Citations

Insertion of tympanostomy tubes is a common elective pediatric surgical procedure and is typically performed under general anesthesia. The potential to reduce general anesthetic requirements for young children has led to increased interest in alternatives for tympanostomy tube placement. A tympanostomy tube system, developed to enable tympanostomy tube placement in a single pass on conscious patients under moderate sedation, was evaluated. A prospective study on 128 children and 253 tympanostomy tube placements conducted at 4 centers in the United States demonstrated an 88.3% success rate in performing the procedure under moderate sedation with adverse events within normal rates reported in the literature. The feasibility of completing tympanostomy tube placement under moderate sedation enables avoidance of general anesthesia and provides additional choices to physicians and parents.

AbstractBackgroundWearable technology is growing in popularity as a result of its ability to interface with normal human movement and function.MethodsUsing proprietary hardware and software, neuronavigation images were captured and transferred wirelessly via a password‐encrypted network to the head‐up display. The operating surgeon wore a loupe‐mounted wearable head‐up display during image‐guided parieto‐occipital ventriculoperitoneal shunt placement in two patients.ResultsThe shunt placement was completed successfully without complications. The tip of the catheter ended well within the ventricles away from the ventricular wall. The wearable device allowed for continuous monitoring of neuronavigation images in the right upper corner of the surgeon's visual field without the need for the surgeon to turn his head to view the monitors.ConclusionsThe adaptable nature of this proposed system permits the display of video data to the operating surgeon without diverting attention away from the operative task. This technology has the potential to enhance image‐guided procedures.

Objectives Congenital absence of the pericardium (CAP) is often confused with other conditions presenting with right ventricular dilatation and usually warrants CT or cardiac MR (CMR) to confirm. It would be desirable to have more specific echocardiographic criteria to provide a conclusive diagnosis. Methods 11 patients who were diagnosed with CAP (four patients with total CAP) based on CT/CMR were consecutively enrolled. Thirteen patients with atrial septal defect (ASD) and 16 normal subjects served as controls. To investigate spatial changes of heart in the thoracic cavity in CAP, following echocardiographic measurements were made in the left and right decubitus positions: the angle between the ultrasound beam and the left ventricular posterior wall (Angle-PW) in end-diastole at the parasternal long axis, and the distance between the chest wall and the most distal part of the left ventricular posterior wall (Distance-PW) at the parasternal mid-ventricular short axis. Results Angle-PW in patients with CAP were significantly greater than in those with ASD (100.1±12.5° vs 74.5±8.6°, p<0.017) or in normal subjects (100.1±12.5° vs 69.9±7.6°, p<0.017) at the left decubitus, and the difference in Angle-PW according to posture (left vs right) was significantly greater in CAP compared with the other groups (CAP 20.7±12.7°, ASD 0.31±1.80°, normal 0.31±1.40°, all p<0.017). The differences in Distance-PW according to patient position (CAP 2.43±0.77°, ASD 0.42±0.45°, normal 0.26±0.55°) or cardiac cycle in each position (left: CAP 1.60±0.76°, ASD 0.41±0.27°, normal 0.17±0.12°; right: CAP 0.70±0.32°, ASD 0.22±0.19°, normal 0.22±0.13°) were significantly higher in the CAP group than in the other groups (all p<0.017). Conclusions Patients with CAP have dynamic alteration in cardiac position depending on posture, which is not observed in ASD or in normal controls. Hence, total or left-sided CAP can be reliably diagnosed with positional changes during routine echocardiography.

2 Background: Testing for HER2 in EAC has become routine given its ability to predict benefit from HER2-targeted therapy. HER2 protein analysis by immunohistochemistry (IHC) is more rapid and generally less expensive than assessment of gene amplification by fluorescence in situ hybridization (FISH). However, the accuracy of IHC for predicting HER2 amplification has not been examined in a large EAC cohort. Methods: Surgical EAC specimens were examined from 675 patients who underwent curative resection at a single institution without preoperative therapy. Tumors were located in the esophagus (47%) or gastroesophageal junction (53%); most were node-positive (73%). Every tumor was evaluated by IHC in parallel with FISH in a blinded manner using FDA-approved assays. A consensus IHC score was determined by 2 pathologists using tumor-specific criteria (negative, 0 or 1+; equivocal, 2+; positive, 3+). Gene amplification by FISH was defined as a HER2/CEP17ratio ≥ 2. Results: HER2 amplification was detected in 89% of IHC 3+ cases, 13% of IHC 2+ cases, and 4% of IHC 0-1+ cases (Table). Accordingly, using FISH as the reference standard, the positive predictive value (PPV) of a positive IHC test (3+) was 89% (79/89 [95% CI 82%-95%]), and the negative predictive value of a negative IHC test (0-1+) was 96% (401/417 [94%-98%]). Importantly, the PPV of an equivocal IHC score (2+) for detecting HER2 amplification was 13% (22/169 [8%-18%]). Conclusions: In the largest study to date comparing HER2 testing methods in EAC, a negative IHC result (0 or 1+) nearly excludes the presence of gene amplification by FISH. Whereas a positive IHC result (3+) strongly predicts for the presence of amplification, an equivocal IHC result (2+) is a weak predictor. These findings in EAC support a HER2 testing algorithm where IHC is used for initial screening and FISH testing is restricted to cases with equivocal IHC results. [Table: see text]

460 Background: The immune response has emerged as a strong prognostic factor in colon cancer. Whereas CD8+ T cells mediate antitumor response, regulatory T cells expressing FoxP3+ can antagonize this effect, though prognostic data conflict. These markers have yet to be analyzed with MMR status, which is important since dMMR tumors show enhanced immune response. Methods: CD8+ and FoxP3+ density were analyzed by immunohistochemistry (IHC) in resected stage II and III colon carcinomas (N = 216) from participants in phase III adjuvant 5-fluorouracil-based trials. High vs low immune density was dichotomized at the median. MMR status, determined by IHC or analysis of microsatellite instability, was categorized as dMMR (12%) or proficient MMR (pMMR). Cox models, stratified by study, were adjusted for age, stage, grade and, where noted, MMR. Results: The association of FoxP3+ density with overall survival (OS) differed by CD8+ density (P for interaction = .040). By multivariable analysis, FoxP3+high was significantly associated with improved OS in CD8+low tumors (hazard ratio 0.43 [95% confidence interval 0.19 – 0.95]; P = .030], but not in CD8+high tumors (P = .91). Results were consistent after MMR adjustment. We then determined their prognostic impact in the larger pMMR subset (N = 119). Tumors with high FoxP3+ were associated with improved OS in cases with low, but not high, CD8+ density ( Table ). These patients (FoxP3+high, CD8+low) had similar 5-year OS rates as 107 dMMR cases from parent studies (89% vs 80%; P = .74), despite having distinct clinicopathologic features. Conclusions: The prognostic impact of FoxP3+ T cells depends on CD8+, indicating the importance of analyzing both in combination. High FoxP3+ exerts a paradoxically favorable survival impact, but only when CD8+ is low. Survival in pMMR tumors with high FoxP3+ and low CD8+ was similar to that of dMMR tumors, indicating that a favorable pMMR subset can be identified. [Table: see text]

Purpose of review APOE4 genotype is the strongest genetic risk factor for Alzheimer's disease. Prevailing evidence suggests that amyloid β plays a critical role in Alzheimer's disease. The objective of this article is to review the recent findings about the metabolism of apolipoprotein E (ApoE) and amyloid β and other possible mechanisms by which ApoE contributes to the pathogenesis of Alzheimer's disease. Recent findings ApoE isoforms have differential effects on amyloid β metabolism. Recent studies demonstrated that ApoE-interacting proteins, such as ATP-binding cassette A1 (ABCA1) and LDL receptor, may be promising therapeutic targets for Alzheimer's disease treatment. Activation of liver X receptor and retinoid X receptor pathway induces ABCA1 and other genes, leading to amyloid β clearance. Inhibition of the negative regulators of ABCA1, such as microRNA-33, also induces ABCA1 and decreases the levels of ApoE and amyloid β. In addition, genetic inactivation of an E3 ubiquitin ligase, myosin regulatory light chain interacting protein, increases LDL receptor levels and inhibits amyloid accumulation. Although amyloid β-dependent pathways have been extensively investigated, there have been several recent studies linking ApoE with vascular function, neuroinflammation, metabolism, synaptic plasticity, and transcriptional regulation. For example, ApoE was identified as a ligand for a microglial receptor, TREM2, and studies suggested that ApoE may affect the TREM2-mediated microglial phagocytosis. Summary Emerging data suggest that ApoE affects several amyloid β-independent pathways. These underexplored pathways may provide new insights into Alzheimer's disease pathogenesis. However, it will be important to determine to what extent each mechanism contributes to the pathogenesis of Alzheimer's disease.

Abstract Kallikrein-related peptidase 6 (Klk6) is elevated in the serum of multiple sclerosis (MS) patients and is hypothesized to participate in inflammatory and neuropathogenic aspects of the disease. To test this hypothesis, we investigated the impact of systemic administration of recombinant Klk6 on the development and progression of MOG35-55-induced experimental autoimmune encephalomyelitis (EAE). First, we determined that Klk6 expression is elevated in the spinal cord of mice with EAE at the peak of clinical disease and in immune cells upon priming with the disease-initiating peptide in vitro. Systemic administration of recombinant Klk6 to mice during the priming phase of disease resulted in an exacerbation of clinical symptoms, including earlier onset of disease and higher levels of spinal cord inflammation and pathology. Treatment of MOG35-55-primed immune cells with Klk6 in culture enhanced expression of pro-inflammatory cytokines, interferon-γ, tumor necrosis factor, and interleukin-17, while reducing anti-inflammatory cytokines interleukin-4 and interleukin-5. Together these findings provide evidence that elevations in systemic Klk6 can bias the immune system towards pro-inflammatory responses capable of exacerbating the development of neuroinflammation and paralytic neurological deficits. We suggest that Klk6 represents an important target for conditions in which pro-inflammatory responses play a critical role in disease development, including MS.