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The healthy mammalian intestine is lined by a single layer of epithelial cells. These cells provide a selectively permeable barrier to luminal contents and normally do so in an efficient and effective manner. Barrier function in the healthy mucosa is provided via several mechanisms including epithelial junctional complexes, mucus production, as well as mucosal-derived antimicrobial proteins. As tissue metabolism is central to the maintenance of homeostasis in the mucosa, intestinal [Formula: see text] levels are uniquely low due to counter-current blood flow and the presence of the microbiota, resulting in the stabilization of the transcription factor hypoxia-inducible factor (HIF). Ongoing studies have revealed that HIF molds normal intestinal metabolism and is central to the coordination of barrier regulation during both homeostasis and active disease. During acute inflammation, HIF is central to controlling the rapid restitution of the epithelium consistent with normal wound healing responses. In contrast, HIF may also contribute to the fibrostenotic response associated with chronic, nonresolving inflammation. As such, HIF may function as a double-edged sword in the overall course of the inflammatory response. Here, we review recent literature on the contribution of HIF to mucosal barrier function, wound healing, and fibrosis.

Background Pain is commonly experienced by patients with inflammatory bowel disease (IBD). Unfortunately, pain management is a challenge in IBD care, as currently available analgesics are associated with adverse events. Our understanding of the impact of opioid use on healthcare utilization among IBD patients remains limited. Methods A systematic search was completed using PubMed, Embase, the Cochrane Library, and Scopus through May of 2020. The exposure of interest was any opioid medication prescribed by a healthcare provider. Outcomes included readmissions rate, hospitalization, hospital length of stay, healthcare costs, emergency department visits, outpatient visits, IBD-related surgeries, and IBD-related medication utilization. Meta-analysis was conducted on study outcomes reported in at least 4 studies using random-effects models to estimate pooled relative risk (RR) and 95% confidence interval (CI). Results We identified 1969 articles, of which 30 met inclusion criteria. Meta-analysis showed an association between opioid use and longer length of stay (mean difference, 2.25 days; 95% CI, 1.29-3.22), higher likelihood of prior IBD-related surgery (RR, 1.72; 95% CI, 1.32-2.25), and higher rates of biologic use (RR, 1.38; 95% CI, 1.13-1.68) but no difference in 30-day readmissions (RR, 1.17; 95% CI, 0.86-1.61), immunomodulator use (RR, 1.13; 95% CI, 0.89-1.44), or corticosteroid use (RR, 1.36; 95% CI, 0.88-2.10) in patients with IBD. On systematic review, opioid use was associated with increased hospitalizations, healthcare costs, emergency department visits, outpatient visits, and polypharmacy. Discussion Opioids use among patients with IBD is associated with increased healthcare utilization. Nonopioid alternatives are needed to reduce burden on the healthcare system and improve patient outcomes.

BackgroundClostridioides difficile infection (CDI) is a leading cause of health care–associated infection and may result in organ dysfunction, colectomy, and death. Published risk scores to predict severe complications from CDI demonstrate poor performance upon external validation. We hypothesized that building and validating a model using geographically and temporally distinct cohorts would more accurately predict risk for complications from CDI.MethodsWe conducted a multicenter retrospective cohort study of adults diagnosed with CDI. After randomly partitioning the data into training and validation sets, we developed and compared 3 machine learning algorithms (lasso regression, random forest, stacked ensemble) with 10-fold cross-validation to predict disease-related complications (intensive care unit admission, colectomy, or death attributable to CDI) within 30 days of diagnosis. Model performance was assessed using the area under the receiver operating curve (AUC).ResultsA total of 3646 patients with CDI were included, of whom 217 (6%) had complications. All 3 models performed well (AUC, 0.88–0.89). Variables of importance were similar across models, including albumin, bicarbonate, change in creatinine, non-CDI-related intensive care unit admission, and concomitant non-CDI antibiotics. Sensitivity analyses indicated that model performance was robust even when varying derivation cohort inclusion and CDI testing approach. However, race was an important modifier, with models showing worse performance in non-White patients.ConclusionsUsing a large heterogeneous population of patients, we developed and validated a prediction model that estimates risk for complications from CDI with good accuracy. Future studies should aim to reduce the disparity in model accuracy between White and non-White patients and to improve performance overall.

BackgroundClostridioides difficile infection (CDI) is a leading cause of healthcare-associated infections and may result in organ dysfunction, colectomy, and death. We recently showed that published risk scores to predict severe complications from CDI demonstrate poor performance upon external validation. We hypothesized that building and validating a model using geographically and temporally distinct cohorts would more accurately identify patients at risk for complicated CDI.MethodsWe conducted a multi-center retrospective cohort study of adult subjects diagnosed with CDI in the US. After randomly partitioning the data into training/validation set, we developed and compared three machine learning algorithms (Lasso regression, random forest, stacked ensemble models) with 10-fold cross-validation that used structured EHR data collected within 48 hours of CDI diagnosis to predict disease-related complications from CDI (intensive care unit admission, colectomy, or death attributable to CDI within 30 days of diagnosis). Model performance was assessed using area under the receiver operating curve (AUC).ResultsA total of 3,762 patients with CDI were included of which 218 (5.8%) had complications. Lasso regression, random forest, and stacked ensemble models all performed well with AUC ranging between 0.89-0.9. Variables of importance were similar across models, including albumin, bicarbonate, change in creatinine, systolic blood pressure, non-CDI-related ICU admission, and concomitant non-CDI antibiotics. Sensitivity analyses indicated that model performance was robust even when varying derivation cohort inclusion and CDI testing approach.ConclusionUsing a large heterogeneous population of patients, we have developed and validated a prediction model based on structured EHR data that accurately estimates risk for complications from CDI.Key PointsMachine learning models using structured electronic health records can be leveraged to accurately predict risk of severe complications related to Clostridiodes difficile infection, including intensive care unit admission, colectomy, and/or death.

Neutrophil (PMN) infiltration during active inflammation imprints changes in the local tissue environment. Such responses are often accompanied by significant extracellular acidosis that result in predictable transcriptional responses. In this study, we explore the mechanisms involved in inflammatory acidification as a result of PMN–intestinal epithelial cell (IEC) interactions. Using recently developed tools, we revealed that PMN transepithelial migration (TEM)-associated inflammatory acidosis is dependent on the total number of PMNs present during TEM and is polarized toward the apical surface. Extending these studies, we demonstrate that physical separation of the PMNs and IECs prevented acidification, whereas inhibition of PMN TEM using neutralizing antibodies enhanced extracellular acidification. Utilizing pharmaceutical inhibitors, we demonstrate that the acidification response is independent of myeloperoxidase and dependent on reactive oxygen species generated during PMN TEM. In conclusion, inflammatory acidosis represents a polarized PMN–IEC-dependent response by an as yet to be fully determined mechanism.

Background Fibrosis is the final common pathway to intestinal failure in Crohn’s disease, but no medical therapies exist to treat intestinal fibrosis. Activated myofibroblasts are key effector cells of fibrosis in multiple organ systems, including the intestine. AXL is a receptor tyrosine kinase that has been implicated in fibrogenic pathways involving myofibroblast activation. We aimed to investigate the AXL pathway as a potential target for the treatment of intestinal fibrosis. Methods To establish proof of concept, we first analyzed AXL gene expression in 2 in vivo models of intestinal fibrosis and 3 in vitro models of intestinal fibrosis. We then tested whether pharmacological inhibition of AXL signaling could reduce fibrogenesis in 3 in vitro models of intestinal fibrosis. In vitro testing included 2 distinct cell culture models of intestinal fibrosis (matrix stiffness and TGF-β1 treatment) and a human intestinal organoid model using TGF-β1 cytokine stimulation. Results Our findings suggest that the AXL pathway is induced in models of intestinal fibrosis. We demonstrate that inhibition of AXL signaling with the small molecule inhibitor BGB324 abrogates both matrix-stiffness and transforming growth factor beta (TGF-β1)–induced fibrogenesis in human colonic myofibroblasts. AXL inhibition with BGB324 sensitizes myofibroblasts to apoptosis. Finally, AXL inhibition with BGB324 blocks TGF-β1-induced fibrogenic gene and protein expression in human intestinal organoids. Conclusions The AXL pathway is active in multiple models of intestinal fibrosis. In vitro experiments suggest that inhibiting AXL signaling could represent a novel approach to antifibrotic therapy for intestinal fibrosis such as in Crohn’s disease.

BACKGROUND: Clostridium difficile infection (CDI) is one of the most common hospital-acquired infections and is associated with significant morbidity and mortality. Since owning a cat or dog could enrich the gut microbiome, we hypothesized that it would be protective against CDI. AIMS: We conducted a survey study on patients tested for CDI in order to assess whether living in the presence of a pet is associated with a decreased risk of CDI. METHODS: We surveyed subjects aged 18–90 over a 14-month period using a retrospective case–control design. Subjects with CDI were matched by gender and age to patients who tested negative and had no prior history of CDI. A web-based survey was provided to subjects by mail or assisted by phone. Conditional logistic regression was used to assess for associations between CDI and the various risk factors. RESULTS: 205 CDI positive and 205 CDI negative subjects (response rate of 50.2%) were included. After matching for age and sex, living with a cat or dog was not associated with negative CDI testing. Exploratory multivariable modeling identified an unexpected association between positive CDI testing and high meat intake (OR 2.13, 95% CI 1.21–3.77) as well as between positive CDI testing and cat allergies (OR 1.88, 95% CI 1.02–3.46). CONCLUSION: Living with a cat or dog was not associated with negative CDI testing. Several novel risk factors for CDI have been identified including high meat intake and cat allergies.

Background and Aims Intestinal strictures are a common complication of Crohn’s disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring. Herein we provide a comprehensive systematic review of studies assessing biomarkers that may predict or diagnose CD-associated strictures. Methods We performed a systematic review of PubMed, EMBASE, ISI Web of Science, Cochrane Library, and Scopus to identify citations pertaining to biomarkers of intestinal fibrosis through July 6, 2020, that used a reference standard of full-thickness histopathology or cross-sectional imaging or endoscopy. Studies were categorized based on the type of biomarker they evaluated (serum, genetic, histopathologic, or fecal). Results Thirty-five distinct biomarkers from 3 major groups were identified: serum (20 markers), genetic (9 markers), and histopathology (6 markers). Promising markers include cartilage oligomeric matrix protein, hepatocyte growth factor activator, and lower levels of microRNA-19-3p (area under the curves were 0.805, 0.738, and 0.67, respectively), and multiple anti-flagellin antibodies (A4-Fla2 [odds ratio, 3.41], anti Fla-X [odds ratio, 2.95], and anti-CBir1 [multiple]). Substantial heterogeneity was observed and none of the markers had undergone formal validation. Specific limitations to acceptance of these markers included failure to use a standardized definition of stricturing disease, lack of specificity, and insufficient relevance to the pathogenesis of intestinal strictures or incomplete knowledge regarding their operating properties. Conclusions There is a lack of well-defined studies on biomarkers of intestinal stricture. Development of reliable and accurate biomarkers of stricture is a research priority. Biomarkers can support the clinical management of CD patients and aid in the stratification and monitoring of patients during clinical trials of future antifibrotic drug candidates.

Background & Aims Despite rescue therapy, more than 30% of patients with acute severe ulcerative colitis (ASUC) require colectomy. Tofacitinib is a rapidly acting Janus kinase inhibitor with proven efficacy in ulcerative colitis. Tofacitinib may provide additional means for preventing colectomy in patients with ASUC. Methods A retrospective case-control study was performed evaluating the efficacy of tofacitinib induction in biologic-experienced patients admitted with ASUC requiring intravenous corticosteroids. Tofacitinib patients were matched 1:3 to controls according to gender and date of admission. Using Cox regression adjusted for disease severity, we estimated the 90-day risk of colectomy. Rates of complications and steroid dependence were examined as secondary outcomes. Results Forty patients who received tofacitinib were matched 1:3 to controls (n = 113). Tofacitinib was protective against colectomy at 90 days compared with matched controls (hazard ratio [HR], 0.28, 95% confidence interval [CI], 0.10–0.81; P = .018). When stratifying according to treatment dose, 10 mg three times daily (HR, 0.11; 95% CI, 0.02–0.56; P = .008) was protective, whereas 10 mg twice daily was not significantly protective (HR, 0.66; 95% CI, 0.21–2.09; P = .5). Rate of complications and steroid dependence were similar between tofacitinib and controls. Conclusions Tofacitinib with concomitant intravenous corticosteroids may be an effective induction strategy in biologic-experienced patients hospitalized with ASUC. Prospective trials are needed to identify the safety, optimal dose, frequency, and duration of tofacitinib for ASUC.

Background Coronavirus disease-2019 (COVID-19) is a global pandemic. Obesity has been associated with increased disease severity in COVID-19, and obesity is strongly associated with hepatic steatosis (HS). However, how HS alters the natural history of COVID-19 is not well characterized, especially in Western populations. Aims To characterize the impact of HS on disease severity and liver injury in COVID-19. Methods We examined the association between HS and disease severity in a single-center cohort study of hospitalized COVID-19 patients at Michigan Medicine. HS was defined by either hepatic steatosis index > 36 (for Asians) or > 39 (for non-Asians) or liver imaging demonstrating steatosis > 30 days before onset of COVID-19. The primary predictor was HS. The primary outcomes were severity of cardiopulmonary disease, transaminitis, jaundice, and portal hypertensive complications. Results In a cohort of 342 patients, metabolic disease was highly prevalent including nearly 90% overweight. HS was associated with increased transaminitis and need for intubation, dialysis, and vasopressors. There was no association between HS and jaundice or portal hypertensive complications. In a sensitivity analysis including only patients with liver imaging > 30 days before onset of COVID-19, imaging evidence of hepatic steatosis remained associated with disease severity and risk of transaminitis. Conclusions HS was associated with increased disease severity and transaminitis in COVID-19. HS may be relevant in predicting risk of complications related to COVID-19.

Background High-deductible health plans (HDHPs) are increasing in prevalence as a cost control device for slowing health care cost growth by reducing nonessential medical service utilization. High cost-sharing associated with HDHPs can lead to significant financial distress and worse disease outcomes. We hypothesize that chronic disease patients are delaying or foregoing necessary medical care due to health care costs. Methods A retrospective cohort analysis of IBD patients at risk for high medical service utilization with continuous enrollment in either an HDHP or THP from 2009 to 2016 were identified using the MarketScan database. Health care costs were compared between insurance plan groups by Kruskal-Wallis test. Temporal trends in office visits, colonoscopies, emergency department (ED) visits, and hospitalizations were evaluated using additive decomposition time series analysis. Results Of 605,862 patients with a diagnosis of IBD, we identified 13,052 eligible patients. Annual out-of-pocket costs were higher in the HDHP group (n = 524) than the THP group (n = 12,458) ($2870 vs $1,864; P < 0.001) without any difference in total health care expenses ($23,029 vs $23,794; P = 0.583). Enrollment in an HDHP influenced colonoscopy, ED visit, and hospitalization utilization timing. Colonoscopies peaked in the fourth quarter, ED visits peaked in the first quarter, and hospitalizations peaked in the third and fourth quarter. Conclusions High-deductible health plan enrollment does not change the cost of care; however, it shifts health care costs onto patients and changes the timing of the care they receive. High-deductible health plans are incentivizing delays in obtaining health care with a potential to cause worse disease outcomes and financial distress. Further evaluation is warranted.

INTRODUCTION: COVID-19 is a global pandemic However, the effects of underlying liver disease on COVID-19 in the United States is not well described We investigated whether COVID-19 was associated with elevations in liver enzymes or hepatic decompensation in patients with underlying hepatic steatosis METHODS: We retrospectively reviewed the charts of consecutive adults with RT-PCR positive for COVID-19 treated at Michigan Medicine between March 1 and April 30, 2020, who had ultrasound, computed tomography, or magnetic resonance imaging >30 days before COVID-19 diagnosis Hepatic steatosis was defined based on imaging Outcomes were: (1) peak ALT or bilirubin following COVID-19 diagnosis, (2) ALT >2 or = times upper limit of normal (ULN), defined as the higher of baseline ALT or 19 U/L in women and 30 U/L in men, (3) jaundice defined as bilirubin >2 or 4mg/ dl, and (4) new/worsening ascites or encephalopathy We conducted regressions with the above outcomes as dependent variables and hepatic steatosis as the primary predictor, adjusting for age, sex, race, recent healthcare exposure, body mass index, hypertension, dyslipidemia, and diabetes These regression models were logistic for outcomes of abnormal ALT or bilirubin, and linear for maximal ALT or bilirubin RESULTS: Of patients with prior imaging, 80/159 (50 3%) had steatosis Overall, 89% of patients were hospitalized, 51% were admitted to intensive care, and 16% died 14% had chronic liver disease other than NAFLD, 5% had cirrhosis, and 2 7% had prior liver decompensation with ascites, variceal bleeding, or hepatic encephalopathy Patients with steatosis were older, had higher body mass index, and were more often Black than those without steatosis (Table 1) Baseline ALT and total bilirubin were higher in the steatosis group (Table 1) Hepatic steatosis was associated with increased incidence of ALT >2x ULN (OR 2 93 [1 23-6 97]) or >5x ULN (OR 6 21 [1 45-26 62]), and with peak ALT (beta 39 7 [7 85-71 49]) (Table 2) Hepatic steatosis was not associated with increased bilirubin (Table 2) Rates of new/worsening ascites and encephalopathy were very low: 1 3% and 2 5%, respectively, with no difference based on NAFLD status (P >0 4 for both) CONCLUSION: Hepatic steatosis is associated with acute hepatocellular injury with COVID-19 infection Steatosis was not associated with jaundice Rates of new/worsening ascites or hepatic encephalopathy were very low and unrelated to steatosis status

Background Fecal calprotectin (fCAL) is a noninvasive biomarker used to differentiate between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Methods A multicenter prospective case–control study evaluating the BÜHLMANN fCAL enzyme-linked immunosorbent assay (ELISA) was conducted in 478 subjects. Sensitivity, specificity, predictive values, and area under the receiver operator characteristic (AuROC) curve are reported and compared to another device. Results In differentiating IBD from IBS, the BÜHLMANN fCAL ELISA is very sensitive (93.3%) at a cutoff 160 μg/g (AuROC 0.933). Conclusions The BÜHLMANN fCAL ELISA demonstrates excellent discriminating between IBD and IBS.

ImportanceLarge regional variations in consumer satisfaction with private health insurance plans have been observed, but the factors driving this variation are unknown.ObjectiveTo identify explanatory state-level and insurance family-level predictors of satsifaction with private health insurance.DesignCross-sectional study examining regional and state variations in consumer health insurance plan satisfaction using National Committee for Quality Assurance data from 2015 to 2018, state-level health data and parent insurance family.SettingUS PopulationParticipantsPrivately insured individuals.ExposureOne of 2176 private health insurance plans.Main OutcomeConsumer satisfaction with the health insurance plan on a 0-5 scale.RESULTSConsumer satisfaction with health insurance was consistently lowest in the West (p<0.0001). Lower private health insurance plan satisfaction was associated with the percentage of the population without a place of usual medical care, the percentage of the state population that is Hispanic, and the percentage of the population reporting any mental illness. Factors associated with increasing insurance satisfaction included higher healthcare spending per capita, a higher number of for-profit beds per capita, and an increased cancer death rate. Increased consumer satisfaction was associated with the Kaiser and Anthem insurance plan families.Conclusions and RelevanceState and insurer family factors are predictive of private health insurance plan satisfaction. Potentially modifiable factors include access to primary care, healthcare spending per capita, and numbers of for-profit hospital beds. This information will help consumers hold insurance providers accountable to provide higher quality and more desirable coverage and provide actionable items to improve health insurance satisfaction.

Irritable bowel syndrome (IBS) is a common gastrointestinal condition with a heterogeneous pathophysiology. An altered gut microbiome has been identified in some IBS patients, and fecal microbiota transplantation (FMT) has been suggested to treat IBS. We performed meta-analyses and systematic review of available randomized controlled trials (RCTs) to evaluate the efficacy of FMT in IBS.We performed a systematic literature search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science. Selection criteria included RCTs of FMT vs placebo using FMT excipients or autologous FMT in IBS. Meta-analyses were conducted to evaluate the summary relative risk (RR) and 95% confidence intervals (CIs) of combined studies for primary outcome of improvement in global IBS symptoms as measured by accepted integrative symptom questionnaires or dichotomous responses to questions of overall symptom improvement.Among 742 citations identified, 7 were deemed to be potentially relevant, of which 4 studies involving 254 participants met eligibility. No significant difference in global improvement of IBS symptoms was observed at 12 weeks in FMT vs placebo (RR = 0.93; 95% CI 0.48-1.79). Heterogeneity among studies was significant (I = 79%). Subgroup analyses revealed benefits of single-dose FMT using colonoscopy and nasojejunal tubes in comparison with autologous FMT for placebo treatment (number needed to treat = 5, RR = 1.59; 95% CI 1.06-2.39; I = 0%) and a reduction in likelihood of improvement of multiple-dose capsule FMT RCTs (number needed to harm = 3, RR = 0.54; 95% CI 0.34-0.85; I = 13%). Placebo response was 33.7% in nonoral FMT RCTs and 67.8% in capsule FMT RCTs. The Grading of Recommendations Assessment, Development and Evaluation quality of the body of evidence was very low.Current evidence from RCTs does not suggest a benefit of FMT for global IBS symptoms. There remain questions regarding the efficacy of FMT in IBS as well as the lack of a clean explanation on the discrepant results among RCTs in subgroup analyses.

INTRODUCTION: Coronavirus disease (COVID)-19 is a global pandemic that carries significant morbidity and mortality However, the effect of COVID-19 on liver disease, and vice versa, is not well-characterized in the United States Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition associated with metabolic disease including diabetes and obesity We examined the association between NAFLD and COVID19 disease severity in a large cohort of patients METHODS: We retrospectively reviewed a cohort of 396 consecutive adult patients with RT-PCR positive for COVID-19 between March 1 and April 30, 2020 at Michigan Medicine NAFLD was defined as either prior imaging evidence of steatosis or hepatic steatosis index >36 for Asians or >39 for non-Asians, with no history of alcohol abuse The primary outcome was disease severity based on admission to intensive care, intubation, death, or the World Health Organization (WHO) ordinal scale We used multivariable logistic regression to assess the predictors of intensive care, intubation, or death and linear regression for disease severity on WHO ordinal scale NAFLD was the primary predictor and models were adjusted for age, sex, race, recent healthcare exposure, hypertension, and dyslipidemia RESULTS: The median age was 60 5 years, 52% were male, 46% were Black, 41% were White and 54% had NAFLD Of 396 patients, 86% were hospitalized, 45% required intensive care, 30% required intubation, and 14% died 213 (54%) patients had NAFLD Patients with NAFLD were older (65 vs 57 years;P < 0 001), had higher body mass index (34 5 vs 26 4;P < 0 001), and higher prevalence of diabetes (45% vs 34%;P = 0 039) than those without NAFLD (Table 1) NAFLD was independently associated with increased odds of requiring admission to the intensive care unit (odds ratio [OR] 1 66 [1 06-2 62], P = 0 027) and intubation (OR 2 46 [1 50-4 04], P < 0 001), as well as higher WHO ordinal scale (beta 0 43 [0 03-0 84], P = 0 036) There was no significant association between NAFLD and death (OR 0 84 [0 46-1 67], P = 0 62) (Table 2 ) CONCLUSION: Our study shows that patients with NAFLD were more likely to develop severe disease with COVID-19 (Table Presented)

There are a growing number of targeted biologic therapies for the treatment of inflammatory bowel disease. Currently, three anti-TNF agents other than infliximab are approved for use in IBD. These medications are adalimumab, certolizumab, and golimumab. This chapter reviews these three anti-TNF-α agents for the treatment of inflammatory bowel disease, focusing on use in pediatric patients. In this chapter the efficacy, safety, and comparative efficacy of these medications for use in IBD is addressed. The emphasis is on use in pediatric patients with Crohn’s disease or ulcerative colitis, but data from trials in adults with IBD or children with psoriasis or rheumatologic diseases is also utilized to augment the information available for pediatric IBD patients.

As many as 25% of patients diagnosed with ulcerative colitis are hospitalized with an episode of acute severe ulcerative colitis (ASUC).1 The standard of care for patients hospitalized with ASUC relies on rapid induction with intravenous (IV) corticosteroids. Up to 30% of patients do not respond to corticosteroids alone.2 Rescue therapy with infliximab or cyclosporine has been shown to reduce rates of colectomy to 20% by 90 days.3,4 This still represents a significant rate of treatment failure, which leads to an unplanned and irreversible surgery. In recent years, increasing numbers of patients admitted with ASUC have already failed infliximab therapy, highlighting the need for additional treatment options for these patients. Tofacitinib is a rapidly acting, oral, small-molecule Janus kinase inhibitor that was recently approved by the Food and Drug Administration for treatment of ulcerative colitis.5 We present the first reported use of off-label, high-intensity tofacitinib in 4 patients admitted to our institution with ASUC predicted to fail medical management.

OBJECTIVE Many low-risk unruptured intracranial aneurysms (UIAs) are followed for growth with surveillance imaging. Growth of UIAs likely increases the risk of rupture. The incidence and risk factors of UIA growth or de novo aneurysm formation require further research. The authors retrospectively identify risk factors and annual risk for UIA growth or de novo aneurysm formation in an aneurysm surveillance protocol. METHODS Over an 11.5-year period, the authors recommended surveillance imaging to 192 patients with 234 UIAs. The incidence of UIA growth and de novo aneurysm formation was assessed. With logistic regression, risk factors for UIA growth or de novo aneurysm formation and patient compliance with the surveillance protocol was assessed. RESULTS During 621 patient-years of follow-up, the incidence of aneurysm growth or de novo aneurysm formation was 5.0%/patient-year. At the 6-month examination, 5.2% of patients had aneurysm growth and 4.3% of aneurysms had grown. Four de novo aneurysms formed (0.64%/patient-year). Over 793 aneurysm-years of follow-up, the annual risk of aneurysm growth was 3.7%. Only initial aneurysm size predicted aneurysm growth (UIA < 5 mm = 1.6% vs UIA ≥ 5 mm = 8.7%, p = 0.002). Patients with growing UIAs were more likely to also have de novo aneurysms (p = 0.01). Patient compliance with this protocol was 65%, with younger age predictive of better compliance (p = 0.01). CONCLUSIONS Observation of low-risk UIAs with surveillance imaging can be implemented safely with good adherence. Aneurysm size is the only predictor of future growth. More frequent (semiannual) surveillance imaging for newly diagnosed UIAs and UIAs ≥ 5 mm is warranted.

Background: Apathy is the most common noncognitive symptom inAlzheimer’s disease (AD). The structural correlates of apathy in AD have not yet been described. Methods: We analyzed magnetic resonance imaging data of 35 AD patients with and without apathy. Results: There was a significant linear association between apathy severity and cortical gray matter atrophy in the bilateral anterior cingulate [Brodmann area (BA) 24; r = 0.39–0.42, p = 0.01] and left medial frontal cortex (BA 8 and 9; r = 0.4, p < 0.02). Left mean cingulate cortical thinning predicted the presence/absence of apathy at the trend level of significance. Conclusion: Our study demonstrates a strong association between apathy and the integrity of medial frontal regions in AD.

Purpose The aim of this study was to investigate the longitudinal positron emission tomography (PET) metabolic changes in the elderly. Procedures Nineteen nondemented subjects (mean Mini-Mental Status Examination 29.4 ± 0.7 SD) underwent two detailed neuropsychological evaluations and resting 2-deoxy-2-[F-18]fluoro-d-glucose (FDG)-PET scan (interval 21.7 ± 3.7 months), baseline structural 3T magnetic resonance (MR) imaging, and apolipoprotein E4 genotyping. Cortical PET metabolic changes were analyzed in 3-D using the cortical pattern matching technique. Results Baseline vs. follow-up whole-group comparison revealed significant metabolic decline bilaterally in the posterior temporal, parietal, and occipital lobes and the left lateral frontal cortex. The declining group demonstrated 10–15% decline in bilateral posterior cingulate/precuneus, posterior temporal, parietal, and occipital cortices. The cognitively stable group showed 2.5–5% similarly distributed decline. ApoE4-positive individuals underwent 5–15% metabolic decline in the posterior association cortices. Conclusions Using 3-D surface-based MR-guided FDG-PET mapping, significant metabolic changes were seen in five posterior and the left lateral frontal regions. The changes were more pronounced for the declining relative to the cognitively stable group.

Background Alzheimer disease (AD) is the most common form of dementia worldwide. Mild cognitive impairment (MCI) is the recent terminology for patients with cognitive deficiencies in the absence of functional decline. Most patients with MCI harbor the pathologic changes of AD and demonstrate transition to dementia at a rate of 10% to 15% per year. Patients with AD and MCI experience progressive brain atrophy. Objective To analyze the structural magnetic resonance imaging data for 24 patients with amnestic MCI and 25 patients with mild AD using an advanced 3-dimensional cortical mapping technique. Design Cross-sectional cohort design. Patients/Methods We analyzed the structural magnetic resonance imaging data of 24 amnestic MCI (mean MMSE, 28.1; SD, 1.7) and 25 mild AD patients (all MMSE scores, >18; mean MMSE, 23.7; SD, 2.9) using an advanced 3-dimensional cortical mapping technique. Results We observed significantly greater cortical atrophy in patients with mild AD. The entorhinal cortex, right more than left lateral temporal cortex, right parietal cortex, and bilateral precuneus showed 15% more atrophy and the remainder of the cortex primarily exhibited 10% to 15% more atrophy in patients with mild AD than in patients with amnestic MCI. Conclusion There are striking cortical differences between mild AD and the immediately preceding cognitive state of amnestic MCI. Cortical areas affected earlier in the disease process are more severely affected than those that are affected late. Our method may prove to be a reliable in vivo disease-tracking technique that can also be used for evaluating disease-modifying therapies in the future.