Stool Protein Mass Spectrometry Identifies Biomarkers for Early Detection of Diffuse-type Gastric Cancer.

There is a high unmet need for early detection approaches for diffuse gastric cancer (DGC). We examined whether the stool proteome of mouse models of gastric cancer (GC) and individuals with hereditary diffuse gastric cancer (HDGC) have utility as biomarkers for early detection. Proteomic mass spectrometry of the stool of a genetically engineered mouse model driven by oncogenic KrasG12D and loss of p53 and Cdh1 in gastric parietal cells [known as Triple Conditional (TCON) mice] identified differentially abundant proteins compared with littermate controls. Immunoblot assays validated a panel of proteins, including actinin alpha 4 (ACTN4), N-acylsphingosine amidohydrolase 2 (ASAH2), dipeptidyl peptidase 4 (DPP4), and valosin-containing protein (VCP), as enriched in TCON stool compared with littermate control stool. Immunofluorescence analysis of these proteins in TCON stomach sections revealed increased protein expression compared with littermate controls. Proteomic mass spectrometry of stool obtained from patients with HDGC with CDH1 mutations identified increased expression of ASAH2, DPP4, VCP, lactotransferrin (LTF), and tropomyosin-2 relative to stool from healthy sex- and age-matched donors. Chemical inhibition of ASAH2 using C6 urea ceramide was toxic to GC cell lines and GC patient-derived organoids. This toxicity was reversed by adding downstream products of the S1P synthesis pathway, which suggested a dependency on ASAH2 activity in GC. An exploratory analysis of the HDGC stool microbiome identified features that correlated with patient tumors. Herein, we provide evidence supporting the potential of analyzing stool biomarkers for the early detection of DGC. Prevention Relevance: This study highlights a novel panel of stool protein biomarkers that correlate with the presence of DGC and has potential use as early detection to improve clinical outcomes.

Early Xenopus gene regulatory programs, chromatin states, and the role of maternal transcription factors.

For decades, the early development of the Xenopus embryo has been an essential model system to study the gene regulatory mechanisms that govern cellular specification. At the top of the hierarchy of gene regulatory networks, maternally deposited transcription factors initiate this process and regulate the expression of zygotic genes that give rise to three distinctive germ layer cell types (ectoderm, mesoderm, and endoderm), and subsequent generation of organ precursors. The onset of germ layer specification is also closely coupled with changes associated with chromatin modifications. This review will examine the timing of maternal transcription factors initiating the zygotic genome activation, the epigenetic landscape of embryonic chromatin, and the network structure that governs the process.

Intraoperative dexmedetomidine attenuates stress responses in patients undergoing major spine surgery.

BACKGROUND: Surgical stress induces stress hormone release and sympathetic hyperactivation, resulting in hemodynamic instability. Dexmedetomidine has sympatholytic and hemodynamic stabilizing effects. We investigated whether dexmedetomidine could attenuate stress responses in major spine surgery. METHODS: In this prospective randomized study, 52 patients undergoing spine fusion surgery were randomized to placebo (N.=26) or to dexmedetomidine (N.=26) groups. Dexmedetomidine at a rate of 0.4 µg/kg/h or saline was infused, starting immediately after anesthetic induction and continuing until the end of surgery. Anesthesia was performed using desflurane and remifentanil in both groups. Serum levels of cortisol, epinephrine, norepinephrine, and interleukin-6 were assessed before surgery (T1), at the surgical incision (T2), at the bone procedure (T3), and one hour after surgery (T4). The hemodynamic variables and the autonomic nervous system balance evaluated with heart rate variability were assessed at the same time points. RESULTS: Epinephrine and norepinephrine levels were higher over time in the control rather than in the dexmedetomidine group (P=0.001 and <0.001, respectively). The changes in cortisol, interleukin-6, and hemodynamics were similar between the groups. In the heart rate variability analysis, high-frequency decreased and low-frequency and low-frequency/high-frequency ratio increased during surgery in the control group, whereas they were maintained at the baseline level in the dexmedetomidine group. The changes in high-frequency, low-frequency, and the low-frequency/high-frequency ratio over time differed between the groups (P=0.009, 0.024, and 0.011, respectively). CONCLUSIONS: Intraoperative dexmedetomidine administration reduced stress hormone release and maintained the balance of the autonomic nervous system. Dexmedetomidine could attenuate surgical stress response without untoward hemodynamic adverse events.

Hospital Discharge Disposition of Stroke Patients in Tennessee.

OBJECTIVES: Early determination of hospital discharge disposition status at an acute admission is extremely important for stroke management and the eventual outcomes of patients with stroke. We investigated the hospital discharge disposition of patients with stroke residing in Tennessee and developed a predictive tool for clinical adoption. Our investigational aims were to evaluate the association of selected patient characteristics with hospital discharge disposition status and predict such status at the time of an acute stroke admission. METHODS: We analyzed 127,581 records of patients with stroke hospitalized between 2010 and 2014. Logistic regression was used to generate odds ratios with 95% confidence intervals to examine the factor outcome association. An easy-to-use clinical predictive tool was built by using integer-based risk scores derived from coefficients of multivariable logistic regression. RESULTS: Among the 127,581 records of patients with stroke, 86,114 (67.5%) indicated home discharge and 41,467 (32.5%) corresponded to facility discharge. All considered patient characteristics had significant correlations with hospital discharge disposition status. Patients were at greater odds of being discharged to another facility if they were women; older; black; patients with a subarachnoid or intracerebral hemorrhage; those with the comorbidities of diabetes mellitus, heart disease, hypertension, chronic kidney disease, arrhythmia, or depression; those transferred from another hospital; or patients with Medicare as the primary payer. A predictive tool had a discriminatory capability with area under the curve estimates of 0.737 and 0.724 for derivation and validation cohorts, respectively. CONCLUSIONS: Our investigation revealed that the hospital discharge disposition pattern of patients with stroke in Tennessee was associated with the key patient characteristics of selected demographics, clinical indicators, and insurance status. These analyses resulted in the development of an easy-to-use predictive tool for early determination of hospital discharge disposition status.

Betahistine reduces postoperative nausea and vomiting after laparoscopic gynecological surgery.

BACKGROUND: Patients undergoing laparoscopic gynecological surgery are at high risk of postoperative nausea and vomiting (PONV). We compared the antiemetic efficacy of ondansetron plus betahistine with that of ondansetron alone in this patient population. METHODS: In this randomized, double-blinded study, 168 patients were randomly allocated to receive placebo (O group) or betahistine 18 mg (OB group) orally 3 hours before surgery and 24 hours thereafter. In both groups, ondansetron 4 mg was administered at the end of surgery and 8 mg were added to an intravenous patient-controlled analgesia (IV-PCA) fentanyl solution. The primary outcome was complete response (no PONV and no rescue antiemetics) during the first 48 hours after surgery. The severity of nausea, pain score, and adverse events were assessed. RESULTS: The incidence of complete response was significantly higher in OB group than in O group (69% vs. 46%, P=0.004). The severity of nausea was lower in OB group than in O group during 30 minutes to 6 hours and 6 to 24 hours after surgery (P=0.001 and P<0.001). Pain score was similar between the groups. The incidence of dizziness was lower in OB group than in O group (13% vs. 40%, P < 0.001). Six patients (7%) in OB group and 15 patients (18%) in O group required early IV-PCA discontinuation, primarily because of PONV and/or dizziness (P=0.038). CONCLUSIONS: Compared to ondansetron alone, ondansetron plus betahistine was more effective to prevent PONV and dizziness in high-risk patients undergoing laparoscopic gynecological surgery.

Positioning of double-lumen tubes based on the minimum peak inspiratory pressure difference between the right and left lungs in short patients: a prospective observational study.

BACKGROUND: Peak inspiratory pressures (PIPs) during one-lung ventilation (OLV) have served as a clinical marker that could indirectly verify the proper positioning of double-lumen tubes (DLTs). Patients of short stature are highly susceptible to initial DLT malpositioning. OBJECTIVES: We investigated the usefulness of positioning left-sided DLTs using minimum PIP differences between the right and left lungs by comparing with the previously used method of auscultation without fibreoptic bronchoscopy (FOB). We also evaluated the difference in PIPs between the two lungs during OLV after the DLT was ideally positioned with FOB examination. DESIGN: Prospective, observational study. SETTING: A university hospital. PATIENTS: One hundred and two female patients of short stature (≤160  cm). INTERVENTIONS: Verification of DLT position was conducted by three sequential steps: auscultation; minimising the difference in PIP during each OLV; and verifying the resulting position by FOB. MAIN OUTCOME MEASUREMENTS: Fibreoptic bronchoscopic view results of DLT position followed by the position adjustment using the minimum PIP difference method. RESULTS: Repositioning the DLT using the minimum PIP difference led to clinically successful positioning of the DLT in 88% of patients and a more ideal placement of the tube than auscultation alone (69.6 vs. 11.8%, P <0.001). Additionally, the ideal position of DLTs verified by FOB showed that PIP differences were zero or ±1  mmHg in 93% of patients. CONCLUSION: Positioning the DLT based on the minimum PIP difference between the right and left lungs as a supplementation to routine auscultation serves as an easy and reliable method for DLT positioning and may improve the accuracy of DLT positioning as an adjuvant to FOB in short patients. TRIAL REGISTRATION: Clinicaltrial.gov identifier: NCT01533012.

A comparison of high volume/low concentration and low volume/high concentration ropivacaine in caudal analgesia for pediatric orchiopexy.

BACKGROUND: It is unclear whether the volume or concentration of local anesthetic influences its spread and quality of caudal analgesia when the total drug dose is fixed. METHODS: We performed this study in a prospective, randomized, observer-blind manner. Children aged 1-5 yr received a constant dose of 2.25 mg/kg of ropivacaine prepared as either 1.0 mL/kg of 0.225% (low volume/high concentration [LVHC], n = 37) or 1.5 mL/kg of 0.15% solution (high volume/low concentration [HVLC], n = 36). Both solutions contained radiopaque dye. RESULTS: The median spread levels with ranges in the HVLC group (confirmed by fluoroscopic examination) were significantly higher (T6, T3-11) than in the LVHC group (T11, T8-L2). There were no significant differences in recovery times, postoperative pain scores, or side effects between the two groups. After discharge, fewer children in the HVLC group required rescue oral acetaminophen compared with the LVHC group (50.0% vs 75.7%). First oral acetaminophen time was found to be significantly longer with HVLC patients than LVHC patients (363.0 min vs 554.5 min). CONCLUSIONS: We confirmed (with fluoroscopy) that a caudal block with 1 mL/kg ropivacaine spreads to T11 and to T6 with 1.5 mL/kg. If the total dose is fixed, caudal analgesia with a larger volume of diluted ropivacaine (0.15%) provides better quality and longer duration after discharge than a smaller volume of more concentrated ropivacaine (0.225%) in children undergoing day-case orchiopexy. The spread level of ropivacaine correlated significantly with the first oral acetaminophen time after discharge.