Impact of an Online Gastrointestinal Symptom History Taker on Physician Documentation and Charting Time: Pragmatic Controlled Trial.

BACKGROUND: A potential benefit of electronic health records (EHRs) is that they could potentially save clinician time and improve documentation by auto-generating the history of present illness (HPI) in partnership with patients prior to the clinic visit. We developed an online patient portal called AEGIS (Automated Evaluation of Gastrointestinal [GI] Symptoms) that systematically collects patient GI symptom information and then transforms the data into a narrative HPI that is available for physicians to review in the EHR prior to seeing the patient. OBJECTIVE: This study aimed to compare whether use of an online GI symptom history taker called AEGIS improves physician-centric outcomes vs usual care. METHODS: We conducted a pragmatic controlled trial among adults aged ≥18 years scheduled for a new patient visit at 4 GI clinics at an academic medical center. Patients who completed AEGIS were matched with controls in the intervention period who did not complete AEGIS as well as controls who underwent usual care in the pre-intervention period. Of note, the pre-intervention control group was formed as it was not subject to contamination bias, unlike for post-intervention controls. We then compared the following outcomes among groups: (1) documentation of alarm symptoms, (2) documentation of family history of GI malignancy, (3) number of follow-up visits in a 6-month period, (4) number of tests ordered in a 6-month period, and (5) charting time (difference between appointment time and time the encounter was closed). Multivariable regression models were used to adjust for potential confounding. RESULTS: Of the 774 patients who were invited to complete AEGIS, 116 (15.0%) finished it prior to their visit. The 116 AEGIS patients were then matched with 343 and 102 controls in the pre- and post-intervention periods, respectively. There were no statistically significant differences among the groups for documentation of alarm symptoms and GI cancer family history, number of follow-up visits and ordered tests, or charting time (all P>.05). CONCLUSIONS: Use of a validated online HPI-generation portal did not improve physician documentation or reduce workload. Given universal adoption of EHRs, further research examining how to optimally leverage patient portals for improving outcomes are needed.

Oncogenic KRAS engages an RSK1/NF1 pathway to inhibit wild-type RAS signaling in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options. Although activating mutations of the KRAS GTPase are the predominant dependency present in >90% of PDAC patients, targeting KRAS mutants directly has been challenging in PDAC. Similarly, strategies targeting known KRAS downstream effectors have had limited clinical success due to feedback mechanisms, alternate pathways, and dose-limiting toxicities in normal tissues. Therefore, identifying additional functionally relevant KRAS interactions in PDAC may allow for a better understanding of feedback mechanisms and unveil potential therapeutic targets. Here, we used proximity labeling to identify protein interactors of active KRAS in PDAC cells. We expressed fusions of wild-type (WT) (BirA-KRAS4B), mutant (BirA-KRAS4BG12D), and nontransforming cytosolic double mutant (BirA-KRAS4BG12D/C185S) KRAS with the BirA biotin ligase in murine PDAC cells. Mass spectrometry analysis revealed that RSK1 selectively interacts with membrane-bound KRASG12D, and we demonstrate that this interaction requires NF1 and SPRED2. We find that membrane RSK1 mediates negative feedback on WT RAS signaling and impedes the proliferation of pancreatic cancer cells upon the ablation of mutant KRAS. Our findings link NF1 to the membrane-localized functions of RSK1 and highlight a role for WT RAS signaling in promoting adaptive resistance to mutant KRAS-specific inhibitors in PDAC.

Kras in Organoids.

Oncogenic Kras are genetic dependencies for the majority of pancreatic and colorectal adenocarcinomas; however, much remains to be understood regarding its tropism to these carcinomas. Recently developed organoid technology presents a more representative model culture system for pancreatic and colon epithelial tissues as well as better fostering the culture of nonimmortalized cells than two-dimensional culture. These advantages enable cancer researchers to directly compare tumor and normal tissue models to better study tumor initiation as well as therapeutic efficacy. Although in vivo models better model the complexity of multiple cell types, the organoid system allows for easier genetic manipulations and isolation of specific cell types. Furthermore, syngeneic orthotopically transplanted organoids recapitulate tumor histologically and gene expression of the tumors from which they were derived. Thus, organoids may extend the use of genetically engineered mouse models. These advantages of organoid cultures allow for many questions, including but not limited to studying the interaction between different cell types within a tumor and elucidating dependencies of Kras-driven tumors.

Activation of the anti-inflammatory reflex blocks lipopolysaccharide-induced decrease in synaptic inhibition in the temporal cortex of the rat.

Stress is a potential trigger for a number of neuropsychiatric conditions, including anxiety syndromes and schizophrenic psychoses. The temporal neocortex is a stress-sensitive area involved in the development of such conditions. We have recently shown that aseptic inflammation and mild electric shock shift the balance between synaptic excitation and synaptic inhibition in favor of the former in this brain area (Garcia-Oscos et al., 2012), as well as in the prefrontal cortex (Garcia-Oscos et al., 2014). Given the potential clinical importance of this phenomenon in the etiology of hyperexcitable neuropsychiatric illness, this study investigates whether inactivation of the peripheral immune system by the "anti-inflammatory reflex" would reduce the central response to aseptic inflammation. For a model of aseptic inflammation, this study used i.p. injections of the bacterial toxin lipopolysaccharide (LPS; 5 µM) and activated the anti-inflammatory reflex either pharmacologically by i.p. injections of the nicotinic α7 receptor agonist PHA543613 or physiologically through electrical stimulation of the left vagal nerve (VNS). Patch-clamp recording was used to monitor synaptic function. Recordings from LPS-injected Sprague Dawley rats show that activation of the anti-inflammatory reflex either pharmacologically or by VNS blocks or greatly reduces the LPS-induced decrease of the synaptic inhibitory-to-excitatory ratio and the saturation level of inhibitory current input-output curves. Given the ample variety of pharmacologically available α7 nicotinic receptor agonists as well as the relative safety of clinical VNS already approved by the FDA for the treatment of epilepsy and depression, our findings suggest a new therapeutic avenue in the treatment of stress-induced hyperexcitable conditions mediated by a decrease in synaptic inhibition in the temporal cortex.

Vagal nerve stimulation blocks interleukin 6-dependent synaptic hyperexcitability induced by lipopolysaccharide-induced acute stress in the rodent prefrontal cortex.

The ratio between synaptic inhibition and excitation (sI/E) is a critical factor in the pathophysiology of neuropsychiatric disease. We recently described a stress-induced interleukin-6 dependent mechanism leading to a decrease in sI/E in the rodent temporal cortex. The aim of the present study was to determine whether a similar mechanism takes place in the prefrontal cortex, and to elaborate strategies to prevent or attenuate it. We used aseptic inflammation (single acute injections of lipopolysaccharide, LPS, 10mg/kg) as stress model, and patch-clamp recording on a prefrontal cortical slice preparation from wild-type rat and mice, as well as from transgenic mice in which the inhibitor of IL-6 trans-signaling sgp130Fc was produced in a brain-specific fashion (sgp130Fc mice). The anti-inflammatory reflex was activated either by vagal nerve stimulation or peripheral administration of the nicotinic α7 receptor agonist PHA543613. We found that the IL-6-dependent reduction in prefrontal cortex synaptic inhibition was blocked in sgp130Fc mice, or - in wild-type animals - upon application sgp130Fc. Similar results were obtained by activating the "anti-inflammatory reflex" - a neural circuit regulating peripheral immune response - by stimulation of the vagal nerve or through peripheral administration of the α7 nicotinic receptor agonist PHA543613. Our results indicate that the prefrontal cortex is an important potential target of IL-6 mediated trans-signaling, and suggest a potential new avenue in the treatment of a large class of hyperexcitable neuropsychiatric conditions, including epilepsy, schizophrenic psychoses, anxiety disorders, autism spectrum disorders, and depression.

Central obesity in the elderly is related to late-onset Alzheimer disease.

The evidence relating obesity measured with body mass index (BMI) in the elderly to late-onset Alzheimer disease (LOAD) is conflicting. Central obesity in middle age is related to a higher risk of LOAD, but data in the elderly are lacking. We explored whether measures of central obesity, waist circumference, and waist to hip ratio (WHR) were better predictors of LOAD compared with BMI in the elderly. Participants were 1459 persons aged 65 years and older without dementia at baseline, with follow-up, and with anthropometric data from a longitudinal study of aging in New York City. Proportional hazards regression was used for multivariable analyses relating BMI, waist circumference, and WHR to LOAD. There were 145 cases of Alzheimer disease in 5734 person-years of follow-up. Only WHR was related to higher LOAD risk (hazard ratio of the fourth quartile compared with the first=2.5; 95% confidence interval=1.3, 4.7) after adjustment for age, sex, education, ethnic group, Apolipoprotein E-ε4, type 2 diabetes, hypertension, non-high-density lipoprotein-cholesterol, high-density lipoprotein cholesterol, and stroke. Our results support the notion that central obesity is related to a higher risk of LOAD.

Concurrent findings of achalasia and duodenal duplication in a Down syndrome patient.

The association between Down syndrome and gastrointestinal anomalies such as duodenal and esophageal atresia, tracheoesophageal fistulas, and Hirschsprung's disease is well documented. More recently, an association between Down syndrome and achalasia was reported. In this report, we describe a 48-year-old woman with a history of Down syndrome who presented with dysphagia. Work-up of the dysphagia showed not only achalasia but also a duodenal duplication. To our knowledge, there have been no reports of Down syndrome associated with duodenal duplication. Whether this finding is simply a coincidence or whether duodenal duplication is associated with Down syndrome will need to be determined with future studies.

Success rate of retrograde double-balloon enteroscopy.

BACKGROUND: Retrograde double-balloon enteroscopy (rDBE) is technically a different procedure from its antegrade counterpart. Its unique indications, success rate, and learning curve have not been specifically reported. OBJECTIVE: To examine technical issues specific to the rDBE approach. DESIGN: Retrospective review. SETTING: Single tertiary-care center. PATIENTS: All patients referred for rDBE. MAIN OUTCOME MEASUREMENTS: Procedure duration, technical success, learning curve, and complications related to rDBE. RESULTS: A total of 59 rDBEs were performed on 56 patients for obscure GI bleeding (46.4%), metastatic carcinoids (23.2%), Crohn's disease (14.3%), and other indications. rDBE enabled a diagnosis in 47.5% of procedures and had a 38% diagnostic rate in finding primary small-bowel lesions that were responsible for metastatic carcinoids. The mean (standard deviation) total procedure time was 111.3 +/- 39.9 minutes. Procedure failure occurred in 12 cases (21%), which is significantly more than reported with antegrade procedures (2%). Failure was more common among patients with a prior abdominal or pelvic surgery (P = .001), and the time to achieve a stable ileal intubation was prolonged in these patients (13.9 vs 38.1 minutes; P = .0006). A trend was noted toward successful small-bowel access and increased lengths of small bowel examined after 20 procedures were performed. LIMITATIONS: Small retrospective study. CONCLUSIONS: rDBE is effective for the evaluation and the treatment of lower small-intestinal lesions; however, maintaining access through the ileocecal valve may be difficult. Prior surgery may be an important factor associated with failure. A minimum of 20 rDBE procedures was needed to minimize procedure failure, examine a substantial segment of the small-bowel, and shorten procedure duration.