Citations

Objectives Chronic pancreatitis (CP) is a chronic fibroinflammatory condition of the pancreas difficult to diagnose in early stages. Novel biomarkers useful to facilitate early diagnosis or treatment responses may be found in biofluids. Although saliva can be easily and noninvasively collected from patients, useful salivary biomarkers from CP patients have not yet been identified. Methods Here, we analyzed the proteome by quantitative proteomics, cytokine/chemokine levels by Luminex analysis, prostaglandin E2 (PGE2) levels by a mass spectrometry-based assay, and bacterial species diversity by 16S ribosomal ribonucleic acid sequencing in saliva samples from confirmed CP patients and healthy controls. Results Our results indicate the presence of various differentially expressed proteins, cytokines/chemokines, and a loss of oral bacterial diversity in the saliva of CP patients. The PGE2 levels trend toward elevation in CP patients. Area under the receiver operating characteristic curve models for proteomic, cytokine, and PGE2 assays ranged from 0.59 to 0.90. Conclusions Collectively, our studies identify a range of putative CP biomarkers and alterations in human saliva requiring further validation. The biomarker discovery approaches we used might lead to identification of biomarkers useful for CP diagnosis and monitoring.

OBJECTIVE Diabetes that arises from chronic pancreatitis (CP) is associated with increased morbidity and mortality. Methods to predict which patients with CP are at greatest risk for diabetes are urgently needed. We aimed to examine independent risk factors for diabetes in a large cohort of patients with CP. RESEARCH DESIGN AND METHODS This cross-sectional study comprised 645 individuals with CP enrolled in the PROCEED study, of whom 276 had diabetes. We conducted univariable and multivariable regression analyses of potential risk factors for diabetes. Model performance was assessed by area under the receiver operating characteristic curve (AUROC) analysis, and accuracy was evaluated by cross validation. Exploratory analyses were stratified according to the timing of development of diabetes relative to the diagnosis of pancreatitis. RESULTS Independent correlates of diabetes in CP included risk factors for type 2 diabetes (older age, overweight/obese status, male sex, non-White race, tobacco use) as well as pancreatic disease–related factors (history of acute pancreatitis complications, nonalcoholic etiology of CP, exocrine pancreatic dysfunction, pancreatic calcification, pancreatic atrophy) (AUROC 0.745). Type 2 diabetes risk factors were predominant for diabetes occurring before pancreatitis, and pancreatic disease–related factors were predominant for diabetes occurring after pancreatitis. CONCLUSIONS Multiple factors are associated with diabetes in CP, including canonical risk factors for type 2 diabetes and features associated with pancreatitis severity. This study lays the groundwork for the future development of models integrating clinical and nonclinical data to identify patients with CP at risk for diabetes and identifies modifiable risk factors (obesity, smoking) on which to focus for diabetes prevention.

Introduction: The voltage-gated proton channel Hv1 is a member of the voltage-gated ion channel family. Hv1 channel controls acid extrusion and regulates pH homeostasis in various cell types. Recent evidence showed that the Hv1 were expressed in the heart. Hypothesis: We propose the Hv1 channel is associated with cardiac function. Methods: To investigate the role of Hv1 in cardiac myocytes, we performed a transcriptomic analysis of wild-type (WT) and Hv1-/- mouse hearts. Results: Hv1 null hearts exhibited a differential transcriptome profile compared with wild-type hearts. The RNA-seq data indicating impaired pH homeostasis in Hv1 null hearts were the downregulated NADPH oxidoreductases (NOXs) and decreased expression of Cl-/HCO3- exchanger. Additionally, Hv1 null hearts exhibited differential expression of cardiac ion channels, suggesting a potential role of Hv1 in cardiac electrophysiological remodeling. Conclusions: The data indicated that Hv1 was involved in cardiac pH homeostasis and showed that Hv1 was a regulator of gene transcriptional networks controlling NOX signaling and CO2 homeostasis in the heart. The study highlights the importance of Hv1 in cardiac function and may present a new target associated with heart diseases.

AbstractBackgroundThe growing adoption of magnetic resonance imaging (MRI)‐guided radiation therapy (RT) platforms and a focus on MRI‐only RT workflows have brought the technical challenge of synthetic computed tomography (sCT) reconstruction to the forefront. Unpaired‐data deep learning‐based approaches to the problem offer the attractive characteristic of not requiring paired training data, but the gap between paired‐ and unpaired‐data results can be limiting.PurposeWe present two distinct approaches aimed at improving unpaired‐data sCT reconstruction results: a cascade ensemble that combines multiple models and a personalized training strategy originally designed for the paired‐data setting.MethodsComparisons are made between the following models: (1) the paired‐data fully convolutional DenseNet (FCDN), (2) the FCDN with the Intentional Deep Overfit Learning (IDOL) personalized training strategy, (3) the unpaired‐data CycleGAN, (4) the CycleGAN with the IDOL training strategy, and (5) the CycleGAN as an intermediate model in a cascade ensemble approach. Evaluation of the various models over 25 total patients is carried out using a five‐fold cross‐validation scheme, with the patient‐specific IDOL models being trained for the five patients of fold 3, chosen at random.ResultsIn both the paired‐ and unpaired‐data settings, adopting the IDOL training strategy led to improvements in the mean absolute error (MAE) between true CT images and sCT outputs within the body contour (mean improvement, paired‐ and unpaired‐data approaches, respectively: 38%, 9%) and in regions of bone (52%, 5%), the peak signal‐to‐noise ratio (PSNR; 15%, 7%), and the structural similarity index (SSIM; 6%, <1%). The ensemble approach offered additional benefits over the IDOL approach in all three metrics (mean improvement over unpaired‐data approach in fold 3; MAE: 20%; bone MAE: 16%; PSNR: 10%; SSIM: 2%), and differences in body MAE between the ensemble approach and the paired‐data approach are statistically insignificant.ConclusionsWe have demonstrated that both a cascade ensemble approach and a personalized training strategy designed initially for the paired‐data setting offer significant improvements in image quality metrics for the unpaired‐data sCT reconstruction task. Closing the gap between paired‐ and unpaired‐data approaches is a step toward fully enabling these powerful and attractive unpaired‐data frameworks.

AbstractIntroductionData on utilization, major complications, and in‐hospital mortality of catheter ablation (CA) for sarcoidosis‐related ventricular tachycardia (VT) are limited. We sought to determine the outcomes of sarcoidosis‐related VT, and incidence and predictors of complications associated with the CA procedure.MethodsWe queried the 2002–2018 National Inpatient Sample database to identify patients aged ≥18 years with sarcoidosis admitted with VT. A 1:3 propensity score‐matched (PSM) analysis was used to compare patient outcomes between CA and medically managed groups. Multivariable regression was performed to determine independent predictors of in‐hospital mortality and procedural complications associated with the CA procedure.ResultsOf 3220 sarcoidosis patients with VT, 132 (4.1%) underwent CA. Patients who underwent CA were younger, male predominant, more likely Caucasian, had differences in baseline comorbidities including more likely to have heart failure, less likely to have prior myocardial infarction, COPD, or severe renal disease, had a higher mean household income, and more likely admitted to a larger/urban teaching hospital. After PSM, we examined 106 CA cases and 318 medically managed cases. There was a trend toward a lower in‐hospital mortality rate in the CA group when compared to the medically managed group (1.9% vs. 6.6%, p = 0.08). The most common complications were pericardial drainage (5.3%), postoperative hemorrhage (3.8%), accidental puncture periprocedure (3.0%), and cardiac tamponade (2.3%). Independent predictors of in‐hospital mortality and procedural complications among the CA group included congestive heart failure (odds ratio [OR], 13.2; 95% confidence interval [CI], 1.7–104.2) and mild to moderate renal disease (OR, 3.9; 95% CI, 1.1–13.3).ConclusionsCompared to patients with sarcoidosis‐related VT who received medical therapy alone, those who underwent CA have a trend for a lower mortality rate despite procedure‐related complications occurring as high as 9.1%. Additional studies are recommended to better evaluate the benefits and risks of VT ablation in this group.

Abstract1q gain (+1q) is the most common high‐risk cytogenetic abnormality (HRCA) in patients with multiple myeloma (MM). However, its prognostic value remains unclear in the era of novel agents. Here, we retrospectively analyzed the impact of +1q on the outcomes of 934 patients newly diagnosed with MM. +1q was identified in 53.1% of patients and verified as an independent variate for inferior overall survival (OS) (hazard ratio, 1.400; 95% confidence interval, 1.097–1.787; p = .007). Concurrence of other HRCAs (particularly t(14;16) and del(17p)) further exacerbated the outcomes of patients with +1q, suggesting prognostic heterogeneity. Thus, a risk‐scoring algorithm based on four risk variates (t(14;16), hypercalcemia, ISS III, and high LDH) was developed to estimate the outcomes of patients with +1q. Of the patients, 376 evaluable patients with +1q were re‐stratified into low (31.6%), intermediate (61.7%), and high risk (6.7%) groups, with significantly different progression‐free survival and OS (p < .0001), in association with early relapse of the disease. The prognostic value of this model was validated in the CoMMpass cohort. While attaining undetectable MRD largely circumvented the adverse impact of +1q, it scarcely ameliorated the outcome of the patients with high risk, who likely represent a subset of patients with extremely poor survival. Hence, patients with +1q are a heterogeneous group of high‐risk patients, therefore underlining the necessity for their re‐stratification. The proposed simple risk‐scoring model can estimate the outcomes of patients with +1q, which may help guide risk‐adapted treatment for such patients.

Lung transplantation (LTx) historically was performed with cardiopulmonary bypass (CPB) or Off-pump. Recent data suggest an increased interest in extracorporeal membrane oxygenation (ECMO) as perioperative circulatory support by many lung transplantation centers worldwide. However, there are no established guidelines for anesthetic management for LTx. We present a patient with a history of systemic sclerosis and interstitial lung disease complicated by acute onset of systemic pulmonary hypertension and right heart failure undergoing LTx. We aim to discuss perioperative circulatory support, including ECMO bridge to LTx, and how best to consider the varied intraoperative strategies of CPB vs ECMO vs off-pump during LTx, intraoperative maintenance, and coagulation management.

Précis: Surgical and clinical success rates were similar among Ahmed FP7, and Baerveldt 250 and 350 glaucoma drainage devices at three years. Purpose: To compare rates of surgical and clinical success in patients with Ahmed FP7 (FP7), Baerveldt 250 (B250), or Baerveldt 350 (B350) glaucoma drainage devices (GDDs). Design: A retrospective cohort study. Methods: A total of 157 eyes of 129 adult patients with FP7, B250, B350 GDDs, and 190 eyes of 99 medically controlled glaucoma patients were enrolled at a tertiary care institution from August 2017 through July 2019. They were followed through April 2020. The main outcome measures included surgical and clinical failure. Surgical failure was defined as intraocular pressure (IOP) outside 5–21 mm Hg, IOP reduced <20% below baseline, additional glaucoma surgery, GDD removal, or no light perception. Eyes that did not meet their goal IOP ranges or required secondary glaucoma interventions were deemed clinical failures. Results: A total of 43 (12.4%) FP7, 36 (10.4%) B250, 78 (22.5%) B350, and 190 (54.8%) medically treated control eyes were enrolled. By the postoperative year 3 visit, 10 (23.2%) FP7, 11 (30.6%) B250, and 32 (41.0%) B350 eyes had met a surgical failure criterion (P=0.127). There were no significant differences in the numbers of eyes meeting their IOP target ranges (P=0.510), and rates of secondary glaucoma surgeries (P=0.270). Overall clinical success was attained among 83.3% FP7, 81.8% B250, and 68.0% B350 eyes (P=0.447). Conclusions: The GDD groups were similar in their rates of success, based on both the surgical and clinical success definitions.

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase ( IDH) –mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1 R132H -driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.

AbstractBackgroundThe current risk stratification system defined by clinicopathological features does not identify the risk of recurrence in early-stage (stage I-II) colorectal cancer (CRC) with sufficient accuracy. We aimed to investigate whether DNA methylation could serve as a novel biomarker for predicting prognosis in early-stage CRC patients.MethodsWe analyzed the genome-wide methylation status of CpG loci using Infinium MethylationEPIC array run on primary tumor tissues and normal mucosa of early-stage CRC patients to identify potential methylation markers for prognosis. The machine-learning approach was applied to construct a DNA methylation–based prognostic classifier for early-stage CRC (MePEC) using the 4 gene methylation markers FAT3, KAZN, TLE4, and DUSP3. The prognostic value of the classifier was evaluated in 2 independent cohorts (n = 438 and 359, respectively).ResultsThe comprehensive analysis identified an epigenetic subtype with high risk of recurrence based on a group of CpG loci in the CpG-depleted region. In multivariable analysis, the MePEC classifier was independently and statistically significantly associated with time to recurrence in validation cohort 1 (hazard ratio = 2.35, 95% confidence interval = 1.47 to 3.76, P &lt; .001) and cohort 2 (hazard ratio = 3.20, 95% confidence interval = 1.92 to 5.33, P &lt; .001). All results were further confirmed after each cohort was stratified by clinicopathological variables and molecular subtypes.ConclusionsWe demonstrated the prognostic statistical significance of a DNA methylation profile in the CpG-depleted region, which may serve as a valuable source for tumor biomarkers. MePEC could identify an epigenetic subtype with high risk of recurrence and improve the prognostic accuracy of current clinical variables in early-stage CRC.