Integration of the Renal Angina Index and Urine Neutrophil Gelatinase-Associated Lipocalin Improves Severe Acute Kidney Injury Prediction in Critically Ill Children and Young Adults.

Introduction: Acute kidney injury (AKI) occurs in one-fourth of children and young adults admitted to pediatric intensive care unit (PICU). Severe AKI (sAKI; Kidney Disease: Improving Global Outcomes stage 2 or 3) is associated with morbidity and mortality. An AKI risk stratification system, the Renal Angina Index (RAI) calculated at 12 hours of admission, exhibits excellent performance to rule out sAKI at 72 hours of admission. We found that integration of urine neutrophil gelatinase-associated lipocalin (NGAL) with RAI improves prediction of sAKI. We now report the first-year results after implementation of our prospective automated RAI-NGAL clinical decision support (CDS) program. Methods: Patients 3 months to 25 years of age were eligible. Admission order sets have a conditional order for urine NGAL released when a 12-hour RAI ≥8. The primary outcome was sAKI any time at days 2 to 4 of admission. We assessed performance of the RAI and RAI+/NGAL to predict the primary outcome. Results: A total of 1427 unique patients accounted for 1575 admissions. In 147 admissions, RAI was ≥8. RAI <8 had negative predictive value (NPV) of 0.98 (95% CI 0.97-0.99); RAI ≥ 8 had positive predictive value (PPV) of 0.37 (95% CI 0.30-0.46) to predict days 2 to 4 sAKI (area under the receiver operating characteristic curve [AUC-ROC] 0.88 [95% CI 0.84-0.92]). Of 147 RAI+ patients, 89 had NGAL available. RAI/NGAL combination improved PPV (0.64, 95% CI 0.50-0.79) without decrement in NPV (0.98, 95% CI 0.97-0.98). Conclusion: AKI biomarker assessment directed by risk stratification improves prediction of sAKI in critically ill children and young adults. This CDS process has potential to enrich the population for interventional study, although improvement to adherence to CDS is needed.

Long-Term Assessment of the Cecal Intubation Rates in High-Performing Colonoscopists: Time for Review.

OBJECTIVES: The cecal intubation rate (CIR) is one of the 3 priority indicators for quality in colonoscopy. Whether continuous measurement of CIR is useful in high performers is uncertain. METHODS: At an academic center, we identified 16 physicians who performed at least 50 procedures over 6 consecutive years. We analyzed all colonoscopy procedures excluding those with poor/inadequate preparation or severe colitis for CIR trend over the years. We calculated the numbers needed to establish CIR over minimum threshold levels with 95% confidence. RESULTS: The overall CIR was 99.4%. None of the 16 physicians had a CIR <96.6% in any year. Sensitivity analyses including patients without intent to reach the cecum and inadequate bowel preparation had little impact on the results. Overall cecal photo documentation rate was 98.4%. No significant correlation was observed between procedure volume at our center and CIR (σ = -0.196, P = 0.483). Physicians with CIR ≥99% need to have only 24 examinations reviewed to establish CIR is >95%. DISCUSSION: Continuous measurement of CIR, at least in high performers, appears to be of limited value. Very high performers need to evaluate small number of cases to demonstrate that CIR is above the recommended thresholds.

Early Sequential Risk Stratification Assessment to Optimize Fluid Dosing, CRRT Initiation and Discontinuation in Critically Ill Children with Acute Kidney Injury: Taking Focus 2 Process Article.

BACKGROUND: Acute Kidney Injury (AKI) is common in critically ill children and is associated with increased morbidity and mortality. Recognition and management of AKI is often delayed, predisposing patients to risk of clinically significant fluid accumulation (Fluid Overload (FO)). Early recognition and intervention in high risk patients could decrease fluid associated morbidity. We aim to assess an AKI Clinical Decision Algorithm (CDA) using a sequential risk stratification strategy integrating the Renal Angina Index (RAI), urine Neutrophil Gelatinase-Associated Lipocalin (NGAL) and the Furosemide Stress Test (FST) to optimize AKI and FO prediction and management in critically ill children. METHODS/DESIGN: This single center prospective observational cohort study evaluates the AKI CDA in a Pediatric Intensive Care Unit (PICU). Every patient ≥ 3 months old has the risk score RAI calculated automatically at 12 hours of admission. Patients with a RAI ≥ 8 (fulfilling renal angina) have risk further stratified with a urine NGAL and, if positive (NGAL ≥ 150ng/mL), subsequently by their response to a standardized dose of furosemide (namely FST). RAI negative or NGAL negative patients are treated per usual care. FST-responders are managed conservatively, while non-responders receive fluid restrictive strategy and/or continuous renal replacement therapy (CRRT) at 10%-15% of FO. 2100 patients over 3 years will be evaluated to capture 210 patients with severe AKI (KDIGO Stage 2 or 3 AKI), 100 patients with >10% FO, and 50 requiring CRRT. Primary analyses: Standardizing a pediatric FST and assessing prediction accuracy of CDA for severe AKI, FO>10% and CRRT requirement in children. Secondary analyses in patients with AKI: Renal function return to baseline, RRT and mortality within 28 days. DISCUSSION: This will be the first prospective evaluation of feasibility of AKI CDA, integrating individual prediction tools in one cohesive and comprehensive approach, and its prediction of FO>10% and AKI, as well as the first to standardize the FST in the pediatric population. This will increase knowledge on current AKI prediction tools and provide actionable insight for early interventions in critically ill children based on their level of risk.

Maintenance of AP-2-Dependent Functional Activities of Nef Restricts Pathways of Immune Escape from CD8 T Lymphocyte Responses.

Nef-specific CD8+ T lymphocytes (CD8TL) are linked to extraordinary control of primate lentiviral replication, but the mechanisms underlying their efficacy remain largely unknown. The immunodominant, Mamu-B*017:01+-restricted Nef195-203MW9 epitope in SIVmac239 partially overlaps a sorting motif important for interactions with host AP-2 proteins and, hence, downmodulation of several host proteins, including Tetherin (CD317/BST-2), CD28, CD4, SERINC3, and SERINC5. We reasoned that CD8TL-driven evolution in this epitope might compromise Nef's ability to modulate these important molecules. Here, we used deep sequencing of SIV from nine B*017:01+ macaques throughout infection with SIVmac239 to characterize the patterns of viral escape in this epitope and then assayed the impacts of these variants on Nef-mediated modulation of multiple host molecules. Acute variation in multiple Nef195-203MW9 residues significantly compromised Nef's ability to downregulate surface Tetherin, CD4, and CD28 and reduced its ability to prevent SERINC5-mediated reduction in viral infectivity but did not impact downregulation of CD3 or major histocompatibility complex class I, suggesting the selective disruption of immunomodulatory pathways involving Nef AP-2 interactions. Together, our data illuminate a pattern of viral escape dictated by a selective balance to maintain AP-2-mediated downregulation while evading epitope-specific CD8TL responses. These data could shed light on mechanisms of both CD8TL-driven viral control generally and on Mamu-B*017:01-mediated viral control specifically.IMPORTANCE A rare subset of humans infected with HIV-1 and macaques infected with SIV can control the virus without aid of antiviral medications. A common feature of these individuals is the ability to mount unusually effective CD8 T lymphocyte responses against the virus. One of the most formidable aspects of HIV is its ability to evolve to evade immune responses, particularly CD8 T lymphocytes. We show that macaques that target a specific peptide in the SIV Nef protein are capable of better control of the virus and that, as the virus evolves to escape this response, it does so at a cost to specific functions performed by the Nef protein. Our results help show how the virus can be controlled by an immune response, which could help in designing effective vaccines.

Minimal training is required to reliably perform quantitative ultrasound of muscle.

INTRODUCTION: Quantitative ultrasound can measure skeletal muscle pathology. We investigated whether inexperienced evaluators could accurately obtain and analyze ultrasound images. METHODS: Two examiners underwent a 20-minute training session before obtaining ultrasound images of several limb muscles in 21 healthy boys and 19 boys with Duchenne muscular dystrophy (DMD). Gray scale levels (GSLs) of muscle and subcutaneous fat were then measured by 2 analysts: a trained research assistant and a radiologist. We compared results between examiners and analysts. RESULTS: Interrater reliability of muscle GSLs was high between examiners (ICC ≥ 0.85) and analysts (ICC ≥ 0.84). As anticipated, GSLs were higher in dystrophic than in healthy muscles (P < 0.001). Fat GSLs were less reliable (ICC = 0.5-0.89) than muscle and increased with age and body size. CONCLUSIONS: GSLs from ultrasound images of healthy and dystrophic skeletal muscle, but not from subcutaneous fat, can be obtained reliably and can be analyzed by inexperienced evaluators with minimal training.

Age- and gender-associated differences in electrical impedance values of skeletal muscle.

Electrical impedance measurements of skeletal muscle may be sensitive to age-associated declines in muscle health. In an effort to evaluate this concept further, we performed electrical impedance myography (EIM) using a handheld array on 38 individuals aged 19-50 years and 41 individuals aged 60-85 years. Individuals either had seven upper extremity or seven lower extremity muscles measured. The 50 kHz reactance, resistance and phase were used as the major outcome variables. Although the phase values were similar in both groups, both reactance and resistance values were lower in the lower extremities of the older individuals as compared to the younger (-23 ± 6%, p = 0.001 for reactance and -27 ± 7%, p = 0.005 for resistance), whereas changes in upper extremity values were not significantly different (-9 ± 5%, p = 0.096 for reactance and +5 ± 9%, p = 0.55 for resistance). When analyzing the genders separately, it became clear that this reduction in lower extremity values was most pronounced in men and less consistently present in women. These findings suggest that age- and gender-associated differences in muscle condition are detectable using EIM. The relationship of these easily obtained parameters to standard functional, imaging, and pathological markers of sarcopenia deserves further study.