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Rationale: The average age of lung transplant recipients is increasing, and the mix of recipient indications for transplantation is changing., Objectives: To determine whether the health-related quality-of-life (HRQL) benefit of lung transplantation differs by recipient age and diagnosis., Methods: In this prospective cohort study, we obtained serial HRQL measurements in adults with advanced lung disease who subsequently underwent lung transplantation (2004-2012). HRQL assessments included the St. George's Respiratory Questionnaire, 36-Item Short-Form Health Survey (SF-36), EQ-5D, Standard Gamble, and Visual Analog Scale for current health. We used linear mixed effects models for associations between age or diagnosis and changes in HRQL with transplantation. To address potential survivorship bias, we fitted Markov models to the distribution of discrete post-transplant health states (HRQL better than pretransplant, not better, or dead) and estimated quality-adjusted life-years post-transplant., Measurements and Main Results: A total of 430 subjects were listed, 387 were transplanted, and 326 provided both pretransplant and post-transplant data. Transplantation conferred large improvements in all HRQL measures: St. George's change of -47 units (95% confidence interval, -48 to -44), 36-Item Short-Form Health Survey physical component summary score of 17.7 (16.5-18.9), EQ-5D of 0.27 (0.24-0.30), Standard Gamble of 0.48 (0.44-0.51), and Visual Analog of 44 (42-47). Age was not associated with meaningful differences in the HRQL benefits of transplantation. There was less HRQL benefit in interstitial lung disease than in cystic fibrosis., Conclusions: Lung transplantation confers large HRQL benefits, which vary by recipient diagnosis, but do not differ substantially in older recipients.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by vascular malformations (VMs) and caused by mutations in TGFβ/BMP9 pathway genes, most commonly ENG or ACVRL1. Patients with HHT have diverse manifestations related to skin and mucosal telangiectases and organ VMs, including arteriovenous malformations (AVM). The clinical heterogeneity of HHT suggests a role for genetic modifiers. We hypothesized that the ACVRL1 c.314-35A>G and ENG c.207G>A polymorphisms, previously associated with sporadic brain AVM, are associated with organ VM in HHT. We genotyped these variants in 716 patients with HHT and evaluated association of genotype with presence of any organ VM, and specifically with brain VM, liver VM and pulmonary AVM, by multivariate logistic regression analyses stratified by HHT mutation. Among all patients with HHT, neither polymorphism was significantly associated with presence of any organ VM; ACVRL1 c.314-35A>G showed a trend toward association with pulmonary AVM (OR = 1.48, P = 0.062). ACVRL1 c.314-35A>G was significantly associated with any VM among patients with HHT with ENG (OR = 2.66, P = 0.022), but not ACVRL1 (OR = 0.79, P = 0.52) mutations. ACVRL1 c.314-35A>G was also associated with pulmonary AVM and liver VM among ENG mutation heterozygotes. There were no significant associations between ENG c.207G>A and any VM phenotype. These results suggest that common polymorphisms in HHT genes other than the mutated gene modulate phenotype severity of HHT disease, specifically presence of organ VM., (© 2015 Wiley Periodicals, Inc.)

Background: Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder associated with pulmonary AVMs (PAVMs), present in about 30-50% of patients. Dyspnea is frequently reported by about one-half of patients with PAVMs and has been related to the degree of right to left shunting. However, many HHT patients with PAVMs remain asymptomatic and those without PAVMs have been observed to have dyspnea, the cause of which has not been characterized. The study objectives were to determine the prevalence of dyspnea and its etiology in the HHT population., Methods: Retrospective review of over 1000 patients at an HHT Center of Excellence from 1997 to 2010. Patients were categorized as definite HHT if they met ≥3 clinical diagnostic criteria or had a positive genetic diagnosis. Patients were unlikely to have HHT (non-HHT) if they had 1 or fewer diagnostic criteria. Data on dyspnea prevalence (MMRC ≥ 1), PAVMs, underlying cardio-pulmonary disease, symptomatic liver venous malformations, anemia and obesity was reviewed., Results: 506 patients were categorized as having HHT, of which 202 (40%) had confirmed PAVMs. Dyspnea prevalence was 35% (178/506) vs. 18% (50/284, p < 0.0001) in the HHT and non-HHT patients, respectively. With multivariable logistic regression, the odds of dyspnea (MMRC ≥1) was 3.45 (95% CI 2.08-5.71) with the presence of PAVMs in HHT patients. Other independent predictors of dyspnea were older age, underlying cardio-pulmonary disease, anemia, and obesity., Conclusion: Prevalence of dyspnea is significant, evident in about one-third of HHT patients, often associated with PAVMs. It is important to consider other etiologies for dyspnea when assessing patients with HHT., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: To determine the cumulative effective dose (CED) of radiation from medical imaging and intervention in patients with hereditary hemorrhagic telangiectasia (HHT) who have pulmonary arteriovenous malformations and to identify clinical factors associated with exposure to high levels of radiation., Methods: All patients with at least 1 pulmonary arteriovenous malformation were identified from the dedicated patient database of a tertiary HHT referral centre. Computerized imaging and electronic patient records were systematically examined to identify all imaging studies performed from 1989-2010. The effective dose was determined for each study, and CED was calculated retrospectively., Results: Among 246 patients (mean age, 53 years; 62.2% women) with a total of 2065 patient-years, 3309 procedures that involved ionizing radiation were performed. CED ranged from 0.2-307.6 mSv, with a mean of 51.7 mSv. CED exceeded 100 mSv in 26 patients (11%). Interventional procedures and computed tomography (CT) were the greatest contributors, which accounted for 51% and 46% of the total CED, respectively. Factors associated with high cumulative exposure were epistaxis (odds ratio 2.7 [95% confidence interval, 1.1-6.3]; P = .02), HHT-related gastrointestinal bleeding (odds ratio 2.0 [95% confidence interval, 1.0-3.8]; P = .04) and number of patient-years (P < .0001)., Conclusions: Patients with HHT are exposed to a significant cumulative radiation dose from diagnostic and therapeutic interventions. Identifiable subsets of patients are at increased risk. A proportion of patients receive doses at levels that are associated with harm. Imaging indications and doses should be optimized to reduce radiation exposure in this population., (Copyright © 2014 Canadian Association of Radiologists. Published by Elsevier Inc. All rights reserved.)

Brain vascular malformations are resource-intensive to manage effectively, are associated with serious neurological morbidity, lack specific medical therapies, and have no validated biomarkers for disease severity and progression. Investigators have tended to work in "research silos" with suboptimal cross-communication. We present here a paradigm for interdisciplinary collaboration to facilitate rare disease research. The Brain Vascular Malformation Consortium (BVMC) is a multidisciplinary, inter-institutional group of investigators, one of 17 consortia in the Office of Rare Disease Research Rare Disease Clinical Research Network (RDCRN). The diseases under study are: familial Cerebral Cavernous Malformations type 1, common Hispanic mutation (CCM1-CHM); Sturge-Weber Syndrome (SWS); and brain arteriovenous malformation in hereditary hemorrhagic telangiectasia (HHT). Each project is developing biomarkers for disease progression and severity, and has established scalable, relational databases for observational and longitudinal studies that are stored centrally by the RDCRN Data Management and Coordinating Center. Patient Support Organizations (PSOs) are a key RDCRN component in the recruitment and support of participants. The BVMC PSOs include Angioma Alliance, Sturge Weber Foundation , and HHT Foundation International . Our networks of clinical centers of excellence in SWS and HHT, as well as our PSOs, have enhanced BVMC patient recruitment. The BVMC provides unique and valuable resources to the clinical neurovascular community, and recently reported findings are reviewed. Future planned studies will apply successful approaches and insights across the three projects to leverage the combined resources of the BVMC and RDCRN in advancing new biomarkers and treatment strategies for patients with vascular malformations.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disease with a wide spectrum of vascular malformations (VMs) involving multiple organs. Nine to 16% of patients with HHT harbor brain arteriovenous malformations (AVMs), which can cause intracranial hemorrhage (ICH). Our objective was to study clinical manifestations of brain AVMs in patients with HHT and correlate these with the specific gene mutated. We reviewed records of 171 patients with HHT and brain AVMs. A history of ICH was found in 27% (41/152) patients, with a mean age of 26 ± 18 range, (0-68) years. All of patients with ICH were neurologically asymptomatic prior to ICH. Multiple brain AVMs were found in 23% (170/39) of patients on initial examination. Genetic test results were available in 109 (64%) patients. Mutations in ENG, ACVRL1, and SMAD4 were present in 75 (69%), 18 (17%), and 2 (2%), respectively. A history of ICH was reported in 24% of patients with an ENG mutation and 27% of patients with an ACVRL1 mutation, with a mean age of 26 ± 16 (range, 2-50) and 18 ± 21 (0-48) years, respectively. No statistically significant differences in age at first brain AVM diagnosis, prevalence of ICH history, age at ICH, or other manifestations of brain AVMs were observed among gene groups. In conclusion, no evidence for differences in brain AVM characteristics was observed among HHT gene groups, although we cannot exclude clinically important differences. Larger studies are needed to further guide brain AVM screening decisions in patients with HHT., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: The frequency of metabolic alkalosis among adults with stable severe CF-lung disease is unknown., Methods: Retrospective chart review., Results: Fourteen CF and 6 COPD (controls) patients were included. FEV1 was similar between the two groups. PaO2 was significantly higher in the COPD (mean ± 2 SD is 72.0 ± 6.8 mmHg,) than in the CF group (56.1 ± 4.1 mmHg). The frequency of metabolic alkalosis in CF patients (12/14, 86%) was significantly greater (p=0.04) than in the COPD group (2/6, 33%). Mixed respiratory acidosis and metabolic alkalosis was evident in 4 CF and 1 COPD patients. Primary metabolic alkalosis was observed in 8 CF and none of the COPD patients. One COPD patient had respiratory and metabolic alkalosis., Conclusions: Metabolic alkalosis is more frequent in stable patients with CF lung disease than in COPD patients. This might be due to defective CFTR function with abnormal electrolyte transport within the kidney and/ or gastrointestinal tract.

Objective: Rare diseases may be difficult to study through conventional research methods, but are amenable to study through certain uncommonly used designs. We sought to explain these designs and to provide a framework to assist researchers in identifying the most appropriate design for a given research question., Study Design and Setting: We systematically searched for literature describing rare disease research frameworks, trial designs, and trials that applied them. We present the advantages and disadvantages of each approach using these published examples, and a practical framework to help researchers in selecting between design choices., Results: When research participants are limited, researchers should consider using: 1) a crossover design; 2) n-of-1 trials; or 3) one of the following adaptive designs: a) a response-adaptive randomization design, b) a ranking and selection design, c) an internal pilot design,or d) a sequential design. Bayesian analysis may be applied to conventional designs, or to any of these uncommon designs. Several of these approaches may also be used in combination. The choice between methods should be guided by factors related to the intervention, disease,anticipated recruitment duration and success, and current state of knowledge about the treatment., Conclusion: These techniques may facilitate research in rare diseases.