National Organization for Rare Disorders

Abstract The fundamental physical properties of Al-10at%Sc alloy were tested experimentally, the residual stress distribution in the diffusion welding process were simulated, and the diffusion welding experiments of Al-10at%Sc target has been conducted. The research results indicated that, for Al-10at%Sc alloy, average coefficient of thermal expansion is 28.8×10⁻⁶/℃(25 ~ 520°C), average thermal conductivity is 158W/(m·K)(25 ~ 600°C), Young’s modulus decreases from 91 GPa at 25°C to 71 GPa at 600°C, density is 2.68 g/cm³ and specific heat capacity is 1.07 J/(g·K); an interlayer is not needed in diffusion welding of Al-10at%Sc alloy and 6061 Al alloy backing plate due to the maximum residual stress of 19.62 MPa at the interface significantly lower than the 50% yield strength of both materials; in the hot isostatic pressing diffusion welding process, a high-strength weld joint can be achieved when the surface roughness is below 0.8 µm, the welding temperature is between 450–500°C, the welding pressure is around 125 MPa, and the holding time is 4–5 hours; Mg atoms from the 6061 Al alloy are enriched around the Al₃Sc phase in the Al-10at%Sc alloy, a stable Mg-Al solid solutions at the weld joint is formed, and there is no noticeable diffusion of Sc into the 6061 Al alloy.

BackgroundChronic respiratory insufficiency from progressive muscle weakness causes morbidity and mortality in late-onset Pompe disease (LOPD). Previous Pompe Registry (NCT00231400) analyses for ≤ 5 years’ alglucosidase alfa treatment showed a single linear time trend of stable forced vital capacity (FVC) % predicted.MethodsTo assess longer term Pompe Registry data, piecewise linear mixed model regression analyses estimated FVC% predicted trajectories in invasive-ventilator-free patients with LOPD aged ≥ 5 years. We estimated annual FVC change 0–6 months, > 6 months–5 years, and > 5–13 years from treatment initiation, adjusting for baseline age, sex, and non-invasive ventilation.FindingsAmong 485 patients (4612 FVC measurements; 8.3 years median follow-up), median ages at symptom onset, diagnosis, and alglucosidase alfa initiation were 34.3, 41.1, and 44.9 years, respectively. FVC% increased during the first 6 months’ treatment (slope 1.83%/year; 95% confidence interval: 0.66, 3.01; P = 0.0023), then modestly declined −0.54%/year (−0.79, −0.30; P < 0.0001) during > 6 months–5 years, and −1.00%/year (−1.36, −0.63; P < 0.0001) during > 5–13 years. The latter two periods’ slopes were not significantly different from each other (Pdifference = 0.0654) and were less steep than published natural history slopes (−1% to −4.6%/year). Estimated individual slopes were ≥ 0%/year in 96.1%, 30.3%, and 13.2% of patients during the 0–6 month, > 6 month–5 year, and > 5–13 year periods, respectively.ConclusionThese real-world data indicate an alglucosidase alfa benefit on FVC trajectory that persists at least 13 years compared with published natural history data. Nevertheless, unmet need remains since most individuals demonstrate lung function decline 5 years after initiating treatment. Whether altered FVC trajectory impacts respiratory failure incidence remains undetermined.Trial registrationThis study was registered (NCT00231400) on ClinicalTrials.gov on September 30, 2005, retrospectively registered.

This document provides a comprehensive summary of evidence on the current situation of rare diseases (RDs) globally and regionally, including conditions, practices, policies, and regulations, as well as the challenges and barriers faced by RD patients, their families, and caregivers. The document builds on a review of academic literature and policies and a process of validation and feedback by a group of seven experts from across the globe. Panelists were selected based on their academic merit, expertise, and knowledge regarding the RD environment. The document is divided into five main sections: (1) methodology and objective; (2) background and context; (3) overview of the current situation and key challenges related to RDs covering six dimensions: burden of disease, patient journey, social impact, disease management, RD-related policies, and research and development; (4) recommendations; and (5) conclusions. The recommendations are derived from the discussion undertaken by the experts on the findings of this review and provide a set of actionable solutions to the challenges and barriers to improving access to RD diagnosis and treatment around the world. The recommendations can support critical decision-making, guiding efforts by a broad range of RDs stakeholders, including governments, international organizations, manufacturers, researchers, and patient advocacy groups.

Rare diseases impact the lives of an estimated 350 million people worldwide, and yet about 90% of rare diseases remain without an approved treatment. New technologies have become available, such as gene and oligonucleotide therapies, that offer great promise in treating rare diseases. However, progress toward the development of therapies to treat these diseases is hampered by a limited understanding of the course of each rare disease, how changes in disease progression occur and can be effectively measured over time, and challenges in designing and running clinical trials in diseases where the natural history is poorly characterized. Data that could be used to characterize the natural history of each disease has often been collected in various ways, including in electronic health records, patient-report registries, clinical natural history studies, and in past clinical trials. However, each data source contains a limited number of subjects and different data elements, and data is frequently kept proprietary in the hands of the study sponsor rather than shared widely across the rare disease community. The Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP) is an FDA-funded effort to overcome these persistent challenges. By aggregating data across all rare diseases and making that data available to the community to support understanding of rare disease natural history and inform drug development, RDCA-DAP aims to accelerate the regulatory approval of new therapies. RDCA-DAP curates, standardizes, and tags data across rare disease datasets to make it findable within the database, and contains a built-in analytics platform to help visualize, interpret, and use it to support drug development. RDCA-DAP will coordinate data and tool resources across non-profit, commercial, and for-profit entities to serve a diverse array of rare disease stakeholders that includes academic researchers, drug developers, FDA reviewers and of course patients and their caregivers. Drug development programs utilizing the RDCA-DAP will be able to leverage existing data to support their efforts and reach definitive decisions on the efficacy of their therapeutics more efficiently and more rapidly than ever.

Background: Suicide is the second leading cause of death among Americans ages 10 to 34. Recent increases in suicide rates among those assigned female at birth are particularly alarming. A large body of evidence points to menstrual cycle influences on self-injurious thoughts and behaviors (STBs), suggesting that neurobiological hormone sensitivities such as those observed in premenstrual dysphoric disorder (PMDD) may drive risk for suicide in females. However, existing studies of the prevalence of STBs in PMDD have used cross-sectional self-report measures of PMDD with poor validity. As a first step to establishing more accurate prevalence rates of STBs in PMDD, we examined the lifetime prevalence of STBs in a large global survey of patients reporting a diagnosis of PMDD based on daily ratings. Method: Individuals with self-reported PMDD symptoms were invited to an online survey through online support groups for PMDD and social media posts from accounts focused on PMDD awareness and information. Participants reported on demographics, whether they had been diagnosed with PMDD by a healthcare provider using daily ratings, STBs using the Columbia Suicide Severity Rating Scale, and history of various lifetime comorbid psychiatric diagnoses. Results: 2,689 unique participants completed the survey. Of those, 599 (23%) reported a provider diagnosis with PMDD based on two months of daily ratings and were included in analyses. We observed high rates of lifetime active suicidal ideation (72%), planning (49%), intent (42%), preparing for an attempt (40%), and attempt (34%), as well as non-suicidal self-injury (51%). The majority (70%) of the sample reported at least one lifetime comorbid psychiatric diagnosis by a medical provider. STB rates were only slightly attenuated among those reporting no history of diagnosed psychiatric comorbidities (i.e., PMDD only). Predictors of lifetime suicidal ideation included nulliparity, low-to-moderate (vs. high) income, and history of diagnosis with major depression or post-traumatic stress disorder. Predictors of lifetime attempts among those reporting lifetime ideation included older age, nulliparity, lower income, and history of diagnosis with post-traumatic stress disorder or borderline personality disorder.Conclusions: These data indicate high rates of STBs among those reporting prospective medical diagnosis of PMDD and highlight the need for more prospective research on mechanisms and prevention of STBs in PMDD. Clinical practice guidelines for PMDD should accommodate comorbidities and recommend frequent screenings for STB risk. Suicidal thoughts and behaviors should be considered for inclusion in future iterations of the DSM PMDD diagnostic criteria.

Background: Premenstrual dysphoric disorder (PMDD) is a severe mood disorder that affects ∼5% of menstruating individuals. Although symptoms are limited to the luteal phase of the menstrual cycle, PMDD causes significant distress and impairment across a range of activities. PMDD is under-recognized by health care providers, can be difficult to diagnose, and lies at the intersection of gynecology and psychiatry. Thus, many patients are misdiagnosed, or encounter challenges in seeking care. The aim of this study was to examine patients' experiences with different health care specialties when seeking care for PMDD symptoms. Methods: We examined data from the 2018 Global Survey of Premenstrual Disorders conducted by the International Association for Premenstrual Disorders (IAPMD). Patients rated their health care providers (general practitioners, psychiatrists, gynecologists, psychotherapists) in three key areas related to treatment of premenstrual mood complaints: interpersonal factors, awareness and knowledge of PMDD, and whether the patient was asked to track symptoms daily. Intraclass correlations examined between- and within-person variance. Multilevel regression models predicted ratings on each provider competency item, with ratings nested within individuals to examine the within-patient effect of provider type on outcomes. Results: The sample included 2,512 patients who reported seeking care for PMDD symptoms. Regarding interpersonal factors, psychotherapists were generally rated the highest. On awareness and knowledge of PMDD, gynecologists and psychiatrists were generally rated the highest. Gynecologists were more likely than other providers to ask patients to track symptoms daily. Conclusions: These findings suggest that different providers have different strengths in assessing and treating PMDD. Further, graduate and medical training programs may benefit from increased curricular development regarding evidence-based evaluation and treatment of PMDD.

Abstract The dog is an exciting genetic system in which many simple and complex traits have now been mapped. For many traits the causal mutation is a polymorphic SINE. To investigate the genome-wide pattern of young SINEC_Cf insertions, we sampled 62 dogs representing 59 breeds and sequenced libraries enriched for SINE flanks. In each dog we detect an average of 10,423 polymorphic loci and all together the libraries identify 81,747 putative polymorphic SINEs. We validated 184 SINEs inserted in protein-coding exons, untranslated regions, introns and intergenic sequence. In dogs both SINEC_Cf and LINEs exhibit a strand bias in introns where antisense copies are more frequent. Antisense polymorphic SINEs also have a higher density in introns. Both SINEs and LINEs drop to very low density near exons. Both sense and antisense polymorphic SINEs also drop to low density upstream of coding exons but not downstream. Antisense polymorphic SINEC_Cfs upstream of coding exons are known to cause narcolepsy, merle, and progressive retinal atrophy in dogs. In other mammals SINE pairs in inverted orientation disrupt gene expression. We find inverted pairs of SINEC_Cf are rare in both introns and intergenic sequence when the two SINEs are separated by less than 100 bp. The lack of inverted pairs is even more pronounced when the SINEs have high sequence identity. Intronic and intergenic LINE pairs show similar patterns. Polymorphic SINEs rarely pair with either SINEC_Cf or SINEC_Cf2. Overall, the high insertion rate of SINEC_Cf provides a natural mutagenesis screen in the dog genome.

In addition to difficulties with treatment and expenses, patients with rare diseases in China greatly lack social support. In around 2000, Chinese patients with rare diseases and their families began to organize a series of charitable activities such as medical aid, public education, and policy advocacy. After nearly 20 years, organizations for Chinese patients with rare diseases have progressed. Many problems still remain, including a relatively small number of organizations, a low level of specialization, a lack of stability, limited social influence, and limited access to social resources. In order to spur the development of Chinese rare disease patient organizations, public education needs to be enhanced, policy support is needed, teams need to be created, and communication and cooperation need to be enhanced.