Ineffective esophageal motility is associated with diabetes mellitus end organ complications.

BACKGROUND: Diabetes Mellitus (DM) is known to induce a wide range of harmful effects on several organs, notably leading to ineffective esophageal motility (IEM). However, the relationship between DM and IEM is not fully elucidated. We aimed to determine the relationship between DM and IEM and to evaluate the impact of DM's end organ complications on IEM severity. METHODS: A multicenter cohort study of consecutive patients undergoing high-resolution esophageal manometry (HREM) was performed. We reviewed medical records of patients diagnosed with IEM using HREM, encompassing data on demographics, DM history, antidiabetic and other medications as well as comorbidities. KEY RESULTS: Two hundred and forty six subjects met the inclusion criteria. There was no significant difference in any of the HREM parameters between diabetics and nondiabetics. Out of 246 patients, 92 were diabetics. Diabetics with neuropathy presented a significantly lower distal contractile integral (DCI) value compared to those without neuropathy (248.2 ± 226.7 mmHg·cm·sec vs. 375.6 ± 232.4 mmHg·cm·sec; p = 0.02) Similarly, the DCI was lower in diabetics with retinopathy compared to those without retinopathy (199.9 ± 123.1 mmHg·cm·sec vs. 335.4 ± 251.7 mmHg·cm·sec; p = 0.041). Additionally, a significant difference was observed in DCI values among DM patients with ≥2 comorbidities compared to those without comorbidities (224.8 ± 161.0 mmHg·cm·sec vs. 394.2 ± 243.6 mmHg·cm·sec; p = 0.025). Around 12.6% of the variation in DCI could be explained by its linear relationship with hemoglobin A1c (HbA1c), with a regression coefficient (ß) of -55.3. CONCLUSION & INFERENCES: DM is significantly associated with IEM in patients with neuropathy, retinopathy, or multiple comorbidities. These results are pivotal for tailoring patient-specific management approaches.

Clinical Predictors of a Positive Ct Angiogram Study Used for the Evaluation of Acute Gastrointestinal Hemorrhage.

BACKGROUND: Acute gastrointestinal (GI) bleeding is one of the leading causes of emergency department visits and hospital admissions. CT angiography (CTA) has had an expanding role in the evaluation of acute GI bleeding because it is rapidly performed, widely available, reasonably sensitive and provides precise localization when positive. We attempted to identify patient and clinical characteristics that predict CTA results in order to help guide the utilization of this modality in patients with acute GI bleeding. METHODS: In this retrospective study, we analyzed all CTAs performed for the evaluation of GI bleeding in the Duke University healthcare system between October 2019 and March 2020. We captured patient characteristics including age, sex, vital signs, hemoglobin, platelets, PT/INR, and anticoagulation status. Study indications were grouped by suspected source of bleeding: upper GI bleeding (hematemesis or coffee-ground emesis) vs small bowel bleeding (melena or "dark stools") vs lower GI bleeding (hematochezia or bright red blood per rectum (BRBPR)). Chi-square, Wilcoxon, t test, and multivariate logistic regression were used to describe and assess the relationship between patient characteristics and study outcomes (Table 1). Table 1 Univariate analysis of patient characteristics by CT angiography outcome Patient Characteristics by Positive CT for GI Bleed No (N = 274) Yes (N = 43) Total (N = 317) p value Gender 0.451  Female 138 (50.4%) 19 (44.2%) 157 (49.5%)  Male 136 (49.6%) 24 (55.8%) 160 (50.5%) Age, median (Q1,Q3) 65 (51,75) 70 (62,80) 66 (52, 76) < 0.012 Heart rate, median (Q1,Q3) 86 (74,100) 89 (72,98) 86 (74, 99) 0.782 MAP, mean (SD) 87.32 (15.52) 81.72 (16.53) 86.56 0.033 Shock index, median (Q1,Q3) 0.70 (0.58, 0.85) 0.78 (0.55, 1.00) 0.71 (0.58, 0.85) 0.352 Hemoglobin 0.332  N 273 43 316  Median (Q1, Q3) 8.50 (6.90, 11.00) 7.70 (6.50, 11.30) 8.45 (6.90, 11.00) Baseline hemoglobin 0.202  N 258 39 297  Median (Q1, Q3) 11.20 (9.40, 13.00) 12.00 (9.40, 14.00) 11.20 (9.40, 13.00) Hemoglobin drop from baseline 0.062  N 258 39 297  Median (Q1, Q3) 2.10 (0.60, 3.70) 2.70 (1.20, 4.80) 2.20 (0.70, 3.80) Platelets, median (Q1, Q3) 219.5 (141, 301) 183 (139, 246) 217 (139, 282) 0.102 INR 0.272  N 263 42 305  Median (Q1, Q3) 1.10 (1.00, 1.30) 1.20 (1.00, 1.30) 1.10 (1.00, 1.30) Anticoagulation 0.131  No 155 (56.6%) 19 (44.2%) 174 (54.9%)  Yes 119 (43.4%) 24 (55.8%) 143 (45.1%) Upper GI bleeding 0.401  No 251 (91.6%) 41 (95.3%) 292 (92.1%)  Yes 23 (8.4%) 2 (4.7%) 25 (7.9%) Small Bowel bleeding 0.761  No 216 (78.8%) 33 (76.7%) 249 (78.5%)  Yes 58 (21.2%) 10 (23.3%) 68 (21.5%) Lower GI bleeding 0.091  No 134 (48.9%) 15 (34.9%) 149 (47.0%)  Yes 140 (51.1%) 28 (65.1%) 168 (53.0%) 1Chi-Square 2Wilcoxon 3Equal Variance T-Test RESULTS: A total of 317 patients underwent CTA between October 2019 and March 2020. Forty-three patients (13.6%) had a CTA positive for active bleeding. Multivariable logistic regression showed that after controlling for age, mean arterial pressure (MAP) and indication, only a hemoglobin drop from baseline was significantly associated with a positive CTA. For each 1 g / dL drop in hemoglobin from the patient's baseline, the odds of a positive CT increased by 1.17 (OR 1.17 95% CI 1.00 - 1.36, p = 0.04). Age (OR 1.02 95% CI 0.99 - 1.04, p = 0.06) and hematochezia / BRBPR (OR 2.09 95% CI 0.94-4.64, p = 0.07) approached statistical significance. CONCLUSIONS: In patients who present to the hospital with GI bleeding, CTA can be a helpful triage tool that is most helpful in older patients with suspected lower GI bleeding with a drop in hemoglobin from baseline. Other clinical factors including MAP and the use of anticoagulants were not predictive of a positive CTA.

The Clinical Utility of Provocative Maneuvers at Esophageal High-resolution Manometry (HRM).

Esophageal high-resolution manometry (HRM) assesses esophageal motor function and is indicated both for evaluation of esophageal symptoms and before antireflux interventions. HRM studies are interpreted and esophageal motor diagnoses made according to the Chicago Classification, version 3.0 algorithm, which is based on ten 5 mL supine water swallows. However, this practice of single liquid swallows performed in the supine position does not reflect typical "real-life" swallowing, and may not reproduce the patient's presenting symptoms. Therefore, provocative maneuvers at HRM-beyond these 10 standard swallows-can afford additional insights into esophageal motor function with clinically significant implications, and represent areas of exciting investigation and innovation. Accordingly, the 2020 American College of Gastroenterology Guidelines on Esophageal Physiologic Testing conditionally recommend their inclusion in the HRM protocol. In this clinical review, we discuss the supporting data for and clinical utility of provocative maneuvers at HRM that include changes in body position or accessories (upright swallows, "bridge" position, straight leg raise, abdominal compression), bolus consistency (solid swallows, test meals, postprandial high-resolution impedance manometry), bolus frequency (multiple rapid swallows), the volume of bolus (rapid drink challenge/multiple water swallows), and the use of pharmacological agents.

Esophageal contractile segment impedance from high-resolution impedance manometry correlates with mean nocturnal baseline impedance and acid exposure time from 24-hour pH-impedance monitoring.

Esophageal baseline impedance (BI) acquired during esophageal contraction (contractile segment impedance [CSI]) is proposed to improve BI accuracy in gastroesophageal reflux disease (GERD). We evaluated associations between CSI and conventional and novel GERD metrics. We analyzed high-resolution impedance manometry (HRIM) and ambulatory pH-impedance studies from 51 patients (58.6 ± 1.5 years; 26% F) with GERD symptoms studied off antisecretory therapy. Patients with achalasia or absent contractility were excluded. CSI (averaged across 10 swallows) and BI-HRIM (from the resting landmark phase) were acquired from the distal impedance sensors (distal sensor and 5 cm above the lower esophageal sphincter). Acid exposure time (AET) and mean nocturnal baseline impedance (MNBI) were calculated. Associations between CSI, BI-HRIM, MNBI, and AET were evaluated using correlation (Pearson) and receiver operating characteristic (ROC) analysis. Presenting symptoms included heartburn (67%), regurgitation (12%), cough (12%), and chest pain (10%). CSI-distal and CSI-5 each correlated with BI-HRIM, AET, and distal MNBI. Associations with AET were numerically stronger for CSI-distal (r = -0.46) and BI-HRIM-distal (r = -0.44) than CSI-5 (r = -0.33), BI-HRIM-5 (r = -0.28), or distal MNBI (r < -0.36). When compared to AET <4%, patients with AET >6% had significantly lower CSI-distal and BI-HRIM-distal values but not CSI-5, BI-HRIM-5, or MNBI. ROC areas under the curve for AET >6% were numerically higher for CSI-distal (0.81) than BI-HRIM-distal (0.77), distal MNBI (0.68-0.75), CSI-5 (0.68), or BI-HRIM-5 (0.68). CSI from HRIM studies inversely correlates with pathologic AET and has potential to augment the evaluation of GERD.

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.

Esophageal Baseline Impedance From High-resolution Impedance Manometry Correlates With Mean Nocturnal Baseline Impedance From pH-impedance Monitoring.

Background/Aims: Esophageal baseline impedance (BI) can be extracted from pH-impedance tracings as mean nocturnal baseline impedance (MNBI), and from high-resolution impedance manometry (HRIM), but it is unknown if values are similar between acquisition methods across HRIM manufacturers. We aim to assess correlations between MNBI and BI from HRIM (BI-HRIM) from 2 HRIM manufacturers in the setting of physiologic acid exposure time (AET). Methods: HRIM and pH-impedance monitoring demonstrating physiologic AET (< 4%) off proton pump inhibitors were required. BI-HRIM was extracted as the average from 5 cm and 10 cm above the lower esophageal sphincter. Distal BI-HRIM (DBI-HRIM) was also extracted from the most distal channel (Medtronic studies). MNBI was extracted from 6 channels. Concordance between BI-HRIM across manufacturers with MNBI was analyzed. Results: Thirty-six patients met the inclusion criteria (59.6 ± 1.7 years; 22% female; body mass index 30.5 ± 0.7; AET 1.6 ± 0.2%). Although MNBI was similar at all channels (P ≥ 0.18), Diversatek BI-HRIM was lower than Medtronic BI-HRIM (P = 0.003). Overall, BI-HRIM correlated with MNBI at corresponding recording sites, 7 cm and 9 cm (P < 0.05), but not at other sites (P ≥ 0.19). Pearson's correlations > 0.5 were seen at MNBI at 7 cm for both systems, and at 9 cm for Medtronic. DBI-HRIM correlated with MNBI at 3 cm and 5 cm (P < 0.03), but not at other locations (P > 0.1). Conclusions: While numeric differences exist between manufacturers, BI-HRIM correlates with MNBI from corresponding channels in patients with physiologic AET. Comparison with AET elevation is needed to determine correlations between pathologic MNBI with BI-HRIM across manufacturers. The optimal HRIM channels from which BI values should be extracted also warrants further study.

Initial axon growth rate from embryonic sensory neurons is correlated with birth date.

Axon growth rate from different populations of sensory neurons is correlated with the distance they have to grow to reach their targets in development: neurons with more distant targets extend axons at intrinsically faster rates. With growth of the embryo, later-born neurons within each population have further to extend their axons to reach their targets than early-born neurons. Here we examined whether the axon growth rate is related to birth date by studying the axon growth from neurons that differentiate in vitro from precursor cells isolated throughout the period of neurogenesis. We first showed that neurons that differentiated in vitro from different precursor cell populations exhibited differences in axon growth rate related to in vivo target distance. We then examined the axon growth rate from neurons that differentiate from the same precursor population at different stages throughout the period of neurogenesis. We studied the epibranchial placode precursors that give rise to nodose ganglion neurons in the chicken embryo. We observed a highly significant, threefold difference in axon growth rate from neurons that differentiate from precursor cells cultured early and late during the period of neurogenesis. Our findings suggest that intrinsic differences in axon growth rate are correlated with the neuronal birth date.

The Utility of Esophageal Motility Testing in Gastroesophageal Reflux Disease (GERD).

PURPOSE OF REVIEW: Here, we discuss how esophageal motor testing plays important roles in patients with suspected gastroesophageal reflux disease (GERD). In addition to guiding appropriate placement of catheters for ambulatory reflux monitoring, esophageal high-resolution manometry (HRM) rules out confounding diagnoses, such as achalasia spectrum disorders, that can present with symptoms similar to that of GERD, but are managed very differently. RECENT FINDINGS: HRM performed with impedance in the post-prandial setting (PP-HRIM) can assess for rumination syndrome or supragastric belching, which should be directed towards behavioral interventions. The recent GERD Classification of Motor Function recommends a hierarchical approach, focusing on (1) the esophagogastric junction (EGJ), (2) the esophageal body, and (3) esophageal contraction reserve, which can be assessed with provocative maneuvers at HRM, such as multiple rapid swallows (MRS). This approach can inform the appropriate tailoring of antireflux surgery. Novel esophageal motility metrics, such as the EGJ-contractile integral from HRM, or post-reflux swallow-induced peristaltic wave indices from 24-h pH-impedance monitoring, may also assist with GERD diagnosis. Assessment of esophageal motor function can contribute in a significant manner to the care of patients with suspected GERD, particularly when esophageal symptoms do not improve with antisecretory therapy, and/or when surgical or endoscopic antireflux therapies are under consideration.

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.

Runners greatly underestimate sweat losses before and after a 1-hr summer run.

The purpose of this study was to determine how accurately runners estimate their sweat losses. Male (n = 19) and female (n = 20) runners (41 ± 10 yr, VO2max 57 ± 9 ml · kg(-1) · min(-1) from the southeastern U.S. completed an ~1-hr run during late summer on a challenging outdoor road course (wet bulb globe temperature 24.1 ± 1.5 °C). Runs began at ~6:45 a.m. or p.m. Before and after running, participants filled race-aid-station paper cups with a volume of fluid they felt would be equivalent to their sweat losses. Total sweat losses and losses by percent body weight differed (p < .01) between men (1,797 ± 449 ml, 2.3% ± 0.6%) and women (1,155 ± 258 ml, 1.9% ± 0.4%). Postrun estimates (738 ± 470 ml) were lower (p < .001) than sweat losses (1,468 ± 484 ml), equaling underestimations of 50% ± 23%, with no differences in estimation accuracy by percentage between genders. Runners who reported measuring changes in pre- and postrun weight to assess sweat losses within the previous month (n = 9, -54% ± 18%) were no more accurate (p = .55) than runners who had not (n = 30, -48% ± 24%). These results suggest that inadequate fluid intake during runs or between runs may stem from underestimations of sweat losses and that runners who do assess sweat-loss changes may be making sweat-loss calculation errors or do not accurately translate changes in body weight to physical volumes of water.

Risk factors for increased BTEX exposure in four Australian cities.

Benzene, toluene, ethylbenzene and xylenes (BTEX) are common volatile organic compounds (VOCs) found in urban airsheds. Elevated levels of VOCs have been reported in many airsheds at many locations, particularly those associated with industrial activity, wood heater use and heavy traffic. Exposure to some VOCs has been associated with health risks. There have been limited investigations into community exposures to BTEX using personal monitoring to elucidate the concentrations to which members of the community may be exposed and the main contributors to that exposure. In this cross sectional study we investigated BTEX exposure of 204 non-smoking, non-occupationally exposed people from four Australian cities. Each participant wore a passive BTEX sampler over 24h on five consecutive days in both winter and summer and completed an exposure source questionnaire for each season and a diary for each day of monitoring. The geometric mean (GM) and range of daily BTEX concentrations recorded for the study population were benzene 0.80 (0.04-23.8 ppb); toluene 2.83 (0.03-2120 ppb); ethylbenzene 0.49 (0.03-119 ppb); and xylenes 2.36 (0.04-697 ppb). A generalised linear model was used to investigate significant risk factors for increased BTEX exposure. Activities and locations found to increase personal exposure included vehicle repair and machinery use, refuelling of motor vehicles, being in an enclosed car park and time spent undertaking arts and crafts. A highly significant difference was found between the mean exposures in each of the four cities, which may be explained by differences in fuel composition, differences in the mix and density of industry, density of motor vehicles and air pollution meteorology.

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.