The largest known molecule in the interstellar medium of galaxies, C60, has been detected in its neutral and cationic form through its vibrational, UV-driven fluorescence emission spectrum and its electronic absorption spectrum, respectively. The detection of several polycyclic aromatic hydrocarbon molecules through their pure rotation spectrum in cold, dense, molecular cloud cores suggests that C60 might be present in these environments as well. The low flux of UV pumping photons in molecular cloud cores and the absence of suitably bright background stars, make detection of C60 and its cation through the commonly used methods impractical. As C60 has no permanent dipole moment, its pure rotational transitions are forbidden, and its presence must be inferred from the rotational transitions of C60 derivatives with permanent dipole moments. Here, we present a study of the predicted rotational spectrum of protonated C60 that has a sizable permanent dipole moment. Protonation of C60 reduces the icosahedral symmetry to Cs and results in a dipole moment of about 3.8 D. The resulting C60H+ is a closed shell system with no electron spin. The ground electronic symmetry is A'. The goal of the present calculations is to simulate rotational spectra in radio astronomy frequency ranges. The simulations are based on geometry and electric dipole moment values from harmonic and anharmonic density functional theory (DFT) calculations at the B3LYP level. Using the PGOPHER spectral simulation program, the rotational structure of the spectra at excitation temperatures of 5 and 10 K were computed to guide future laboratory studies and facilitate radio astronomy searches for protonated C60 in cold dark molecular clouds.

Hemophilia A, a bleeding disorder caused by a deficiency of clotting factor VIII (FVIII), is commonly treated with FVIII prophylaxis. Mobile applications help personalize prophylactic regimens by creating individual pharmacokinetic (PK) profiles. This study evaluated how patients with hemophilia A use mobile applications for PK-guided prophylaxis and explored preferences and patterns of usage across different age groups. Between May and September 2022, patients from Bulgaria, Czechia, Hungary, Lithuania, and Romania participated in a cross-sectional survey. The survey collected information on demographics, documentation preferences (mobile applications or paper diaries), usage patterns, and user satisfaction. Of 84 participants, 40.5% used either a mobile application or paper diary exclusively. Czechia had the highest application usage (94.1%), followed by Romania (50.0%). While 84.2% of the application users were satisfied, many suggested improvements including better medication tracking and smartwatch compatibility. No correlation was found between age and documentation type or application preference. Mobile applications were perceived useful, but physician engagement was higher with paper diaries. These findings suggest potential to enhance mobile applications for better patient-physician interaction and user experience.

Introduction Development of hemophilic arthropathy and chronic joint pain occurs even with the current standard of care (SoC) for hemophilia A. The completed Phase 3 study XTEND-1 (NCT04161495) showed once-weekly efanesoctocog alfa was well tolerated in adults and adolescents with severe hemophilia A and provided superior bleed prevention to prior FVIII prophylaxis. Here, we report changes in joint health from baseline to Week 52 using the Hemophilia Joint Health Score (HJHS) v2.1 in patients from the XTEND-1 study.

Background: Joint damage affects the quality of life of persons with hemophilia A. The long-term safety and efficacy of turoctocog alfa pegol (N8-GP) prophylaxis in persons with hemophilia A has been investigated in pivotal phase 3 trials in children, adolescents, and adults (pathfinder program). However, there is a lack of data on joint health in adult persons with hemophilia A treated with N8-GP. Objectives: To describe the design of the ongoing pathfinderReal study investigating the joint health status in adult persons with hemophilia A after switching to N8-GP. Methods: pathfinderReal is a multicountry, noninterventional, single-arm study (NCT05621746) of joint health in adult (>= 18 years) male persons with hemophilia A who have switched to N8-GP. Patients enrolled in other interventional studies and those who have previously terminated N8-GP treatment will be excluded. Approximately 124 adults with hemophilia A will be enrolled and followed up for a maximum of 24 months. Data from routine clinical assessments of patients' joint health will be collected. The primary endpoint is change in Hemophilia Joint Health Score (defined as a change in total score of <= 2) from initiation of N8-GP treatment until the end of the study. Secondary endpoints include number of bleeding episodes, number and resolution of target joints, patient-reported outcomes of problem joint score, pain score, and change in physical function levels. An exploratory endpoint is included to measure the number of patients achieving improved Hemophilia Joint Health Score from the initiation of N8-GP until the end of the study. Conclusion: The pathfinderReal study will provide insights regarding the impact of N8- GP on joint health in persons with hemophilia A in a real-world setting.

An important aspect of improving care for people with hemophilia B (HB) is developing optimal treatment strategies. Here we aimed to provide in-silico evidence, comparing the estimated optimal posology of factor IX (FIX) products to support the patient-physician decision-making process. A population pharmacokinetic (popPK) model-based assessment comparing the performance of FIX products (rFIX, rIX-FP, rFIXFc, N9-GP) was developed. PopPK analyses were used to determine a product’s optimal posology to target predefined steady-state FIX activity trough levels in a hypothetical population of 10,000 people with severe HB. Model-derived optimal posologies were compared across several parameters including trough levels, proportion of patients per regimen and consumption, considering 64 hypothetical patient scenarios of different FIX trough level targets and ages. Results indicated a marked difference between FIX products estimated to achieve target trough levels, consumption and dosing frequencies. rIX-FP was associated with higher trough levels than rFIX and rFIXFc, at a lower weekly dose and administration frequency, across all age groups. N9-GP use in adolescents and adults was associated with lower consumption compared with rIX-FP. Insights from this study may be utilized by clinicians to inform decision-making, by considering the model-generated estimated optimal posologies alongside multiple clinical factors and patient preferences.

Antithrombin (AT) is the major plasma inhibitor of thrombin (FIIa) and activated factor X (FXa), and antithrombin deficiency (ATD) is one of the most severe thrombophilic disorders. In this study, we identified nine novel AT mutations and investigated their genotype–phenotype correlations. Clinical and laboratory data from patients were collected, and the nine mutant AT proteins (p.Arg14Lys, p.Cys32Tyr, p.Arg78Gly, p.Met121Arg, p.Leu245Pro, p.Leu270Argfs*14, p.Asn450Ile, p.Gly456delins_Ala_Thr and p.Pro461Thr) were expressed in HEK293 cells; then, Western blotting, N-Glycosidase F digestion, and ELISA were used to detect wild-type and mutant AT. RT-qPCR was performed to determine the expression of AT mRNA from the transfected cells. Functional studies (AT activity in the presence and in the absence of heparin and heparin-binding studies with the surface plasmon resonance method) were carried out. Mutations were also investigated by in silico methods. Type I ATD caused by altered protein synthesis (p.Cys32Tyr, p.Leu270Argfs*14, p.Asn450Ile) or secretion disorder (p.Met121Arg, p.Leu245Pro, p.Gly456delins_Ala_Thr) was proved in six mutants, while type II heparin-binding-site ATD (p.Arg78Gly) and pleiotropic-effect ATD (p.Pro461Thr) were suggested in two mutants. Finally, the pathogenic role of p.Arg14Lys was equivocal. We provided evidence to understand the pathogenic nature of novel SERPINC1 mutations through in vitro expression studies.

Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who have a history of severe and frequent bleeds. However, data from prospective studies are scarce. WIL-31, a prospective, noncontrolled, international phase 3 trial, investigated the ef ficacy and safety of Wilate prophylaxis in severe patients with VWD. Male and female patients 6 years or older with VWD types 1, 2 (except 2N), or 3 who had completed a prospective, 6-month, on-demand, run -in study (WIL-29) were eligible to receive Wilate prophylaxis for 12 months. At baseline, patients (n = 33) had a median age of 18 years. Six (18%) patients had severe type 1, 5 (15%) had type 2, and 22 (67%) had type 3 VWD. The primary end point of a >50% reduction in mean total annualized bleeding rate (TABR) with Wilate prophylaxis vs prior on-demand treatment was met; mean TABR during prophylaxis was 5.2, representing an 84.4% reduction. The bleeding reduction was consistent across age, sex, and VWD types. The mean spontaneous ABR was 3.2, representing an 86.9% reduction vs on-demand treatment. During prophylaxis, 10 (30.3%) patients had 0 bleeding events and 15 (45.5%) patients had 0 spontaneous bleeding events. Of 173 BEs, 84.4% were minor and 69.9% treated. No serious adverse events related to study treatment and no thrombotic events were recorded. Overall, WIL-31 showed that Wilate prophylaxis was ef ficacious and well-tolerated in pediatric and adult patients with VWD of all types. The WIL-29 and WIL-31 trials were registered at www.ClinicalTrials.gov as #NCT04053699 and #NCT04052698, respectively.

Introduction The Hungarian von Willebrand patient registry contains data on patient demographic characteristics and treatment modalities.

florio® HAEMO is a hemophilia treatment monitoring application (app) offering activity tracking and wearable device connectivity. Its use might support everyday activities for people with hemophilia. The aim of this study was to evaluate user satisfaction, long-term usage and the impact on data entry when pairing a wearable with a hemophilia monitoring app. This is a follow-up of a two-part user survey conducted in Central Europe. People with hemophilia and parents/caregivers of children with hemophilia using florio HAEMO and who completed part one were invited to complete a second online questionnaire at least 4 months later. Fifty participants (83.3

BackgroundJoint damage affects the quality-of-life of patients with hemophilia A (PwHA). The long-term safety and efficacy of turoctocog alfa pegol (N8-GP) prophylaxis in PwHA has been investigated in pivotal phase 3 trials in children, adolescents, and adults (pathfinder program). However, there is a lack of data on joint health in adult PwHA treated with N8-GP.ObjectiveTo describe the design of the ongoing pathfinderReal study investigating the joint health status in adult PwHA after switching to N8-GP.MethodspathfinderReal is a multi-country, non-interventional, single-arm study (NCT05621746) of joint health in adult (≥18 years) male PwHA who have switched to N8-GP. Patients enrolled in other interventional studies and those who have previously terminated N8-GP treatment will be excluded. Approximately 124 adults with HA will be enrolled and followed-up for a maximum of 24 months. Data from routine clinical assessments of patients’ joint health will be collected. The primary endpoint is change in Hemophilia Joint Health Score (HJHS; defined as a change in total score ≤2) from initiation of N8-GP treatment until the end of the study. Secondary endpoints include number of bleeding episodes, number and resolution of target joints, patient-reported outcomes of problem joint score, pain score, and change in physical function levels. An exploratory endpoint is included to measure the number of patients achieving improved HJHS from the initiation of N8-GP until the end of the study.ConclusionThe pathfinderReal study will provide insights regarding the impact of N8-GP on joint health in PwHA in a real-world setting.

The apolar fullerenes C60 and C70 are not accessible for radio astronomy. Upon ionization static Jahn-Teller effects occur in C70+ that distort the D5h neutral symmetry to Cs. This point group is polar thus ionization induces a permanent electric dipole moment in C70. The goal of the present calculations is to compute the equilibrium geometry and dipole moment of the C70+ cation by various DFT methods and to simulate microwave spectra. Using quantum chemistry rotational constants, Cartesian dipole moment components and the resultant dipole, as well as Jahn-Teller stabilization energies and HOMO-LUMO gaps were obtained. Microwave rotational spectrum simulations for the slightly asymmetric top ion were carried out for gas phase temperatures 2.73 K and 10 K. These spectra may serve as starting point for laboratory microwave measurements and as screening guide in radio astronomical searches. In addition it was found that the static Jahn-Teller effect in C70+ is the consequence of the mixing of the two highest ground state occupied orbitals, thus it is a pseudo Jahn-Teller effect.

INTRODUCTION:Turoctocog alfa pegol (N8-GP) is a glycoPEGylated, extended half-life (EHL), human recombinant factor VIII (FVIII) approved for the treatment and prevention of bleeding episodes in patients with haemophilia A. Since its launch in August 2019, > 800 patients have been treated worldwide.AIM:To present data from identified post-marketing cases of less-than-expected FVIII activity in previously treated patients (PTPs) without inhibitors after switching to N8-GP.METHODS:The post-marketing safety database was searched using keywords such as 'coagulation FVIII level decreased'. Identified cases reported prior to 13 October 2021 were included in this report. Cases in which patients had FVIII inhibitors were excluded.RESULTS:Here we report 14 cases of less-than-expected FVIII activity. Details varied greatly amongst the cases. At presentation, FVIII activity ranged from 1% (15 min post-dose) to 51% (2 days post-dose). Seven patients experienced bleeding episodes after switching to N8-GP with heterogeneity in bleeding presentations. Six out of seven patients who were tested for anti-PEG IgG and/or IgM antibodies were positive. In all known cases, FVIII activity returned to the expected range when switched to an alternative FVIII replacement product.CONCLUSION:In conclusion, the 14 reported cases of less-than-expected FVIII activity, without presence of detectable FVIII inhibitors, presented with heterogenous characteristics, and wide variations in FVIII activity and anti-PEG antibody titre. FVIII activity returned to the expected range after switching to alternative FVIII products. In line with WFH guidelines, monitoring of FVIII activity can ensure FVIII activity in the expected range. The safety surveillance of N8-GP continues.

This work communicates cavity ring-down spectroscopy (CRDS) of methylidyne (CH) in a chemiluminescent plasma that is produced in a microwave cavity. Of interest are the rotational lines of the 0-0 vibrational transition for the A–X band and the 1-0 vibrational transition for the B–X band. The reported investigations originate from research on the CH radical in 1996, which constituted the first case of applying CRDS to the CH radical. The report also includes a recent analysis that shows excellent agreement of the measured and computed data, and it communicates CH line strength data. The CH radical is an important diatomic molecule in hydrocarbon combustion diagnosis and the analysis of stellar plasma emissions, to name just two examples of analytical plasma chemistry.

florio HAEMO is a new hemophilia treatment monitoring application consisting of a patient smartphone application (app) and a web‐based dashboard for healthcare professionals, providing several novel features, including activity tracking, wearable connectivity, kids and caregiver mode, and real‐time pharmacokinetic factor level estimation.

The next frontier in hemophilia A management has arrived. However, questions remain regarding the broader applicability of new and emerging hemophilia A therapies, such as the long-term safety and efficacy of non-factor therapies and optimal regimens for individual patients. With an ever-evolving clinical landscape, it is imperative for physicians to understand how available and future hemophilia A therapies could potentially be integrated into real-life clinical practice to improve patient outcomes. Against this background, nine hemophilia experts from Central European countries participated in a pre-advisory board meeting survey. The survey comprised 11 multiple-choice questions about current treatment practices and future factor and non-factor replacement therapies. The survey questions were developed to reflect current unmet needs in hemophilia management reflected in the literature. The experts also took part in a follow-up advisory board meeting to discuss the most important unmet needs for hemophilia management as well as the pre-meeting survey results. All experts highlighted the challenge of maintaining optimal trough levels with prophylaxis as their most pressing concern. Targeting trough levels of ≥30–50 IU/L or even higher to achieve less bleeding was highlighted as their preferred strategy. However, the experts had an equal opinion on how this could be achieved (i.e., more efficacious non-factor therapies or factor therapy offering broader personalization possibilities such as targeting trough levels to individual pharmacokinetic data). In summary, our study favors personalized prophylaxis to individual pharmacokinetic data rather than a "one-size-fits-all" approach to hemophilia A management to maintain optimal trough levels for individual patients.

Background: N8-GP (turoctocog alfa pegol; Esperoct) is a glycoPEGylated human recombinant factor VIII (FVIII). Objectives: Pathfinder8 (NCT01480180) was a phase 3, multinational, open-label, nonrandomized trial to investigate the long-term safety and efficacy of N8-GP in people of all ages with severe hemophilia A previously treated with N8-GP. Patients/Method: Patients were recruited from the completed phase 3 pathfinder2 and pathfinder5 trials to receive intravenous N8-GP prophylaxis for up to 104 weeks, administered every 7 days, twice weekly, or three times weekly. Primary and secondary end points were the number of adverse events (AEs) reported and efficacy of treatment, respectively. Results: Overall, 160 patients were exposed to N8-GP for a mean of 179 exposure days and 681 calendar days (e1.9 years) per patient. In total, 119 patients experienced 510 AEs, corresponding to a rate of 1.71 AEs per patient-year of exposure; 97.5% of AEs were mild or moderate in severity, and no AEs led to withdrawal. No patients developed FVIII inhibitors during the trial. The Poisson estimate of mean annualized bleeding rate for all bleeds (excluding surgery) and across all regimens was median, 0.00), and for spontaneous bleeds was 0.61 (median, 0.00). Most (55.6%) patients experienced no bleeds that required FVIII treatment (excluding perioperative bleeds). The estimated hemostatic success rate for the treatment of 322 bleeding episodes (excluding surgery) was 95.8%, including missing values as failure. Conclusions: Long-term prophylactic use of N8-GP appeared safe and efficacious across all age groups in people with severe hemophilia A previously treated with N8-GP.