively. Among vegetable samples, the concentrations were in the order: leafy vegetables (299.08 ng/g) > fruits (192.65 ng/g) > vegetable roots (152.05 ng/g). The source apportionment of PAHs was identified using positive matrix factorization. The primary sources of PAHs in soil samples are oil spills, traffic emissions, coal combustion, and coke combustion. The main sources of PAHs in vegetable samples are oil spills and burning of grass, wood, coal, and coke. In soil samples, the ecological risk caused by PAHs is at a safe level, and the incremental lifetime cancer risks (ILCRs) of ingestion exposure exceed 1.0 × 10-6, which will pose potential risks to human body. The ILCRs of vegetable samples revealed that all groups had potential risks from onion and cabbage consumption (ILCRs > 1.0 × 10-6). In particular, adult women had a higher risk of cancer (ILCRs > 1.0 × 10-4). These results emphasize the importance of combating PAHs pollution in vegetable bases.

Humanistic Burden of Huntington Disease: Evidence From the Huntington Disease Burden of Illness Study.

Background and Objectives: Huntington disease (HD) is a rare, inherited, and highly complex neurodegenerative disorder with no currently approved disease-modifying treatments. We investigated the effect of HD on health-related quality of life and other patient-reported outcomes in the Huntington's Disease Burden of Illness (HDBOI) study. Methods: The HDBOI study is a retrospective, cross-sectional study conducted between September 2020 and May 2021 in France, Germany, Italy, Spain, the United Kingdom, and the United States. People with symptomatic onset HD (PwHD) were recruited by their HD-treating physicians and categorized as early (ES), mid (MS), or advanced stage (AS) HD. Physicians provided sociodemographic and clinical information from the participant's medical records in electronic case report forms (eCRF); participants or their proxies completed online Patient Public Involvement Engagement questionnaires (PPIE-P). Patient-reported outcomes included the 5-level EQ-5D version (EQ-5D-5L), Short-Form-(SF)-36 v2 (and SF-6-Dimension [SF-6D] utility), Huntington Quality of Life Instrument (H-QoL-I), and the Work Productivity and Activity Impairment Specific Health Problem. All outcomes were summarized using descriptive statistics, and differences between disease stages were assessed by Kruskal-Wallis tests. Results: A total of 2,094 PwHD were enrolled with completed eCRFs (100%) and PPIE-P forms (n = 482, 23%). Participants' mean age was 47.3 years; they were generally evenly distributed across countries, with the majority being ES (40%) followed by MS (33%) and LS (26%). The mean EQ-5D-5L (n = 336) utility score was 0.59 (SD, 0.27), with the highest mean utility scores [SD] in ES (0.72 [0.22]) followed by MS (0.62 [0.18]) and AS (0.37 [0.30]), p < 0.001. The mean SF-6D score (n = 482) was 0.57 (SD, 0.10), with mean values decreasing with advanced disease (ES, 0.61; MS, 0.56; AS, 0.50, p < 0.001). H-QoL-I mean scores (n = 482) also worsened with more advanced disease, from 0.58 for ES to 0.49 for MS and 0.37 for AS, p < 0.001. Impairment in daily activities and in work productivity also increased with more advanced disease. Overall proxy respondents reported on average worse outcomes than PwHD (self-reported) across all outcomes and disease stages suggesting a possible unawareness of deficits by PwHD. Discussion: The HDBOI study provides new insights into the characteristics and humanistic burden of PwHD and offers a meaningful contribution to this underserved research area.

Levels, sources, and risk assessment of PAHs residues in soil and plants in urban parks of Northwest China.

Polycyclic aromatic hydrocarbons (PAHs) will be ingested by people through different ways to threaten their health during play, so the environmental quality of the park directly affects the health of tourists and residents. Using eight typical parks in Urumqi in Northwest China as the study area, we used GC-MS to detect the PAHs content in the park surface soil and 10 common plants in the park in different seasons. The results showed that the content of PAHs in park soil in the summer was 5-6 times that in the winter, and the monomer PAHs in some park soil sampling points were higher than the soil pollution risk screening value. And the contamination level at these sampling sites was also higher compared to other sampling sites. In summer, the plants with high PAHs content in leaves are short herbs, while in winter, they are tall arbors. The PAHs of the park soil are mainly composed of high-cyclic aromatic hydrocarbons, and are mainly of traffic origin. The proportion of low-ring aromatic hydrocarbons in the winter was significantly higher than that in the summer. The source of PAHs in plants in summer is similar to that in soil, but the source of PAHs in plants in winter is more complex. The toxicity equivalent concentration method values of soil PAHs in South Park, Zhiwu Park, Shihua Park and Toutunhe Park were higher than that in other parks. The lifetime carcinogenic risk (ILCRs) values of some sampling points in these four parks in the summer were relatively high. The average ILCRs of adults and children in all parks reached a low-risk level in summer. The carcinogenic risk in children is much higher than that of adults.

A static force model to analyze the nuclear deformation on cell adhesion to vertical nanostructures.

Vertical nanostructures have been found to induce the deformation of the nuclear envelope during cell adhesion. However, there has been a lack of quantitative analysis of the influence of nanostructures morphology on the degree of nuclear deformation. Here, a theoretical model was proposed to investigate the mechanism of nuclear deformation by analyzing the mechanical force balance. Based on the established model, we analyzed the effects of the morphology of the nanopillar array on nuclear deformation and gave the quantitative relationship of the deformation depth of the nucleus with the pitch and radius of nanopillars. Our theoretical results seem to show broad agreements with experimental observations, which implies that the work can provide useful guidance to the design of nanostructures for biomedical applications.

[Typical Pesticide Residues and Their Risk Assessment in Farmland Environment of Different Plant Types in Shaya County, Xinjiang].

In order to investigate the characteristics of typical pesticide residues in farmland soil of different plant types in Shaya County and to evaluate the level of human health risk and ecological risk caused by pesticide residues, a total of 55 samples of plants, soil, and water from nine areas of Shaya county were collected on September 29, 2020. The occurrence levels of 47 typical pesticides in the samples were analyzed using gas chromatography-mass spectrometry (GC-MS). The results showed that a total of 23 pesticides were detected in three environmental media, and the maximum concentrations of pesticides in soil, plants, and water were 70.58 µg·kg-1, 1832.18 µg·kg-1, and 188.53 µg·L-1, respectively. The levels of pesticide residues in the three environmental media in Shaya county were characterized as plants>water>soil. From the detection of pesticides in different plant types, P1, P2, P6, and P8 in the center of the county were the most seriously polluted. The plants with a high pesticide load level in the corresponding areas were cotton, walnut, red jujube, and poplar, and the pesticides with a high concentration contribution were hexachlorocyclohexanes, chlorpyrifos, cyhalothrin, fluvalinate, metalaxyl, difenoconazole, and procymidone. The human health risks of adults and children caused by oral intake, skin contact, and respiratory inhalation were evaluated. The results showed that oral intake was the main exposure route, and the risk level of children was significantly higher than that of adults but was within the acceptable range. The ecological risk level of earthworms in soil was subsequently evaluated. The results showed that the potential ecological risk level of a single pesticide was low, and the potential ecological risk level of bifenthrin was the largest. The calculation of the total ecological risk of mixed pesticides showed that areas P1, P4, P7, and P9 were at moderate risk, whereas other areas were at low risk. Therefore, the use of some pesticides in Shaya County should be restricted.

Isolation and identification of mucin-degrading bacteria originated from human faeces and their potential probiotic efficacy according to host-microbiome enterotype.

AIM: Mucin-degrading bacteria are known to be beneficial for gut health. We aimed to isolate human-derived mucin-degrading bacteria and identify potential probiotic characteristics and their effects on the bacterial community and short-chain fatty acid (SCFA) production according to three different enterotypes of the host. METHODS AND RESULTS: Bacteria with mucin decomposition ability from human faeces were isolated and identified by 16S rRNA sequencing and MALDI-TOF. Heat resistance, acid resistance, antibiotic resistance, and antibacterial activity were analysed in the selected bacteria. Their adhesion capability to the Caco-2 cell was determined by scanning electron microscopy. Their ability to alter the bacterial community and SCFA production of the isolated bacteria was investigated in three enterotypes. The three isolated strains were Bifidobacterium(Bif.) animalis SPM01 (CP001606.1, 99%), Bif. longum SPM02 (NR_043437.1, 99%), and Limosilactobacillus(L.) reuteri SPM03 (CP000705.1, 99%) deposited in Korean Collection for Type Culture (KCTC-18958P). Among them, Bif. animalis exhibited the highest mucin degrading ability. They exhibited strong resistance to acidic conditions, moderate resistance to heat, and the ability to adhere tightly to Caco-2 cells. Three isolated mucin-degrading bacteria incubation increased Lactobacillus in the faecal bacteria from Bacteroides and Prevotella enterotypes. However, only L. reuteri elevated Lactobacillus in the faecal bacteria from the Ruminococcus enterotype. B. longum and B. animalis increased the α-diversity in the Ruminococcus enterotype, while their incubation with other intestinal types decreased the α-diversity. Bifidobacterium animalis and L. reuteri increased the butyric acid level in faecal bacteria from the Prevotella enterotype, and L. reuteri elevated the acetic acid level in those from the Ruminococcus enterotype. However, the overall SCFA changes were minimal. CONCLUSIONS: The isolated mucin-degrading bacteria act as probiotics and modulate gut microbiota and SCFA production differently according to the host's enterotypes. SIGNIFICANCE AND IMPACT OF STUDY: Probiotics need to be personalized according to the enterotypes in clinical application.

Association of factor expression levels with health-related quality of life and direct medical costs for people with haemophilia B.

AIMS: Gene therapy trials aim to provide a functional cure for patients with haemophilia B (HB), and treatment impact is analyzed by factor IX expression levels (FELs). We investigated the relationship of FELs with health-related quality of life (HRQoL) and costs. MATERIALS AND METHODS: This was a retrospective cross-sectional analysis of the European (CHESS I-II) and US (CHESS-US) CHESS population studies. Physicians recruited consecutive patients and extracted information from the medical records; patients completed questionnaires between 2014 and 2015 (CHESS-I), 2018-2019 (CHESS-II) and 2019 (CHESS US). Patients with inhibitors were excluded. HRQoL was assessed using the EQ-5D-5L. Twelve-month haemophilia-related direct medical costs included office visits and hospitalizations based on country-level unit costs. A Tobit model was used to analyze FELs and HRQoL and generalized linear models for direct medical costs. RESULTS: A total of 191 men with HB completed the EQ-5D questionnaire; the mean age was 36.8 years, with a mean FEL of 10.1 IU/dL (median, 4.0). Mean EQ-5D was 0.77 (SD, 0.23). The Tobit model adjusting for age, body mass index and blood-borne viruses showed every 1% increase in FEL was associated with +0.006 points in the mean EQ-5D score (p = .003). Mean haemophilia-related direct medical costs excluding factor replacement therapy were €2,028/year (median, €919) in CHESS I-II (EU, n = 226), and $7,171/year (median, $586) in CHESS US (n = 181). Adjusted EU and US models showed every 1% increase in FEL was associated with a decrease in haemophilia-related direct medical costs of €108/year and $529/year, respectively. LIMITATIONS: Direct medical costs were based on physician extraction of encounters from medical records, potentially underestimating costs of care. The voluntary nature of participation may have introduced selection biases. CONCLUSIONS: We observed a significant association of increases in FEL with increased HRQoL and decreased costs in Europe and the United States among men with HB and no inhibitors.

Anthocyanin from Lycium ruthenicum Murr. in the Qaidam Basin Alleviates Ultraviolet-Induced Apoptosis of Human Skin Fibroblasts by Regulating the Death Receptor Pathway.

Purpose: The study aimed to investigate the potential protective role of anthocyanin from Lycium ruthenicum Murr. in the Qaidam Basin against ultraviolet B (UVB)-induced apoptosis of human skin fibroblasts (HSFs). Methods: HSFs cultured in vitro were randomly divided into a control group, UVB group, and anthocyanin groups (0.1, 0.5, and 1.0 mg/mL). HSFs in the UVB and anthocyanin groups were exposed to 30 mJ/cm2 UVB to establish a photoaging model. Then, apoptosis rate, tumor necrosis factor-α (TNF-α), cysteinyl aspartate specific proteinase-3 (caspase-3), cysteinyl aspartate specific proteinase-7 (caspase-7), and survivin expression were evaluated. Results: UVB irradiation can increase the apoptosis rate of HSFs and expression of TNF-α, caspase-7, and survivin. Anthocyanin pretreatment (0.1, 0.5, and 1.0 mg/mL) decreased UVB-induced apoptosis rate and TNF-α and caspase-7 expression and increased survivin expression. Compared with the control group, the apoptosis rate and expression of TNF-α, caspase-7, and survivin of anthocyanin groups in UVB-irradiated HSFs were high. Among the three doses of anthocyanin (0.1, 0.5, and 1.0 mg/mL) groups, the apoptosis rate and TNF-α expression of anthocyanin at 1.0 mg/mL were the lowest. There was no significant change in caspase-3 expression in each group. Conclusion: Anthocyanin from Lycium ruthenicum Murr. in the Qaidam Basin could alleviate UVB-induced apoptosis by regulating the death receptor pathway.

Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-d]pyrimidine RET Inhibitors.

The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-d]pyrimidine scaffold. The optimization of this pyrrolo[2,3-d]pyrimidine core resulted in compound 1, which demonstrated potent in vitro RET kinase inhibition and robust in vivo efficacy in RET-driven tumor xenografts upon multiday dosing in mice. The administration of 1 was well-tolerated at established efficacious doses (10 and 30 mg/kg, po, qd), and plasma exposure levels indicated a minimal risk of KDR or hERG inhibition in vivo, as evaluated by Miles assay and free plasma concentrations, respectively.

Clinical, humanistic, and economic burden of severe haemophilia B in adults receiving factor IX prophylaxis: findings from the CHESS II real-world burden of illness study in Europe.

BACKGROUND: Real-world studies of the burden of severe haemophilia B in the context of recent therapeutic advances such as extended half-life (EHL) factor IX (FIX) products are limited. We analysed data from the recent CHESS II study to better understand the clinical, humanistic, and economic burden of severe haemophilia B in Europe. Data from male adults with severe haemophilia B receiving prophylaxis were analysed from the retrospective cross-sectional CHESS II study conducted in Germany, France, Italy, Spain and the United Kingdom. Inhibitors were exclusionary. Patients and physicians completed questionnaires on bleeding, joint status, quality of life, and haemophilia-related direct and indirect costs (2019-2020). All outcomes were summarised using descriptive statistics. RESULTS: A total of 75 CHESS II patients were eligible and included; 40 patients (53%) provided self-reported outcomes. Mean age was 36.2 years. Approximately half the patients were receiving EHL versus standard half-life (SHL) prophylaxis (44% vs 56%). Most patients reported mild or moderate chronic pain (76%) and had ≥ 2 bleeding events per year (70%), with a mean annualised bleed rate of 2.4. Mean annual total haemophilia-related direct medical cost per patient was €235,723, driven by FIX costs (€232,328 overall, n = 40; €186,528 for SHL, €290,620 for EHL). Mean annual indirect costs (€8,973) were driven by early retirement or work stoppage due to haemophilia. Mean quality of life (EQ-5D) score was 0.67. CONCLUSIONS: These data document a substantial, persistent real-world burden of severe haemophilia B in Europe. Unmet needs persist for these patients, their caregivers, and society.

Hemophilia Gene Therapy Value Assessment: Methodological Challenges and Recommendations.

Gene therapy for hemophilia is designed to produce health gains for patients over many years. Rewarding that value creation on the basis of a one-time treatment implies a large upfront cost. This cost can only be justified by long-term health benefits and being cost-effective compared with conventional treatments. Yet, uncertainties about the long-term benefits make it challenging to assess clinical and economic value of gene therapies at launch. We identify and discuss key methodological challenges in assessing the value of gene therapy for hemophilia, including the immaturity of evidence on the durability of benefits, lack of definition and valuation of cure for chronic diseases, absence of randomized controlled trials, limitations of traditional quality of life measures in hemophilia, approach for qualifying cost-savings compared with current treatments, and choice of perspective. The Institute for Clinical and Economic Review has developed a framework for assessing single or short-term therapies (ICER-SST) and has applied it in hemophilia. After reviewing this framework and its application, we recommend the following when assessing the value of hemophilia gene therapies: (1) leveraging expert clinical opinion to justify assumptions on the durability of benefits; (2) using external synthetic controls and lead-in, self-controlled trials to assess comparative effectiveness; (3) addressing limitations of traditional quality of life measures through the use of modified utility collection approaches; (4) adjusting cost offsets from gene therapies with caution; (5) considering outcome-based contracting to address uncertainties about prices and long-term outcomes; and (6) presenting societal and healthcare system perspectives in parallel.

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

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

Health care resource utilization and cost burden of hemophilia B in the United States.

Hemophilia B is a rare congenital blood disorder characterized by factor IX deficiency. Clinical profiles of hemophilia B range from mild to severe forms of the disease. The objective of this study was to characterize the economic burden associated with differing clinical profiles of hemophilia B from a US health system perspective. Using the IBM MarketScan database (June 2011-February 2019), a claims-based algorithm was developed to identify 4 distinct profiles (mild, moderate, moderate-severe, and severe) in adult males with hemophilia B based on the frequency of hemorrhage events and factor IX replacement claims. Mean annual health care resource use (HRU) and costs were statistically compared between patients with hemophilia B (N = 454) and 1:1 demographic-matched controls (N = 454), both overall and with stratification by clinical profile. Compared with matched controls, patients with hemophilia B had a significantly higher comorbidity burden (Charlson Comorbidity Index, mean ± standard deviation [SD]: 0.9 ± 1.7 vs 0.3 ± 0.9, P < .001). Across all clinical profiles, patients with hemophilia B had significantly higher HRU vs matched controls (mean ± SD: 0.3 ± 0.6 vs 0.1 ± 0.3 inpatient admissions; 0.6 ± 1.2 vs 0.2 ± 0.6 emergency department visits; 17.7 ± 22.9 vs 8.0 ± 11.0 outpatient visits; all P < .001). Annual total health care costs per patient among patients with hemophilia B were more than 25-fold higher vs matched controls (mean ± SD: $201 635 ± $411 530 vs $7879 ± $29 040, respectively, P < .001). Annual total health care costs per patient increased with increasing severity (mean ± SD: mild, $80 811 ± $284 313; moderate, $137 455 ± $222 021; moderate-severe, $251 619 ± $576 886; severe, $632 088 ± $501 270). The findings of this study highlight the substantial burden of illness associated with hemophilia B.