Delirium is associated with loss of feedback cortical connectivity.

INTRODUCTION: Post-operative delirium (POD) is associated with increased morbidity and mortality but is bereft of treatments, largely due to our limited understanding of the underlying pathophysiology. We hypothesized that delirium reflects a disturbance in cortical connectivity that leads to altered predictions of the sensory environment. METHODS: High-density electroencephalogram recordings during an oddball auditory roving paradigm were collected from 131 patients. Dynamic causal modeling (DCM) analysis facilitated inference about the neuronal connectivity and inhibition-excitation dynamics underlying auditory-evoked responses. RESULTS: Mismatch negativity amplitudes were smaller in patients with POD. DCM showed that delirium was associated with decreased left-sided superior temporal gyrus (l-STG) to auditory cortex feedback connectivity. Feedback connectivity also negatively correlated with delirium severity and systemic inflammation. Increased inhibition of l-STG, with consequent decreases in feed-forward and feed-back connectivity, occurred for oddball tones during delirium. DISCUSSION: Delirium is associated with decreased feedback cortical connectivity, possibly resulting from increased intrinsic inhibitory tone. HIGHLIGHTS: Mismatch negativity amplitude was reduced in patients with delirium. Patients with postoperative delirium had increased feedforward connectivity before surgery. Feedback connectivity was diminished from left-side superior temporal gyrus to left primary auditory sensory area during delirium. Feedback connectivity inversely correlated with inflammation and delirium severity.

Optimizing the Utility of Anorectal Manometry for Diagnosis and Therapy: A Roundtable Review and Recommendations.

BACKGROUND & AIMS: Anorectal manometry (ARM) is a comprehensive diagnostic tool for evaluating patients with constipation, fecal incontinence, or anorectal pain; however, it is not widely utilized for reasons that remain unclear. The aim of this roundtable discussion was to critically examine the current clinical practices of ARM and biofeedback therapy by physicians and surgeons in both academic and community settings. METHODS: Leaders in medical and surgical gastroenterology and physical therapy with interest in anorectal disorders were surveyed regarding practice patterns and utilization of these technologies. Subsequently, a roundtable was held to discuss survey results, explore current diagnostic and therapeutic challenges with these technologies, review the literature, and generate consensus-based recommendations. RESULTS: ARM identifies key pathophysiological abnormalities such as dyssynergic defecation, anal sphincter weakness, or rectal sensory dysfunction, and is a critical component of biofeedback therapy, an evidence-based treatment for patients with dyssynergic defecation and fecal incontinence. Additionally, ARM has the potential to enhance health-related quality of life and reduce healthcare costs. However, it has significant barriers that include a lack of education and training of healthcare providers regarding the utility and availability of ARM and biofeedback procedures, as well as challenges with condition-specific testing protocols and interpretation. Additional barriers include understanding when to perform, where to refer, and how to use these technologies, and confusion over billing practices. CONCLUSIONS: Overcoming these challenges with appropriate education, training, collaborative research, and evidence-based guidelines for ARM testing and biofeedback therapy could significantly enhance patient care of anorectal disorders.

Tolerability and Feasibility of the Upper Esophageal Sphincter Assist Device in Preventing Acute and Chronic Allograft Rejection Among Lung Transplant Recipients.

GOALS: We aimed to evaluate a novel upper esophageal sphincter (UES) assist device loaner program for the prevention of acute cellular rejection and chronic lung allograft dysfunction among lung transplant (LTx) recipients. BACKGROUND: Laryngopharyngeal reflux can lead to chronic microaspiration and LTx rejection. The UES assist device applies external pressure at the level of UES to decrease reflux. STUDY: We prospectively enrolled and issued UES assist devices to consecutive transplant patients referred for gastrointestinal motility testing from 2016 to 2020. Device tolerability was defined by successful utilization as a bridge to ambulatory pH monitoring and/or antireflux procedure, or as permanent therapy. Incidence of rejection was analyzed before, during, and after device implementation. RESULTS: Twenty-six participants were issued devices (15 pathologic, 5 physiological, 6 unknown reflux status), none of whom developed acute rejection episodes or chronic lung allograft dysfunction while using the device. Thirteen adopted the device promptly after transplantation (mean 1.7 mo) and remained free of rejection episodes over a mean 24.7 months of follow-up. Among those with pathologic reflux, lag time to device adoption strongly correlated with the development of rejection ( r =0.8, P =0.0006). There was no such correlation among those with physiological reflux. Five developed acute rejection after device return. CONCLUSIONS: The device was tolerated by a majority of LTx patients and appears feasible as a barrier measure in the prevention of rejection. Delayed treatment of laryngopharyngeal reflux may lead to early allograft failure; therefore, the UES assist device should be given important consideration in transplant protection.

Prospective analysis of plasma amyloid beta and postoperative delirium in the Interventions for Postoperative Delirium: Biomarker-3 study.

BACKGROUND: The effect of postoperative delirium on the amyloid cascade of Alzheimer's dementia is poorly understood. Using early postoperative plasma biomarkers, we explored whether surgery and delirium are associated with changes in amyloid pathways. METHODS: We analysed data from 100 participants in the Interventions for Postoperative Delirium: Biomarker-3 (IPOD-B3) cohort study in the USA (NCT03124303 and NCT01980511), which recruited participants aged >65 yr undergoing non-intracranial surgery. We assessed the relationship between the change in plasma amyloid beta ratio (AßR; Aß42:Aß40) and delirium incidence (defined by the 3-Minute Diagnostic Confusion Assessment Method) and severity (quantified by the Delirium Rating Scale-Revised-98, the study's primary outcome). We also tested the relationship between plasma amyloid beta and intraoperative variables. RESULTS: Across all participants, the plasma AßR increased from the preoperative period to postoperative Day 1 (Wilcoxon P<0.001). However, this increase was not associated with delirium incidence (Wilcoxon P=0.22) or peak severity after adjusting for confounders (log[incidence rate ratio]=0.43; P=0.14). Postoperative Day 1 change in plasma AßR was not associated with postoperative Day 1 change in plasma tau, neurofilament light, or inflammatory markers (interleukin [IL]-1ß, IL-1Ra, IL-2, IL-4, IL-6, IL-8, IL-10, and IL-12), or with operative time or low intraoperative arterial pressure. CONCLUSIONS: Perioperative changes in plasma amyloid do not appear to be associated with postoperative delirium. Our findings do not support associations of dynamic changes in amyloid with postoperative delirium. CLINICAL TRIAL REGISTRATION: .NCT03124303 and NCT01980511.

Resolution of elevated interleukin-6 after surgery is associated with return of normal cognitive function.

BACKGROUND: Unresolved surgical inflammation might induce chronic cognitive decline in older adults. Although inflammatory biomarkers have been correlated with perioperative cognitive impairment and delirium, the effects of prolonged inflammation on cognition are not well studied. This prospective cohort study investigated 1-yr dynamics in plasma interleukin-6 levels and executive function. METHODS: Patients undergoing major surgery (n=170) aged ≥65 yr completed Trail Making Test B and other neuropsychological assessments with plasma interleukin-6 levels collected on postoperative days 1-9 and 90, and at 1-yr. Mixed-effects analyses were conducted for Trail Making Test B (and other assessments), including interleukin-6 levels, time, and additional confounders (fixed effects), and a random effect for participant. RESULTS: Changes in interleukin-6 levels were associated with changes in Trail Making Test B over 1 yr in a generalised additive model (ß=0.074, P<0.001) supporting that unresolved inflammation impaired executive function. This result was robust to confounders, outlier rejection, and fitting to non-linear models. Changes in interleukin-6 levels also correlated with changes in Trail Making Test A and Controlled Oral Word Association Test. Sensitivity analyses conducted on binary definitions of cognitive decline (>1, >1.5, or >2 standard deviations from baseline) were also associated with interleukin-6 changes. CONCLUSIONS: Delayed resolution of inflammation is associated with cognitive impairment after surgery. Monitoring interleukin-6 might provide an opportunity to intervene with anti-inflammatory therapies in vulnerable patients. CLINICAL TRIAL REGISTRATION: NCT01980511, NCT03124303.

Sevoflurane dose and postoperative delirium: a prospective cohort analysis.

BACKGROUND: Recent trials are conflicting as to whether titration of anaesthetic dose using electroencephalography monitoring reduces postoperative delirium. Titration to anaesthetic dose itself might yield clearer conclusions. We analysed our observational cohort to clarify both dose ranges for trials of anaesthetic dose and biological plausibility of anaesthetic dose influencing delirium. METHODS: We analysed the use of sevoflurane in an ongoing prospective cohort of non-intracranial surgery. Of 167 participants, 118 received sevoflurane and were aged >65 yr. We tested associations between age-adjusted median sevoflurane (AMS) minimum alveolar concentration fraction or area under the sevoflurane time×dose curve (AUC-S) and delirium severity (Delirium Rating Scale-98). Delirium incidence was measured with 3-minute Diagnostic Confusion Assessment Method (3D-CAM) or CAM-ICU. Associations with previously identified delirium biomarkers (interleukin-8, neurofilament light, total tau, or S100B) were tested. RESULTS: Delirium severity did not correlate with AMS (Spearman's ρ=-0.014, P=0.89) or AUC-S (ρ=0.093, P=0.35), nor did delirium incidence (AMS Wilcoxon P=0.86, AUC-S P=0.78). Further sensitivity analyses including propofol dose also demonstrated no relationship. Linear regression confirmed no association for AMS in unadjusted (log (IRR)=-0.06 P=0.645) or adjusted models (log (IRR)=-0.0454, P=0.735). No association was observed for AUC-S in unadjusted (log (IRR)=0.00, P=0.054) or adjusted models (log (IRR)=0.00, P=0.832). No association of anaesthetic dose with delirium biomarkers was identified (P>0.05). CONCLUSION: Sevoflurane dose was not associated with delirium severity or incidence. Other biological mechanisms of delirium, such as inflammation and neuronal injury, appear more plausible than dose of sevoflurane. CLINICAL TRIAL REGISTRATION: NCT03124303, NCT01980511.

Perioperative ischaemic brain injury and plasma neurofilament light: a secondary analysis of two prospective cohort studies.

BACKGROUND: Ischaemic brain infarction can occur without acute neurological symptoms (covert strokes) or with symptoms (overt strokes), both associated with poor health outcomes. We conducted a pilot study of the incidence of preoperative and postoperative (intraoperative or postoperative) covert strokes, and explored the relationship of postoperative ischaemic brain injury to blood levels of neurofilament light, a biomarker of neuronal damage. METHODS: We analysed 101 preoperative (within 2 weeks of surgery) and 58 postoperative research MRIs on postoperative days 2-9 from two prospective cohorts collected at the University of Wisconsin (NCT01980511 and NCT03124303). Participants were aged >65 yr and undergoing non-intracranial, non-carotid surgery. RESULTS: Preoperative covert stroke was identified in 2/101 participants (2%; Bayesian 95% confidence interval [CI], 0.2-5.4). This rate was statistically different from the postoperative ischaemic brain injury rate of 7/58 (12%, 4.9-21.3%; P=0.01) based on postoperative imaging. However, in a smaller group of participants with paired imaging (n=30), we did not identify the same effect (P=0.67). Patients with postoperative brain injury had elevated peak neurofilament light levels (median [inter-quartile range], 2.34 [2.24-2.64] log10 pg ml-1) compared with those without (1.86 [1.48-2.21] log10 pg ml-1; P=0.025). Delirium severity scores were higher in those with postoperative brain injury (19 [17-21]) compared with those without (7 [4-12]; P=0.01). CONCLUSION: Although limited by a small sample size, these data suggest that preoperative covert stroke occurs more commonly than previously anticipated. Plasma neurofilament light is a potential screening biomarker for postoperative ischaemic brain injury.

Weight loss outcomes are not compromised in bariatric patients using cannabis.

BACKGROUND: The legalization of cannabis in several states has led to increased documented use in the population. Bariatric surgery patients are no exception with estimates of anywhere from 6 to 8%. Cannabis is known to be associated with increased appetite, mood disorders, hyperphagia, and rarely, hyperemesis, which can potentially affect post-surgical weight loss. We aim to study the differences in bariatric surgery outcomes between cannabis users and non-users. METHODS: A retrospective review identified patients undergoing bariatric surgery. Patients were divided into two groups, cannabis users (CU) and non-cannabis users (non-CU). Cannabis users (defined as using at least once weekly) and a group of non-users were called to obtain additional information. Primary outcome was weight loss. Secondary outcomes included incidence of post-operative nausea and vomiting (PONV), length of stay (LOS), readmission, and need for additional intervention. RESULTS: A cohort of 364 sleeve gastrectomy patients met inclusion criteria, 31 (8.5%) CU and 333 (91.5%) non-CU. There was no difference in EWL between CU and non-CU at 1 week, 1 month, 3 months, 6 months, 9 months, 1 year, and 2 years. However, the CU group trended towards greater EWL at 3 years (52.9% vs. 38.1%, p = 0.094) and at 5 years (49.8% vs. 32.7%, p = 0.068). There were no significant differences between CU and non-CU with respect to either incidence or severity of PONV at one year after surgery or longer follow-up. CONCLUSION: Cannabis users did not experience inferior weight loss after bariatric surgery despite common assumptions that appetite stimulation can lead to suboptimal weight loss outcomes. Our findings add to other work challenging this dogma. Larger, long-term, multicenter studies are warranted.

Postoperative delirium and changes in the blood-brain barrier, neuroinflammation, and cerebrospinal fluid lactate: a prospective cohort study.

BACKGROUND: Case-control studies have associated delirium with blood-brain barrier (BBB) permeability. However, this approach cannot determine whether delirium is attributable to high pre-existing permeability or to perioperative changes. We tested whether perioperative changes in cerebrospinal fluid/plasma albumin ratio (CPAR) and plasma S100B were associated with delirium severity. METHODS: Participants were recruited to two prospective cohort studies of non-intracranial surgery (NCT01980511, NCT03124303, and NCT02926417). Delirium severity was assessed using the Delirium Rating Scale-98. Delirium incidence was diagnosed with the 3D-Confusion Assessment Method (3D-CAM) or CAM-ICU (CAM for the ICU). CSF samples from 25 patients and plasma from 78 patients were analysed for albumin and S100B. We tested associations between change in CPAR (n=11) and S100B (n=61) and delirium, blood loss, CSF interleukin-6 (IL-6), and CSF lactate. RESULTS: The perioperative increase in CPAR and S100B correlated with delirium severity (CPAR ρ=0.78, P=0.01; S100B ρ=0.41, P<0.001), delirium incidence (CPAR P=0.012; S100B P<0.001) and CSF IL-6 (CPAR ρ=0.66 P=0.04; S100B ρ=0.75, P=0.025). Linear mixed-effect analysis also showed that decreased levels of S100B predicted recovery from delirium symptoms (P=0.001). Linear regression demonstrated that change in plasma S100B was independently associated with surgical risk, cardiovascular surgery, blood loss, and hypotension. Blood loss also correlated with CPAR (ρ=0.64, P=0.04), S100B (ρ=0.70, P<0.001), CSF lactate (R=0.81, P=0.01), and peak delirium severity (ρ=0.36, P=0.01). CONCLUSION: Postoperative delirium is associated with a breakdown in the BBB. This increased permeability is dynamic and associated with a neuroinflammatory and lactate response. Strategies to mitigate blood loss may protect the BBB.

Relationships between preoperative cortical thickness, postoperative electroencephalogram slowing, and postoperative delirium.

BACKGROUND: It is unclear how preoperative neurodegeneration and postoperative changes in EEG delta power relate to postoperative delirium severity. We sought to understand the relative relationships between neurodegeneration and delta power as predictors of delirium severity. METHODS: We undertook a prospective cohort study of high-risk surgical patients (>65 yr old) to identify predictors of peak delirium severity (Delirium Rating Scale-98) with twice-daily delirium assessments (NCT03124303). Participants (n=86) underwent preoperative MRI; 54 had both an MRI and a postoperative EEG. Cortical thickness was calculated from the MRI and delta power from the EEG. RESULTS: In a linear regression model, the interaction between delirium status and preoperative mean cortical thickness (suggesting neurodegeneration) across the entire cortex was a significant predictor of delirium severity (P<0.001) when adjusting for age, sex, and performance on preoperative Trail Making Test B. Next, we included postoperative delta power and repeated the analysis (n=54). Again, the interaction between mean cortical thickness and delirium was associated with delirium severity (P=0.028), as was postoperative delta power (P<0.001). When analysed across the Desikan-Killiany-Tourville atlas, thickness in multiple individual cortical regions was also associated with delirium severity. CONCLUSIONS: Preoperative cortical thickness and postoperative EEG delta power are both associated with postoperative delirium severity. These findings might reflect different underlying processes or mechanisms. CLINICAL TRIAL REGISTRATION: NCT03124303.

Postoperative troponin increases after noncardiac surgery are associated with raised neurofilament light: a prospective observational cohort study.

BACKGROUND: Myocardial and neuronal injury occur commonly after noncardiac surgery. We examined whether patients who had perioperative myocardial injury (PMI) also incurred neuronal injury, and whether myocardial and neuronal injury were associated with similar changes in inflammatory markers or overlapping clinical predictors. METHODS: A total of 114 individuals >65 yr old were recruited from two ongoing perioperative cohort studies (NCT02926417; NCT03124303). Plasma samples were collected before and daily after surgery to process assays for troponin I (PMI), neurofilament light (NfL; neuronal injury) and multiplexed plasma cytokines (inflammation). The primary outcome was the change in NfL in individuals with PMI (>40 pg ml-1 increase in troponin above preoperative values). We conducted logistic regression to identify if there were shared clinical predictors for myocardial and neuronal injury. RESULTS: Ninety-six patients had paired NfL and troponin data. Twenty-three of 94 subjects (24%) with PMI had greater increases in NfL (median [inter-quartile range, IQR]: 29 pg ml-1 [3-95 pg ml-1]; 2.8-fold increase) compared with subjects with no troponin increase (8 pg ml-1 [3-20]; 1.3-fold increase; P=0.008). PMI was associated with increased interleukin (IL)-1ra (P=0.005), IL-2 (P=0.045), IL-8 (P=0.002), and IL-10 (P<0.001). Logistic regression showed that intraoperative hypotension was associated with PMI (P=0.043). Preoperative stroke (P=0.041) and blood loss (P=0.002), but not intraoperative hypotension, were associated with increased NfL. CONCLUSIONS: Postoperative troponin increases were associated with changes in NfL and inflammatory cytokines. Increases in troponin, but not NfL, were associated with intraoperative hypotension, suggesting differences in the mechanisms contributing to neuronal and myocardial injury.

Endoscopic ultrasound: a powerful tool to modify treatment algorithms in opioid-induced achalasia.

BACKGROUND: Opioid use in the U.S. has increased dramatically over the last 15 years, recently being declared a public health emergency. Opioid use is associated with esophageal dysmotility lending to a confusing clinical picture compared to true achalasia. Patients exhibit symptoms and elicit diagnostic results consistent with esophageal motility disorders, in particular type III achalasia. Modified therapeutic strategies and outcomes become challenging. Differentiating true achalasia from opioid-induced achalasia is critical. Conventional surgical interventions, i.e., myotomy, are ineffective in the absence of true achalasia. We assess the utility of esophageal muscle layer mapping with endoscopic ultrasound (EUS) in distinguishing primary from opioid-induced achalasia. METHODS: From 2016 to 2019, patients with abnormal manometry and suspected achalasia underwent esophagogastroduodenoscopy and EUS mapping of esophageal round muscle layer thickness. Maximum round layer thickness and length of round muscle layer thickness > 1.8 mm were collected and compared between opioid users and non-opioid users using Wilcoxon Rank sum test. RESULTS: 45 patients were included: 12 opioid users, 33 non-opioid users. Mean age 56.8 years (range 24-93), 53.3% male patients. Mean BMI in the opioid-induced achalasia group was 30.2 kg/m2, mean BMI in the primary achalasia group 26.8 kg/m2 (p = 0.11). In comparing endoscopic maximum round layer thickness between groups, non-opioid patients had a thicker round muscle layer (2.7 mm vs 1.8 mm, p = 0.05). Length of abnormally thickened esophageal muscle (greater than 1.8 mm) also differed between the two groups; patients on opioids had a shorter length of thickening (4.0 cm vs 0.0 cm, p = 0.04). Intervention rate was higher in the non-opioid group (p = 0.79). Of the patients that underwent therapeutic intervention, symptom resolution was higher in the non-opioid group (p = 0.002), while re-intervention post-procedure for persistent symptomatology was elevated in the opioid subset (p = 0.06). Patients in the opioid group were less likely to undergo invasive treatment (Heller). As of 2017 all interventions in the opioid group have been endoscopic. CONCLUSION: Endoscopic ultrasound is an essential tool that has improved our treatment algorithm for suspected achalasia in patients with chronic opioid usage. Incorporation of EUS findings into treatment approach may prevent unnecessary surgery in opioid users.

More beads, more peristaltic reserve, better outcomes: factors predicting postoperative dysphagia after magnetic sphincter augmentation.

INTRODUCTION: Magnetic sphincter augmentation (MSA) offers a minimally invasive anti-reflux alternative to fundoplication for gastroesophageal reflux disease. The most common side effect of MSA is dysphagia, which may require dilation or even device removal. The incidence of dysphagia may be reduced by MSA sizing and preoperative motility studies. Multiple rapid swallows (MRS) is a provocative maneuver during high-resolution esophageal manometry (HRM) that assesses peristaltic reserve. We evaluated factors predicting development of dysphagia following MSA. MATERIALS AND METHODS: A retrospective review of a prospectively maintained database identified patients undergoing MSA. Preoperative work-up included barium swallow, esophagogastroduodenoscopy, and esophageal manometry. Peristaltic augmentation was defined as a ratio > 1 of the distal contractile integral (DCI) following MRS and the mean DCI of the 10 baseline wet swallows during manometry. Demographics, MSA implant size, and postoperative symptom data were gathered on all patients. RESULTS: Sixty-eight patients underwent MSA. Mean age was 51.7 years, average BMI was 25.8 kg/m2. 15 (22.1%) of patients had severe dysphagia requiring endoscopic dilation. Peristaltic augmentation with MRS was significantly higher in patients without dysphagia (46.1% vs 6.3% p = 0.026). 33.3% of patients requiring dilatation exhibited complete absence of smooth muscle contraction following MRS (DCI = 0). The ratio of the DCI of MRS/wet swallows predicting dysphagia following MSA was 0.56. Patients with a small (12-14 beads) versus a larger MSA implant (15-17 beads) had a significantly higher rate of postoperative dysphagia (58.5% vs 30.0% p = 0.026). CONCLUSION: Adequate peristaltic reserve and larger device size correlate with decreased incidence of dysphagia following MSA implantation without compromising the anti-reflux barrier. Routine assessment of peristaltic reserve during preoperative HRM should be considered prior to MSA placement.

Loop analysis of the anal sphincter complex in fecal incontinent patients using functional luminal imaging probe.

Cardiac loops have been used extensively to study myocardial function. With changes in cardiac pump function, loops are shifted to the right or left. Functional luminal imaging probe (FLIP) recordings allow for loop analysis of the anal sphincter and puborectalis muscle (PRM) function. The goal was to characterize anal sphincter area-pressure/tension loop changes in fecal incontinence (FI) patients. Fourteen healthy subjects and 14 patients with FI were studied. A custom-designed FLIP was placed in the vagina and then in the anal canal, and deflated in 20-ml steps, from 90 to 30 ml. At each volume, subjects performed maximal voluntary squeezes. Area-pressure (AP) and area-tension (AT) loops were generated for each squeeze cycle. Three-dimensional ultrasound imaging of the anal sphincter and PRM were obtained to determine the relationship between anal sphincter muscle damage and loop movements. With the increase in bag volume, AP loops and AT loops shifted to the right and upward in normal subjects (both anal and vaginal). The shift to the right was greater, and the upward movement was less in FI patients. The difference in the location of AP loops and AT loops was statistically significant at volumes of 50 ml to 90 ml (P < 0.05). A similar pattern was found in the vaginal loops. There is a significant relationship between the damage to the anal sphincter and PRM, and loop location of FI patients. We propose AP and AT loops as novel ways to assess the anal sphincter and PRM function. Such loops can be generated by real-time measurement of pressure and area within the anal canal.NEW & NOTEWORTHY We describe the use of area-pressure (AP) and area-tension (AT)-loop analysis of the anal sphincters and puborectalis muscles in normal subjects and fecal incontinent patients using the functional luminal imaging probe (FLIP). There are differences in the magnitude of the displacement of the loops with increase in the FLIP bag volume between normal subjects and patients with fecal incontinence. The latter group shifts more to the right in AP and AT space.

Spatial Patterns From High-Resolution Electrogastrography Correlate With Severity of Symptoms in Patients With Functional Dyspepsia and Gastroparesis.

BACKGROUND & AIMS: Invasive gastric electrical mapping has revealed spatial abnormalities of the slow wave in subjects with gastroparesis and functional gastrointestinal disorders. Cutaneous high-resolution electrogastrography (HR-EGG) is a non-invasive method that can detect spatial features of the gastric slow wave. We performed HR-EGG in subjects with active foregut symptoms to evaluate associations between gastric myoelectric abnormalities, symptoms (based on a validated questionnaire), and gastric emptying. METHODS: We performed a case-control study of 32 subjects, including 7 healthy individuals (controls), 7 subjects with functional dyspepsia and normal gastric emptying, and 18 subjects with gastroparesis, from a tertiary care program. All subjects were assessed by computed tomography imaging of the abdomen and HR-EGG and completed the PAGI-SYM questionnaire on foregut symptoms, which includes the gastroparesis cardinal symptom index. We performed volume reconstruction of the torso and stomach from computed tomography images to guide accurate placement of the HR-EGG array. RESULTS: Spatial slow-wave abnormalities were detected in 44% of subjects with foregut symptoms. Moreover, subjects with a higher percentage of slow waves with aberrant propagation direction had a higher total gastroparesis cardinal symptom index score (r = 0.56; P < .001) and more severe abdominal pain (r = 0.46; P = .009). We found no correlation between symptoms and traditional EGG parameters. CONCLUSIONS: In case-control study, we found that the genesis of symptoms of functional dyspepsia and gastroparesis is likely multifactorial, including possible contribution from gastric myoelectric dysfunction. Abnormal spatial parameters, detected by cutaneous HR-EGG, correlated with severity of upper gastrointestinal symptoms, regardless of gastric emptying. This noninvasive, repeatable approach might be used to identify patients for whom gastric myoelectric dysfunction contributes to functional dyspepsia and gastroparesis.

Intestinal Permeability, Irritable Bowel Syndrome with Constipation, and the Role of Sodium-Hydrogen Exchanger Isoform 3 (NHE3).

Increased intestinal permeability has been identified as one of the many pathophysiological factors associated with the development of irritable bowel syndrome (IBS), a common disorder of gut-brain interaction. The layer of epithelial cells that lines the intestine is permeable to a limited degree, and the amount of paracellular permeability is tightly controlled to enable the absorption of ions, nutrients, and water from the lumen. Increased intestinal permeability to macromolecules can be triggered by a variety of insults, including infections, toxins from food poisoning, or allergens, which in turn cause an inflammatory response and are associated with abdominal pain in patients with IBS. This review article discusses increased intestinal permeability in IBS, focusing on IBS with constipation (IBS-C) through the lens of a patient case with a reported prior diagnosis of "leaky gut syndrome" upon initial contact with a gastrointestinal specialist. We review advantages and disadvantages of several methods of measuring intestinal permeability in patients and discuss when measuring intestinal permeability is appropriate in the therapeutic journey of patients with IBS-C. Furthermore, we discuss a possible mechanism of restoring the intestinal barrier to its healthy state through altering intracellular pH by inhibiting sodium-hydrogen exchanger isoform 3 (NHE3). Tenapanor is a minimally absorbed, small-molecule inhibitor of NHE3 that has been approved by the US Food and Drug Administration for the treatment of IBS-C in adults. Preclinical studies showed that tenapanor may restore the intestinal barrier in IBS-C by affecting the conformation of tight junction proteins via NHE3 inhibition to block the paracellular transport of macromolecules from the intestinal lumen. Testing for increased permeability in patients with IBS-C who experience abdominal pain may help inform the choice of therapeutics and alter patients' misconceptions about "leaky gut syndrome".