N-myristoyltransferase 2-based Blood Test for the Detection of Colorectal Adenomatous Polyps and Cancer.

Background: Colorectal cancer is the second leading cause of cancer-related deaths. This study demonstrates the utility of a simple blood test with high sensitivity and specificity for colorectal adenomatous polyps and cancer. A simple blood test with high sensitivity and specificity for adenomas would help identify individuals for a follow-up colonoscopy during which any adenomatous polyps found could be removed, thus preventing colorectal cancer (CRC). Methods: We determined the H-score by using immunohistochemical analyses of N-myristoyltransferase 2 (NMT2) in peripheral blood mononuclear cells (PBMC) isolated from the blood. We determined the sensitivity and specificity of the NMT2-based blood test in identifying colorectal adenomatous polyps and cancer. Design: All experimental procedures were performed by research personnel blinded to the colonoscopy status of the participants. Setting: In this cohort study, participants were recruited from those coming for an outpatient colonoscopy at a referral center. Participants: PBMC were collected from 74 subjects at the Health Sciences Centre, Winnipeg, Canada. Samples were collected from colonoscopy patients prior to colonoscopy. All 74 subjects were included in CRC vs. non-CRC analysis, whereas only 70 subjects were analyzed for colorectal adenomatous polyps and cancer versus individuals with no evidence of disease and non-adenomatous polyps. NMT2 expression was tested in samples by immunohistochemistry. Results: The expression of NMT2 was significantly higher in PBMC of subjects with colorectal adenomatous polyps and cancer (n = 34) compared with individuals with non-adenomatous polyps or no evidence of disease (n = 36) (P < 0.0001). The test had an overall sensitivity of 91% (95% confidence intervals: 84.49-97.80) and specificity of 81% (95% confidence intervals: 71.28-89.83) in detecting colorectal adenomatous polyps and cancer (all stages). Conclusions: Our results suggest that the sensitivity of NMT2 in detecting adenomatous polyps is high (91%). A simple blood-based CRC screening test using NMT2 expression detects colorectal adenomatous polyps and cancer with high sensitivity and specificity has the potential of increasing the compliance for CRC screening as has been reported for other blood-based CRC screening tests.

Factors That Contribute to Cost Differences Based on ICU of Admission in Neonates Undergoing Congenital Heart Surgery: A Novel Decomposition Analysis.

OBJECTIVES: We leveraged decomposition analysis, commonly used in labor economics, to understand determinants of cost differences related to location of admission in children undergoing neonatal congenital heart surgery. DESIGN: A retrospective cohort study. SETTING: Pediatric Health Information Systems database. PATIENTS: Neonates (<30 d old) undergoing their index congenital heart surgery between 2004 and 2013. MEASUREMENTS AND MAIN RESULTS: A decomposition analysis with bootstrapping determined characteristic (explainable by differing covariate levels) and structural effects (if covariates are held constant) related to cost differences. Covariates included center volume, age at admission, prematurity, sex, race, genetic or major noncardiac abnormality, Risk Adjustment for Congenital Heart Surgery-1 score, payor, admission year, cardiac arrest, infection, and delayed sternal closure.Of 19,984 infants included (10,491 [52%] to cardiac ICU/PICU and 9,493 [48%] to neonatal ICU), admission to the neonatal ICU had overall higher average costs ($24,959 ± $3,260; p < 0.001) versus cardiac ICU/PICU admission. Characteristic effects accounted for higher costs in the neonatal ICU ($28,958 ± $2,044; p < 0.001). Differing levels of prematurity, genetic syndromes, hospital volume, age at admission, and infection contributed to higher neonatal ICU costs, with infection rate providing the most significant contribution ($13,581; p < 0.001). Aggregate structural effects were not associated with cost differences for those admitted to the neonatal ICU versus cardiac ICU/PICU (p = 0.1). Individually, prematurity and age at admission were associated with higher costs due to structural effects for infants admitted to the neonatal ICU versus cardiac ICU/PICU. CONCLUSIONS: The difference in cost between neonatal ICU and cardiac ICU/PICU admissions is largely driven by differing prevalence of risk factors between these units. Infection rate was a modifiable factor that accounted for the largest difference in costs between admitting units.

Cardiac Stress Testing during Workup for Abdominal Aortic Aneurysm Repair Is Not Associated with Improved Patient Outcomes.

BACKGROUND: Cardiac stress testing (CST) is commonly used to help determine whether patients with abdominal aortic aneurysms (AAAs) are better candidates for open versus endovascular repair, although it is unknown whether the use of CST achieves its goal of optimizing patient selection and postoperative outcomes. METHODS: We retrospectively identified 3,635 patients in the Vascular Quality Initiative database (2010-2012) with an AAA ≥ 5.0 cm who were candidates for either open or endovascular AAA repair. The Vascular Study Group Cardiac Risk Index (VSG-CRI) was used to stratify patient risk. We applied generalized estimating equations with inverse probability weighting (IPW) to adjust for patient factors and hospital-level CST utilization to evaluate the effect of CST on composite of 30-day major adverse cardiac events or mortality (MACE-M) following AAA repair. RESULTS: CST was utilized in 1,627 (45%) patients during AAA workup, including 451 of 794 (57%) patients selected for open repair and 1,176 of 2,841 (41%) selected for endovascular repair. After IPW, the use of CST was not associated with the probability of patients receiving open versus endovascular repair (OR: 1.00; 95% CI: 0.77-1.32). As compared to patients without CST during AAA workup, adjusted analyses revealed that CST utilization was not associated with improved MACE or mortality outcomes following AAA repair. Among patients receiving CST, an abnormal CST was not significantly associated with selection of open versus endovascular repair or with postoperative outcomes after adjustment for the VSG-CRI score. Similar results were found for patients with either low or high VSG-CRI scores. CONCLUSIONS: Utilization of CST during workup for AAA is not associated with procedure selection and improved outcomes. Identifying risk factors for individuals who would benefit from preoperative CST before AAA repair will help reduce health care utilization and improve postoperative outcomes.

Candidate Surrogate End Points for ESRD after AKI.

AKI, a frequently transient condition, is not accepted by the US Food and Drug Association as an end point for drug registration trials. We assessed whether an intermediate-term change in eGFR after AKI has a sufficiently strong relationship with subsequent ESRD to serve as an alternative end point in trials of AKI prevention and/or treatment. Among 161,185 United States veterans undergoing major surgery between 2004 and 2011, we characterized in-hospital AKI by Kidney Disease Improving Global Outcomes creatinine criteria and decline in eGFR from prehospitalization to postdischarge time points and quantified associations of these values with ESRD and mortality over a median of 3.8 years. An eGFR decline of ≥30% at 30, 60, and 90 days after discharge occurred in 3.1%, 2.5%, and 2.6%, of survivors without AKI and 15.9%, 12.2%, and 11.7%, of survivors with AKI. For patients with in-hospital AKI compared with those with no AKI and stable eGFR, a 30% decline in eGFR at 30, 60, and 90 days after discharge demonstrated adjusted hazard ratios (95% confidence intervals) of ESRD of 5.60 (4.06 to 7.71), 6.42 (4.76 to 8.65), and 7.27 (5.14 to 10.27), with corresponding estimates for 40% decline in eGFR of 6.98 (5.21 to 9.35), 8.03 (6.11 to 10.56), and 10.95 (8.10 to 14.82). Risks for mortality were smaller but consistent in direction. A 30%-40% decline in eGFR after AKI could be a surrogate end point for ESRD in trials of AKI prevention and/or treatment, but additional trial evidence is needed.

Variation in pediatric outpatient adenotonsillectomy costs in a multihospital network.

OBJECTIVES/HYPOTHESIS: Identify hospital costs for same-day pediatric adenotonsillectomy (T&A) surgery, and evaluate surgeon, hospital, and patient factors influencing variation in costs, and compare relationship of costs to complications for T&A. STUDY DESIGN: Observational retrospective cohort study. METHODS: A multihospital network's standardized activity-based accounting system was used to determine hospital costs per T&A from 1998 to 2012. Children 1 to 18 years old who underwent same-day T&A surgery were included. Subjects with additional procedures were excluded. Mixed effects analyses were performed to identify variation in mean costs due to surgeon, hospital, and patient factors. Surgeons' mean cost/case was related to subsequent complications, defined as any unplanned visit within 21 days in the healthcare system. RESULTS: The study cohort included 26,626 T&As performed by 66 surgeons at 18 hospitals. Mean cost per T&A was $1,355 ± $505. Mixed effects analysis using patient factors as fixed effects and surgeon and hospital as a random effect identified significant variation in mean costs per surgeon, with 95% of surgeons having a mean cost/case between 67% and 150% of the overall mean (range, $874-$2,232/case). Similar variability was found among hospitals, with 95% of the facilities having mean costs between 64% to 156% of the mean (range, $1,029-$2,385/case). Severity of illness and several other patient factors exhibited small but statistically significant associations with cost. Surgeons' mean cost/case was moderately associated with an increased complication rate. CONCLUSIONS: Significant variation in same-day pediatric T&A surgery costs exists among different surgeons and hospitals within a multihospital network. Reducing variation in costs while maintaining outcomes may improve healthcare value and eliminate waste. LEVEL OF EVIDENCE: 4.

Association of histologic variants in FSGS clinical trial with presenting features and outcomes.

BACKGROUND AND OBJECTIVES: FSGS histologic variants have correlated with outcomes in retrospective studies. The FSGS Clinical Trial provided a unique opportunity to study the clinical impact of histologic variants in a well defined prospective cohort with steroid-resistant primary FSGS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Renal biopsies of 138 FSGS Clinical Trial participants aged 2-38 years enrolled from 2004 to 2008 were analyzed using the Columbia classification by core pathologists. This study assessed the distribution of histologic variants and examined their clinical and biopsy characteristics and relationships to patient outcomes. RESULTS: The distribution of histologic variants was 68% (n=94) FSGS not otherwise specified, 12% (n=16) collapsing, 10% (n=14) tip, 7% (n=10) perihilar, and 3% (n=4) cellular. Individuals with not otherwise specified FSGS were more likely to have subnephrotic proteinuria (P=0.01); 33% of teenagers and adults had tip or collapsing variants compared with 10% of children, and subjects with these variants had greater proteinuria and hypoalbuminemia than not otherwise specified patients. Tip variant had the strongest association with white race (86%) and the lowest pathologic injury scores, baseline creatinine, and rate of progression. Collapsing variant had the strongest association with black race (63%, P=0.03) and the highest pathologic injury scores (P=0.003), baseline serum creatinine (P=0.003), and rate of progression. At 3 years, 47% of collapsing, 20% of not otherwise specified, and 7% of tip variant patients reached ESRD (P=0.005). CONCLUSIONS: This is the first prospective study with protocol-defined immunomodulating therapies confirming poor renal survival in collapsing variant and showing better renal survival in tip variant among steroid-resistant patients.

Design of clinical trials in AKI: a report from an NIDDK workshop. Trials of patients with sepsis and in selected hospital settings.

AKI remains an important clinical problem, with a high mortality rate, increasing incidence, and no Food and Drug Administration-approved therapeutics. Advances in addressing this clinical need require approaches for rapid diagnosis and stratification of injury, development of therapeutic agents based on precise understanding of key pathophysiological events, and implementation of well designed clinical trials. In the near future, AKI biomarkers may facilitate trial design. To address these issues, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a meeting, "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers," in December of 2010 that brought together academic investigators, industry partners, and representatives from the National Institutes of Health and the Food and Drug Administration. Important issues in the design of clinical trials for interventions in AKI in patients with sepsis or AKI in the setting of critical illness after surgery or trauma were discussed. The sepsis working group discussed use of severity of illness scores and focus on patients with specific etiologies to enhance homogeneity of trial participants. The group also discussed endpoints congruent with those endpoints used in critical care studies. The second workgroup emphasized difficulties in obtaining consent before admission and collaboration among interdisciplinary healthcare groups. Despite the difficult trial design issues, these clinical situations represent a clinical opportunity because of the high event rates, severity of AKI, and poor outcomes. The groups considered trial design issues and discussed advantages and disadvantages of several short- and long-term primary endpoints in these patients.

Design of clinical trials in acute kidney injury: a report from an NIDDK workshop--prevention trials.

AKI is an important clinical problem that has become increasingly more common. Mortality rates associated with AKI remain high despite advances in supportive care. Patients surviving AKI have increased long-term mortality and appear to be at increased risk of developing CKD and progressing to ESRD. No proven effective pharmacologic therapies are currently available for the prevention or treatment of AKI. Advances in addressing this unmet need will require the development of novel therapeutic agents based on precise understanding of key pathophysiological events and the implementation of well designed clinical trials. To address this need, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored the "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" workshop in December 2010. The event brought together representatives from academia, industry, the National Institutes of Health, and the US Food and Drug Administration. We report the discussions of workgroups that developed outlines of clinical trials for the prevention of AKI in two patient populations: patients undergoing elective surgery who are at risk for or who develop AKI, and patients who are at risk for contrast-induced AKI. In both of these populations, primary prevention or secondary therapy can be delivered at an optimal time relative to kidney injury. The workgroups detailed primary and secondary endpoints for studies in these groups, and explored the use of adaptive clinical trial designs for trials of novel preventive strategies to improve outcomes of patients with AKI.