The main clinical features of pseudohypoparathyroidism (PHP)/inactivating parathyroid hormone/parathyroid hormone-related protein signaling disorders (iPPSD), including parathyroid hormone (PTH) resistance, brachydactyly and short stature, develop during middle and late childhood. Very few studies have addressed hearing loss in PHP/iPPSD patients, and these studies have yielded widely divergent conclusions. The aim of our study was to assess hearing and determine the predictive factors of hearing loss in patients with PHP/iPPSD. Our retrospective cohort study was conducted between March 2019 and May 2020 in the Otolaryngology Department and the calcium phosphate reference center for rare diseases in Bicêtre Paris-Saclay Hospital, France. We retrospectively collected data from patients with PHP/iPPSDs (age, sex, genetic mutations, height, body mass index (BMI), PTH resistance, presence or absence of ectopic ossifications and brachydactyly). All patients underwent auditory investigations, including tonal and vocal audiometry. The primary outcome was the pure tone average (PTA). The PTA was compared with the norm according to the International Organization for Standardization. Hearing loss was defined as a PTA ≥ 20 db. The median age of the patients was 15.6 years [9.5, 28.5]. Thirty-six patients were diagnosed with iPPSD2, and eight were diagnosed with iPPSD3. Twenty-six of them (59%) were female. Hearing impairment was confirmed in 17 patients (39%). The mean PTA and the mean SRT of the deaf ears were 40 ± 26 db and 31 ± 14 db. The mean difference in the PTA between the patients and the normal controls was 11.4 db (p = 0.00002). Short stature and the presence of ectopic ossifications were two significant predictive factors of hearing loss (p = 0.009 and p = 0.03, respectively). Sex, BMI, PTH resistance, mutation category and brachydactyly were not associated with an increased risk of hearing loss (p = 0.19, p = 0.41, p = 0.13, p = 0.50, p = 0.19, respectively). Our study confirmed the frequency of hearing loss in patients with PHP/iPPSD disease (prevalence = 39%). A diagnosis of PHP/iPPSD should trigger auditory investigations and follow-up, especially when short stature and/or ectopic ossifications are present.
{"title":"Prevalence of hearing loss in pseudohypoparathyroidism","authors":"Cassandre Djian, Jugurtha Berkenou, Anya Rothenbuhler, Jérémie Botton, Agnès Linglart, Jérôme Nevoux","doi":"10.1186/s13023-024-03299-3","DOIUrl":"https://doi.org/10.1186/s13023-024-03299-3","url":null,"abstract":"The main clinical features of pseudohypoparathyroidism (PHP)/inactivating parathyroid hormone/parathyroid hormone-related protein signaling disorders (iPPSD), including parathyroid hormone (PTH) resistance, brachydactyly and short stature, develop during middle and late childhood. Very few studies have addressed hearing loss in PHP/iPPSD patients, and these studies have yielded widely divergent conclusions. The aim of our study was to assess hearing and determine the predictive factors of hearing loss in patients with PHP/iPPSD. Our retrospective cohort study was conducted between March 2019 and May 2020 in the Otolaryngology Department and the calcium phosphate reference center for rare diseases in Bicêtre Paris-Saclay Hospital, France. We retrospectively collected data from patients with PHP/iPPSDs (age, sex, genetic mutations, height, body mass index (BMI), PTH resistance, presence or absence of ectopic ossifications and brachydactyly). All patients underwent auditory investigations, including tonal and vocal audiometry. The primary outcome was the pure tone average (PTA). The PTA was compared with the norm according to the International Organization for Standardization. Hearing loss was defined as a PTA ≥ 20 db. The median age of the patients was 15.6 years [9.5, 28.5]. Thirty-six patients were diagnosed with iPPSD2, and eight were diagnosed with iPPSD3. Twenty-six of them (59%) were female. Hearing impairment was confirmed in 17 patients (39%). The mean PTA and the mean SRT of the deaf ears were 40 ± 26 db and 31 ± 14 db. The mean difference in the PTA between the patients and the normal controls was 11.4 db (p = 0.00002). Short stature and the presence of ectopic ossifications were two significant predictive factors of hearing loss (p = 0.009 and p = 0.03, respectively). Sex, BMI, PTH resistance, mutation category and brachydactyly were not associated with an increased risk of hearing loss (p = 0.19, p = 0.41, p = 0.13, p = 0.50, p = 0.19, respectively). Our study confirmed the frequency of hearing loss in patients with PHP/iPPSD disease (prevalence = 39%). A diagnosis of PHP/iPPSD should trigger auditory investigations and follow-up, especially when short stature and/or ectopic ossifications are present.","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1186/s13023-024-03341-4
L. Sangiorgi, M. Boarini, M. Mordenti, V. Wang, I. Westerheim, R. T. Skarberg, M. Cavaller-Bellaubi, James Clancy, R. Pinedo-Villanueva, E. J. V. Lente, M. Marchetti
SATURN (Systematic Accumulation of Treatment practices and Utilisation, Real world evidence, and Natural history data) for the rare condition osteogenesis imperfecta (OI) has the objective to create a common core dataset by utilising existing, well-established data sources to meet the needs of the various stakeholders (physicians, registry/dataset owners, patients and patient associations, OI community leaders, European [EU] policymakers, regulators, health technology assessments [HTA]s, and healthcare systems including payers). This paper describes the steps taken to assess the feasibility of one existing OI registry (i.e., the Registry of OI [ROI]) as a candidate for SATURN. The same methodology will be applied to other existing OI registries in the future and this same concept could be utilised for other rare disease registries. The approach to assessing the feasibility of the ROI registry consisted of three steps: (1) an assessment of the registry characteristics using the Registry Evaluation and Quality Standards Tool (REQueST); (2) a gap analysis comparing SATURN required Core Variables to those being captured in the registry’s Case Report Form (CRF); and (3) a compliance check on the data exchange process following the Title 21 of Code of Federal Regulations (CFR) Part 11/EudraLex Annex 11 Compliance Checklist. The first registry that SATURN has assessed is the ROI database at the Istituto Ortopedico Rizzoli (IOR) in Italy. The results from the ROI REQueST have demonstrated satisfactory complete responses in terms of methodology, essential standards, interpretability, and interoperability—readiness for data linkage, data sources, and ethics to meet the needs of data customers. However, the ROI data is from a tertiary referral centre which may limit the ability to understand the full patient journey. The gap analysis has revealed that an exact or logical match between SATURN requested variables and the ROI current variables exists for the following items: patient characteristics, treatment of OI (medical and surgical) and treatment of pain (with the exception of frequency of treatment and reasons for discontinuation), fracture history and bone density. However, data on safety was missing. The compliance check has implied that the ROI implemented appropriate controls for the web-based platform (i.e., Genotype–phenotype Data Integration Platform [GeDI]) that is involved in processing the electronic patient data, and GeDI is a validated/compliant application that follows relevant 21 CFR Part 11/EudraLex Annex 11 regulations. This robust feasibility process highlights potential limitations and opportunities to develop and to refine the collaboration with the ROI as the SATURN programme moves forward. It also ensures that the existing datasets in the rare condition OI are being maximised to respond to the needs of patients, data customers and decision-makers. This feasibility process has allowed SATURN to build a compliant methodology that align
针对罕见疾病成骨不全症（OI）的 SATURN（治疗实践和利用、现实证据和自然病史数据的系统性积累）旨在利用现有的、成熟的数据源创建一个通用的核心数据集，以满足不同利益相关者（医生、注册表/数据集所有者、患者和患者协会、OI 社区领袖、欧洲[欧盟]政策制定者、监管者、健康技术评估[HTA]和医疗保健系统，包括支付者）的需求。本文介绍了为评估将一个现有的 OI 登记处（即 OI 登记处 [ROI]）作为 SATURN 候选者的可行性而采取的步骤。同样的方法今后将应用于其他现有的 OI 登记处，同样的概念也可用于其他罕见病登记处。评估 ROI 登记册可行性的方法包括三个步骤：(1) 使用登记册评估和质量标准工具 (REQueST) 评估登记册的特征；(2) 将 SATURN 要求的核心变量与登记册病例报告表 (CRF) 中捕获的核心变量进行差距分析；(3) 按照《联邦法规汇编》(CFR) 第 21 篇第 11 部分/EudraLex 附件 11 合规性检查表对数据交换过程进行合规性检查。SATURN 评估的第一个登记处是意大利 Istituto Ortopedico Rizzoli (IOR) 的 ROI 数据库。ROI REQueST 的结果表明，在方法、基本标准、可解释性和互操作性--数据链接、数据来源和伦理道德的准备程度等方面，完全符合数据客户的需求，令人满意。然而，投资回报率数据来自三级转诊中心，这可能会限制了解患者整个就医过程的能力。差距分析表明，SATURN 要求的变量与 ROI 当前变量在以下项目上存在精确或逻辑匹配：患者特征、OI 治疗（内科和外科）和疼痛治疗（治疗频率和中断原因除外）、骨折史和骨密度。但是，缺少有关安全性的数据。合规性检查表明，投资回报率对处理患者电子数据的网络平台（即基因型-表型数据集成平台 [GeDI]）实施了适当的控制，GeDI 是一个经过验证/合规的应用程序，遵循相关的 21 CFR Part 11/EudraLex Annex 11 法规。随着 SATURN 计划的推进，这一稳健的可行性流程凸显了潜在的局限性以及发展和完善与 ROI 合作的机会。它还能确保罕见病 OI 中的现有数据集最大限度地满足患者、数据客户和决策者的需求。这一可行性过程使 SATURN 能够建立符合欧洲药品管理局 (EMA) 和 HTA 要求的方法。随着越来越多的登记处加入 SATURN，更多的数据变量将继续得到开发和完善。因此，SATURN 将成为一个有意义的、真正合作性的核心数据集，这也将有助于加深对 OI 诊断、治疗和护理的理解。
{"title":"SATURN: assessing the feasibility of utilising existing registries for real-world evidence data collection to meet patients, regulatory, health technology assessment and payer requirements","authors":"L. Sangiorgi, M. Boarini, M. Mordenti, V. Wang, I. Westerheim, R. T. Skarberg, M. Cavaller-Bellaubi, James Clancy, R. Pinedo-Villanueva, E. J. V. Lente, M. Marchetti","doi":"10.1186/s13023-024-03341-4","DOIUrl":"https://doi.org/10.1186/s13023-024-03341-4","url":null,"abstract":"SATURN (Systematic Accumulation of Treatment practices and Utilisation, Real world evidence, and Natural history data) for the rare condition osteogenesis imperfecta (OI) has the objective to create a common core dataset by utilising existing, well-established data sources to meet the needs of the various stakeholders (physicians, registry/dataset owners, patients and patient associations, OI community leaders, European [EU] policymakers, regulators, health technology assessments [HTA]s, and healthcare systems including payers). This paper describes the steps taken to assess the feasibility of one existing OI registry (i.e., the Registry of OI [ROI]) as a candidate for SATURN. The same methodology will be applied to other existing OI registries in the future and this same concept could be utilised for other rare disease registries. The approach to assessing the feasibility of the ROI registry consisted of three steps: (1) an assessment of the registry characteristics using the Registry Evaluation and Quality Standards Tool (REQueST); (2) a gap analysis comparing SATURN required Core Variables to those being captured in the registry’s Case Report Form (CRF); and (3) a compliance check on the data exchange process following the Title 21 of Code of Federal Regulations (CFR) Part 11/EudraLex Annex 11 Compliance Checklist. The first registry that SATURN has assessed is the ROI database at the Istituto Ortopedico Rizzoli (IOR) in Italy. The results from the ROI REQueST have demonstrated satisfactory complete responses in terms of methodology, essential standards, interpretability, and interoperability—readiness for data linkage, data sources, and ethics to meet the needs of data customers. However, the ROI data is from a tertiary referral centre which may limit the ability to understand the full patient journey. The gap analysis has revealed that an exact or logical match between SATURN requested variables and the ROI current variables exists for the following items: patient characteristics, treatment of OI (medical and surgical) and treatment of pain (with the exception of frequency of treatment and reasons for discontinuation), fracture history and bone density. However, data on safety was missing. The compliance check has implied that the ROI implemented appropriate controls for the web-based platform (i.e., Genotype–phenotype Data Integration Platform [GeDI]) that is involved in processing the electronic patient data, and GeDI is a validated/compliant application that follows relevant 21 CFR Part 11/EudraLex Annex 11 regulations. This robust feasibility process highlights potential limitations and opportunities to develop and to refine the collaboration with the ROI as the SATURN programme moves forward. It also ensures that the existing datasets in the rare condition OI are being maximised to respond to the needs of patients, data customers and decision-makers. This feasibility process has allowed SATURN to build a compliant methodology that align","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1186/s13023-024-03351-2
Shona Fang, Peter Hedera, Julia Borchert, Michael Schultze, Karl Heinz Weiss
Wilson disease (WD) is a rare disorder of copper metabolism, causing copper accumulation mainly in the liver and the brain. The prevalence of WD was previously estimated around 20 to 33.3 patients per million for the United States, Europe, and Asia, but data on the prevalence of WD in Germany are limited. To describe patient characteristics and to assess prevalence of WD in Germany using a representative claims database. WD patients were identified in the WIG2 (Wissenschaftliches Institut für Gesundheitsökonomie und Gesundheitssystemforschung; Scientific Institute for Health Economics and Health Systems Research) benchmark database of 4.5 million insured Germans by combining ICD-10-coding with WD-specific lab tests and treatments. The study period ranged from 2013 to 2016 for assessing patient characteristics, and to 2018 for prevalence, respectively. Seventy unique patients were identified. Most patients (86%) were between 18 and 64 years of age and more often male (60%) than female. Two patients (3%) younger than 18 years were included, as well as 8 patients (11%) older than 64 years. Most common WD subtypes were hepatic (57%), psychiatric (49%), and neurologic (44%). Average prevalence was 20.3 patients per million (range: 17.8–24.4), with similar results for two-year prevalence. Generally, prevalence increased steadily over the study period. Observed mortality was low, with only one death during the study period. This study adds valuable real-world data on the prevalence and patient characteristics of WD in Germany. Generally, our findings align with other reports and contribute to the global understanding of WD epidemiology. Still, regional and temporal trends remain to be investigated more thoroughly to further the understanding of the natural history and epidemiology of this rare disease.
威尔逊病（WD）是一种罕见的铜代谢紊乱疾病，主要导致铜在肝脏和大脑中蓄积。据估计，WD 在美国、欧洲和亚洲的患病率约为每百万人中有 20 至 33.3 名患者，但有关 WD 在德国患病率的数据却很有限。目的：利用具有代表性的索赔数据库描述患者特征并评估 WD 在德国的患病率。WIG2（Wissenschaftliches Institut für Gesundheitsökonomie und Gesundheitssystemforschung; Health Economics and Health Systems Research科学研究所）基准数据库中有450万德国投保人，通过将ICD-10编码与WD特异性实验室检查和治疗相结合，确定了WD患者。评估患者特征的研究时间段为 2013 年至 2016 年，评估患病率的研究时间段为 2018 年。共确定了 70 名独特的患者。大多数患者（86%）年龄在 18 至 64 岁之间，男性（60%）多于女性。其中有两名小于 18 岁的患者（3%）和 8 名大于 64 岁的患者（11%）。最常见的 WD 亚型是肝病（57%）、精神病（49%）和神经病（44%）。平均患病率为每百万人中有 20.3 名患者（范围：17.8-24.4），两年患病率的结果类似。总体而言，患病率在研究期间稳步上升。观察到的死亡率很低，研究期间仅有一人死亡。这项研究为我们提供了有关德国 WD 患病率和患者特征的宝贵真实数据。总体而言，我们的研究结果与其他报告一致，有助于全球对 WD 流行病学的了解。不过，为了进一步了解这种罕见疾病的自然史和流行病学，我们仍需对地区和时间趋势进行更深入的调查。
{"title":"Epidemiology of Wilson disease in Germany – real-world insights from a claims data study","authors":"Shona Fang, Peter Hedera, Julia Borchert, Michael Schultze, Karl Heinz Weiss","doi":"10.1186/s13023-024-03351-2","DOIUrl":"https://doi.org/10.1186/s13023-024-03351-2","url":null,"abstract":"Wilson disease (WD) is a rare disorder of copper metabolism, causing copper accumulation mainly in the liver and the brain. The prevalence of WD was previously estimated around 20 to 33.3 patients per million for the United States, Europe, and Asia, but data on the prevalence of WD in Germany are limited. To describe patient characteristics and to assess prevalence of WD in Germany using a representative claims database. WD patients were identified in the WIG2 (Wissenschaftliches Institut für Gesundheitsökonomie und Gesundheitssystemforschung; Scientific Institute for Health Economics and Health Systems Research) benchmark database of 4.5 million insured Germans by combining ICD-10-coding with WD-specific lab tests and treatments. The study period ranged from 2013 to 2016 for assessing patient characteristics, and to 2018 for prevalence, respectively. Seventy unique patients were identified. Most patients (86%) were between 18 and 64 years of age and more often male (60%) than female. Two patients (3%) younger than 18 years were included, as well as 8 patients (11%) older than 64 years. Most common WD subtypes were hepatic (57%), psychiatric (49%), and neurologic (44%). Average prevalence was 20.3 patients per million (range: 17.8–24.4), with similar results for two-year prevalence. Generally, prevalence increased steadily over the study period. Observed mortality was low, with only one death during the study period. This study adds valuable real-world data on the prevalence and patient characteristics of WD in Germany. Generally, our findings align with other reports and contribute to the global understanding of WD epidemiology. Still, regional and temporal trends remain to be investigated more thoroughly to further the understanding of the natural history and epidemiology of this rare disease.","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1186/s13023-024-03322-7
Chiuhui Mary Wang, Amy Heagle Whiting, Ana Rath, Roberta Anido, Diego Ardigò, Gareth Baynam, Hugh Dawkins, Ada Hamosh, Yann Le Cam, Helen Malherbe, Caron M. Molster, Lucia Monaco, Carmencita D. Padilla, Anne R. Pariser, Peter N. Robinson, Charlotte Rodwell, Franz Schaefer, Stefanie Weber, Flaminia Macchia
Improving health and social equity for persons living with a rare disease (PLWRD) is increasingly recognized as a global policy priority. However, there is currently no international alignment on how to define and describe rare diseases. A global reference is needed to establish a mutual understanding to inform a wide range of stakeholders for actions. A multi-stakeholder, global panel of rare disease experts, came together and developed an Operational Description of Rare Diseases. This reference describes which diseases are considered rare, how many persons are affected and why the rare disease population demands specific attention. The operational description of rare diseases is framed in two parts: a core definition of rare diseases, complemented by a descriptive framework of rare diseases. The core definition includes parameters that permit the identification of which diseases are considered rare, and how many persons are affected. The descriptive framework elaborates on the impact and burden of rare diseases on patients, their caregivers and families, healthcare systems, and society overall. The Operational Description of Rare Diseases establishes a common point of reference for decision-makers across the world who strive to understand and address the unmet needs of persons living with a rare disease. Adoption of this reference is essential to improving the visibility of rare conditions in health systems across the world. Greater recognition of the burden of rare diseases will motivate new actions and policies to address the unmet needs of the rare disease community.
{"title":"Operational description of rare diseases: a reference to improve the recognition and visibility of rare diseases","authors":"Chiuhui Mary Wang, Amy Heagle Whiting, Ana Rath, Roberta Anido, Diego Ardigò, Gareth Baynam, Hugh Dawkins, Ada Hamosh, Yann Le Cam, Helen Malherbe, Caron M. Molster, Lucia Monaco, Carmencita D. Padilla, Anne R. Pariser, Peter N. Robinson, Charlotte Rodwell, Franz Schaefer, Stefanie Weber, Flaminia Macchia","doi":"10.1186/s13023-024-03322-7","DOIUrl":"https://doi.org/10.1186/s13023-024-03322-7","url":null,"abstract":"Improving health and social equity for persons living with a rare disease (PLWRD) is increasingly recognized as a global policy priority. However, there is currently no international alignment on how to define and describe rare diseases. A global reference is needed to establish a mutual understanding to inform a wide range of stakeholders for actions. A multi-stakeholder, global panel of rare disease experts, came together and developed an Operational Description of Rare Diseases. This reference describes which diseases are considered rare, how many persons are affected and why the rare disease population demands specific attention. The operational description of rare diseases is framed in two parts: a core definition of rare diseases, complemented by a descriptive framework of rare diseases. The core definition includes parameters that permit the identification of which diseases are considered rare, and how many persons are affected. The descriptive framework elaborates on the impact and burden of rare diseases on patients, their caregivers and families, healthcare systems, and society overall. The Operational Description of Rare Diseases establishes a common point of reference for decision-makers across the world who strive to understand and address the unmet needs of persons living with a rare disease. Adoption of this reference is essential to improving the visibility of rare conditions in health systems across the world. Greater recognition of the burden of rare diseases will motivate new actions and policies to address the unmet needs of the rare disease community.","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1186/s13023-024-03345-0
Ingunn Westerheim, Valerie Cormier-Daire, Scott Gilbert, Sean O’Malley, Richard Keen
Osteogenesis imperfecta (OI) is a heritable skeletal disorder and comprises various subtypes that differ in clinical presentation, with Type I considered the least severe and Types III/IV the most severe forms. The study aim was to understand the OI patient diagnostic and treatment journey across Europe. We conducted a qualitative, descriptive study to understand the OI patient journey. A selection of people with OI/their caregivers and clinicians involved in OI-patient care from across Europe were interviewed using a specially developed questionnaire. Between May 2022 and July 2022, 22 people with OI/caregivers and 22 clinicians (endocrinologists, orthopaedic surgeons, geneticists and metabolic specialists) from across Europe were interviewed. Our study showed various areas of concerns for the OI community. Timely diagnosis of OI is essential; misdiagnoses and a delay to treatment initiation are all too common. There are a lack of consensus guidelines regarding optimal treatments (including when bisphosphonate therapy should be initiated and the route of administration) and patient management throughout the duration of the patient’s life. Adult OI patients do not have a medical home and are often managed by endocrinologists and rheumatologists. Adult care is often reactive based on the development of new symptoms. The psychosocial burden of OI impacts on the patient’s quality of life. There is an urgent need for increased awareness about OI and its wide range of symptoms. In particular, there is a need for consensus guidelines outlining the optimum care throughout the duration of the OI patient’s life.
成骨不全症（OI）是一种遗传性骨骼疾病，由多种亚型组成，临床表现各不相同，其中 I 型被认为是最不严重的类型，而 III/IV 型则是最严重的类型。该研究旨在了解欧洲各地 OI 患者的诊断和治疗过程。我们开展了一项定性描述性研究，以了解开放性肺结核患者的治疗历程。我们使用专门编制的调查问卷，对欧洲各地的部分 OI 患者/其护理人员和参与 OI 患者护理的临床医生进行了访谈。2022 年 5 月至 2022 年 7 月期间，我们对来自欧洲各地的 22 名 OI 患者/护理人员和 22 名临床医生（内分泌科医生、整形外科医生、遗传学家和代谢专家）进行了访谈。我们的研究显示了开放性阻塞性肺病群体关注的各个领域。及时诊断 OI 至关重要；误诊和延误开始治疗的情况非常普遍。对于最佳治疗方法（包括何时开始使用双膦酸盐治疗以及给药途径）和患者的全程管理，目前还缺乏一致的指导原则。成人骨质疏松症患者没有医疗之家，通常由内分泌科医生和风湿免疫科医生负责管理。成人护理通常是在出现新症状时才做出反应。OI 带来的社会心理负担会影响患者的生活质量。目前迫切需要提高对 OI 及其各种症状的认识。尤其需要制定共识指南，概述在开放性阻塞性肺病患者的整个生命周期内应采取的最佳护理措施。
{"title":"Osteogenesis Imperfecta: A study of the patient journey in 13 European countries","authors":"Ingunn Westerheim, Valerie Cormier-Daire, Scott Gilbert, Sean O’Malley, Richard Keen","doi":"10.1186/s13023-024-03345-0","DOIUrl":"https://doi.org/10.1186/s13023-024-03345-0","url":null,"abstract":"Osteogenesis imperfecta (OI) is a heritable skeletal disorder and comprises various subtypes that differ in clinical presentation, with Type I considered the least severe and Types III/IV the most severe forms. The study aim was to understand the OI patient diagnostic and treatment journey across Europe. We conducted a qualitative, descriptive study to understand the OI patient journey. A selection of people with OI/their caregivers and clinicians involved in OI-patient care from across Europe were interviewed using a specially developed questionnaire. Between May 2022 and July 2022, 22 people with OI/caregivers and 22 clinicians (endocrinologists, orthopaedic surgeons, geneticists and metabolic specialists) from across Europe were interviewed. Our study showed various areas of concerns for the OI community. Timely diagnosis of OI is essential; misdiagnoses and a delay to treatment initiation are all too common. There are a lack of consensus guidelines regarding optimal treatments (including when bisphosphonate therapy should be initiated and the route of administration) and patient management throughout the duration of the patient’s life. Adult OI patients do not have a medical home and are often managed by endocrinologists and rheumatologists. Adult care is often reactive based on the development of new symptoms. The psychosocial burden of OI impacts on the patient’s quality of life. There is an urgent need for increased awareness about OI and its wide range of symptoms. In particular, there is a need for consensus guidelines outlining the optimum care throughout the duration of the OI patient’s life.","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1186/s13023-024-03353-0
Stephen Morris, Holly Walton, Amy Simpson, Kerry Leeson-Beevers, Lara Bloom, Amy Hunter, Angus I. G. Ramsay, Naomi J. Fulop, Lyn S. Chitty, Joe Kai, Alastair G. Sutcliffe, Maria Kokocinska, Larissa Kerecuk, Christine A. Taylor, Pei Li Ng
Evidence suggests that coordination of care for people affected by rare diseases is poor. In order to improve the way that care is coordinated it is necessary to understand the preferences of people affected by these conditions, and providers. The aim of this study was to examine patient, parent and carer, and health care professional preferences for different attributes of care coordination for people affected by rare diseases. We conducted a discrete choice experiment using online surveys. There were no restrictions on participants in terms of rare conditions, demographic factors other than age, or geographical location within the UK. Choice scenarios were based on the following attributes: annual cost of attending appointments; access to health records; access to clinical expertise; support of a care coordinator; access to a specialist centre; and, the existence of a documented plan for emergency care. Data were analysed using alternative-specific conditional logit regression models. Valid responses were obtained from 996 individuals (528 patients, 280 carers, 188 health care professionals) between August and December 2019. All attributes significantly influenced the type of service respondents preferred. Patients, carers and health professionals’ preferences for care coordination were influenced by: the cost of attending appointments; access to health records; clinical expertise; role of care coordinators; access to specialist centres; and the existence of plan for emergency care. There were no statistically significant differences in the preferences between patients and carers. Preferences of health professionals differed to those of patients and carers. Both patients and carers selected responses which granted them a greater degree of autonomy in relation to the role of care coordinators, whereas health professionals preferred services where care coordinators had more autonomy. Health care professionals also expressed a stronger preference for a documented formal emergency plan to be in place. The findings highlight that people value better coordinated care, in line with policy documents emphasising commitments to coordinated care for people affected by rare diseases. This study highlights the factors that could be included in service provision as ways of improving the coordination of care for people affected by rare diseases.
{"title":"Preferences for coordinated care for rare diseases: discrete choice experiment","authors":"Stephen Morris, Holly Walton, Amy Simpson, Kerry Leeson-Beevers, Lara Bloom, Amy Hunter, Angus I. G. Ramsay, Naomi J. Fulop, Lyn S. Chitty, Joe Kai, Alastair G. Sutcliffe, Maria Kokocinska, Larissa Kerecuk, Christine A. Taylor, Pei Li Ng","doi":"10.1186/s13023-024-03353-0","DOIUrl":"https://doi.org/10.1186/s13023-024-03353-0","url":null,"abstract":"Evidence suggests that coordination of care for people affected by rare diseases is poor. In order to improve the way that care is coordinated it is necessary to understand the preferences of people affected by these conditions, and providers. The aim of this study was to examine patient, parent and carer, and health care professional preferences for different attributes of care coordination for people affected by rare diseases. We conducted a discrete choice experiment using online surveys. There were no restrictions on participants in terms of rare conditions, demographic factors other than age, or geographical location within the UK. Choice scenarios were based on the following attributes: annual cost of attending appointments; access to health records; access to clinical expertise; support of a care coordinator; access to a specialist centre; and, the existence of a documented plan for emergency care. Data were analysed using alternative-specific conditional logit regression models. Valid responses were obtained from 996 individuals (528 patients, 280 carers, 188 health care professionals) between August and December 2019. All attributes significantly influenced the type of service respondents preferred. Patients, carers and health professionals’ preferences for care coordination were influenced by: the cost of attending appointments; access to health records; clinical expertise; role of care coordinators; access to specialist centres; and the existence of plan for emergency care. There were no statistically significant differences in the preferences between patients and carers. Preferences of health professionals differed to those of patients and carers. Both patients and carers selected responses which granted them a greater degree of autonomy in relation to the role of care coordinators, whereas health professionals preferred services where care coordinators had more autonomy. Health care professionals also expressed a stronger preference for a documented formal emergency plan to be in place. The findings highlight that people value better coordinated care, in line with policy documents emphasising commitments to coordinated care for people affected by rare diseases. This study highlights the factors that could be included in service provision as ways of improving the coordination of care for people affected by rare diseases.","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1186/s13023-024-03342-3
Claudia Cruz Oliveira, Periklis Charalampous, Julien Delaye, Diana Alecsandra Grad, Pavel Kolkhir, Enkeleint A. Mechili, Brigid Unim, Brecht Devleesschauwer, Juanita A. Haagsma
Initiatives aiming to assess the impact of rare diseases on population health might be hampered due to the complexity of disability-adjusted life years (DALYs) estimation. This study aimed to give insight into the epidemiological data sources and methodological approaches used in studies that estimated DALYs for chronic non-communicable rare diseases (CNCRD), and compare its results. A literature strategy was developed for peer-review search in Embase and Medline, and also performed on grey literature databases and population health and/or rare disease-focused websites. We included studies that determined the burden of CNCRD listed on the Orphanet’s and/or the Genetic and Rare Diseases information center (GARD) websites. We excluded communicable and occupational diseases, rare cancers, and cost-effectiveness/benefit studies. Two researchers independently screened the identified records and extracted data from the final included studies. We used the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) statement to assess the quality of reporting of the included studies. The data synthesis depicted the studies’ characteristics, their distribution by geographic coverage and the group of disease(s) they focused on, the methods and data input sources used and estimated DALY per case. In total, 533 titles were screened, and 18 studies were included. These studies covered 19 different CNCRDs, of which most fell in the disease category “Diseases of the nervous system”. Diverse methodological approaches and data input sources were observed among burden of CNCRD studies. A wide range of DALY per case was observed across the different studies and diseases included. A low number of burden of CNCRD studies was observed and most estimates resulted from multi-country studies, underlining the importance of international cooperation to further CNCRD research. This study revealed a lack of epidemiological data and harmonization of methods which hampers comparisons across burden of CNCRD studies.
{"title":"A systematic review of studies that estimated the burden of chronic non-communicable rare diseases using disability-adjusted life years","authors":"Claudia Cruz Oliveira, Periklis Charalampous, Julien Delaye, Diana Alecsandra Grad, Pavel Kolkhir, Enkeleint A. Mechili, Brigid Unim, Brecht Devleesschauwer, Juanita A. Haagsma","doi":"10.1186/s13023-024-03342-3","DOIUrl":"https://doi.org/10.1186/s13023-024-03342-3","url":null,"abstract":"Initiatives aiming to assess the impact of rare diseases on population health might be hampered due to the complexity of disability-adjusted life years (DALYs) estimation. This study aimed to give insight into the epidemiological data sources and methodological approaches used in studies that estimated DALYs for chronic non-communicable rare diseases (CNCRD), and compare its results. A literature strategy was developed for peer-review search in Embase and Medline, and also performed on grey literature databases and population health and/or rare disease-focused websites. We included studies that determined the burden of CNCRD listed on the Orphanet’s and/or the Genetic and Rare Diseases information center (GARD) websites. We excluded communicable and occupational diseases, rare cancers, and cost-effectiveness/benefit studies. Two researchers independently screened the identified records and extracted data from the final included studies. We used the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) statement to assess the quality of reporting of the included studies. The data synthesis depicted the studies’ characteristics, their distribution by geographic coverage and the group of disease(s) they focused on, the methods and data input sources used and estimated DALY per case. In total, 533 titles were screened, and 18 studies were included. These studies covered 19 different CNCRDs, of which most fell in the disease category “Diseases of the nervous system”. Diverse methodological approaches and data input sources were observed among burden of CNCRD studies. A wide range of DALY per case was observed across the different studies and diseases included. A low number of burden of CNCRD studies was observed and most estimates resulted from multi-country studies, underlining the importance of international cooperation to further CNCRD research. This study revealed a lack of epidemiological data and harmonization of methods which hampers comparisons across burden of CNCRD studies.","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1186/s13023-024-03340-5
Jingjing Xiang, Yang Ding, Hui Tang, Wei Zhang, Jun Mao, Quanze He, Qin Zhang, Ting Wang
Whole exome sequencing (WES) has been recommended to investigate the genetic cause of fetal structural anomalies. In this retrospective study, we aimed to evaluate the diagnostic yield of WES in our cohort of families with pregnancy loss or termination of pregnancy due to structural anomalies. As aneuploidy, triploidy and copy number variations (CNVs) could be detected by exome-based CNV analysis, only WES is performed in this study. And the results of 375 cases assessed by WES were analyzed. The overall detection rate was 32.3% (121/375), including aneuploidy and triploidy (7.5%, 28/375), CNVs (5.1%, 19/375) and single-nucleotide variants (SNVs) /insertions or deletions (Indels) (19.7%, 74/375). Among these, the diagnostic yield for likely pathogenic (LP) or pathogenic (P) CNVs is 4.8% (18/375), and the diagnostic yield for LP or P SNVs/Indels is 15.2% (57/375). And an additional 4.8% (18/375) of cases had CNVs or SNVs/Indels classified as variants of uncertain significance (VUS) with potential clinical significance. Our findings expand the known mutation spectrum of genetic variants related to fetal abnormalities, increase our understanding of prenatal phenotypes, and enable more accurate counseling of recurrence risk for future pregnancies.
{"title":"Genetic analysis of pregnancy loss and fetal structural anomalies by whole exome sequencing","authors":"Jingjing Xiang, Yang Ding, Hui Tang, Wei Zhang, Jun Mao, Quanze He, Qin Zhang, Ting Wang","doi":"10.1186/s13023-024-03340-5","DOIUrl":"https://doi.org/10.1186/s13023-024-03340-5","url":null,"abstract":"Whole exome sequencing (WES) has been recommended to investigate the genetic cause of fetal structural anomalies. In this retrospective study, we aimed to evaluate the diagnostic yield of WES in our cohort of families with pregnancy loss or termination of pregnancy due to structural anomalies. As aneuploidy, triploidy and copy number variations (CNVs) could be detected by exome-based CNV analysis, only WES is performed in this study. And the results of 375 cases assessed by WES were analyzed. The overall detection rate was 32.3% (121/375), including aneuploidy and triploidy (7.5%, 28/375), CNVs (5.1%, 19/375) and single-nucleotide variants (SNVs) /insertions or deletions (Indels) (19.7%, 74/375). Among these, the diagnostic yield for likely pathogenic (LP) or pathogenic (P) CNVs is 4.8% (18/375), and the diagnostic yield for LP or P SNVs/Indels is 15.2% (57/375). And an additional 4.8% (18/375) of cases had CNVs or SNVs/Indels classified as variants of uncertain significance (VUS) with potential clinical significance. Our findings expand the known mutation spectrum of genetic variants related to fetal abnormalities, increase our understanding of prenatal phenotypes, and enable more accurate counseling of recurrence risk for future pregnancies.","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142212970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-07DOI: 10.1186/s13023-024-03331-6
Man Jin Kim, Jee-Soo Lee, Seung Won Chae, Sung Im Cho, Jangsup Moon, Jung Min Ko, Jong-Hee Chae, Moon-Woo Seong
Background: Ectodermal dysplasia (ED) is a rare genetic disorder that affects structures derived from the ectodermal germ layer.
Results: In this study, we analyzed the genetic profiles of 27 Korean patients with ED. Whole exome sequencing (WES) was performed on 23 patients, and targeted panel sequencing was conducted on the remaining 4 patients. Among the patients in the cohort, 74.1% (20/27) tested positive for ED. Of these positive cases, EDA and EDAR mutations were found in 80% (16/20). Notably, 23.1% (3/13) of EDA-positive cases exhibited copy number variations. Among the 23 patients who underwent WES, we conducted a virtual panel analysis of eight well-known genes, resulting in diagnoses for 56.5% (13/23) of the cases. Additionally, further analysis of approximately 5,000 OMIM genes identified four more cases, increasing the overall positivity rate by approximately 17%. These findings underscore the potential of WES for improving the diagnostic yield of ED. Remarkably, 94.1% of the patients manifesting the complete triad of ED symptoms (hair/skin/dental) displayed detectable EDA/EDAR mutations. In contrast, none of the 7 patients without these three symptoms exhibited EDA/EDAR mutations.
Conclusions: When conducting molecular diagnostics for ED, opting for targeted sequencing of EDA/EDAR mutations is advisable for cases with classical symptoms, while WES is deemed an effective strategy for cases in which these symptoms are absent.
{"title":"Genetic profiling and diagnostic strategies for patients with ectodermal dysplasias in Korea.","authors":"Man Jin Kim, Jee-Soo Lee, Seung Won Chae, Sung Im Cho, Jangsup Moon, Jung Min Ko, Jong-Hee Chae, Moon-Woo Seong","doi":"10.1186/s13023-024-03331-6","DOIUrl":"https://doi.org/10.1186/s13023-024-03331-6","url":null,"abstract":"<p><strong>Background: </strong>Ectodermal dysplasia (ED) is a rare genetic disorder that affects structures derived from the ectodermal germ layer.</p><p><strong>Results: </strong>In this study, we analyzed the genetic profiles of 27 Korean patients with ED. Whole exome sequencing (WES) was performed on 23 patients, and targeted panel sequencing was conducted on the remaining 4 patients. Among the patients in the cohort, 74.1% (20/27) tested positive for ED. Of these positive cases, EDA and EDAR mutations were found in 80% (16/20). Notably, 23.1% (3/13) of EDA-positive cases exhibited copy number variations. Among the 23 patients who underwent WES, we conducted a virtual panel analysis of eight well-known genes, resulting in diagnoses for 56.5% (13/23) of the cases. Additionally, further analysis of approximately 5,000 OMIM genes identified four more cases, increasing the overall positivity rate by approximately 17%. These findings underscore the potential of WES for improving the diagnostic yield of ED. Remarkably, 94.1% of the patients manifesting the complete triad of ED symptoms (hair/skin/dental) displayed detectable EDA/EDAR mutations. In contrast, none of the 7 patients without these three symptoms exhibited EDA/EDAR mutations.</p><p><strong>Conclusions: </strong>When conducting molecular diagnostics for ED, opting for targeted sequencing of EDA/EDAR mutations is advisable for cases with classical symptoms, while WES is deemed an effective strategy for cases in which these symptoms are absent.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thalassemia poses a major public health concern in Bangladesh with a high prevalence of carriers. However, there is a substantial knowledge gap regarding its epidemiology, clinical aspects, and treatment outcomes. Despite its high prevalence, there is a notable lack of awareness regarding thalassemia in the Bangladeshi population. The absence of precisely validated data impedes a comprehensive understanding of this disease.Premarital thalassemia screening is reportedly a successful strategy for countries such as Saudi Arabia and Iran and has also been proposed for Bangladesh. Mandatory screening coupled with genetic counseling is promising for reducing the prevalence of thalassemia by identifying carriers and providing relevant health education. However, sociocultural barriers, challenges, financial constraints, and health risks associated with prenatal diagnosis and abortion could hinder the success of such programs.Positive outcomes from other countries underscore the effectiveness of such programs in reducing thalassemia incidence. The early identification of carriers and genetic counseling can significantly reduce the burden of thalassemia. Additionally, the strain on the healthcare system would be eased, and the quality of life of thalassemia patients would be improved.In conclusion, based on evidence mandatory premarital screening with genetic counseling could be an effective measure to reduce the prevalence of thalassemia in Bangladesh. Leveraging positive attitudes, adopting successful international models, and addressing existing challenges are crucial for the successful implementation of programs that contribute to the overall health and well-being of the country's population.
{"title":"Urgent call for compulsory premarital screening: a crucial step towards thalassemia prevention in Bangladesh.","authors":"Md Jubayer Hossain, Manisha Das, Ummi Rukaiya Munni","doi":"10.1186/s13023-024-03344-1","DOIUrl":"10.1186/s13023-024-03344-1","url":null,"abstract":"<p><p>Thalassemia poses a major public health concern in Bangladesh with a high prevalence of carriers. However, there is a substantial knowledge gap regarding its epidemiology, clinical aspects, and treatment outcomes. Despite its high prevalence, there is a notable lack of awareness regarding thalassemia in the Bangladeshi population. The absence of precisely validated data impedes a comprehensive understanding of this disease.Premarital thalassemia screening is reportedly a successful strategy for countries such as Saudi Arabia and Iran and has also been proposed for Bangladesh. Mandatory screening coupled with genetic counseling is promising for reducing the prevalence of thalassemia by identifying carriers and providing relevant health education. However, sociocultural barriers, challenges, financial constraints, and health risks associated with prenatal diagnosis and abortion could hinder the success of such programs.Positive outcomes from other countries underscore the effectiveness of such programs in reducing thalassemia incidence. The early identification of carriers and genetic counseling can significantly reduce the burden of thalassemia. Additionally, the strain on the healthcare system would be eased, and the quality of life of thalassemia patients would be improved.In conclusion, based on evidence mandatory premarital screening with genetic counseling could be an effective measure to reduce the prevalence of thalassemia in Bangladesh. Leveraging positive attitudes, adopting successful international models, and addressing existing challenges are crucial for the successful implementation of programs that contribute to the overall health and well-being of the country's population.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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