Cortico-limbic interactions and carotid atherosclerotic burden during chronic stress exposure.

BACKGROUND AND AIMS: Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis. METHODS: Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala). RESULTS: Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score. CONCLUSIONS: In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings.

HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma.

BACKGROUND AND AIMS: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. APPROACH AND RESULTS: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations ( E pCAM + CD63 + , C D147 + CD63 + , and G PC3 + CD63 + HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort ( n  = 106) and an independent validation cohort ( n  = 72).Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). CONCLUSION: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.

A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19.

Rationale: There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. Objectives: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19-induced respiratory failure. Methods: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. Measurements and Main Results: At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (n = 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk [RR], 0.88; 95% confidence interval, 0.64-1.21; P = 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 [interquartile range, 60.0-169.5] in cell patients and 102.0 [interquartile range, 54.0-162.5] in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57-3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. Conclusions: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19-related acute respiratory distress syndrome.

Impact of primary tumor side on clinical outcomes of first-line cetuximab plus FOLFOX-4 in RAS wild-type metastatic colorectal cancer.

Aim: To examine the impact of tumor sidedness on clinical outcomes in Chinese patients with metastatic colorectal cancer treated with folinic acid/fluorouracil/oxaliplatin (FOLFOX-4) ± cetuximab in the TAILOR trial. Patients & methods: Clinical data from 391 patients were evaluated for tumor sidedness. Results: Patients with left-sided tumors who received cetuximab plus FOLFOX-4 had a significantly longer overall survival (medians: 22.0 vs 18.3 months; p = 0.007) and progression-free survival (medians: 9.3 vs 7.9 months; p = 0.006) compared with FOLFOX-4 alone. Overall survival (medians: 11.5 vs 9.4 months; p = 0.664) and progression-free survival (medians: 7.4 vs 4.5 months; p = 0.068) also improved in patients with right-sided tumors. Conclusion: Adding cetuximab to first-line FOLFOX-4 in patients with metastatic colorectal cancer improved clinical outcomes irrespective of primary tumor side.

Cetuximab is a drug used to treat people with advanced metastatic colorectal cancer (mCRC) with a gene called RAS wild-type (wt) and is given along with standard chemotherapy. The TAILOR study showed that in people with RAS wt mCRC cetuximab together with chemotherapy worked better than chemotherapy alone and had similar side effects. This analysis of the TAILOR study looked at whether Chinese people with RAS wt mCRC responded differently to treatment with cetuximab plus chemotherapy depending on the primary tumor location (whether left or right side of the colon). This analysis found that people with left- or right-sided primary tumors who received cetuximab plus chemotherapy lived longer and their cancer progressed more slowly compared with those who received chemotherapy alone.

Rationale and design of a randomized trial evaluating an external support device for saphenous vein coronary grafts.

BACKGROUND: Coronary artery bypass grafting (CABG) is the most common revascularization approach for the treatment of multi-vessel coronary artery disease. While the internal mammary artery is nearly universally used to bypass the left anterior descending coronary artery, autologous saphenous vein grafts (SVGs) are still the most frequently used conduits to grafts the remaining coronary artery targets. Long-term failure of these grafts, however, continues to limit the benefits of surgery. METHODS: The Cardiothoracic Surgical Trials Network trial of the safety and effectiveness of a Venous External Support (VEST) device is a randomized, multicenter, within-patient trial comparing VEST-supported versus unsupported saphenous vein grafts in patients undergoing CABG. Key inclusion criteria are the need for CABG with a planned internal mammary artery to the left anterior descending and two or more saphenous vein grafts to other coronary arteries. The primary efficacy endpoint of the trial is SVG intimal hyperplasia (plaque + media) area assessed by intravascular ultrasound at 12 months post randomization. Occluded grafts are accounted for in the analysis of the primary endpoint. Secondary confirmatory endpoints are lumen diameter uniformity and graft failure (>50% stenosis) assessed by coronary angiography at 12 months. The safety endpoints are the occurrence of major adverse cardiac and cerebrovascular events and hospitalization within 5 years from randomization. CONCLUSIONS: The results of the VEST trial will determine whether the VEST device can safely limit SVG intimal hyperplasia in patients undergoing CABG as treatment for coronary atherosclerotic disease.

First Series Using Ultrasonic Propulsion and Burst Wave Lithotripsy to Treat Ureteral Stones.

PURPOSE: Our goal was to test transcutaneous focused ultrasound in the form of ultrasonic propulsion and burst wave lithotripsy to reposition ureteral stones and facilitate passage in awake subjects. MATERIALS AND METHODS: Adult subjects with a diagnosed proximal or distal ureteral stone were prospectively recruited. Ultrasonic propulsion alone or with burst wave lithotripsy was administered by a handheld transducer to awake, unanesthetized subjects. Efficacy outcomes included stone motion, stone passage, and pain relief. Safety outcome was the reporting of associated anticipated or adverse events. RESULTS: Twenty-nine subjects received either ultrasonic propulsion alone (n = 16) or with burst wave lithotripsy bursts (n = 13), and stone motion was observed in 19 (66%). The stone passed in 18 (86%) of the 21 distal ureteral stone cases with at least 2 weeks follow-up in an average of 3.9±4.9 days post-procedure. Fragmentation was observed in 7 of the burst wave lithotripsy cases. All subjects tolerated the procedure with average pain scores (0-10) dropping from 2.1±2.3 to 1.6±2.0 (P = .03). Anticipated events were limited to hematuria on initial urination post-procedure and mild pain. In total, 7 subjects had associated discomfort with only 2.2% (18 of 820) propulsion bursts. CONCLUSIONS: This study supports the efficacy and safety of using ultrasonic propulsion and burst wave lithotripsy in awake subjects to reposition and break ureteral stones to relieve pain and facilitate passage.

Challenges facing the urologist in low- and middle-income countries.

PURPOSE: The challenges in providing urologic care across borders and in resource-constrained settings are poorly understood. We sought to better characterize the impediments to the delivery of urological care in low- and middle-income countries (LMICs) compared to high-income countries (HICs). METHODS: A 70 question online survey in RedCap™ was distributed to urologists who had practiced in countries outside of the United States and Europe categorized by World Bank income groups. RESULTS: 114 urologists from 27 countries completed the survey; 35 (39%) practiced in HICs while 54 (61%) practiced in LMICs. Forty-three percent of urologists received training outside their home country. Most commonly treated conditions were urolithiasis (30%), BPH (15%) and prostate cancer (13%) which did not vary by group. Only 19% of urologists in LMICs reported sufficient urologists in their country. Patients in LMICs were less likely to get urgent drainage for infected obstructing kidney stones or endoscopic treatment for a painful kidney stone or obstructing prostate. Urologists visiting LMICs were more likely to cite deficits in knowledge, inadequate operative facilities and limited access to disposables as the major challenges whereas local LMIC urologists were more likely to cite financial challenges, limited access to diagnostics and support staff as the barriers to care. CONCLUSIONS: LMICs lack enough training opportunities and urologists to care for their population. There is disconnect between the needs identified by local and visiting urologists. International collaborations should target broader interventions in LMICs to address local priorities such as diagnostic studies, support staff and financial support.

The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.

Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits. Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that α-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit ß is identified as a novel binding protein of α-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan. We show that α-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by α-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by α-KG requires ATP synthase subunit ß and is dependent on target of rapamycin (TOR) downstream. Endogenous α-KG levels are increased on starvation and α-KG does not extend the lifespan of dietary-restricted animals, indicating that α-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.

Predicting development of sustained unresponsiveness to milk oral immunotherapy using epitope-specific antibody binding profiles.

BACKGROUND: In a recent trial of milk oral immunotherapy (MOIT) with or without omalizumab in 55 patients with milk allergy treated for 28 months, 44 of 55 subjects passed a 10-g desensitization milk protein challenge; 23 of 55 subjects passed the 10-g sustained unresponsiveness (SU) challenge 8 weeks after discontinuing MOIT. OBJECTIVE: We sought to determine whether IgE and IgG4 antibody binding to allergenic milk protein epitopes changes with MOIT and whether this could predict the development of SU. METHODS: By using a novel high-throughput Luminex-based assay to quantitate IgE and IgG4 antibody binding to 66 sequential epitopes on 5 milk proteins, serum samples from 47 subjects were evaluated before and after MOIT. Machine learning strategies were used to predict whether a subject would have SU after 8 weeks of MOIT discontinuation. RESULTS: MOIT profoundly altered IgE and IgG4 binding to epitopes, regardless of treatment outcome. At the initiation of MOIT, subjects achieving SU exhibited significantly less antibody binding to 40 allergenic epitopes than subjects who were desensitized only (false discovery rate ≤ 0.05 and fold change > 1.5). Based on baseline epitope-specific antibody binding, we developed predictive models of SU. Using simulations, we show that, on average, IgE-binding epitopes alone perform significantly better than models using standard serum component proteins (average area under the curve, >97% vs 80%). The optimum model using 6 IgE-binding epitopes achieved a 95% area under the curve and 87% accuracy. CONCLUSION: Despite the relatively small sample size, we have shown that by measuring the epitope repertoire, we can build reliable models to predict the probability of SU after MOIT. Baseline epitope profiles appear more predictive of MOIT response than those based on serum component proteins.

Two-Year Outcomes of Surgical Treatment of Moderate Ischemic Mitral Regurgitation.

BACKGROUND: In a trial comparing coronary-artery bypass grafting (CABG) alone with CABG plus mitral-valve repair in patients with moderate ischemic mitral regurgitation, we found no significant difference in the left ventricular end-systolic volume index (LVESVI) or survival after 1 year. Concomitant mitral-valve repair was associated with a reduced prevalence of moderate or severe mitral regurgitation, but patients had more adverse events. We now report 2-year outcomes. METHODS: We randomly assigned 301 patients to undergo either CABG alone or the combined procedure. Patients were followed for 2 years for clinical and echocardiographic outcomes. RESULTS: At 2 years, the mean (±SD) LVESVI was 41.2±20.0 ml per square meter of body-surface area in the CABG-alone group and 43.2±20.6 ml per square meter in the combined-procedure group (mean improvement over baseline, -14.1 ml per square meter and -14.6 ml per square meter, respectively). The rate of death was 10.6% in the CABG-alone group and 10.0% in the combined-procedure group (hazard ratio in the combined-procedure group, 0.90; 95% confidence interval, 0.45 to 1.83; P=0.78). There was no significant between-group difference in the rank-based assessment of the LVESVI (including death) at 2 years (z score, 0.38; P=0.71). The 2-year rate of moderate or severe residual mitral regurgitation was higher in the CABG-alone group than in the combined-procedure group (32.3% vs. 11.2%, P<0.001). Overall rates of hospital readmission and serious adverse events were similar in the two groups, but neurologic events and supraventricular arrhythmias remained more frequent in the combined-procedure group. CONCLUSIONS: In patients with moderate ischemic mitral regurgitation undergoing CABG, the addition of mitral-valve repair did not lead to significant differences in left ventricular reverse remodeling at 2 years. Mitral-valve repair provided a more durable correction of mitral regurgitation but did not significantly improve survival or reduce overall adverse events or readmissions and was associated with an early hazard of increased neurologic events and supraventricular arrhythmias. (Funded by the National Institutes of Health and Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00806988.).

Intramyocardial Injection of Mesenchymal Precursor Cells and Successful Temporary Weaning From Left Ventricular Assist Device Support in Patients With Advanced Heart Failure: A Randomized Clinical Trial.

Importance: Left ventricular assist device (LVAD) therapy improves myocardial function, but few patients recover sufficiently for explant, which has focused attention on stem cells to augment cardiac recovery. Objective: To assess efficacy and adverse effects of intramyocardial injections of mesenchymal precursor cells (MPCs) during LVAD implant. Design, Setting, and Participants: A randomized phase 2 clinical trial involving patients with advanced heart failure, undergoing LVAD implant, at 19 North American centers (July 2015-August 2017). The 1-year follow-up ended August 2018. Interventions: Intramyocardial injections of 150 million allogeneic MPCs or cryoprotective medium as a sham treatment in a 2:1 ratio (n = 106 vs n = 53). Main Outcomes and Measures: The primary efficacy end point was the proportion of successful temporary weans (of 3 planned assessments) from LVAD support within 6 months of randomization. This end point was assessed using a Bayesian analysis with a predefined threshold of a posterior probability of 80% to indicate success. The 1-year primary safety end point was the incidence of intervention-related adverse events (myocarditis, myocardial rupture, neoplasm, hypersensitivity reactions, and immune sensitization). Secondary end points included readmissions and adverse events at 6 months and 1-year survival. Results: Of 159 patients (mean age, 56 years; 11.3% women), 155 (97.5%) completed 1-year of follow-up. The posterior probability that MPCs increased the likelihood of successful weaning was 69%; below the predefined threshold for success. The mean proportion of successful temporary weaning from LVAD support over 6 months was 61% in the MPC group and 58% in the control group (rate ratio [RR], 1.08; 95% CI, 0.83-1.41; P = .55). No patient experienced a primary safety end point. Of 10 prespecified secondary end points reported, 9 did not reach statistical significance. One-year mortality was not significantly different between the MPC group and the control group (14.2% vs 15.1%; hazard ratio [HR], 0.89; 95%, CI, 0.38-2.11; P = .80). The rate of serious adverse events was not significantly different between groups (70.9 vs 78.7 per 100 patient-months; difference, -7.89; 95% CI, -39.95 to 24.17; P = .63) nor was the rate of readmissions (0.68 vs 0.75 per 100 patient-months; difference, -0.07; 95% CI, -0.41 to 0.27; P = .68). Conclusions and Relevance: Among patients with advanced heart failure, intramyocardial injections of mesenchymal precursor cells, compared with injections of a cryoprotective medium as sham treatment, did not improve successful temporary weaning from left ventricular assist device support at 6 months. The findings do not support the use of intramyocardial mesenchymal stem cells to promote cardiac recovery as measured by temporary weaning from device support. Trial Registration: clinicaltrials.gov Identifier: NCT02362646.

Integrated multiomic predictors for ovarian cancer survival.

Increasingly affordable high-throughput molecular profiling technologies have made feasible the measurement of omics-wide interindividual variations for the purposes of predicting cancer prognosis. While multiple types of genetic, epigenetic and expression changes have been implicated in ovarian cancer, existing prognostic biomarker strategies are constrained to analyzing a single class of molecular variations. The extra predictive power afforded by the integration of multiple omics types remains largely unexplored. In this study, we performed integrative analysis on tumor-based exome-, transcriptome- and methylome-wide molecular profiles from The Cancer Genome Atlas (TCGA) for variations in cancer-relevant genes to construct robust, cross-validated multiomic predictors for ovarian cancer survival. These integrated polygenic survival scores (PSSs) were able to predict 5-year overall (OS) and progression-free survival in the Caucasian subsample with high accuracy (AUROC = 0.87 and 0.81, respectively). These findings suggest that the PSSs are able to predict long-term OS in TCGA patients with accuracy beyond that of previously proposed protein-based biomarker strategies. Our findings reveal the promise of an integrated omics-based approach in enhancing existing prognostic strategies. Future investigations should be aimed toward prospective external validation, strategies for standardizing application and the integration of germline variants.

Surgical ablation of atrial fibrillation during mitral-valve surgery.

BACKGROUND: Among patients undergoing mitral-valve surgery, 30 to 50% present with atrial fibrillation, which is associated with reduced survival and increased risk of stroke. Surgical ablation of atrial fibrillation has been widely adopted, but evidence regarding its safety and effectiveness is limited. METHODS: We randomly assigned 260 patients with persistent or long-standing persistent atrial fibrillation who required mitral-valve surgery to undergo either surgical ablation (ablation group) or no ablation (control group) during the mitral-valve operation. Patients in the ablation group underwent further randomization to pulmonary-vein isolation or a biatrial maze procedure. All patients underwent closure of the left atrial appendage. The primary end point was freedom from atrial fibrillation at both 6 months and 12 months (as assessed by means of 3-day Holter monitoring). RESULTS: More patients in the ablation group than in the control group were free from atrial fibrillation at both 6 and 12 months (63.2% vs. 29.4%, P<0.001). There was no significant difference in the rate of freedom from atrial fibrillation between patients who underwent pulmonary-vein isolation and those who underwent the biatrial maze procedure (61.0% and 66.0%, respectively; P=0.60). One-year mortality was 6.8% in the ablation group and 8.7% in the control group (hazard ratio with ablation, 0.76; 95% confidence interval, 0.32 to 1.84; P=0.55). Ablation was associated with more implantations of a permanent pacemaker than was no ablation (21.5 vs. 8.1 per 100 patient-years, P=0.01). There were no significant between-group differences in major cardiac or cerebrovascular adverse events, overall serious adverse events, or hospital readmissions. CONCLUSIONS: The addition of atrial fibrillation ablation to mitral-valve surgery significantly increased the rate of freedom from atrial fibrillation at 1 year among patients with persistent or long-standing persistent atrial fibrillation, but the risk of implantation of a permanent pacemaker was also increased. (Funded by the National Institutes of Health and the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00903370.).

Retrospective comparison of measured stone size and posterior acoustic shadow width in clinical ultrasound images.

PURPOSE: Posterior acoustic shadow width has been proposed as a more accurate measure of kidney stone size compared to direct measurement of stone width on ultrasound (US). Published data in humans to date have been based on a research using US system. Herein, we compared these two measurements in clinical US images. METHODS: Thirty patient image sets where computed tomography (CT) and US images were captured less than 1 day apart were retrospectively reviewed. Five blinded reviewers independently assessed the largest stone in each image set for shadow presence and size. Shadow size was compared to US and CT stone sizes. RESULTS: Eighty percent of included stones demonstrated an acoustic shadow; 83% of stones without a shadow were ≤ 5 mm on CT. Average stone size was 6.5 ± 4.0 mm on CT, 10.3 ± 4.1 mm on US, and 7.5 ± 4.2 mm by shadow width. On average, US overestimated stone size by 3.8 ± 2.4 mm based on stone width (p < 0.001) and 1.0 ± 1.4 mm based on shadow width (p < 0.0098). Shadow measurements decreased misclassification of stones by 25% among three clinically relevant size categories (≤ 5, 5.1-10, > 10 mm), and by 50% for stones ≤ 5 mm. CONCLUSIONS: US overestimates stone size compared to CT. Retrospective measurement of the acoustic shadow from the same clinical US images is a more accurate reflection of true stone size than direct stone measurement. Most stones without a posterior shadow are ≤ 5 mm.

Feasibility of Antegrade Contrast-enhanced US Nephrostograms to Evaluate Ureteral Patency.

Purpose To demonstrate the feasibility of contrast material-enhanced ulrasonographic (US) nephrostograms to assess ureteral patency after percutaneous nephrolithotomy (PCNL) in this proof-of-concept study. Materials and Methods For this HIPAA-compliant, institutional review board-approved prospective blinded pilot study, patients undergoing PCNL provided consent to undergo contrast-enhanced US and fluoroscopic nephrostograms on postoperative day 1. For contrast-enhanced US, 1.5 mL of Optison (GE Healthcare, Oslo, Norway) microbubble contrast agent solution (perflutren protein-type A microspheres) was injected via the nephrostomy tube. Unobstructed antegrade ureteral flow was defined by the presence of contrast material in the bladder. Contrast-enhanced US results were compared against those of fluoroscopic nephrostograms for concordance. Results Ten studies were performed in nine patients (four women, five men). Contrast-enhanced US demonstrated ureteral patency in eight studies and obstruction in two. One patient underwent two studies, one showing obstruction and the second showing patency. Concordance between US and fluoroscopic assessments of ureteral patency was evaluated by using a Clopper-Pearson exact binomial test. These results were perfectly concordant with fluoroscopic nephrostogram results, with a 95% confidence interval of 69.2% and 100%. No complications or adverse events related to contrast-enhanced US occurred. Conclusion Contrast-enhanced US nephrostograms are simple to perform and are capable of demonstrating both patency and obstruction of the ureter. The perfect concordance with fluoroscopic results across 10 studies demonstrated here is not sufficient to establish diagnostic accuracy of this technique, but motivates further, larger scale investigation. If subsequent larger studies confirm these preliminary results, contrast-enhanced US may provide a safer, more convenient way to evaluate ureteral patency than fluoroscopy. © RSNA, 2016 Online supplemental material is available for this article.

Contrast Enhanced Ultrasound as a Radiation-Free Alternative to Fluoroscopic Nephrostogram for Evaluating Ureteral Patency.

PURPOSE: We compared contrast enhanced ultrasound and fluoroscopic nephrostography in the evaluation of ureteral patency following percutaneous nephrolithotomy. MATERIALS AND METHODS: This prospective cohort, noninferiority study was performed after obtaining institutional review board approval. We enrolled eligible patients with kidney and proximal ureteral stones who underwent percutaneous nephrolithotomy at our center. On postoperative day 1 patients received contrast enhanced ultrasound and fluoroscopic nephrostogram within 2 hours of each other to evaluate ureteral patency, which was the primary outcome of this study. RESULTS: A total of 92 pairs of imaging studies were performed in 82 patients during the study period. Five study pairs were excluded due to technical errors that prevented imaging interpretation. Females slightly predominated over males with a mean ± SD age of 50.5 ± 15.9 years and a mean body mass index of 29.6 ± 8.6 kg/m2. Of the remaining 87 sets of studies 69 (79.3%) demonstrated concordant findings regarding ureteral patency for the 2 imaging techniques and 18 (20.7%) were discordant. The nephrostomy tube was removed on the same day in 15 of the 17 patients who demonstrated antegrade urine flow only on contrast enhanced ultrasound and they had no subsequent adverse events. No adverse events were noted related to ultrasound contrast injection. While contrast enhanced ultrasound used no ionizing radiation, fluoroscopic nephrostograms provided a mean radiation exposure dose of 2.8 ± 3.7 mGy. CONCLUSIONS: A contrast enhanced ultrasound nephrostogram can be safely performed to evaluate for ureteral patency following percutaneous nephrolithotomy. This imaging technique was mostly concordant with fluoroscopic findings. Most discordance was likely attributable to the higher sensitivity for patency of contrast enhanced ultrasound compared to fluoroscopy.

Statins Associated With Decreased Risk of New Onset Inflammatory Bowel Disease.

OBJECTIVES: Prior studies suggest that medication exposures may be associated with new onset inflammatory bowel disease (IBD). The aim of this study was to determine the effect of statins on the risk of new onset IBD in a large United States health claims database. METHODS: We conducted a retrospective matched case-control study with a national medical claims and pharmacy database from Source Healthcare Analytics LLC. We included any patient aged 18 or older with ICD-9 code 555.x for Crohn's disease (CD) or 556.x for ulcerative colitis (UC) between January 2008 and December 2012. IBD patients diagnosed in 2012 were compared with the age group, gender, race, and geographically matched controls. Controls had no ICD-9 codes for CD, UC, or IBD-associated diseases and no prescriptions for IBD-related medications. New onset IBD patients were defined as having at least three separate CD or UC ICD-9 codes and no IBD-related ICD-9 or prescription before first IBD ICD-9. Statin exposure was assessed by Uniform System of Classification level 5 code. To account for diagnostic delay, exposures within 6 months of first ICD-9 were excluded. Exposures within 12 and 24 months were excluded in sensitivity analyses. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for new onset IBD, CD, and UC. RESULTS: A total of 9,617 cases and 46,665 controls were included in the analysis. Any statin exposure was associated with a significantly decreased risk of IBD (OR 0.68, 95% CI 0.64-0.72), CD (0.64, 95% CI 0.59-0.71), and UC (OR 0.70, 95% CI 0.65-0.76). This effect was similar for most specific statins and regardless of intensity of therapy. The protective effect against new onset CD was strongest among older patients. Statins' association with a lower risk of IBD was similar after adjusting for antibiotics, hormone replacement therapy, oral contraceptives, comorbidities, and cardiovascular medications. CONCLUSIONS: Statins may have a protective effect against new onset IBD, CD, and UC. This decreased risk is similar across most statins and appears to be stronger among older patients, particularly in CD.

Luminal B subtype: a key factor for the worse prognosis of young breast cancer patients in China.

BACKGROUND: The prognoses of young breast cancer patients are poor. The purpose of this study is to evaluate the different characteristics and prognoses among different subtypes of young breast cancer patients. METHODS: The study included 1360 patients <40 years-old (y) and 3110 patients 40-50y with operable breast cancer in Shanghai Cancer Center, Fudan University. The characteristics, overall survival (OS) and disease-free survival (DFS) were compared. RESULTS: The median follow-up was 54.1 months. More grade III tumors and more lymph-vascular invasions (P < 0.01) were presented in <40y group when compared with 40-50y group. More patients <40y presented with Luminal B (25.3% vs. 17.5%, P < 0.01) and triple negative (16.7% vs. 13.4%, P < 0.05) breast cancer while fewer had Luminal A tumor (48.5% vs. 59.2%, P < 0.01). Younger patients with tumors of both Luminal A and Luminal B types were at increased risk for worse DFS (P = 0.03, HR = 1.69, 95% CI = 1.05-2.72; P < 0.01, HR = 3.61, 95% CI = 2.50-5.22) when compared with the older patients. Patients <40y with Luminal B tumor had a two point five fold higher risk of death compared with older counterparts (P < 0.01, HR = 2.54, 95% CI = 1.35-4.79), however, a worse overall survival rate was not observed in the younger women with Luminal A breast cancer (P > 0.05). In multivariate analysis, Luminal B subtype was also a strong predictor of disease relapse (HR = 1.09, 95% CI = 1.01 to 1.19, P < 0.01) in younger patients with Luminal subtype tumors. CONCLUSION: Characteristics of breast cancer suggested a more aggressive biology in Chinese patients with breast cancer diagnosed at young age. Luminal B subtype may have a negative effect on the prognosis of young patients in China which should be validated further.