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Human untargeted metabolomics studies annotate only ~10% of molecular features. We introduce reference-data-driven analysis to match metabolomics tandem mass spectrometry (MS/MS) data against metadata-annotated source data as a pseudo-MS/MS reference library. Applying this approach to food source data, we show that it increases MS/MS spectral usage 5.1-fold over conventional structural MS/MS library matches and allows empirical assessment of dietary patterns from untargeted data.

Obesity is variably associated with treatment response in biologic-treated patients with inflammatory bowel diseases (IBD). We evaluated the association between obesity and risk of hospitalization, surgery, or serious infections in patients with IBD in new users of biologic agents in a large, multicenter, electronic health record (EHR)-based cohort (CA-IBD).We created an EHR-based cohort of adult patients with IBD who were new users of biologic agents (tumor necrosis factor [TNF-α] antagonists, ustekinumab, and vedolizumab) between January 1, 2010, and June 30, 2017, from 5 health systems in California. Patients were classified as those with normal body mass index (BMI), overweight, or obese based on the World Health Organization classification. We compared the risk of all-cause hospitalization, IBD-related surgery, or serious infections among patients with obesity vs those overweight vs those with normal BMI, using Cox proportional hazard analyses, adjusting for baseline demographic, disease, and treatment characteristics.Of 3,038 biologic-treated patients with IBD (69% with Crohn's disease and 76% on TNF-α antagonists), 28.2% (n = 858) were overweight, and 13.7% (n = 416) were obese. On a follow-up after biologic initiation, obesity was not associated with an increased risk of hospitalization (adjusted hazard ratio [aHR] vs normal BMI, 0.90; [95% confidence interval, 0.72-1.13]); IBD-related surgery (aHR, 0.62 [0.31-1.22]); or serious infection (aHR, 1.11 [0.73-1.71]). Similar results were observed on stratified analysis by disease phenotype (Crohn's disease vs ulcerative colitis) and index biologic therapy (TNF-α antagonists vs non-TNF-α antagonists).In a multicenter, EHR-based cohort of biologic-treated patients with IBD, obesity was not associated with hospitalization, surgery, or serious infections. Further studies examining the effect of visceral obesity on patient-reported and endoscopic outcomes are needed.

Background and Aims Despite increasing interest in histologic remission as a treatment target in ulcerative colitis (UC), the accuracy of histologic findings in left colon in detecting pancolonic histologic remission is unknown. Methods In a retrospective cohort study of patients with endoscopically active pancolitis undergoing treat-to-target interventions, we evaluated the diagnostic accuracy of left-sided (distal to splenic flexure) histologic and endoscopic findings on colonoscopy for detecting histologic and endoscopic healing elsewhere in the colon. Results Of 86 patients with moderate to severely active pancolitis who underwent 2 consecutive colonoscopies during treat-to-target interventions, 38% and 51% achieved histologic and endoscopic remission, respectively. Substantial agreement (kappa, 0.67; 95% confidence interval (CI), 0.51-0.83) was observed in histologic findings between left and right colon on follow-up colonoscopy. Histologic, and endoscopic, findings in left colon showed excellent accuracy in detecting pancolonic histologic remission (area under the curve (AUC), 0.96 [95% CI, 0.93-1.0]; misclassification rate, 5.9%), histologic normalization (AUC, 1.0, 0%), endoscopic improvement (AUC, 0.95 [0.96-1.0], 3.5%) and endoscopic remission (AUC, 0.98 [0.96-1.00], 5.8%), respectively. Conclusions In patients with active pancolitis undergoing treat-to-target interventions, histologic and endoscopic findings in the left colon on colonoscopy have excellent accuracy for detecting pancolonic histologic remission, histologic normalization, endoscopic improvement, and endoscopic remission. Flexible sigmoidoscopy may suffice for monitoring histologic and endoscopic activity in patients with pancolitis.

Background & Aims We aimed to compare safety and effectiveness of vedolizumab to tumor necrosis factor (TNF)-antagonist therapy in ulcerative colitis in routine practice. Methods A multicenter, retrospective, observational cohort study (May 2014 to December 2017) of ulcerative colitis patients treated with vedolizumab or TNF-antagonist therapy. Propensity score weighted comparisons for development of serious adverse events and achievement of clinical remission, steroid-free clinical remission, and steroid-free deep remission. A priori determined subgroup comparisons in TNF-antagonist–naive and –exposed patients, and for vedolizumab against infliximab and subcutaneous TNF-antagonists separately. Results A total of 722 (454 vedolizumab, 268 TNF antagonist) patients were included. Vedolizumab-treated patients were more likely to achieve clinical remission (hazard ratio [HR], 1.651; 95% confidence interval [CI], 1.229-2.217), steroid-free clinical remission (HR, 1.828; 95% CI, 1.135-2.944), and steroid-free deep remission (HR, 2.819; 95% CI, 1.496-5.310) than those treated with TNF antagonists. Results were consistent across subgroup analyses in TNF-antagonist–naive and −exposed patients, and for vedolizumab vs infliximab and vs subcutaneous TNF-antagonist agents separately. Overall, there were no statistically significant differences in the risk of serious adverse events (HR, 0.899; 95% CI, 0.502-1.612) or serious infections (HR, 1.235; 95% CI, 0.608-2.511) between vedolizumab-treated and TNF-antagonist−treated patients. However, in TNF-antagonist−naive patients, vedolizumab was less likely to be associated with serious adverse events than TNF antagonists (HR, 0.192; 95% CI, 0.049-0.754). Conclusions Treatment of ulcerative colitis with vedolizumab is associated with higher rates of remission than treatment with TNF-antagonist therapy in routine practice, and lower rates of serious adverse events in TNF-antagonist−naive patients.

With unparalleled sensitivities, nanocomposites are believed to be key components in future bodily sensor and healthcare devices. However, there is a lack in understanding of how repeated strain cycles effect their electromechanical performance and what measures can be taken to accommodate changes in measurement using modelling and signal processing. Here, the author examines published cyclic data from a wide range of nanocomposite strain sensors. From the datasets, the author reports a near universal scaling in electromechanical signal with cycle number (C) as a result of the Mullin’s effect. Using a modified model based on Basquin’s law of fatigue, for all nanocomposites, signal was found to following a nearly identical C-0.1 power law scaling with cycle number. Using the presented model, the author demonstrated that a critical conditioning cycle number for a nanocomposite at which a steady state signal occurs, known as the endurance limit, can be predicted. Endurance limit was reported to be highly dependent on the scaling exponent noted in the cyclic data.

BACKGROUND Biologic therapies in patients with Crohn's disease often yield low clinical and endoscopic remission rates. After multiple failed therapies, combining two biologic therapies is possibly the sole medical alternative to recurrent surgery. However, data on this approach are limited. AIMS To assess the efficacy and safety of concomitant use of two biologic therapies in the largest cohort to date of refractory Crohn's disease patients. METHODS Data were extracted from Crohn's disease patients started on dual biologic therapy at two referral centres. Biologics utilised include infliximab, adalimumab, vedolizumab, ustekinumab, certolizumab and golimumab. The primary outcome was endoscopic improvement (>50% reduction in Simplified Endoscopic Score-Crohn's disease [SES-CD] or explicitly stated). Endoscopic remission (SES-CD

Chronic diseases, including inflammatory bowel disease (IBD) urgently need new biomarkers as a significant proportion of patients, do not respond to current medications. Inflammation is a common factor in these diseases, and microbial sensing in the intestinal tract is critical to initiate the inflammation. We have identified ELMO1 (engulfment and cell motility protein 1) as a microbial sensor in epithelial and phagocytic cells that turns on inflammatory signals. Using a stem cell-based 'gut-in-a-dish' coculture model, we studied the interactions between microbes, epithelium, and monocytes in the context of IBD. To mimic the invivo cell physiology, enteroid-derived monolayers (EDMs) were generated from the organoids isolated from WT and ELMO1-/- mice and colonic biopsies of IBD patients. The EDMs were infected with the IBD-associated microbes to monitor the inflammatory responses. ELMO1-depleted EDMs displayed a significant reduction in bacterial internalization, a decrease in pro-inflammatory cytokine productions and monocyte recruitment. The expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria of IBD patients where the higher expression is positively correlated with the elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-α. MCP-1 is released from the epithelium and recruits monocytes to the site of inflammation. Once recruited, monocytes require ELMO1 to engulf the bacteria and propagate a robust TNF-α storm. These findings highlight that the dysregulated epithelial ELMO1→MCP-1 axis can serve as an early biomarker in the diagnostics of IBD and other inflammatory disorders.

In Ireland, traditionally, most public Adult Mental Health Services (AMHSs) had a small cohort of service users with eating disorders (EDs) in their service. However, over the last 5 years, the National Clinical Programmes have been encouraging Mental Health Services to develop ED programmes in each catchment area. This has culminated in a model of care for EDs for children and adults. It appears that in relation to AMHSs, meaningful inclusion of families/significant other(s) in ED programmes is somewhat inconsistent. This paper will discuss the possible impact of excluding or minimising family/significant other(s)’ inclusion. It will also outline a suggested approach of including families/significant other(s) in a meaningful way in an out-patient ED programme.

Electrically conductive composite materials are highlighted as a potential tech path toward future flexible devices for wearable health technologies. To be commercially viable, these materials must not only be mechanically soft, highly sensitive to deformation, and report a sustainable signal but also utilize manufacturing methods that facilitate large-scale production. An ideal candidate for these envisioned technologies is the viscous, electromechanically sensitive composite material g-putty. Inks based on g-putty here are shown to transform a commercial polymer foam into a sensitive strain sensing material through a simple, scalable soaking procedure. Foam composites reported here have sensitives as high as ∼20 in terms of compressive strain and ∼0.4 kPa

Crohn’s disease (CD) is an inflammatory bowel disease, which can involve any region of the gastrointestinal tract. First described in 1932 as terminal ileitis or regional enteritis, it predominately involves the ileum with or without colonic involvement. Isolated colonic CD was first described in 1960 and since then the phenotypic classification of CD has evolved to stratify patients into isolated ileal, ileocolonic, or isolated colonic involvement. In the current review we evaluate the published literature regarding differences in epidemiology, natural history, pathogenesis, response to therapy, and disease monitoring, when stratified by disease location. Based on the available evidence consideration could be given to a new classification for CD, which splits it into ileum dominant (isolated ileal and ileocolonic) and isolated colonic disease. This may allow for a more optimized approach to clinical care and scientific research for CD.

Electrically conductive nanocomposites are an exciting ever expanding area of research that has yielded many new technologies for wearable health devices. Acting as strain sensing materials, they have paved the way towards real time medical diagnostic tools that may very well lead to a golden age of healthcare. Currently, the goal in research is to create a material that simultaneously has both a large gauge factor G and sensing range. However, a weakness in the area of electromechanical research is the lack of standardisation in the reporting of the figure of merit, i.e. G, and the need for new metrics to give researchers a more complete view of the research landscape of resistive type sensors. A paradigm shift in the way in which data is reported is required, to push research in the right direction and to facilitate achieving research goals. Here, we report a standardised method for reporting strain sensing performance and the introduction of the working factor W and the Young's modulus Y of a material as two new material criteria. Using this new method, we can now for the first time define the benchmarks for an optimum sensing material, G > 7, W > 1, Y < 300 kPa, using limits set by standard commercial materials and the human body. Using extrapolated data from 200 publications normalised to this standard method, we can review what composite types meet these benchmark limits, what governs composite performances, the literary trends in composites and individual nanomaterial performance and the future prospects of research., 7 Figures

Background There has been limited evaluation of the association between vedolizumab trough concentration and clinical outcomes in patients with inflammatory bowel diseases (IBD). Aim To perform a systematic review and meta-analysis to evaluate the potential role of therapeutic drug monitoring (TDM) for vedolizumab. Methods Through a systematic literature search through 28 February 2019, we identified five cohort studies (558 patients, 42% with ulcerative colitis) reporting the association between vedolizumab trough concentration and clinical outcomes in patients with IBD. We calculated mean difference (MD) in vedolizumab trough concentration in patients achieving vs not achieving clinical outcomes, and qualitatively synthesized thresholds associated with favourable outcomes. Results In patients with UC, median vedolizumab trough concentrations were consistently higher in patients achieving clinical remission (median, 14.3 μg/mL vs 10.5 μg/mL; MD, 5.1 μg/mL, 95% CI, 2.8-7.4) or endoscopic remission (median, 13.0 μg/mL vs 9.7; MD, 5.1 μg/mL, 95% CI, 2.2-7.9). In patients with CD, there was no significant difference in median vedolizumab trough concentrations in patients achieving vs not achieving clinical remission (MD, 2.0 μg/mL; 95% CI, -0.5 to 4.5) or endoscopic remission (MD, 3.6 μg/mL; 95% CI, -1.4 to 8.6). In patients with UC, week 6 vedolizumab trough concentrations ≥18.5-20.8 μg/mL, and maintenance trough concentrations ≥9.0-12.6 μg/mL were associated with favourable clinical outcomes. Antibodies to vedolizumab were reported in 1.7%-3.0% patients on maintenance therapy. Conclusion Based on meta-analysis, patients with UC who achieve endoscopic and clinical remission have significantly higher vedolizumab trough concentration during maintenance therapy. Vedolizumab trough concentration >20 μg/mL at week 6, and >12 μg/mL during maintenance may be associated with better outcomes, though cause-effect relationship remains unclear. Prospective studies on reactive and proactive therapeutic drug monitoring of vedolizumab (vs empiric dose escalation) are warranted.

Background Vedolizumab effectiveness estimates immediately after Food and Drug Administration (FDA) approval for ulcerative colitis (UC) and Crohn’s disease (CD) are limited by use in refractory populations. We aimed to compare treatment patterns and outcomes of vedolizumab in 2 time frames after FDA approval. Methods We used 2 data sets for time trend analysis, an academic multicenter vedolizumab consortium (VICTORY) and the Truven MarketScan database, and 2 time periods, May 2014–June 2015 (Era 1) and July 2015–June 2017 (Era 2). VICTORY cumulative 12-month clinical remission, corticosteroid-free remission, and mucosal healing rates, and Truven 12-month hospitalization and surgery rates, were compared between Eras 1 and 2 using time-to-event analyses. Results A total of 3661 vedolizumab-treated patients were included (n = 1087 VICTORY, n = 2574 Truven). In both cohorts, CD and UC patients treated during Era 2 were more likely to be biologic naïve. Compared with Era 1, Era 2 CD patients in the VICTORY consortium had higher rates of clinical remission (31% vs 40%, P = 0.03) and mucosal healing (42% vs 58%, P < 0.01). These trends were not observed for UC. In the Truven database, UC patients treated during Era 2 had lower rates of inflammatory bowel disease–related hospitalization (22.4% vs 9.6%, P < 0.001) and surgery (17.2% vs 9.4%, P = 0.008), which was not observed for CD. Conclusion Since FDA approval, remission and mucosal healing rates have increased for vedolizumab-treated CD patients, and vedolizumab-treated UC patients have had fewer hospitalizations and surgeries. This is likely due to differences between patient populations treated immediately after drug approval and those treated later., There has been a shift in utilization of vedolizumab in both Crohn’s disease and ulcerative colitis toward earlier use in the treatment sequencing algorithm. This shift in utilization is associated with improvements in response and disease outcomes.

While nanocomposite electromechanical sensors are expected to display reasonable conductivity and high sensitivity, little consideration is given to eliminating hysteresis and strain rate/frequency dependence from their response. For example, while G-putty, a composite of graphene and polysiloxane, has very high electromechanical sensitivity, its extreme viscoelasticity renders it completely unsuitable for real sensors due to hysteretic and rate-/frequency-dependent effects. Here it is shown that G-putty can be converted to an ink and printed into patterned thin films on elastic substrates. A partial graphene-polymer phase segregation during printing increases the thin-film conductivity by ×106 compared to bulk, while the mechanical effects of the substrate largely suppress hysteresis and completely remove strain rate and frequency dependence. This allows the fabrication of practical, high-gauge-factor, wearable sensors for pulse measurements as well as patterned sensors for low-signal vibration sensing.

Background Clinical remission is the recommended treatment target in ulcerative colitis. The predictors and outcomes of achieving histologic remission within a treat-to-target paradigm are not well established. Aim To evaluate the predictors and outcomes of achieving histologic remission in patients with ulcerative colitis treated-to-target of endoscopic healing (modified Mayo endoscopy score 0 or 1). Methods We conducted a retrospective cohort study in adults with active ulcerative colitis (modified Mayo endoscopy score 2 or 3), whose treatment was iteratively optimised to achieve endoscopic healing. We identified predictors of achieving histologic remission, and outcomes (risk of symptomatic relapse, and ulcerative colitis-related hospitalisation and/or surgery) of achieving histologic remission vs persistent histologic activity, using Cox proportional hazard analysis. Results Of the 411 patients with clinically active ulcerative colitis, 270 achieved endoscopic healing. Of the 270 patients, 55% simultaneously achieved histologic remission. Depth of endoscopic healing at final endoscopic assessment was the only independent determinant of histologic remission (modified Mayo endoscopy score 0 vs 1: odds ratio, 0.31 [95% confidence intervals, 0.18-0.52]). Over 28 months, achieving histologic remission was associated with a lower risk of clinical relapse (1-year cumulative risk: 18.7% vs 29.5%; adjusted hazard ratio, 0.56 [0.37-0.85]), and lower risk of hospitalisation (hazard ratio, 0.44 [0.20-0.94]). The incremental benefit of achieving histologic remission was observed only in patients achieving Mayo endoscopy score 1, but not Mayo endoscopy score 0. Conclusions In patients with active ulcerative colitis treated-to-target of endoscopic healing, 55% simultaneously achieved histologic remission. Histologic remission, particularly in patients achieving modified Mayo endoscopy score 1, was associated with favourable outcomes. Treating to a target of histologic remission over endoscopic healing requires prospective evaluation.

Background We quantified loss of response (LOR) to vedolizumab (VDZ) in clinical practice and assessed the effectiveness of VDZ dose intensification for managing LOR. Methods Retrospective review (May 2014–December 2016) of a prospectively maintained inflammatory bowel disease (IBD) registry. Kaplan-Meier estimates were used to determine rates of LOR to VDZ . Independent predictors of LOR were identified using univariate and multivariable Cox proportional hazard regression. Success of recapturing response (>50% reduction in symptoms from baseline) and remission (complete resolution of symptoms) after dose intensification was quantified. Results Cumulative rates for VDZ LOR were 20% at 6 months and 35% at 12 months, with slightly lower rates in Crohn’s disease than in ulcerative colitis (6 months 15% vs 18% and 12 months 30% vs 39%, P = 0.03). On multivariable analysis, LOR to a tumor necrosis factor (TNF) antagonist before VDZ use was associated with an increased risk for LOR to VDZ [hazard ratio (HR) 1.93; 95% confidence interval (CI) 1.25–2.97] in all patients. For Crohn’s disease patients specifically, higher baseline C-reactive protein concentration was associated with increased risk for LOR to VDZ (HR 1.01 per mg/dL increase, 95% CI 1.01–1.02). Shortening of VDZ infusion interval from 8 to every 4 or 6 weeks recaptured response in 49% and remission in 18% of patients. Conclusions LOR to a TNF antagonist before VDZ use and higher baseline C-reactive protein are important predictors of VDZ LOR. Treatment response can be recaptured in almost half of these patients with VDZ infusion interval shortening.

Background and aims: Colectomy with ileoanal pouch is the standard of care for most patients with ulcerative colitis (UC) who require surgery. However, 5%-38% of patients with ileoanal pouch develop pouch strictures that can severely impact the functional results. We retrospectively evaluated the efficacy and safety of endoscopic balloon dilation of ileoanal pouch strictures in patients with inflammatory bowel disease (IBD). Methods: All consecutive patients with IBD that underwent endoscopic balloon dilatation of a pouch stricture at our institution between January 1, 2011, and April 31, 2016, were included. Clinical, endoscopic, and surgical variables were collected retrospectively. Stricture-related pouch failure was defined by the need for surgical management of pouch stricture including pouch excision, diversion ileostomy, or stricturoplasty. Secondary outcomes included technical success, clinical success, and safety. Results: Eighty-eight endoscopic balloon dilatations were identified in 20 patients. Sixty percent of patients were female, with a median age at ileoanal pouch of 28.6 years (interquartile range [IQR], 25.5-37.2). Ileoanal pouch was performed for UC in 95% of cases; 95% of patients underwent J pouch; and 65% had a stapled anastomosis, whereas 35% had a handsewn anastomosis. Strictures were diagnosed at a median of 4.6 years (0.2-10.6) after surgery, and half of patients were symptomatic. The most frequent location of stricture was the anal-pouch anastomosis (87%). Half of patients were found to have associated pouchitis, 4 (20%) had at least 1 fistula, and 5 (25%) had ulcerations of the pouch. At the end of follow-up, 6 patients (30%) underwent a change in diagnosis from UC to Crohn's disease (CD) of the pouch, and in 1 patient (5%) a diagnosis of ischemic stricture was made. A median of 3.5 dilatations per patient (IQR, 2.0-7.0) were performed. Technical efficacy was observed in 87 procedures (98%). Twenty-two procedures were preceded by obstructive symptoms, and a clinical improvement after endoscopic balloon dilatation was observed in 95% of cases. After a median follow-up of 3.0 years (2.1-3.5), only 1 patient had stricture-related pouch failure. After the first dilatation, 4 patients were hospitalized for obstructive symptoms. Conservative management with another endoscopic balloon dilation was clinically effective in all cases. No major complications related to dilation were observed. Conclusion: Endoscopic balloon dilatation of ileoanal pouch strictures is largely effective and safe and can be recommended as the first line strategy to treat ileoanal pouch strictures in patients with IBD.

Background and Aims We sought to analyze whether response to a second-line biologic varies depending on the reason for discontinuation of the primary anti-TNF agent (primary non-response [PNR], secondary loss of response [LOR] after initial response, or intolerance), through a systematic review and meta-analysis. Methods Through a systematic search through May 31, 2017, we identified eight randomized controlled trials [RCTs] of biologics in patients with IBD with prior exposure to anti-TNF agents, that stratified response to second-line therapy by reason for discontinuing primary anti-TNF therapy [PNR vs. LOR vs. intolerance]. We estimated relative risk [RR] (and 95% confidence interval [CI]) of achieving clinical remission in patients with PNR as compared with patients with LOR, and intolerance, through random effects meta-analysis. Results As compared with patients who discontinued prior anti-TNF due to intolerance, patients with prior PNR were 24% less likely to achieve remission with second-line biologics (RR,0.76 [0.61–0.96]). As compared with patients who discontinued prior anti-TNF due to LOR, patients with prior PNR were 27% less likely to achieve remission with induction therapy with second-line biologics (RR,0.73 [0.56–0.97]), particularly to ustekinumab (RR,0.64 [0.52–0.80]). There was no difference in response to vedolizumab in patients with prior PNR or LOR to anti-TNF agents (RR,1.16 [0.85–1.58]). Conclusion Patients with PNR to anti-TNF agents are less likely to respond to second-line non-TNF biologics, as compared with patients who discontinued therapy due to secondary LOR or intolerance. This may be attributed to underlying pharmacokinetics and pharmacodynamics of anti-TNF agents in patients with PNR.

In an attempt to further advance the understanding of plutonium coordination chemistry, we report a robust method for recycling and obtaining plutonium aqueous stock solutions that can be used as a convenient starting material in plutonium synthesis. This approach was used to prepare and characterize plutonium(IV) tetrachloride tris-diphenylsulfoxide, PuCl4(OSPh2)3, by single crystal X-ray diffraction. The PuCl4(OSPh2)3 compound represents a rare example of a 7-coordinate plutonium(IV) complex. Structural characterization of PuCl4(OSPh2)3 by X-ray diffraction utilized a new containment method for radioactive crystals. The procedure makes use of epoxy, polyimide loops, and a polyester sheath to provide a robust method for safely containing and easily handling radioactive samples. The described procedure is more user friendly than traditional containment methods that employ fragile quartz capillary tubes. Additionally, moving to polyester, instead of quartz, lowers the background scattering from the heavier silicon atoms.

Ustekinumab IV 6 mg/kg Loading Dose Re-induction Improves Clinical and Endoscopic Response in Crohn’s disease: A Case Series

We assessed the real-world effectiveness and safety of vedolizumab (VDZ) in moderate-severe Crohn's disease (CD).Retrospective cohort study of seven medical centers, from May 2014 to December 2015. Adults with moderate-severe CD treated with VDZ, with follow-up after initiation of therapy, were included. Using the multivariable Cox proportional hazard analyses, we identified independent predictors of clinical remission or mucosal healing with VDZ. Rates of serious infection (requiring antibiotics, resulting in discontinuation of VDZ, hospitalization or death) and serious adverse events (discontinuation of VDZ, hospitalization or death) were described quantitatively.We included 212 patients with moderate-severe CD (median age 34 years; 40% male; 90% tumor necrosis factor (TNF)-antagonist exposed) with a median follow-up (IQR) of 39 weeks (25-53). Twelve-month cumulative rates of clinical remission, mucosal healing, and deep remission (clinical remission+mucosal healing) were 35%, 63%, and 26%, respectively. Individuals with prior TNF-antagonist exposure (hazard ratio (HR) 0.40; 95% confidence interval (CI): 0.20-0.81), smoking history (HR 0.47; 95% CI: 0.25-0.89), active perianal disease (HR 0.49; 95% CI: 0.27-0.88), and severe disease activity (HR 0.54; 95% CI: 0.31-0.95) were less likely to achieve clinical remission. Those with prior TNF-antagonist exposure (HR 0.29; 95% CI: 0.12-0.73), and severe disease activity (HR 0.54; 95% CI: 0.31-0.95) were less likely to achieve mucosal healing. During 160 patient years of follow-up (PYF) and 1,433 VDZ infusions, 5 patients developed infusion reactions (3.5 per 1,000 infusions), 21 developed serious infections (13 per 100 PYF), and 17 developed serious adverse events (10 per 100 PYF). A minority of adverse events required discontinuation of therapy (6 per 100 PYF).VDZ is a safe and effective treatment option for moderate-severe CD in routine practice. Clinical remission and deep remission (clinical remission and mucosal healing) can be achieved in 1/3 of individuals, and a minority of individuals require discontinuation of therapy due to adverse events.

Hypervalent UO2, UO2(+x) formed by both addition of excess O and photoexcitation, exhibits a number of unusual or often unique properties that point to it hosting a polaronic Bose–Einstein(-Mott) condensate. A more thorough analysis of the O X-ray absorption spectra of UO2, U4O9, and U3O7 shows that the anomalous increase in the width of the spectral features assigned to predominantly U 5f and 6d final states that points to increased dispersion of these bands occurs on the low energy side corresponding to the upper edge of the gap bordered by the conduction or upper Hubbard band. The closing of the gap by 1.5 eV is more than twice as much as predicted by calculations, consistent with the dynamical polaron found by structural measurements. In addition to fostering the excitation that is the proposed mechanism for the coherence, the likely mirroring of this effect on the occupied, valence side of the gap below the Fermi level points to increased complexity of the electronic structure that could be associated with the Fermi topology of BEC–BCS crossover and two band superconductivity.

Here we describe using nanosheets of both graphene and boron nitride, produced by liquid phase exfoliation, as fillers in composite fibres. The fibres were prepared by coagulation spinning using polyvinylalcohol as a matrix. We obtained good quality fibres with diameter and nanosheet volume fraction which could be controlled via the ratio of nanosheet to polymer injection rates. The mechanical stiffness (modulus, Y) and strength, σ B , increased relatively slowly with volume fraction (dY/dV f ≤ 160 GPa and dσ B /dV f ≤ 0.8 GPa). However, both stiffness and strength continued increasing with nanosheet content to loading levels of ∼20vol%, after which the properties fell off. Such relatively high loading levels result in impressive mechanical properties with stiffness and strength of up to 30 GPa and 260 MPa observed. In addition, we found the graphene-filled fibres to be electrically conducting with conductivities of up to 3 S/m.

Background & aimsWe created and validated a clinical decision support tool (CDST) to predict outcomes of vedolizumab therapy for ulcerative colitis (UC).MethodsWe performed logistic regression analyses of data from the GEMINI 1 trial, from 620 patients with UC who received vedolizumab induction and maintenance therapy (derivation cohort), to identify factors associated with corticosteroid-free remission (full Mayo score of 2 or less, no subscore above 1). We used these factors to develop a model to predict outcomes of treatment, which we called the vedolizumab CDST. We evaluated the correlation between exposure and efficacy. We validated the CDST in using data from 199 patients treated with vedolizumab in routine practice in the United States from May 2014 through December2017.ResultsAbsence of exposure to a tumor necrosis factor (TNF) antagonist (+3 points), disease duration of 2 y or more (+3 points), baseline endoscopic activity (moderate vs severe) (+2 points), and baseline albumin concentration (+0.65 points per 1 g/L) were independently associated with corticosteroid-free remission during vedolizumab therapy. Patients in the derivation and validation cohorts were assigned to groups of low (CDST score, 26 points or less), intermediate (CDST score, 27-32 points), or high (CDST score, 33 points or more) probability of vedolizumab response. We observed a statistically significant linear relationship between probability group and efficacy (area under the receiver operating characteristic curve, 0.65), as well as drug exposure (P < .001) in the derivation cohort. In the validation cohort, a cutoff value of 26 points identified patients who did not respond to vedolizumab with high sensitivity (93%); only the low and intermediate probability groups benefited from reducing intervals of vedolizumab administration due to lack of response (P = .02). The vedolizumab CDST did not identify patients with corticosteroid-free remission during TNF antagonist therapy.ConclusionsWe used data from a trial of patients with UC to develop a scoring system, called the CDST, which identified patients most likely to enter corticosteroid-free remission during vedolizumab therapy, but not anti-TNF therapy. We validated the vedolizumab CDST in a separate cohort of patients in clinical practice. The CDST identified patients most likely to benefited from reducing intervals of vedolizumab administration due to lack of initial response. ClinicalTrials.gov no: NCT00783718.

Background & Aims Clinical remission, defined by a composite of patient reported outcomes and Mayo endoscopy subscore (MES) 0 or 1 is a recommended treatment target in patients with ulcerative colitis (UC). We estimated whether incorporating more rigorous remission definitions, of endoscopic remission (MES 0) and histologic remission, affects risk of relapse. Methods Through a systematic review, we identified cohort studies in adults with UC in clinical remission that reported a minimum 12-month risk of clinical relapse, based on MES (0 vs 1) and/or histologic disease activity, in patients with endoscopic remission. Using random effects meta-analysis, we calculated relative and absolute risk of clinical relapse in patients with UC achieving different treatment targets. Results In a meta-analysis of 17 studies that included 2608 patients with UC in clinical remission, compared to patients achieving MES 1, patients achieving MES 0 had a 52% lower risk of clinical relapse (relative risk, 0.48; 95% CI, 0.37–0.62). The median 12-month risk of clinical relapse in patients with MES 1 was 28.7%; the estimated annual risk of clinical relapse in patients with MES 0 was 13.7% (95% CI, 10.6–17.9). In a meta-analysis of 10 studies in patients in endoscopic remission (MES 0), patients who achieved histologic remission had a 63% lower risk of clinical relapse vs patients with persistent histologic activity (relative risk, 0.37; 95% CI, 0.24–0.56). Estimated annual risk of clinical relapse in who achieved achieving histologic remission was 5.0% (95% CI, 3.3–7.7). CONCLUSIONS In a systematic review and meta-analysis of patients with UC in clinical remission, we observed that patients achieving more rigorous treatment endpoints (endoscopic and histologic remission) have a substantially lower risk of clinical relapse compared with patients achieving clinical remission.

Chemical signatures correlated with uranium oxide processing are of interest to forensic science for inferring sample provenance. Identification of temporal changes in chemical structures of process uranium materials as a function of controlled temperatures and relative humidities may provide additional information regarding sample history. In this study, a high-purity α-U3O8 sample and three other uranium oxide samples synthesized from reaction routes used in nuclear conversion processes were stored under controlled conditions over 2-3.5 years, and powder X-ray diffraction analysis and X-ray absorption spectroscopy were employed to characterize chemical speciation. Signatures measured from the α-U3O8 sample indicated that the material oxidized and hydrated after storage under high humidity conditions over time. Impurities, such as uranyl fluoride or schoepites, were initially detectable in the other uranium oxide samples. After storage under controlled conditions, the analyses of the samples revealed oxidation over time, although the signature of the uranyl fluoride impurity diminished. The presence of schoepite phases in older uranium oxide material is likely indicative of storage under high humidity and should be taken into account for assessing sample history. The absence of a signature from a chemical impurity, such as uranyl fluoride hydrate, in an older material may not preclude its presence at the initial time of production. LA-UR-15-21495.

The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8+ T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.

Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.

Cronkhite Canada Syndrome: Significant Response to Infliximab and a Possible Clue to Pathogenesis

Integrated sensors for bodily measurements require a sensing material that is highly conductive, flexible, thin and sensitive. It is important that these materials are non-invasive in application but robust in nature to allow for effective, continuous measurement. Herein, we report a comparative study of two simple, scalable methods to produce silver nanowire (AgNW) polyurethane (PU) composite materials: layer-by-layer (LBL) and mixed filtration. Both types of composites formed were ultrathin (∼50 μm) and highly conductive (104 S m−1), with the LBL method ultimately found to be superior due to its low percolation threshold. Electrical resistance of the LBL composites was found to vary with strain, making these materials suitable for strain sensing. LBL composites displayed a working strain up to ∼250% and a high gauge factor (G), with values of G ∼70 reported. The sensors reported here were ∼109-times more conductive and ∼104-times thinner than their carbon-based composite sensor counterparts with similar gauge factor. This made the strain sensors presented here among one of the most flexible, highly sensitive, thinnest, conductive materials in literature. We demonstrated that with these properties, the LBL composites formed were ideal for bodily motion detection.

Understanding the uranium 5f/6d orbital mixing with oxygen 2p valence orbitals in uranium oxides is important for advancing nuclear technology. Unfortunately, U–O orbital mixing is difficult to probe experimentally. In this manuscript, U–O bonding is evaluated in U 3 O 8 using O K-edge X-ray absorption spectroscopy (XAS). To confirm that the O K-edge XAS spectra were correct and did not contain contributions from surface contamination, three different sample types were investigated using three unique detection methods. Specifically an epitaxial film of U 3 O 8 deposited on Al 2 O 3 (PAD-U 3 O 8 ) was probed using grazing-incidence fluorescence yield (GIFY) detection, a bulk powder of α-phase U 3 O 8 was analyzed with fluorescence yield (FY) detection at normal incidence, and particles of α-phase U 3 O 8 were studied in transmission mode using a scanning transmission X-ray microscope (STXM). Experimental spectra have been presented in the context of previously published computational results from DFT using the Heyd–Scuseria–Ernzerhof (HSE) screened hybrid functional. Overall, the comparative analyses of PAD-U 3 O 8 and α-phase U 3 O 8 samples enabled identification of unique signatures associated with oxygen 2p orbital mixing with both U V and U VI 5f and 6d valence orbitals.

To progress from the laboratory to commercial applications, it will be necessary to develop industrially scalable methods to produce large quantities of defect-free graphene. Here we show that high-shear mixing of graphite in suitable stabilizing liquids results in large-scale exfoliation to give dispersions of graphene nanosheets. X-ray photoelectron spectroscopy and Raman spectroscopy show the exfoliated flakes to be unoxidized and free of basal-plane defects. We have developed a simple model that shows exfoliation to occur once the local shear rate exceeds 10(4) s(-1). By fully characterizing the scaling behaviour of the graphene production rate, we show that exfoliation can be achieved in liquid volumes from hundreds of millilitres up to hundreds of litres and beyond. The graphene produced by this method performs well in applications from composites to conductive coatings. This method can be applied to exfoliate BN, MoS2 and a range of other layered crystals.

Bilirubin, a breakdown product of heme metabolism, has been shown to be protective against cardiovascular mortality; however, it is also a marker of liver function. There are limited data on the longitudinal changes in bilirubin with aging in a population-based cohort of older adults. This study was designed to determine whether serum bilirubin changes with age in older adults, and to evaluate whether age attenuates the association between bilirubin and mortality.This is a prospective cohort study of 2364 participants with a mean age of 70 years, who completed a research clinic visit from 1984 to 1987, and 1703 participants who returned for a second research visit approximately 8 years later. Cross-sectional and longitudinal multivariable-adjusted analyses were performed to examine the association between serum bilirubin, aging, and mortality.In cross-sectional analyses, when the cohort was divided into quartiles of age, higher baseline serum bilirubin levels were associated with older age in analyses adjusted for sex, body mass index (BMI), alanine aminotransferase (ALT), albumin, and metabolic traits (P-value0.001). In longitudinal analyses, among the subset of participants who had two research visits, aging remained significantly associated with an increase in bilirubin in multivariable-adjusted models (P-value0.0001). When the longitudinal cohort was divided into bilirubin quartiles, Kaplan-Meier analysis showed an incremental reduction in survival with higher bilirubin levels (P-value = 0.002); however, this association between bilirubin quartile and mortality was no longer significant after adjusting for age (P-value 0.30), suggesting higher bilirubin in older age does not confer survival advantage.Serum bilirubin levels gradually increase with age in older adults. Elevated bilirubin in older individuals is not associated with improved survival as previously reported in middle-aged populations.

Background & aimsPatients with Crohn's disease (CD) often have bile acid diarrhea (BAD), due to bile acid malabsorption following ileal resection (IR). Bile acid malabsorption increases production of 7α-hydroxy-4-cholesten-3-one (C4), a bile acid precursor. We investigated relationships between serum concentrations of C4 and BAD in patients with CD.MethodsWe collected demographic data, serum samples, and information on the presence of diarrhea (>3 liquid bowel movements/day), as well as clinical, endoscopic, and histologic scores from 26 patients with CD and IR, 21 patients with CD without IR, and 37 patients with ulcerative colitis (UC). We compared serum concentrations of C4 and fibroblast growth factor 19 (FGF19) between groups. We performed area under the receiver operating characteristic curve (AUROC) analysis to identify the optimal cutoff C4 concentrations for the diagnosis of diarrhea attributable to bile acid malabsorption (BAD), defined as diarrhea and a serum concentration of FGF19

Background & Aims There are few real-world data on the safety of vedolizumab for treatment of Crohn’s disease (CD) or ulcerative colitis (UC). We quantified rates and identified factors significantly associated with infectious and non-infectious adverse events in clinical practice. Methods We performed a retrospective review of data from a multicenter consortium database (from May 2014 through June 2017). Infectious and non-infectious adverse events were defined as those requiring antibiotics, hospitalization, vedolizumab discontinuation, or resulting in death. Rates were quantified as proportions and events per 100 patient years of exposure (PYE) or follow up (PYF). We performed multivariable logistic regression analyses to identify factors significantly associated with events and reported as odds ratios (OR) with 95% CIs. Results Our analysis comprised 1087 patients (650 with CD and 437 with UC; 55% female; median age, 37 years) with 861 PYE and 955 PYF. Infections were observed in 68 patients (6.3%; 7.9 per 100 PYE, 7.1 per 100 PYF); gastrointestinal infections (n = 31, 2.4 per 100 PYE, 2.2 per 100 PYF) and respiratory infections (n = 14, 1.6 per 100 PYE, 1.5 per 100 PYF) were the most common. Arthralgias were the most common non-infectious adverse events (n = 31, 2.9%; 3.6 per 100 PYE). Two patients developed malignancies (squamous cell skin cancer and colorectal cancer; 0.23 per 100 PYE, 0.21 per 100 PYF). Active smoker status (OR, 3.39) and number of concomitant immunosuppressive agents (corticosteroids or immunomodulators; OR, 1.72 per agent) used were independently associated with infections. Conclusion In a retrospective cohort study of patients with IBD, we found vedolizumab to be well tolerated with an overall favorable safety profile. Active smoking and concomitant use of immunosuppressive agents were independently associated with infections