The Rare Disease Research Scholars Program: A training curriculum for clinical researchers with mixed methods evaluation study

Rare disease clinician investigators are essential to ensure appropriate diagnosis, care, and treatment for the rapidly growing rare disease population. As these researchers are spread across many specialties, learning the unique skill set for rare disease research (RDR) can be a hurdle and may hinder progress in the field. The need for an RDR focused training program for investigators in many specialties and backgrounds was identified in a needs assessment of trainees in the NIH funded Rare Diseases Clinical Research Network. Based on this information, the Rare Disease Research Scholars Program (RDRSP) was developed. We describe the needs assessment, curriculum creation, scholar recruitment, and outcome evaluation based on four years of programmatic data (2015–2019). This one year-long RDRSP uses a blended approach that includes in-person, web-based, synchronous and asynchronous learning. We evaluated the RDRSP using quantitative and qualitative approaches. Quantitative measures included pre and post questionnaires about knowledge, self-efficacy, and intent to remain in RDR. Data were analyzed using descriptive statistics and a paired t-test. Qualitative semi-structured interviews explored the RDR scholars’ perceptions of the RDRSP; thematic analysis examined the textual data. Quantitative pre- and post-measures were statistically significant in the following areas: 1) improved knowledge content in RDR, 2) enhanced self-efficacy in clinical research, and 3) intent to remain in the field of RDR. Qualitative data analysis found the program supported the development of the scholar’s research skills as well as ‘soft-skills’. By combining training of skills unique to RDR with the more general topics of leadership, mentorship and collaboration among participants in diverse specialties, we created a program that supports the development of the next generation of rare disease clinician investigators and serves as a model for training in other niche research areas.

Report of the 2021 Primary ciliary dyskinesia foundation annual meeting

In August 2021, the Primary Ciliary Dyskinesia (PCD) Foundation hosted a 2-day international virtual conference designed to share discoveries in PCD genetics, cilia biology, and clinical research and care. The conference was organized around the theme of building a community for clinical research. This article provides a report of the proceedings.

Efficacy and safety of long-term sirolimus use as part of multidisciplinary care in a pediatric patient with CLOVES syndrome: Case report

BACKGROUND: CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal/spinal) syndrome is a rare and progressive genetic disorder resulting from somatic mosaicism in activating mutations in the phosphatidylinositol-4,5- bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene. PIK3CA is a cell growth master regulator where gain of function mutations give rise to abnormal activation of the PI3K-AKT- mammalian target of rapamycin (mTOR) pathway. Treatment with sirolimus, an mTOR inhibitor, may therefore be of benefit in patients with CLOVES syndrome. OBJECTIVE: Here we describe the efficacy and toxicity of sirolimus in a pediatric patient with progressive CLOVES syndrome. RESULTS: The child presented with a large and painful abdominal malformation, massive overgrowth of his feet, limb length discrepancy and genu valgum. There was dramatic clinical and radiographic improvement in the size and comfort of his abdominal mass within several months of initiating medical therapy. This, combined with orthopaedic care of his genu valgum, leg length discrepancy, and overgrowth of his feet, has allowed for significant functional gains. CONCLUSIONS: Multidisciplinary care is essential for comfort and functional gains in patients with CLOVES syndrome, particularly those with severe symptoms. Close monitoring while on sirolimus medical therapy combined with frequent reassessment of orthopedic needs can dramatically improve patient quality of life and outcomes.

Opportunities, barriers, and recommendations in down syndrome research

BACKGROUND: Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community. OBJECTIVE: The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan. METHODS: NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS. RESULTS: This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade. CONCLUSIONS: This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy.

Treating neuroendocrine neoplasms in the setting of HIV infection

BACKGROUND: There is a paucity of knowledge regarding neuroendocrine neoplasms (NEN) in patients with HIV infection. OBJECTIVE: To explore the incidence, characteristics and treatment outcomes of NEN in HIV-positive individuals. METHODS: This is a single-center, descriptive cohort study. Patients with HIV and biopsy-confirmed NEN were identified from our data registry. Data were collected retrospectively from medical records. Progression-free and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: Nineteen HIV-positive patients with neuroendocrine tumors (NET) (n = 14), neuroendocrine carcinomas (NEC) (n = 2) or Merkel cell carcinoma (MCC) (n = 3) were included (median age at NEN diagnosis, 53 years). In 15 (79%) patients, HIV diagnosis preceded NEN diagnosis by a median of 11 years and 14 were receiving antiretroviral therapy (ART). Of those with data available, 75% had a viral load < 50 copies/ml and mean CD4 771 cells/mm3. The median OS in the NEC/MCC cohort was 8 months (range 5–29). The median OS in the NET cohort was not reached but based on the 25th centile, 75% of patients are expected to survive for at least 57 months. Treatment outcomes will be described. CONCLUSIONS: Within the limits of a small descriptive cohort study, our study shows no evidence in the era of ART that patients with HIV and NEN are diagnosed at a younger age, nor have a poorer prognosis compared with the wider NEN population. Thus, they should receive maximal NEN therapies to support best outcomes.

Rett syndrome: Novel correlations linking >96% genotype, disease severity, and seizures

BACKGROUND: Rett Syndrome (RTT), an incurable neurodevelopmental disorder associated in >96% with the X-linked gene, MECP2 includes seizures, among its most difficult issues, impacting many features and increasing morbidity and mortality. Linking these seizures with clinical severity in RTT is critical for estimating risk and guiding therapy. OBJECTIVE: Our primary purpose was to identify associations between type and frequency of seizures, disease severity, and specific MECP2 mutations to address the hypothesis that seizure frequency correlates with specific mutations and directly impacts clinical severity. METHODS: Mutation, seizure type and frequency, and clinical severity assessed by the Clinical Severity Scale (CSS) were extracted from the 5211 Natural History Study of Rett Syndrome and Related Disorders [1]. This involved observations from 222 Persons with classic or variant RTT and MECP2 mutation positive non-Rett diagnoses. Descriptive analyses were assessed utilizing SPSS software. Mutations include R106W, R133C, R168X, R294X, R306C, other point mutations, and early truncations. RESULTS: Greater frequency of generalized seizures and seizures of any type were associated with R106W mutations; R168X mutations had the highest disease severity, and R133C mutations had the lowest disease severity. CONCLUSION: Important correlations exist across several common MECP2 mutations, including the novel association between generalized seizure frequency and mild CSS.

Multimodal imaging in urea cycle-related neurological disease – What can imaging after hyperammonemia teach us?

BACKGROUND: Urea cycle-related brain disease may take on variable neuroimaging manifestations, ranging from normal to abnormal with or without a signature appearance. In the past, we have described the usefulness of multimodal imaging in identifying biomarkers of neuronal injury in UCD patients. In this study, we report unique findings in an adolescent male with neonatal-onset OTC deficiency after an episode of hyperammonemia. MATERIALS AND METHODS: Multiplanar, multisequence MR imaging (T1WI, T2WI, T2 FLAIR, diffusion weighted images and gradient echo) of the brain was performed on seven separate occasions over the course following the acute illness; first five exams were performed within 28 days of admission and the final two exams were performed approximately 3 and 5 months later. RESULTS: 1.The initial MR revealed increased signal on T2WI in the basal ganglia, claustrum and frontoparietal white matter; which remained stable over time. By the 5th exam, signal changes had developed in frontal cortex; reflecting permanent injury. 2. DTI tractography of the corticospinal tracts displayed revealed diminution of the number of projectional and commissural fibers over time. 3. Blood flow measurements demonstrated hypoperfusion on the fifth exams followed by hyperperfusion on the final two studies. 4. MR spectroscopy demonstrated that glutamine was elevated during hyperammonemia with myoinositol reduction, reflecting osmotic buffering. CONCLUSION: This particular multimodal magnetic resonance neuroimaging showed novel, temporally specific manifestations over the disease course in OTC deficiency. This prospective imaging study expands our understanding of the effect of hyperammonemia on the structure and biochemistry of the nervous system.