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INTRODUCTION: Haemophilia A (HA) is a congenital bleeding disorder caused by a deficiency/absence of factor VIII (FVIII) and characterised by frequent, acute and prolonged spontaneous or traumatic bleeding events, often leading to haemophilic arthropathy and progressive joint deterioration. HA severity is characterized by endogenous FVIII activity: mild (> 5-40%), moderate (1-5%), or severe (< 1%). HA poses a substantial clinical and socioeconomic burden on people with HA (PWHA), their caregivers, and society. This analysis evaluates clinical and patient-centric outcomes of a cohort of individuals with non-inhibitor HA sampled from France, Germany, Italy, Spain, and the UK in the 'Cost of Haemophilia in Europe: A Socioeconomic Survey II' (CHESS II) study. METHODS: CHESS II was a cross-sectional burden-of-illness study collecting clinical and socioeconomic data on adult (≥ 18 years) individuals with haemophilia A or B of any severity with or without inhibitors from eight European countries. Descriptive analyses were conducted examining physician-reported demographics, clinical and health resource utilisation information. PWHA-reported health-related quality of life (HRQoL) using the EQ-5D-5L and Work Productivity and Activity Impairment (WPAI) were also examined. Outcomes were stratified by HA severity and reported at country level. RESULTS: Demographics and clinical characteristics of the cohort (N = 880) were generally consistent across countries. Individuals with severe HA experienced more frequent bleeding events and joint disease despite broad use of factor replacement therapy long-term prophylaxis. A minority of those with mild or moderate HA also experienced such challenges. HRQoL and workforce participation diminished, and chronic pain increased, with increasing HA severity. CONCLUSION: This analysis provides up-to-date insights on the impact of HA across five European countries. Increasing HA severity was generally associated with worse clinical outcomes, HRQoL and workforce participation. These findings suggest a place for continued evidence-based tailored treatment and clinical management approaches in addressing the residual burden of HA.
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BACKGROUND: Gene therapy is designed to provide people with haemophilia B with a steady and elevated factor IX activity, thereby strengthening protection and relieving the burden of replacement therapy frequent infusions. The European Medicines Agency has approved a gene therapy for the severe and moderately severe forms of haemophilia B that uses the factor IX Padua variant (etranacogene dezaparvovec). The aim is to provide a document dedicated to haemophilia B gene therapy and give a comprehensive overview of the topic. METHODS: An Italian group of experts in haemophilia has carried out a narrative review of the literature and has discussed during a virtual meeting several key aspects of the delivery of this treatment in Italy. The discussion covered the organisational model, the role of the multidisciplinary team, the laboratory surveillance and the patient journey, from the follow-up to the identification of safety issues and outcome measures. RESULTS: This article highlights the need to follow the Hub and Spoke organisational model and sheds light on the role of each professional figure within the multidisciplinary teams to favour patient engagement, management, and retention. Moreover, this article stresses the need to perform laboratory tests for patient screening and follow-up and proposes a checklist to help patient identification. Finally, the needs of Italian haemophilia centres have been considered to ensure an efficient implementation of the care delivery model. CONCLUSION: It is crucial to ensure that centres are appropriately organized, equipped and trained to adequately select patients, deliver the gene therapy and perform follow-up.
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Hemophilia is a rare X-linked congenital bleeding disorder due to a deficiency of factor VIII (hemophilia A [HA]) or factor IX (hemophilia B [HB]). Replacement and nonreplacement treatments are available but have limitations. Gene therapy (GT) provides an effective, long-term, single-dose treatment option, now approaching clinical practice. This study aimed to understand patient perspectives on GT for HA and HB in Italy using a qualitative questionnaire distributed through Italian patient associations, addressing patient views on daily life, treatments, unmet needs, quality of life (QoL), and GT for hemophilia. In total, 141 participants had HA, and 14 had HB (severe 78.6%). Daily life was most affected by pain and/or joint function limitations (57.5% of participants), high infusion frequency (42.5%), management of breakthrough bleeding episodes (40.3%), and anxiety/fear of severe or sudden bleeding (38.8%). Despite current treatments, about half of the participants experienced three or more annual bleeding episodes. Most participants knew of GT (87.2%) and expected improvements in QoL (60.5%), reduced frequency of current treatments (53.5%), and a permanent cure (49.1%); 46.4% were unaware of its once-off dosage and 46.4% were not concerned about the costs they anticipated to be associated with GT. Although several fears were reported, 25.0% of participants were willing to undergo GT with the support of a multidisciplinary team. This survey provided valuable insight into patient perspectives on hemophilia and GT in Italy. Overall, relevant proportions of patients still experience limitations affecting their daily life. Most were positive about GT and anticipated improvements in their clinical outcomes and QoL.
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INTRODUCTION: Considering the advances in haemophilia management and treatment observed in the last decades, a new set of value-based outcome indicators is needed to assess the quality of care and the impact of these medical innovations. AIM: The Value-Based Healthcare in Haemophilia project aimed to define a set of clinical outcome indicators (COIs) and patient-reported outcome indicators (PROIs) to assess quality of care in haemophilia in high-income countries with a value-based approach to inform and guide the decision-making process. METHODS: A Value-based healthcare approach based on the available literature, current guidelines and the involvement of a multidisciplinary group of experts was applied to generate a set of indicators to assess the quality of care of haemophilia. RESULTS: A final list of three COIs and five PROIs was created and validated. The identified COIs focus on two domains: musculoskeletal health and function, and safety. The identified PROIs cover five domains: bleeding frequency, pain, mobility and physical activities, Health-Related Quality of Life and satisfaction. Finally, two composite outcomes, one based on COIs, and one based on PROIs, were proposed as synthetic outcome indicators of quality of care. CONCLUSION: The presented standard set of health outcome indicators provides the basis for harmonised longitudinal and cross-sectional monitoring and comparison. The implementation of this value-based approach would enable a more robust assessment of quality of care in haemophilia, within a framework of continuous treatment improvements with potential added value for patients. Moreover, proposed COIs and PROIs should be reviewed and updated routinely.
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Hemofilia A , Humanos , Hemofilia A/tratamiento farmacológico , Calidad de Vida , Estudios Transversales , Atención Médica Basada en Valor , Evaluación de Resultado en la Atención de SaludRESUMEN
In clinical medicine, shared decision making (SDM) is a well-recognized strategy to enhance engagement of both patients and clinicians in medical decisions. The success of liver-directed gene therapy (GT) to transform severe congenital haemophilia A (HA) from an incurable to a curable disease has launched a shift beyond current standards of treatment. However, GT acceptance remains low in the community of HA persons. We argue for both persons with haemophilia (PWH) and specialists in HA care including clinicians, as needing SDM-oriented educational programs devoted to GT. Here, we provide an ad hoc outline to implement education to SDM and tailor clinician information on GT to individual PWHs. Based on routine key components of SDM: patient priorities; recommendations based on individual risk reduction; adverse effects; drug-drug interactions; alternatives to GT; and ongoing re-assessment of the objectives as risk factors (and individual priorities) change, this approach is finalized to exploit efficacious communication.
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Toma de Decisiones Conjunta , Hemofilia A , Humanos , Hemofilia A/genética , Hemofilia A/terapia , Toma de Decisiones , Objetivos , Terapia Genética , HígadoRESUMEN
INTRODUCTION: Current treatment for haemophilia A involves factor VIII replacement or non-replacement (emicizumab) therapies, neither of which permanently normalise factor VIII levels. Gene therapy using adeno-associated viral (AAV) vectors is an emerging long-term treatment strategy for people with severe haemophilia A (PwSHA) that is likely to be available for clinical use in the near future. AIM: This article proposes practical guidelines for the assessment, treatment, and follow-up of potential PwSHA candidates for AAV-based gene therapy. METHOD: Using the Delphi method, a working group of Italian stakeholders with expertise in and knowledge of the care of adults with haemophilia A analysed literature for AAV-based gene therapy and drafted a list of statements that were circulated to a panel of Italian peers. During two rounds of voting, panel members voted on their agreement with each statement to reach a consensus. RESULTS: The Delphi process yielded 40 statements regarding haemophilia A gene therapy, across five topics: (1) organisational model; (2) multidisciplinary team; (3) patient engagement; (4) laboratory surveillance; and (5) patient follow-up and gene therapy outcomes. The consensus was reached for all 40 statements, with the second round of voting needed for five statements. CONCLUSION: Use of the hub-and-spoke organisational model and multidisciplinary teams are expected to optimise patient selection for gene therapy, as well as the management of dosing and patient follow-up, patient engagement, laboratory surveillance, and patient expectations regarding outcomes. This approach should allow the benefits of AAV-based gene therapy for haemophilia A to be maximised.
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Hemofilia A , Humanos , Hemofilia A/genética , Hemofilia A/terapia , Factor VIII , Técnica Delphi , Italia , Terapia GenéticaRESUMEN
Atmospheric aerosols are important drivers of Arctic climate change through aerosol-cloud-climate interactions. However, large uncertainties remain on the sources and processes controlling particle numbers in both fine and coarse modes. Here, we applied a receptor model and an explainable machine learning technique to understand the sources and drivers of particle numbers from 10 nm to 20 µm in Svalbard. Nucleation, biogenic, secondary, anthropogenic, mineral dust, sea salt and blowing snow aerosols and their major environmental drivers were identified. Our results show that the monthly variations in particles are highly size/source dependent and regulated by meteorology. Secondary and nucleation aerosols are the largest contributors to potential cloud condensation nuclei (CCN, particle number with a diameter larger than 40 nm as a proxy) in the Arctic. Nonlinear responses to temperature were found for biogenic, local dust particles and potential CCN, highlighting the importance of melting sea ice and snow. These results indicate that the aerosol factors will respond to rapid Arctic warming differently and in a nonlinear fashion.
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Contaminantes Atmosféricos , Aerosoles/análisis , Contaminantes Atmosféricos/análisis , Polvo/análisis , Aprendizaje Automático , Tamaño de la Partícula , SvalbardRESUMEN
An empirical model to predict hourly global solar irradiance under all-sky conditions as a function of absorbing and scattering factors has been applied at the Dome C station in the Antarctic, using measured solar radiation and meteorological variables. The calculated hourly global solar irradiance agrees well with measurements at the ground in 2008-2011 (the model development period) and at the top of the atmosphere (TOA). This model is applied to compute global solar irradiance at the ground and its extinction in the atmosphere caused by absorbing and scattering substances during the 2006-2016 period. A sensitivity study shows that the responses of global solar irradiance to changes in water vapor and scattering factors (expressed by water vapor pressure and S/G, respectively; S and G are diffuse and global solar irradiance, respectively) are nonlinear and negative, and that global solar irradiance is more sensitive to changes in scattering than to changes in water vapor. Applying this empirical model, the albedos at the TOA and the surface in 2006-2016 are estimated and found to agree with the satellite-based retrievals. During 2006-2016, the annual mean observed and estimated global solar exposures decreased by 0.05% and 0.09%, respectively, and the diffuse exposure increased by 0.68% per year, associated with the yearly increase of the S/G ratio by 0.57% and the water vapor pressure by 1.46%. The annual mean air temperature increased by about 1.80 °C over the ten years, and agrees with the warming trends for all of Antarctica. The annual averages were 316.49 Wm-2 for the calculated global solar radiation, 0.332 for S/G, -46.23 °C for the air temperature and 0.10 hPa for the water vapor pressure. The annual mean losses of solar exposure due to absorbing and scattering substances and the total loss were 4.02, 0.19 and 4.21 MJ m-2, respectively. The annual mean absorbing loss was much larger than the scattering loss; their contributions to the total loss were 95.49% and 4.51%, respectively, indicating that absorbing substances are dominant and play essential roles. The annual absorbing, scattering and total losses increased by 0.01%, 0.39% and 0.28% per year, respectively. The estimated and satellite-retrieved annual albedos increased at the surface. The mechanisms of air-temperature change at two pole sites, as well as a mid-latitude site, are discussed.
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Energía Solar , Vapor , Regiones Antárticas , Atmósfera , Luz SolarRESUMEN
The present study discusses the effect of the ozone depletion that occurred over the Arctic in 2020 on the ozone column in central and southern Europe by analysing a data set obtained from ground-based measurements at six stations placed from 79 to 42°N. Over the northernmost site (Ny-Ålesund), the ozone column decreased by about 45% compared to the climatological average at the beginning of April, and its values returned to the normal levels at the end of the month. Southwards, the anomaly gradually reduced to nearly 15% at 42°N (Rome) and the ozone minimum was detected with a delay from about 6 days at 65°N to 20 days at 42°N. At the same time, the evolution of the ozone column at the considered stations placed below the polar circle corresponded to that observed at Ny-Ålesund, but at 42°-46°N, the ozone column turned back to the typical values at the end of May. This similarity in the ozone evolutional patterns at different latitudes and the gradually increasing delay of the minimum occurrences towards the south allows the assumption that the ozone columns at lower latitudes were affected by the phenomenon in the Arctic. The ozone decrease observed at Aosta (46°N) combined with predominantly cloud-free conditions resulted in about an 18% increase in the erythemally weighted solar ultraviolet irradiance reaching the Earth's surface in May.
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Variations in total ozone column and sun exposures able to cause erythema and damage the DNA molecules were observed by the narrow-band filter radiometer UV-RAD in Bologna, Italy from 2005 to 2010. The ozone columns determined from the UV-RAD measurements were found to be close to those provided by the satellite Ozone Monitoring Instrument (OMI) showing an average discrepancy of 1% with standard deviation of ± 6%. Analysis of the data highlights a well-marked annual cycle of the ozone column variations while the oscillations with periods of 8, 18 and 34 months present much smaller amplitudes. The influence of the frequency of solar irradiance measurements on the accuracy of the evaluated daily exposure dose has been studied and it was found that time intervals no longer than 5-10 min between the measurements of erythema and DNA damage effective UV irradiances provide a satisfactory assessment of the corresponding daily exposures. The latter do not present significant year-to-year variations for the period under study, while their annual distributions show slight changes likely due to the specific cloud cover and ozone column variability for different years. The annual erythemal exposure dose for 2007-2010 varied between 603.7 and 638.1 kJ m(-2), while the corresponding sun exposure affecting DNA changed from 6.38 to 7.91 kJ m(-2).
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Modelos Teóricos , Ozono/análisis , Dosis de Radiación , Rayos Ultravioleta , Daño del ADN , ItaliaRESUMEN
An approach is proposed to assess the periods of human skin exposure to solar ultraviolet-A (UV-A, 315-400 nm) irradiance in natural conditions that are able to yield doses found to trigger carcinogenesis in laboratory experiments. Weighting functions, adopted to perform such estimate are constructed, allowing for a comparison between environmental and laboratory doses. Furthermore, the impact of stratum corneum (SC) thickness on the studied environmental doses was investigated. Based on laboratory studies, it was found that exposure periods of less than a month, at mid-latitudes, could provide irradiance doses capable of causing tumor formation. The duration of these exposure periods closely depends on the exposure regime, atmospheric conditions and SC thickness. It is believed that the presented evaluations could provide a useful preliminary estimation of the risk associated with environmental UV-A exposure prior to the formulation of the corresponding action spectra and determination of the threshold doses.
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Exposición a Riesgos Ambientales/efectos adversos , Rayos Ultravioleta/efectos adversos , Línea Celular Tumoral , Humanos , Laboratorios , Neoplasias Inducidas por Radiación , Dosis de Radiación , Medición de Riesgo , Piel/efectos de la radiación , Factores de TiempoRESUMEN
Precise calculations of the total Rayleigh-scattering optical depth have been performed at 88 wavelengths ranging from 0.20 to 4.00 microm for the six well-known standard atmosphere models by integrating the volume Rayleigh-scattering coefficient along the vertical atmospheric path from sea level to a 120-km height. The coefficient was determined by use of an improved algorithm based on the Ciddor algorithm [Appl. Opt. 35, 1566 (1996)], extended by us over the 0.20-0.23-microm wavelength range to evaluate the moist air refractive index as a function of wavelength, air pressure, temperature, water-vapor partial pressure, and CO2 volume concentration. The King depolarization factor was also defined taking into account the moisture conditions of air. The results indicate that the influence of water vapor on Rayleigh scattering cannot be neglected at tropospheric altitudes: for standard atmospheric conditions represented in terms of the U.S. Standard Atmosphere (1976) model, the relative variations produced by water vapor in the Rayleigh scattering parameters at a 0.50-microm wavelength turn out to be equal to -0.10% in the moist air refractivity at sea level (where the water-vapor partial pressure is equal to approximately 7.8 hPa), -0.04% in the sea-level King factor, -0.24% in the sea-level Rayleigh-scattering cross section, and -0.06% in the Rayleigh-scattering optical depth.