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Background Since its introduction in 2010, per oral endoscopic myotomy (POEM) has offered an alternative to laparoscopic Heller myotomy for the treatment of achalasia. A gastric myotomy length of 3 cm has been recommended; however, it can be difficult to ensure that adequate submucosal dissection has been performed during the procedure. Commonly accepted endoscopic markers of the gastric side can be inaccurate, particularly in patients with prior endoscopic treatments, such as balloon dilation or Botox injection of the lower esophageal sphincter. We hypothesized that the use of a second endoscope would result in a more complete gastric myotomy. Methods One hundred consecutive achalasia patients were randomized into single- and double-scope POEM groups. In the treatment group, a second endoscope was used to obtain a retroflexed view of the gastric cardia, while the dissecting scope transilluminated from the end of the submucosal tunnel. Prospectively collected data were analyzed, including myotomy lengths, procedure times, adverse events, and clinical outcomes. Results POEM was completed with high rates of technical (98–100 %) and clinical success (93–97 %) in both groups, with a low rate of serious adverse events (2 %). The second endoscope resulted in a 17 min increase in procedure time (94 vs. 77 min), myotomy extension in 34 % of cases, and an increase in the average gastric myotomy length from 2.6 to 3.2 cm ( p  = 0.01). Conclusion A second endoscope is useful for ensuring a complete gastric myotomy during POEM. With minimal increase in procedure time and no increase in morbidity, it may be particularly useful in cases of sigmoid esophagus or otherwise altered anatomy that makes identification of the gastroesophageal junction difficult.

BackgroundSince Inoue performed the first POEM in 2008, safety and efficacy have been well-established. Early studies focused on refining the technique and avoiding incomplete myotomy. Following the discovery that many patients with abnormal acid exposure are asymptomatic, the focus shifted to post-POEM reflux, but no studies have identified any associated procedural factors. In this study, we examined the intermediate-term results of our previous randomized controlled trial, with particular attention to post-POEM reflux.MethodsPreviously, 100 consecutive patients were randomized to either double- or single-scope POEM. Endoscopy was conducted 2 months post-POEM and annually thereafter. Patients were included in the present study if they completed endoscopy ≥ 6 months post-POEM, and the clinical results of both groups were analyzed with particular attention to clinical efficacy and post-POEM reflux.ResultsMedian follow-up was 3 years, and most myotomies were performed in the posterior location. The final gastric myotomy length was longer in the double-scope group (3.3 vs. 2.6 cm). Clinical efficacy (≥ 80%) and rates of post-POEM reflux (~ 60%) were similar; however, there was a higher incidence of moderate esophagitis (Los Angeles Grade B) in the double-scope group (25% vs. 4%). There were no cases of severe esophagitis (Los Angeles Grade C/D). Among patients with normal endoscopy at 2 months, > 40% developed erosive esophagitis on intermediate-term follow-up.ConclusionsThis is the first study to demonstrate a procedural factor that increases post-POEM esophagitis. Gastric myotomy > 2.5 cm results in increased rates of moderate esophagitis without improving clinical efficacy. Some patients developed esophagitis in a delayed fashion, emphasizing the importance of ongoing surveillance. We also believe that preserving the gastric sling fibers may help to reduce reflux rates. The double-scope method may help to control myotomy length (2.0–2.5 cm) and direction (lesser curve to avoid the gastric sling) to help maximize clinical efficacy while minimizing post-POEM reflux.

Background The altered anatomy of Roux-en-Y gastric bypass presents a challenge when duodenal access is required for ERCP. One technique, laparoscopic transgastric ERCP, was first described in 2002. Since that time, a total of 77 laparoscopic or percutaneous transgastric ERCPs have been reported. The largest case series includes 26 ERCPs, and no reports specifically address complications. We reviewed our experience with 85 transgastric ERCPs and report the limitations and complications associated with access and ERCP. Methods Retrospective review was conducted of gastric bypass patients who underwent transgastric ERCP in our practice from 2004–2014. Results Forty-one patients underwent 85 transgastric ERCPs during the study period. Conversion from laparoscopic to open procedure occurred in 4.8 %, and selective cannulation rate was 93 %. Forty-seven percent of cases were repeat ERCPs performed through a gastrostomy tube tract. During 15-month median follow-up, the overall complication rate was 19 %, with 88 % of complications related to access rather than ERCP. Most complications were minor; there were no deaths or cases of severe pancreatitis. Additional intervention, including repair of a posterior stomach laceration or transfusion for bleeding, occurred in 4.7 % of cases. Operative intervention occurred in two cases: repair of a duodenal perforation, and debridement of an abdominal wall abscess. Post-ERCP hyperamylasemia was common but did not result in increased length of stay or significant clinical pancreatitis. Conclusions Roux-en-Y gastric bypass eliminates the normal approach to the duodenum for ERCP. Transgastric access has a high rate of successful cannulation but is associated with complications. Conversion to open procedure occurred in 4.8 %, and 16 % developed a complication related to the access site, though the rate of operative intervention was low (2.4 %). Our study is limited by its retrospective design, which may underestimate the complication rate, and by our homogenous patient population (94 % female, 68 % sphincter of Oddi dysfunction).

Schizophrenia is a debilitating psychiatric disorder, leading to both physical and social morbidity. Worldwide 1% of the population is struggling with the disease, with 100,000 new cases annually only in the United States. Despite its importance, the goal of finding effective treatments for schizophrenia remains a challenging task, and previous work conducted expensive large-scale phenotypic screens. This work investigates the benefits of Machine Learning for graphs to optimize drug phenotypic screens and predict compounds that mitigate abnormal brain reduction induced by excessive glial phagocytic activity in schizophrenia subjects. Given a compound and its concentration as input, we propose a method that predicts a score associated with three possible compound effects, i.e., reduce, increase, or not influence phagocytosis. We leverage a high-throughput screening to prove experimentally that our method achieves good generalization capabilities. The screening involves 2218 compounds at five different concentrations. Then, we analyze the usability of our approach in a practical setting, i.e., prioritizing the selection of compounds in the SWEETLEAD library. We provide a list of 64 compounds from the library that have the most potential clinical utility for glial phagocytosis mitigation. Lastly, we propose a novel approach to computationally validate their utility as possible therapies for schizophrenia.

BackgroundIndigo naturalis (IN) is an herbal medicine that has been used for ulcerative colitis with an unclear mechanism of action. Indigo and indirubin, its main constituents, are ligands of the aryl hydrocarbon receptor (AhR). We assessed the safety, efficacy, and colon AhR activity of IN given orally to patients with treatment-refractory ulcerative colitis. The role of AhR in IN benefit was further evaluated with an AhR antagonist in a murine colitis model.MethodsThis open-label, dose-escalation study sequentially treated 11 patients with ulcerative colitis with either IN 500 mg/day or 1.5 g/day for 8 weeks, followed by a 4-week non-treatment period. The primary efficacy endpoint was clinical response at week 8, assessed by total Mayo score. Secondary endpoints included clinical remission, Ulcerative Colitis Endoscopic Index of Severity, quality of life, and colon AhR activity measured by cytochrome P450 1A1 (CYP1A1) RNA expression.ResultsTen of 11 (91%) patients, including 8/9 (89%) with moderate-to-severe disease, achieved a clinical response. Among these 10 patients, all had failed treatment with 5-aminosalicylic acid, 8 patients with a tumour necrosis factor (TNF)-alpha inhibitor, and 6 patients with TNF-alpha inhibitor and vedolizumab. Five patients were corticosteroid dependent. Clinical response was observed in all five patients who had been recommended for colectomy. Three patients achieved clinical remission. All patients experienced improved endoscopic severity and quality of life. Four weeks after treatment completion, six patients had worsened partial Mayo scores. Four patients progressed to colectomy after study completion. Colon CYP1A1 RNA expression increased 12 557-fold at week 8 among six patients evaluated. No patient discontinued IN due to an adverse event. Concomitant administration of 3-methoxy-4-nitroflavone, an AhR antagonist, in a murine colitis model abrogated the benefit of IN.ConclusionIN is a potentially effective therapy for patients with treatment-refractory ulcerative colitis. This benefit is likely through AhR activation.Trial registration numberNCT02442960.

Background The risk for several common cancers is influenced by the transcriptomic landscape of the respective tissue-of-origin. Vitamin D influences in vitro gene expression and cancer cell growth. We sought to determine whether oral vitamin D induces beneficial gene expression effects in human rectal epithelium and identify biomarkers of response. Methods Blood and rectal mucosa was sampled from 191 human subjects and mucosa gene expression (HT12) correlated with plasma vitamin D (25-OHD) to identify differentially expressed genes. Fifty subjects were then administered 3200IU/day oral vitamin D3 and matched blood/mucosa resampled after 12 weeks. Transcriptomic changes (HT12/RNAseq) after supplementation were tested against the prioritised genes for gene-set and GO-process enrichment. To identify blood biomarkers of mucosal response, we derived receiver-operator curves and C-statistic (AUC) and tested biomarker reproducibility in an independent Supplementation Trial (BEST-D). Results Six hundred twenty-nine genes were associated with 25-OHD level ( P < 0.01), highlighting 453 GO-term processes (FDR<0.05). In the whole intervention cohort, vitamin D supplementation enriched the prioritised mucosal gene-set (upregulated gene-set P < 1.0E−07; downregulated gene-set P < 2.6E−05) and corresponding GO terms ( P = 2.90E−02), highlighting gene expression patterns consistent with anti-tumour effects. However, only 9 individual participants (18%) showed a significant response (NM gene-set enrichment P < 0.001) to supplementation. Expression changes in HIPK2 and PPP1CC expression served as blood biomarkers of mucosal transcriptomic response (AUC=0.84 [95%CI 0.66–1.00]) and replicated in BEST-D trial subjects ( HIPK2 AUC=0.83 [95%CI 0.77–0.89]; PPP1CC AUC=0.91 [95%CI 0.86–0.95]). Conclusions Higher plasma 25-OHD correlates with rectal mucosa gene expression patterns consistent with anti-tumour effects, and this beneficial signature is induced by short-term vitamin D supplementation. Heterogenous gene expression responses to vitamin D may limit the ability of randomised trials to identify beneficial effects of supplementation on CRC risk. However, in the current study blood expression changes in HIPK2 and PPP1CC identify those participants with significant anti-tumour transcriptomic responses to supplementation in the rectum. These data provide compelling rationale for a trial of vitamin D and CRC prevention using easily assayed blood gene expression signatures as intermediate biomarkers of response.

Schizophrenia is a debilitating condition necessitating more efficacious therapies. Previous studies suggested that schizophrenia development is associated with aberrant synaptic pruning by glial cells. We pursued an interdisciplinary approach to understand whether therapeutic reduction in glial cell—specifically astrocytic—phagocytosis might benefit neuropsychiatric patients. We discovered that beta-2 adrenergic receptor (ADRB2) agonists reduced phagocytosis using a high-throughput, phenotypic screen of over 3200 compounds in primary human fetal astrocytes. We used protein interaction pathways analysis to associate ADRB2, to schizophrenia and endocytosis. We demonstrated that patients with a pediatric exposure to salmeterol, an ADRB2 agonist, had reduced in-patient psychiatry visits using a novel observational study in the electronic health record. We used a mouse model of inflammatory neurodegenerative disease and measured changes in proteins associated with endocytosis and vesicle-mediated transport after ADRB2 agonism. These results provide substantial rationale for clinical consideration of ADRB2 agonists as possible therapies for patients with schizophrenia.

The bacterial genus Myroides, like other members of the Flavobacteriaceae family, consists of aerobic, non-motile, Gram-negative bacilli. Myroides spp. is considered predominantly opportunistic pathogens as, historically, most documented infections have been in immunocompromised individuals. Along with advancements in molecular assay testing, there are growing reports of clinically relevant Myroides spp. infections in immunocompetent individuals. These organisms display broad antimicrobial resistance, and while research into their mechanisms of resistance is progressing, genetic testing has revealed metallo-β-lactamases present in their genome. The sporadic identification of Myroides spp. and ongoing clarification of resistance patterns make empiric treatment difficult. This report documents two cases of extensively drug-resistant Myroides odoratus isolated from critically ill but otherwise immunocompetent patients followed by a review of available literature on Myroides spp. antibiotic sensitivities. Our findings indicate that minocycline and moxifloxacin have the highest documented in vitro activity against Myroides spp.

In some cases, drug combinations affect adverse outcome phenotypes by binding the same protein; however, drug‐binding proteins are associated through protein–protein interaction (PPI) networks within the cell, suggesting that drug phenotypes may result from long‐range network effects. We first used PPI network analysis to classify drugs based on proteins downstream of their targets and next predicted drug combination effects where drugs shared network proteins but had distinct binding proteins (e.g., targets, enzymes, or transporters). By classifying drugs using their downstream proteins, we had an 80.7% sensitivity for predicting rare drug combination effects documented in gold‐standard datasets. We further measured the effect of predicted drug combinations on adverse outcome phenotypes using novel observational studies in the electronic health record. We tested predictions for 60 network‐drug classes on seven adverse outcomes and measured changes in clinical outcomes for predicted combinations. These results demonstrate a novel paradigm for anticipating drug synergistic effects using proteins downstream of drug targets.

Cross-synaptic synchrony—correlations in transmitter release across output synapses of a single neuron—is a key determinant of how signal and noise traverse neural circuits. The anatomical connectivity between rod bipolar and A17 amacrine cells in the mammalian retina, specifically that neighboring A17s often receive input from many of the same rod bipolar cells, provides a rare technical opportunity to measure cross-synaptic synchrony under physiological conditions. This approach reveals that synchronization of rod bipolar cell synapses is near perfect in the dark and decreases with increasing light level. Strong synaptic synchronization in the dark minimizes intrinsic synaptic noise and allows rod bipolar cells to faithfully transmit upstream signal and noise to downstream neurons. Desynchronization in steady light lowers the sensitivity of the rod bipolar output to upstream voltage fluctuations. This work reveals how cross-synaptic synchrony shapes retinal responses to physiological light inputs and, more generally, signaling in complex neural networks. The human eye is capable of detecting a single photon of starlight. This level of sensitivity is made possible by the high sensitivity of photoreceptors called rods. There are around 120 million rods in the retina, and they support vision in levels of light that are too low to activate the photoreceptors called cones that allow us to see in color. This is why we cannot see colors in the dark. Signals are relayed through the retina via a circuit made up of multiple types of neurons. The activation of rods leads to activation of cells known as ‘rod bipolar cells’ which, in turn, activate amacrine cells and ganglion cells, with the latter sending signals via the optic nerve to the brain. All of these neurons communicate with one another at junctions called synapses. Activation of a rod bipolar cell, for example, triggers the release of molecules called neurotransmitters: these molecules bind to and activate receptors on the amacrine cells, enabling the signal to be transmitted. For the brain to detect that a single photon has struck a rod, the eye must transmit information along this chain of neurons in a way that is highly reliable while adding very little noise to the signal. Grimes et al. have now revealed a key step in how this is achieved. Electrical recordings from the mouse retina revealed that, in the dark, small fluctuations in the activity of rod bipolar cells lead to the near-deterministic release of neurotransmitters. This reduces the impact of random fluctuations in neurotransmitter release produced at individual synapses and ensures that the signals from rod bipolar cells (and thus from rods) are transmitted faithfully through the circuit with minimal added noise. As light levels increase, this tight synchrony of transmitter release breaks down, reducing the sensitivity to individual photons. Given that many other brain regions share the features that enable retinal cells to coordinate the release of neurotransmitters, this mechanism might be used throughout the brain to increase the signal-to-noise ratio for the transmission of information through neural circuits.