Clinical Outcomes at 8-16 Weeks After Upadacitinib Initiation for Acute Severe Ulcerative Colitis: A Case Series in the United States.

In 9 patients hospitalized for acute severe ulcerative colitis, 8 were successfully discharged without the need for colectomy. Six of 7 patients with sufficient follow-up achieved steroid-free clinical remission at 8 to 16 weeks, and 1 of 2 patients achieved endoscopic response.

Drug-induced acute pancreatitis due to medications used for inflammatory bowel disease: A VigiBase pharmacovigilance database study.

BACKGROUND: Nearly all medications used for inflammatory bowel disease (IBD) have been reported as causes of acute pancreatitis (AP), with the thiopurines being among the most frequently described. However, with the development of newer medications, thiopurine monotherapy has largely been replaced by newer immunosuppressive drugs. There are few data on the association between AP and biologic/small molecule agents. METHODS: VigiBase, the World Health Organization's Global Individual Case Safety Report database, was used to assess the association between AP and common IBD medications. A case/non-case disproportionality analysis was performed and disproportionality signals were reported as a reporting odds ratio (ROR) with 95% confidence intervals (CIs). RESULTS: A total of 4,223 AP episodes were identified for common IBD medications. Azathioprine (ROR 19.18, 95% CI 18.21-20.20), 6-mercaptopurine (ROR 13.30, 95% CI 11.73-15.07), and 5-aminosalicylic acid (ROR 17.44, 95% CI 16.24-18.72) all had strong associations with AP, while the biologic/small molecule agents showed weaker or no disproportionality. The association with AP was much higher for thiopurines when used for Crohn's disease (ROR 34.61, 95% CI 30.95-38.70) compared to ulcerative colitis (ROR 8.94, 95% CI 7.47-10.71) or rheumatologic conditions (ROR 18.87, 95% CI 14.72-24.19). CONCLUSIONS: We report the largest real-world database study investigating the association between common IBD medications and AP. Among commonly used IBD medications including biologic/small molecule agents, only thiopurines and 5-aminosalicylic acid are strongly associated with AP. The association between thiopurines and AP is much stronger when the drug is used for Crohn's disease compared to ulcerative colitis and rheumatologic conditions.

Creating a Successful Virtual Reality-Based Medical Simulation Environment: Tutorial.

Innovation in medical education is not only inevitable but a requirement. Manikin-based simulation is currently the gold standard for supplemental clinical training; however, this modality requires significant equipment and personnel to operate. Virtual reality (VR) is emerging as a new method of delivering medical simulation sessions that requires less infrastructure but also allows for greater accessibility and flexibility. VR has slowly been integrated into the medical curriculum in some hospitals; however, more widespread adoption would transform the delivery of medical education for future clinicians. This tutorial introduces educators to the BUILD REALITY (begin, use, identify, leverage, define, recreate, educate, adapt, look, identify, test, amplify) framework, a series of practical tips for designing and implementing a VR-based medical simulation environment in their curriculum. The suggestions are based on the relevant literature and the authors' personal experience in creating and implementing VR environments for medical trainees. Altogether, this paper provides guidance on conducting a needs assessment, setting objectives, designing a VR environment, and incorporating the session into the broader medical curriculum.

Transoral incisionless fundoplication is cost-effective for treatment of gastroesophageal reflux disease.

Background and study aims Given the sizable number of patients with symptomatic gastroesophageal reflux disease (GERD) despite proton pump inhibitor (PPI) therapy, non-pharmacologic treatment has become increasingly utilized. The aim of this study was to analyze the cost-effectiveness of medical, endoscopic, and surgical treatment of GERD. Patients and methods A deterministic Markov cohort model was constructed from the US healthcare payer's perspective to evaluate the cost-effectiveness of three competing strategies: 1) omeprazole 20 mg twice daily; 2) transoral incisionless fundoplication (TIF 2.0); and 3) laparoscopic Nissen fundoplication [LNF]. Cost was reported in US dollars with health outcomes recorded in quality-adjusted life years (QALYs). Ten-year and lifetime time horizons were utilized with 3 % discount rate and half-cycle corrections applied. The main outcome was incremental cost-effectiveness ratio (ICER) with a willingness-to-pay threshold of $ 100,000 per QALY. Probabilistic sensitivity analyses were also performed. Results In our base-case analysis, the average cost of TIF 2.0 was $ 13,978.63 versus $ 17,658.47 for LNF and $ 10,931.49 for PPI. Compared to the PPI strategy, TIF 2.0 was cost-effective with an incremental cost of $ 3,047 and incremental effectiveness of 0.29 QALYs, resulting in an ICER of $ 10,423.17 /QALY gained. LNF was strongly dominated by TIF 2.0. Over a lifetime horizon, TIF 2.0 remained the cost-effective strategy for patients with symptoms despite twice-daily 20-mg omeprazole. TIF 2.0 remained cost-effective after varying parameter inputs in deterministic and probabilistic sensitivity analyses and for scenario analyses in multiple age groups. Conclusions Based upon this study, TIF 2.0 was cost-effective for patients with symptomatic GERD despite low-dose, twice-daily PPI.

Mimics of Crohn's Disease.

Crohn's disease is a chronic inflammatory disease that can affect any portion of the gastrointestinal tract. Associated symptoms can vary based on the severity of disease, extent of involvement, presence of extraintestinal manifestations, and development of complications. Diagnosis is based on a constellation of findings. Many diseases can mimic Crohn's disease and lead to diagnostic conundrums. These include entities associated with the gastrointestinal luminal tract, vascular disease, autoimmune processes, various infections, malignancies and complications, drug- or treatment-induced conditions, and genetic diseases. Careful consideration of possible causes is necessary to establish the correct diagnosis.

Fecal Microbiota Transplantation: The Evolving Risk Landscape.

Fecal microbiota transplantation (FMT) has been recommended in clinical guidelines for the treatment of recurrent Clostridioides difficile infection (CDI). However, it is considered investigational by most regulatory agencies. As the adoption of FMT has increased from a small group of CDI experts alone to more widespread use, there has been a corresponding increase in concern regarding potential risk. FMT is largely considered a safe procedure although risks described range from mild gastrointestinal symptoms to serious infection. Currently, there is variability in how "FMT" is characterized specifically regarding testing approach, which, in turn, impacts the risk profile. This has been highlighted by the rare cases of multidrug-resistant organisms, Shiga toxin-producing Escherichia and enteropathogenic E. coli, recently reported, where these organisms were not screened. These cases have prompted additional screening mandates from the US Food and Drug Administration (FDA), which has maintained its policy of enforcement discretion for the use of FMT for CDI not responding to standard therapy. Here, we examine the evolving risk landscape of FMT.

Cost-effectiveness analysis of sequential fecal microbiota transplantation for fulminant Clostridioides difficile infection.

BACKGROUND AND AIM: Fulminant Clostridioides difficile infections (FCDI) account for 8% of cases and substantial healthcare burden. Fecal microbiota transplantation is recommended for recurrent CDI, but emerging data support use for FCDI. We aimed to assess the cost-effectiveness of a sequential fecal microbiota transplantation (sFMT) protocol for FCDI compared with current standard therapy. METHODS: A Markov model simulated patients with FCDI in a 1-year time horizon. The treatment algorithm for up to three sFMTs, clinical probabilities, and direct costs were used from published sources. Outcomes were quality-adjusted life years (QALYs) and costs. The healthcare sector perspective was used with a willingness-to-pay threshold of $100 000 per QALY. RESULTS: Sequential fecal microbiota transplantation (FMT) for FCDI was associated with lower overall cost ($28 309 vs $33 980) and higher QALY (0.765 vs 0.686) compared with standard therapy. sFMT is cost-effective in 100% of iterations. sFMT remained cost-effective at cure rates > 44.8% for the first FMT and at stool preparation cost < $6944 per instillation. We find a wide range of efficacies for the first versus second FMT at which sFMT is still preferred. Value of information analysis estimates the expected value of perfect information to be low at $1.89 per person, quantified with net monetary benefit. CONCLUSIONS: An sFMT strategy strongly dominates standard therapy, with lower cost and higher QALY. Sensitivity analysis demonstrates benefit even if FMT cure rates are lower than expected and when multiple FMTs are required. FMT material in 2020 was priced at $1695 per treatment but remains cost-effective at a much higher cost.

Predictors of Ustekinumab Failure in Crohn's Disease After Dose Intensification.

BACKGROUND: Many patients with Crohn's disease (CD) who lose response to the standard ustekinumab dose interval of every 8 weeks (q8w) undergo dose intensification to q4w or q6w. However, baseline factors that predict success or failure after dose intensification are unknown. We sought to identify predictors of failure of ustekinumab after dose intensification for patients with CD. METHODS: This was a retrospective cohort study of adult CD patients undergoing ustekinumab dose intensification at a tertiary referral center between January 1, 2016, and January 31, 2019. Electronic health records were reviewed to obtain patient demographics, CD history, and laboratory data. The primary outcome was failure to achieve corticosteroid-free remission (Harvey-Bradshaw Index <5) within 12 months after intensification. The secondary outcome assessed was time to new biologic therapy after dose intensification. We used multivariable logistic regression and Cox regression to identify predictors of these outcomes. RESULTS: We included 123 patients who underwent ustekinumab dose intensification to q4w (n = 64), q5w (n = 1), q6w (n = 55), or q7w (n = 3). Multivariable logistic regression demonstrated that perianal disease, Harvey-Bradshaw Index, and opioid use at time of intensification were associated with failure to achieve remission. Cox regression demonstrated that perianal disease and corticosteroid use at time of intensification were associated with shorter time to a new biologic. CONCLUSION: Perianal disease, Harvey-Bradshaw Index, current opioid use, and current corticosteroid use are associated with ustekinumab failure after dose intensification in CD. Larger, prospective studies are needed to corroborate these findings and guide therapeutic strategies for patients who lose response to standard ustekinumab dosing.

Lumen apposing metal stents are superior to plastic stents in pancreatic walled-off necrosis: a large international multicenter study.

Background and study aims The use of lumen apposing metal stents (LAMS) during EUS-guided transmural drainage (EUS-TD) of pancreatic walled-off necrosis (WON) has gained popularity. Data supporting their use in WON over plastic stents (PS), however, remain scarce. The aim of this study was to compare the clinical efficacy of LAMS (Axios, Boston Scientific) with PS in WON. Patients and methods This was a multicenter, retrospective study involving 14 centers. Consecutive patients who underwent EUS-TD of WON (2012 - 2016) were included. The primary end point was clinical success defined as WON size ≤ 3 cm within a 6-month period without need for percutaneous drainage (PCD) or surgery. Results A total of 189 patients (mean age 55.2 ±â€Š15.6 years, 34.9 % female) were included (102 LAMS and 87 PS). Technical success rates were similar: 100 % in LAMS and 98.9 % in PS ( P  = 0.28). Clinical success was attained in 80.4 % of LAMS and 57.5 % of PS ( P  = 0.001). Rate of PCD was similar (13.7 % LAMS vs. 16.3 % PS, P  = 0.62), while PS was associated with a greater need for surgery (16.1 % PS vs. 5.6 % LAMS, P  = 0.02). Adverse events (AEs) were observed in 9.8 % of LAMS and 10.3 % of PS ( P  = 0.90) and were rated as severe in 2.0 % and 6.9 %, respectively ( P  = 0.93). After excluding patients with < 6 months follow-up, the rate of WON recurrence following initial clinical success was greater with PS (22.9 % PS vs. 5.6 % LAMS, P  = 0.04). Conclusions When compared to PS, LAMS in WON is associated with higher clinical success, shorter procedure time, lower need for surgery, and lower rate of recurrence.

Lumen-apposing stents versus plastic stents in the management of pancreatic pseudocysts: a large, comparative, international, multicenter study.

BACKGROUND: Larger caliber lumen-apposing stents (LAMSs) have been increasingly used in the management of pancreatic fluid collections, specifically when solid debris is present; however, their advantages over smaller caliber plastic stents in the management of pancreatic pseudocysts are unclear. The aim of this study was to investigate the safety and efficacy of LAMS specifically in the management of pancreatic pseudocysts compared with double-pigtail plastic stents (DPPSs). METHODS: We performed a multicenter, international, retrospective study between January 2012 and August 2016. A total of 205 patients with a diagnosis of pancreatic pseudocysts were included, 80 patients received LAMSs and 125 received DPPSs. Measured outcomes included clinical success, technical success, adverse events, stent dysfunction, pancreatic pseudocyst recurrence, and need for surgery. RESULTS: Technical success was similar between the LAMS and the DPPS groups (97.5 % vs. 99.2 %; P = 0.32). Clinical success was higher for LAMSs than for DPPSs (96.3 % vs. 87.2 %; P = 0.03). While the need for surgery was similar between the two groups (1.3 % vs. 4.9 %, respectively; P = 0.17), the use of percutaneous drainage was significantly lower in the LAMS group (1.3 % vs. 8.8 %; P = 0.03). At 6-month follow-up, the recurrence rate was similar between the groups (6.7 % vs 18.8 %, respectively; P = 0.12). The rate of adverse events was significantly higher in the DPPS group (7.5 % vs. 17.6 %; P = 0.04). There was no difference in post-procedure mean length of hospital stay (6.3 days [standard deviation 27.9] vs. 3.7 days [5.7]; P = 0.31). CONCLUSION: When compared to DPPSs, LAMSs are a safe, feasible, and effective modality for the treatment of pancreatic pseudocysts and are associated with a higher rate of clinical success, shorter procedure time, less need for percutaneous interventions, and a lower overall rate of adverse events.

Differentiation in stem/progenitor cells along fetal or adult hepatic stages requires transcriptional regulators independently of oscillations in microRNA expression.

Understanding mechanisms in lineage differentiation is critical for organ development, pathophysiology and oncogenesis. To determine whether microRNAs (miRNA) may serve as drivers or adjuncts in hepatic differentiation, we studied human embryonic stem cell-derived hepatocytes and primary hepatocytes representing fetal or adult stages. Model systems were used for hepatic lineage advancement or regression under culture conditions with molecular assays. Profiles of miRNA in primary fetal and adult hepatocytes shared similarities and distinctions from pluripotent stem cells or stem cell-derived early fetal-like hepatocytes. During phenotypic regression in fetal or adult hepatocytes, miRNA profiles oscillated to regain stemness-associated features that had not been extinguished in stem cell-derived fetal-like hepatocytes. These oscillations in stemness-associated features were not altered in fetal-like hepatocytes by inhibitory mimics for dominantly-expressed miRNA, such as hsa-miR-99b, -100, -214 and -221/222. The stem cell-derived fetal-like hepatocytes were permissive for miRNA characterizing mature hepatocytes, including mimics for hsa-miR-122, -126, -192, -194 and -26b, although transfections of the latter did not advance hepatic differentiation. Examination of genome-wide mRNA expression profiles in stem cell-derived or primary fetal hepatocytes indicated targets of highly abundant miRNA regulated general processes, e.g., cell survival, growth and proliferation, functional maintenance, etc., without directing cell differentiation. Among upstream regulators of gene networks in stem cell-derived hepatocytes included HNF4A, SNAI1, and others, which affect transcriptional circuits directing lineage development or maintenance. Therefore, miRNA expression oscillated in response to microenvironmental conditions, whereas lineage-specific transcriptional regulators, such as HNF4A, were necessary for directing hepatic differentiation. This knowledge will be helpful for understanding the contribution of stem cells in pathophysiological states and oncogenesis, as well as for applications of stem cell-derived hepatocytes.

Human microbiome signatures of differential colorectal cancer drug metabolism.

It is well appreciated that microbial metabolism of drugs can influence treatment efficacy. Microbial ß-glucuronidases in the gut can reactivate the excreted, inactive metabolite of irinotecan, a first-line chemotherapeutic for metastatic colorectal cancer. Reactivation causes adverse drug responses, including severe diarrhea. However, a direct connection between irinotecan metabolism and the composition of an individual's gut microbiota has not previously been made. Here, we report quantitative evidence of inter-individual variability in microbiome metabolism of the inactive metabolite of irinotecan to its active form. We identify a high turnover microbiota metabotype with potentially elevated risk for irinotecan-dependent adverse drug responses. We link the high turnover metabotype to unreported microbial ß-glucuronidases; inhibiting these enzymes may decrease irinotecan-dependent adverse drug responses in targeted subsets of patients. In total, this study reveals metagenomic mining of the microbiome, combined with metabolomics, as a non-invasive approach to develop biomarkers for colorectal cancer treatment outcomes.

Extensive alterations of blood metabolites in pediatric cerebral malaria.

Cerebral malaria (CM) presents as an encephalopathy and is due to infection with Plasmodium falciparum. Patients are comatose, often with fever, recurrent seizures and this condition is associated with a high mortality rate. The etiology of the coma and seizures are poorly understood. Circulating small molecules and lipids have bioactive functions and alterations in their concentrations have been implicated in seizure disorders and other forms of encephalopathy. We carried out a comprehensive analysis of blood metabolites during CM to explore a biochemical basis of this encephalopathy. A paired metabolomics analysis was performed on the plasma samples of Malawian children (n = 11) during CM and at convalescence thirty days later, to identify differentially abundant molecules associated with CM. We also report plasma molecules associated with CM mortality (n = 4) compared to survival (n = 19). Plasma metabolites were identified through ultra high performance liquid chromatography/tandem mass spectrometry and gas chromatography/mass spectrometry to maximize compound detection and accuracy and then compared to a library for identification. We detected a total of 432 small molecules in the plasma and 247 metabolites were significantly differentially abundant between CM and convalescence (p < 0.05, FDR < 0.10). These represented global changes across many classes of molecules including lipids, amino acids and hemoglobin metabolites. We observed significant changes in molecules that could impact neurologic function during CM; these include increased levels of kynurenate and decreased indolepropionate, glutamate, arginine and glutamine. Moreover, 1-methylimidazoleacetate, kyurenate, arachidonic acid and dimethylarginine were associated with mortality (p < 0.05, fold change > 1.2). These results highlight the broad changes in blood chemistry during CM. We have identified metabolites that may impact central nervous system physiology and disease outcomes and can be further explored for their mechanistic roles into the pathophysiology of CM.

Lipid metabolites of the phospholipase A2 pathway and inflammatory cytokines are associated with brain volume in paediatric cerebral malaria.

BACKGROUND: Cerebral malaria (CM) remains a significant cause of morbidity and mortality in children in sub-Saharan Africa. CM mortality has been associated with increased brain volume, seen on neuroimaging studies. METHODS: To examine the potential role of blood metabolites and inflammatory mediators in increased brain volume in Malawian children with CM, an association study was performed between plasma metabolites, cytokine levels and phospholipase A2 (PLA2) activity with brain volume. RESULTS: The metabolomics analysis demonstrated arachidonic acid and other lysophospholipids to be positively associated with brain swelling. These lipids are products of the PLA2 enzyme and an association of plasma PLA2 enzymatic activity with brain swelling was confirmed. TNFα, which can upregulate PLA2 activity, was associated with brain volume. In addition, CCL2 and IL-8 were also associated with brain volume. Some of these cytokines can alter endothelial cell tight junction proteins and increase blood brain barrier permeability. CONCLUSIONS: Taken together, paediatric CM brain volume was associated with products of the PLA2 pathway and inflammatory cytokines. Their role in causality is unknown. These molecules will need to undergo testing in vitro and in animal models to understand their role in processes of increased brain volume. These observations provide novel data on host physiology associated with paediatric CM brain swelling, and may both inform pathogenesis models and suggest adjunct therapies that could improve the morbidity and mortality associated with paediatric CM.

PEAS V1.0: a package for elementary analysis of SNP data.

We have developed a software package named PEAS to facilitate analyses of large data sets of single nucleotide polymorphisms (SNPs) for population genetics and molecular phylogenetics studies. PEAS reads SNP data in various formats as input and is versatile in data formatting; using PEAS, it is easy to create input files for many popular packages, such as STRUCTURE, frappe, Arlequin, Haploview, LDhat, PLINK, EIGENSOFT, PHASE, fastPHASE, MEGA and PHYLIP. In addition, PEAS fills up several analysis gaps in currently available computer programs in population genetics and molecular phylogenetics. Notably, (i) It calculates genetic distance matrices with bootstrapping for both individuals and populations from genome-wide high-density SNP data, and the output can be streamlined to MEGA and PHYLIP programs for further processing; (ii) It calculates genetic distances from STRUCTURE output and generates MEGA file to reconstruct component trees; (iii) It provides tools to conduct haplotype sharing analysis for phylogenetic studies based on high-density SNP data. To our knowledge, these analyses are not available in any other computer program. PEAS for Windows is freely available for academic users from http://www.picb.ac.cn/~xushua/index.files/Download_PEAS.htm.