Citations

INTRODUCTION: Gastroesophageal reflux plays a significant role in idiopathic pulmonary fibrosis (IPF). Given the morbidity and mortality associated with IPF, understanding the mechanisms responsible for reflux is essential if patients are to receive optimal treatment and management, especially given the lack of clear benefit of antireflux therapies. Our aim was to understand the inter-relationships between esophageal motility, lung mechanics and reflux (particularly proximal reflux—a prerequisite of aspiration), and pulmonary function in patients with IPF. METHODS: We prospectively recruited 35 patients with IPF (aged 53–75 years; 27 men) who underwent high-resolution impedance manometry and 24-hour pH-impedance, together with pulmonary function assessment. RESULTS: Twenty-two patients (63%) exhibited dysmotility, 16 (73%) exhibited ineffective esophageal motility (IEM), and 6 (27%) exhibited esophagogastric junction outflow obstruction. Patients with IEM had more severe pulmonary disease (% forced vital capacity: P = 0.032) and more proximal reflux ( P = 0.074) than patients with normal motility. In patients with IEM, intrathoracic pressure inversely correlated with the number of proximal events (r = −0.429; P = 0.098). Surprisingly, inspiratory lower esophageal sphincter pressure (LESP) positively correlated with the percentage of reflux events reaching the proximal esophagus (r = 0.583; P = 0.018), whereas in patients with normal motility, it inversely correlated with the bolus exposure time (r = −0.478; P = 0.098) and number of proximal events (r = −0.542; P = 0.056). % forced vital capacity in patients with IEM inversely correlated with the percentage of reflux events reaching the proximal esophagus (r = −0.520; P = 0.039) and inspiratory LESP (r = −0.477; P = 0.062) and positively correlated with intrathoracic pressure (r = 0.633; P = 0.008). DISCUSSION: We have shown that pulmonary function is worse in patients with IEM which is associated with more proximal reflux events, the latter correlating with lower intrathoracic pressures and higher LESPs.

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) (<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 < .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.

Introduction: Retinal vascular features predict cognitive performance and retinal imaging is a non-invasive tool to study brain health. Patients with Alzheimer’s disease (AD)-related cognitive disorders exhibit both retinal vascular abnormalities and intraretinal accumulation of amyloid-beta (Aβ) plaque. Curcumin-enhanced retinal fluorescence imaging (CRFI) was recently translated as a safe imaging tool for retinal Aβ plaque quantification. In this study, we sought to determine whether and which retinal arterial and venous parameters are predictive of retinal Aβ burden and cognitive Z-scores. Methods: We used scanning laser ophthalmoscopy with RetiaTM (Centervue, Inc) to obtain CRFI in a cohort of patients with cognitive decline. Retinal blood vessels were segmented in a predefined circumpapillary region of interest. For each centerline, vessel tortuosity index (VTI), vessel inflection index (VII), and branching angle (VBA) were quantified, independently for arteries and veins. Additionally, we automatically quantified retinal amyloid count in the supero-temporal quadrant and its subregions: posterior pole (PP), proximal mid-periphery (PMP), and distal mid-periphery (DMP). All quantifications were done blinded to the subjects’ clinical characteristics. Linear regression models were used to assess the correlations between retinal vascular and amyloid parameters. Results: 29 subjects (55% female, mean age 64±6 years) were included in the analysis: 11 had normal cognition, 16 mild cognitive impairment and 2 probable AD. Venous VTI was the only vascular parameter significantly different across levels of Clinical Dementia Rate scores and between cognitively normal and impaired. Venous VBA was a significant predictor of DMP amyloid count (p=0.03). Arterial VII significantly predicted PP amyloid count (p=0.02). VBA predicted Wechsler Adult Intelligence Scale Z-score (p=0.08). The combined VTI-PMP amyloid index significantly predicted Wechsler Memory Scale, California Verbal Learning Test and SF-36 mental component score Z-scores (p<0.05). Conclusion: Retinal venous tortuosity discriminates across cognitive scores and in combination with PMP amyloid count may predict verbal memory and related quality-of-life scores.

Introduction: Previous analyses of randomized trials comparing carotid artery stenting (CAS) versus carotid endarterectomy (CEA) have revealed varying sex-associated risk. To better understand sex as an effect modifier in the asymptomatic population, we combined the asymptomatic patients from CREST with the asymptomatic patients from ACT I. Methods: We analyzed data from 2544 subjects with ≥ 70% carotid stenosis randomized to CAS or CEA in addition to standard management of cardiovascular risk factors. CREST enrolled 1091 (548 CAS, 543 CEA) and ACT I enrolled 1453 (1089 CAS, 364 CEA) asymptomatic patients less than 80 years old (upper age eligibility in ACT I). We examined the impact of sex on risk within CAS-treated and CEA-treated patients using Kaplan-Meier methods. The pre-specified, primary composite endpoint was stroke, myocardial infarction, or death during the periprocedural period (within 30 days of randomization) or any ipsilateral stroke within 4 years after randomization. Results: For patients assigned to CAS, there was no difference in risk between the sexes (female-to-male HR = 1.04, 95% CI 0.65 -- 1.66, P = 0.87). For patients assigned to CEA, the difference in risk detected was not significant (female-to-male HR = 1.43, 95% CI 0.77 - 2.67, P = 0.26). Conclusions: Sex-differences in risk were not significant for those assigned CAS nor those assigned CEA in this largest pooled analysis of asymptomatic patients comparing CAS to CEA.

Abstract Coronary artery disease (CAD) is a leading cause of death, yet its genetic determinants are not fully elucidated. We report a multi-ethnic genome-wide association study of CAD involving nearly a quarter of a million cases, incorporating the largest cohorts to date of Whites, Blacks, and Hispanics from the Million Veteran Program with existing studies including CARDIoGRAMplusC4D, UK Biobank, and Biobank Japan. We verify substantial and nearly equivalent heritability of CAD across multiple ancestral groups, discover 107 novel loci including the first nine on the X-chromosome, identify the first eight genome-wide significant loci among Blacks and Hispanics, and demonstrate that two common haplotypes are largely responsible for the risk stratification at the well-known 9p21 locus in most populations except those of African origin where both haplotypes are virtually absent. We identify 15 loci for angiographically derived burden of coronary atherosclerosis, which robustly overlap with the strongest and earliest loci reported to date for clinical CAD. Phenome-wide association analyses of novel loci and externally validated polygenic risk scores (PRS) augment signals from the insulin resistance cluster of risk factors and consequences, extend previously established pleiotropic associations of loci with traditional risk factors to include smoking and family history, and confirm a substantially reduced transferability of existing PRS to Blacks. Downstream integrative genomic analyses reinforce the critical role of endothelial, fibroblast, and smooth muscle cells within the coronary vessel wall in CAD susceptibility. Our study highlights the value of a multi-ethnic design in efficiently characterizing the genetic architecture of CAD across all human populations.

Phylogenetic analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is focused on a single isolate of bat coronaviruses (bat CoVs) which does not adequately represent genetically related coronaviruses (CoVs) [...]

Teplizumab treatment of nondiabetic relatives at high risk for T1D induces partially exhausted CD8 + T cells and improves beta cell function.

PurposeChannelized Hotelling observer (CHO) models have been implemented to assess imaging performance in x‐ray angiography systems. While current methods are appropriate for assessing unprocessed images of moving test objects upon uniform‐exposure backgrounds, they are inadequate for assessing conditions which more appropriately mimic clinical imaging conditions including the combination of moving test objects, complex anthropomorphic backgrounds, and image processing. In support of this broad goal, the purpose of this work was to develop theory and methods to automatically select a subset of task‐specific efficient Gabor channels from a task‐generic Gabor channel base set. Also, previously described theory and methods to manage detectability index (d′) bias due to nonrandom temporal variations in image electronic noise will be revisited herein.MethodsStarting with a base set of 96 Gabor channels, backward elimination of channels was used to automatically identify an “efficient” channel subset which reduced the number of channels retained in the subset while maintaining the magnitude of the d′ estimate. The concept of a pixelwise Hotelling observer (PHO) model was introduced and similarly implemented to assess the performance of the efficient‐channel CHO model. Bias in d′ estimates arising from temporally variable nonstationary noise was modeled as a bivariate probability density function for normal distributions, where one variable corresponds to the signal from the test object and the other variable corresponds to the signal from temporally variable nonstationary noise. Theory and methods were tested on uniform‐exposure unprocessed angiography images with detector target dose (DTD) of 6, 18, and 120 nGy containing static disk‐shaped test objects with diameter in the range of 0.5 to 4 mm.ResultsConsidering all DTD levels and test object sizes, the proposed method reduced the number of Gabor channels in the final subset by 63–82% compared to the original 96 Gabor channel base set, while maintaining a mean relative performance () of 95% 4% with respect to the reference PHO model. Experimental results demonstrated that the bivariate approach to account for bias due to temporally variable nonstationary noise resulted in improved correlation between the CHO and PHO models as compared to a previously proposed univariate approach.ConclusionsComputationally efficient backward elimination can be used to select an efficient subset of Gabor channels from an initial channel base set without substantially compromising the magnitude of the d′ estimate. Bias due to temporally variable nonstationary noise can be modeled through a bivariate approach leading to an improved unbiased estimate of d′.

Abstract Inherited genetic risk factors play a role in multiple myeloma (MM), yet considerable missing heritability exists. Rare risk variants at genome-wide association study (GWAS) loci are a new avenue to explore. Pleiotropy between lymphoid neoplasms (LNs) has been suggested in family history and genetic studies, but no studies have interrogated sequencing for pleiotropic genes or rare risk variants. Sequencing genetically enriched cases can help discover rarer variants. We analyzed exome sequencing in familial or early-onset MM cases to identify rare, functionally relevant variants near GWAS loci for a range of LNs. A total of 149 distinct and significant LN GWAS loci have been published. We identified six recurrent, rare, potentially deleterious variants within 5 kb of significant GWAS single nucleotide polymorphisms in 75 MM cases. Mutations were observed in BTNL2, EOMES, TNFRSF13B, IRF8, ACOXL and TSPAN32. All six genes replicated in an independent set of 255 early-onset MM or familial MM or precursor cases. Expansion of our analyses to the full length of these six genes resulted in a list of 39 rare and deleterious variants, seven of which segregated in MM families. Three genes also had significant rare variant burden in 733 sporadic MM cases compared with 935 control individuals: IRF8 (P = 1.0 × 10−6), EOMES (P = 6.0 × 10−6) and BTNL2 (P = 2.1 × 10−3). Together, our results implicate six genes in MM risk, provide support for genetic pleiotropy between LN subtypes and demonstrate the utility of sequencing genetically enriched cases to identify functionally relevant variants near GWAS loci.