Optimization of impedance-measured reflux events in GORD utilizing acid exposure time.

BACKGROUND: Combining impedance with pH monitoring improves the detection and characterization of gastro-oesophageal reflux (GOR), yet the two modalities frequently differ in GOR quantification. Ambulatory 24-h pH-impedance monitoring often reveals more significant oesophageal acid exposure than impedance-measured reflux activity in patients with symptomatic gastro-oesophageal reflux disease (GORD). The purpose of this study is to elucidate the discrepancies between these modalities by assessing the predictive accuracy of impedance compared to acid exposure standards. METHODS: A single-institution, retrospective review of sequential 24-h pH-impedance results of 72 patients with symptomatic GOR off anti-secretory therapy was conducted. Reflux events measured by impedance were stratified by patient position and compared to oesophageal acid exposure time (AET). Oesophageal AET limits for GORD detection were utilized as gold standards to generate serial receiver operator characteristics (ROC) curves to assess the sensitivity and specificity of current impedance GORD detection limits and identify optimized impedance standards based on area under the curve (AUC) analysis. RESULTS: Mean total AET time was 10.5% (± 9.9%), and 63.8% of patients had elevated AET. By impedance, median GOR frequency was 43 (IQR 21-68), and 22.2% exceeded conventional GOR frequency limits of normal. ROC curve analysis revealed the current impedance standard of > 73 GOR events has a sensitivity of 32.6% and specificity of 96.5% (AUC 0.74) for GORD detection. By AUC analysis, an impedance threshold of > 41 GOR events is optimal for GORD detection (sensitivity 69.6%, specificity 80.7%, AUC 0.83). CONCLUSION: Conventional impedance standards for abnormal GOR frequency are weakly sensitive for the detection of GORD, providing a possible explanation to discrepancies in AET and impedance interpretation. Lowering impedance-measured GOR frequency limits to > 41 optimizes sensitivity and specificity while increasing congruence between pH and impedance metrics.

Nkx2-5 Second Heart Field Target Gene Ccdc117 Regulates DNA Metabolism and Proliferation.

The cardiac transcription factor Nkx2-5 is essential for normal outflow tract (OFT) and right ventricle (RV) development. Nkx2-5-/- null mouse embryos display severe OFT and RV hypoplasia and a single ventricle phenotype due to decreased proliferation of Second Heart Field (SHF) cells, a pool of cardiac progenitors present in anterior pharyngeal arch mesoderm at mid-gestation. However, definition of the precise role of Nkx2-5 in facilitating SHF expansion is incomplete. We have found that Nkx2-5 positively and directly regulates a novel target gene, Ccdc117, in cells of the SHF at these stages. The nuclear/mitotic spindle associated protein Ccdc117 interacts with the MIP18/MMS19 cytoplasmic iron-sulfur (FeS) cluster assembly (CIA) complex, which transfers critical FeS clusters to several key enzymes with functions in DNA repair and replication. Loss of cellular Ccdc117 expression results in reduced proliferation rates associated with a delay at the G1-S transition, decreased rates of DNA synthesis, and unresolved DNA damage. These results implicate a novel role for Nkx2-5 in the regulation of cell cycle events in the developing heart, through Ccdc117's interaction with elements of the CIA pathway and the facilitation of DNA replication during SHF expansion.

Effect of Multimodal Analgesia on Opioid Use After Open Ventral Hernia Repair.

BACKGROUND: There is limited data on enhanced recovery after surgery (ERAS) protocols after ventral hernia repair (VHR). This study reports the impact of multimodal analgesia on opioid use after open VHR. METHODS: Retrospective review of open VHR treated during the initial 6 months after ERAS implementation. Protocol focused on opioid sparing using intraoperative ketamine and/or lidocaine infusion, selective epidural anesthesia, and postoperative ketamine infusion, ketorolac, and acetaminophen. Four groups were analyzed: 1-ERAS protocol with epidural analgesia, 2-historical controls with epidural analgesia prior to ERAS, 3-ERAS protocol without epidural, and 4-historical controls without epidural analgesia, prior to ERAS. Continuous variables were analyzed using ANOVA or Kruskal-Wallis tests, and subgroup analysis using Student's t test or Mann-Whitney U test. Discrete variables were analyzed using Pearson's chi-square test or Fisher's exact test. RESULTS: Patients differed in hernia width, but were similar in comorbidity and operative technique. There was no difference in length of stay or readmission. Use of ERAS nearly eliminated patient-controlled analgesia use (group 1, 2.7%; group 2, 68.4%; group 3, 0%; group 4, 65.7%; p < 0.001). ERAS significantly reduced narcotic requirements on postoperative days 0, 1, and 2 (p < 0.001). To account for the bias of selective epidural analgesia, groups 1 and 2 (epidural) and groups 3 and 4 (no epidural) were compared separately. Opioid requirement and PCA use remained significantly lower in patients in the ERAS pathway. CONCLUSION: Implementation of multimodal analgesia in the perioperative and postoperative setting significantly reduced opioid use after VHR.

Placental Nkx2-5 and target gene expression in early-onset and severe preeclampsia.

OBJECTIVE: Preeclampsia (PE) affects 2-8% of pregnancies worldwide and is a significant source of maternal and neonatal morbidity and mortality. However, the mechanisms underlying PE are poorly understood and major questions regarding etiology and risk factors remain to be addressed. Our objective was to examine whether abnormal expression of the cardiovascular developmental transcription factor, Nkx2-5, was associated with early onset and severe preeclampsia (EOSPE). METHODS: Using qPCR and immunohistochemical assay, we examined expression of Nkx2-5 and target gene expression in EOSPE and control placental tissue. We tested resulting mechanistic hypotheses in cultured cells using shRNA knockdown, qPCR, and western blot. RESULTS: Nkx2-5 is highly expressed in racially disparate fashion (Caucasians > African Americans) in a subset of early EOSPE placentae. Nkx2-5 mRNA expression is highly correlated (Caucasians > African Americans) to mRNA expression of the preeclampsia marker sFlt-1, and of the Nkx2-5 target and RNA splicing factor, Sam68. Knockdown of Sam68 expression in cultured cells significantly impacts sFlt-1 mRNA isoform generation in vitro, supporting a mechanistic hypothesis that Nkx2-5 impacts EOSPE severity in a subset of patients via upregulation of Sam68 to increase sFlt-1 expression. Expression of additional Nkx2-5 targets potentially regulating metabolic stress response is also elevated in a racially disparate fashion in EOSPE. CONCLUSIONS: Expression of Nkx2-5 and its target genes may directly influence the genesis and racially disparate severity, and define a mechanistically distinct subclass of EOSPE.

Coupling light into few-mode optical fibres I: The diffraction limit.

Multimode fibres are widely used in astronomy because of the ease of coupling light into them at a telescope focus. The photonics industry has given rise to a broad range of products but these are almost exclusively restricted to single-mode fibres, although some can be adapted for use in fibres that allow several modes to propagate. Now that astronomical telescopes are moving toward diffraction-limited performance through the use of adaptive optics (AO), we address the problem of coupling light into a few-mode fibre (FMF). We find that fibres with as few as ~5 guided modes share important characterisitcs with multimode fibres, in particular high coupling efficiency.We anticipate that future astronomical instruments at an AO-corrected focus will be able to exploit a broad class of photonic devices.