Citations

AbstractBackgroundHeterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown.ObjectiveTo determine whether potentially pathogenic CFTR variants associate with disease severity and whether individuals with two potentially pathogenic variants exist in a severe asthma‐enriched cohort.MethodsWe analyzed sequencing data spanning a 190.5Kb region of CFTR in participants from the Severe Asthma Research Program (SARP1‐3). Potentially pathogenic, rare CFTR variants (frequency < 0.05) were classified as CF‐causing or of varying clinical consequences (VVCC) (CFTR2. org). Regression‐based models tested for association between CFTR genotypes (0‐2 potentially pathogenic variants) and severity outcomes.ResultsOf 1401 participants, 9.5% (134) had one potentially pathogenic variant, occurring more frequently in non‐Hispanic white (NHW, 10.1% [84 of 831]) compared to African American individuals (AA, 5.2% [22 of 426]). We found ≥2 potentially pathogenic CFTR variants in 1.4% (19); 0.5% (4) of NHW and 2.8% (12) of AA. Potentially pathogenic CFTR variant genotypes (≥1 or ≥2 variants) were not cumulatively associated with lung function or exacerbations. In NHW, we found three F508del compound heterozygotes with F508del and a VVCC (two 5 T; TG12[c.1210‐11 T > G] and one Arg1070Trp) and a homozygote for the VVCC, 5 T; TG12.ConclusionsWe found potentially pathogenic CFTR variants within a severe asthma‐enriched cohort, including three compound heterozygote genotypes variably associated with CF in NHW individuals. These findings provide the rationale for CFTR sequencing and phenotyping of CF‐related traits in individuals with severe asthma.

Background: Heterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown. Objective: To determine whether potentially pathogenic CFTR variants associate with disease severity and whether individuals with two potentially pathogenic variants exist in a severe asthma-enriched cohort . Methods : We analyzed sequencing data spanning a 190.5Kb region of CFTR in participants from the Severe Asthma Research Program (SARP1-3). Potentially pathogenic, rare CFTR variants (frequency<0.05) were classified as CF-causing or of varying clinical consequences (VVCC) (CFTR2.org). Regression-based models tested for association between CFTR genotypes (0-2 potentially pathogenic variants) and severity outcomes. Results: Of 1401 participants, 9.5% (134) had one potentially pathogenic variant, occurring more frequently in non-Hispanic white (NHW, 10.1% [84 of 831]) compared to African American individuals (AA, 5.2% [22 of 426]). We found ≥2 potentially pathogenic CFTR variants in 1.4% (19); 0.5% (4) of NHW and 2.8% (12) of AA. Potentially pathogenic CFTR variant genotypes (≥1 or ≥2 variants) were not cumulatively associated with lung function or exacerbations. In NHW, we found three F508del compound heterozygotes with F508del and a VVCC (two 5T;TG12[c.1210-11T>G] and one Arg1070Trp) and a homozygote for the VVCC, 5T;TG12. Conclusions: We found potentially pathogenic CFTR variants within a severe asthma-enriched cohort , including three compound heterozygote genotypes variably associated with CF in NHW individuals. These findings provide the rationale for CFTR sequencing and phenotyping of CF-related traits in individuals with severe asthma.

Abstract Objective To provide a review of challenges in clinical trials for the preventive treatment of cluster headache (CH) and highlight considerations for future studies. Background Current guidelines for preventive treatment of CH are largely based on off‐label therapies supported by a limited number of small randomized controlled trials. Guidelines for clinical trial design for CH treatments from the International Headache Society were last issued in 1995. Methods/Results Randomized controlled clinical trials were identified in the European and/or United States clinical trial registries with a search term of “cluster headache,” and manually reviewed. Cumulatively, there were 27 unique placebo‐controlled prevention trials for episodic and/or chronic CH, of which 12 were either ongoing, not yet recruiting, or the status was unknown. Of the remaining 15 trials, 5 were terminated early and 7 of the 10 completed trials enrolled fewer patients than planned or did not report the planned sample size. A systematic search of PubMed was also utilized to identify published manuscripts reporting results from placebo‐controlled preventive trials of CH. This search yielded 16 publications, of which 7 were registered. Through critical review of trial data and published manuscripts, challenges and complexities encountered in clinical trials for the preventive treatment of CH were identified. For example, the excruciating pain associated with CH demands a suitably limited baseline duration, rapid treatment efficacy onset, and poses a specific issue regarding duration of investigational treatment period and length of exposure to placebo. In episodic CH, spontaneous remission as part of natural history, and the unpredictability and irregularity of cluster periods across patients present additional key challenges. Conclusions Optimal CH trial design should balance sound methodology to demonstrate efficacy of a potential treatment with patient needs and the natural history of the disease, including unique outcome measures and endpoint timings for chronic versus episodic CH.

Angiotensin II receptor blockers (telmisartan) prevent rodents from diet-induced obesity and improve their metabolic status. Hyperglycemia and obesity are associated with reduced cerebral blood flow and neurovascular uncoupling which may lead to behavioral deficits. We wanted to know whether a treatment with telmisartan prevents these changes in obesity. We put young mice on high-fat diet and simultaneously treated them with telmisartan. At the end of treatment, we performed laser speckle imaging and magnetic resonance imaging to assess the effect on neurovascular coupling and cerebral blood flow. Different behavioral tests were used to investigate cognitive function. Mice developed diet-induced obesity and after 16, not 8 weeks of high-fat diet, however, the response to whisker pad stimulation was about 30% lower in obese compared to lean mice. Simultaneous telmisartan treatment increased the response again by 10% compared to obese mice. Moreover, telmisartan treatment normalized high-fat diet-induced reduction of cerebral blood flow and prevented a diet-induced anxiety-like behavior. In addition to that, telmisartan affects cellular senescence and string vessel formation in obesity. We conclude, that telmisartan protects against neurovascular unit impairments in a diet-induced obesity setting and may play a role in preventing obesity related cognitive deficits in Alzheimer’s disease.

Abstract Background There is a critical need to identify patient characteristics associated with long-term ovarian cancer survival. Methods Quality of life (QOL), measured by the Functional Assessment of Cancer Therapy-Ovarian-Trial Outcome Index (FACT-O-TOI), including physical, functional, and ovarian-specific subscales, was compared between long-term survivors (LTS) (8+ years) and short-term survivors (STS) (&lt;5 years) of GOG 218 at baseline; before cycles 4, 7, 13, 21; and 6 months post-treatment using linear and longitudinal mixed models adjusted for covariates. Adverse events (AEs) were compared between survivor groups at each assessment using generalized linear models. All P values are 2-sided. Results QOL differed statistically significantly between STS (N = 1115) and LTS (N = 260) (P &lt; .001). Baseline FACT-O-TOI and FACT-O-TOI change were independently associated with long-term survival (odds ratio = 1.05, 95% confidence interval = 1.03 to 1.06 and odds ratio = 1.06, 95% confidence interval = 1.05 to 1.07, respectively). A 7-point increase in baseline QOL was associated with a 38.0% increase in probability of LTS, and a 9-point increase in QOL change was associated with a 67.0% increase in odds for LTS. QOL decreased statistically significantly with increasing AE quartiles (cycle 4 quartiles: 0-5 vs 6-8 vs 9-11 vs ≥12 AEs, P = .01; cycle 21 quartiles: 0-2 vs 3 vs 4-5 vs ≥6 AEs, P = .001). Further, LTS reported statistically significantly better QOL compared with STS (P = .03 and P = .01, cycles 4 and 21, respectively), with similar findings across higher AE grades. Conclusions Baseline and longitudinal QOL change scores distinguished LTS vs STS and are robust prognosticators for long-term survival. Results have trial design and supportive care implications, providing meaningful prognostic value in this understudied population.

BACKGROUNDTo ensure that National Institutes of Health‐funded research is relevant to the population's needs, specific emphasis on proportional representation of minority/sex groups into National Cancer Institute (NCI) cancer centers' clinical research programs is reported to the NCI.METHODSEMPaCT investigators at 5 regionally diverse comprehensive cancer centers compared data reported to the NCI for their most recent Cancer Center Support Grant competitive renewal to assess and compare the centers' catchment area designations, data definitions, data elements, collection processes, reporting, and performance regarding proportional representation of race/ethnicity and sex subsets.RESULTSCancer centers' catchment area definitions differed widely in terms of their cancer patient versus general population specificity, levels of specificity, and geographic coverage. Racial/ethnic categories were similar, yet were defined differently, across institutions. Patients' socioeconomic status and insurance status were inconsistently captured across the 5 centers.CONCLUSIONSCatchment area definitions and the collection of patient‐level demographic factors varied widely across the 5 comprehensive cancer centers. This challenged the assessment of success by cancer centers in accruing representative populations into the cancer research enterprise. Accrual of minorities was less than desired for at least 1 racial/ethnic subcategory at 4 of the 5 centers. Institutions should clearly and consistently declare their primary catchment area and the rationale and should report how race/ethnicity and sex are defined, determined, collected, and reported. More standardized, frequent, consistent collection, reporting, and review of these data are recommended, as is a commitment to collecting socioeconomic data, given that socioeconomic status is a primary driver of cancer disparities in the United States. Cancer 2014;120(7 suppl):1113–21. © 2014 American Cancer Society.