bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating heat-related mortality in near real time for national heatwave plans
Authors: Lo Y T Eunice , Mitchell Dann M , Thompson Ross , O’Connell Emer , Gasparrini Antonio
Published: January 2022

Heatwaves are a serious threat to human life. Public health agencies that are responsible for delivering heat-health action plans need to assess and reduce the mortality impacts of heat. Statistical models developed in epidemiology have previously been used to attribute past observed deaths to high temperatures and project future heat-related deaths. Here, we investigate the novel use of summer temperature-mortality associations established by these models for monitoring heat-related deaths in regions in England in near real time. For four summers in the period 2011–2020, we find that coupling these associations with observed daily mean temperatures results in England-wide heatwave mortality estimates that are consistent with the excess deaths estimated by UK Health Security Agency. However, our results for 2013, 2018 and 2020 highlight that the lagged effects of heat and characteristics of individual summers contribute to disagreement between the two methods. We suggest that our method can be used for heatwave mortality monitoring in England because it has the advantages of including lagged effects and controlling for other risk factors. It could also be employed by health agencies elsewhere for reliably estimating the health burden of heat in near real time and near-term forecasts.
Permutation invariant Gaussian two-matrix models
Authors: Barnes George , Padellaro Adrian , Ramgoolam Sanjaye
Published: January 2022

We construct the general permutation invariant Gaussian two-matrix model for matrices of arbitrary size D. The parameters of the model are given in terms of variables defined using the representation theory of the symmetric group S

D
. A correspondence is established between the permutation invariant polynomial functions of the matrix variables (the observables of the model) and directed colored graphs, which sheds light on stability properties in the large D counting of these invariants. A refined counting of the graphs is given in terms of double cosets involving permutation groups defined by the local structure of the graphs. Linear and quadratic observables are transformed to an S

D
representation theoretic basis and are used to define the convergent Gaussian measure. The perturbative rules for the computation of expectation values of graph-basis observables of any degree are given in terms of the representation theoretic parameters. Explicit results for a number of observables of degree up to four are given along with a Sage programme that computes general expectation values.
Bisulfite-initiated crosslinking of gelatin methacryloyl hydrogels for embedded 3D bioprinting
Authors: Bilici Çiğdem , Tatar Asena G , Şentürk Efsun , Dikyol Caner , Koç Bahattin
Published: January 2022

Recent studies on three-dimensional (3D) bioprinting of cell-laden gelatin methacryloyl (GelMA) hydrogels have provided promising outcomes for tissue engineering applications. However, the reliance on the use of photo-induced gelation processes for the bioprinting of GelMA and the lack of an alternative crosslinking process remain major challenges for the fabrication of cell-laden structures. Here, we present a novel crosslinking approach to form cell-laden GelMA hydrogel constructs through 3D embedded bioprinting without using any external irradiation that could drastically affect cell viability and functionality. This approach consists of a one-step type of crosslinking via bisulfite-initiated radical polymerization, which is combined with embedded bioprinting technology to improve the structural complexity of printed structures. By this means, complex-shaped hydrogel bio-structures with cell viability higher than 90% were successfully printed within a support bath including sodium bisulfite. This study offers an important alternative to other photo-induced gelation processes to improve the bio-fabrication of GelMA hydrogel with high cell viability.
High energy electron beam generation during interaction of a laser accelerated proton beam with a gas-discharge plasma
Authors: XU Wangwen , HU Zhanghu , HUI Dexuan , WANG Younian
Published: January 2022

The study of the interaction between ion beam and plasma is very important to the areas of inertial fusion energy and high energy density physics. With detailed one-dimensional electromagnetic particle-in-cell simulations, we investigate here the interaction of a laser-accelerated proton beam assuming an ideal monoenergetic beam with a gas-discharge plasma. After the saturation stage of the two-stream instability excited by the proton beam, significant high energy electrons are observed, with maximum energy approaching 2 MeV, and a new two-stream instability occurs between the high energy electrons and background electrons. The trajectories of plasma electrons are studied, showing the process of electron trapping and de-trapping from the wakefield.
OP01 Withdrawal of infliximab or anti-metabolite therapy in Crohn’s Disease patients in sustained remission on combination therapy: A randomized unblinded controlled trial (SPARE)
Authors: Louis J E , Resche-Rigon M , Laharie D , Satsangi J , Ding N , Preiss J , D’Haens G , Picon L , Bossuyt P , Vuitton L , Irving P , Bouhnik Y , Viennot S , Lamb C , Pollock R , Baert F , Nachury M , Mathurin F , Gilletta C , Colombel J F , Hertervig E
Published: January 2022

Background

Combination therapy with infliximab and anti-metabolites is a standard option for patients with Crohn’s disease (CD). The implications of long term use of combination therapy may lead patients and clinicians to contemplate treatment de-escalation once steroid-free remission has been achieved. The aim of our study was to assess the relapse rates and time spent in remission over 2 years, after withdrawal of infliximab or anti-metabolite compared to continuation of combination therapy.

Methods

CD patients treated with a combination therapy of infliximab (IFX) and anti-metabolite > 8 months and in sustained steroid-free remission > 6 months were recruited in 64 centers in France, United Kingdom, Belgium, Sweden, Australia, Germany and The Netherlands. Patients were randomized into 3 arms - continuing combination therapy (arm A); stopping IFX (arm B); or stopping anti-metabolite (arm C). In case of a relapse [defined by CDAI and an objective marker of inflammation (CRP or fecal calprotectin)], patients were retreated by resuming infliximab in arm B or the anti-metabolite in arm C, according to a pre-defined scheme, including optimization of IFX up to 10 mg/Kg if necessary in all arms. The two co-primary endpoints were the relapse rate and mean survival time spent in remission over 2 years. A major secondary endpoint was treatment failure (complications or not recapturing remission).

Results

254 patients were screened, 211 randomized, 5 withdrew consent and 1 was lost to follow-up, leaving 205 patients for the analysis - 67 randomized to arm A, 71 to arm B and 67 to arm C. Demographic and clinical characteristics are shown in Table 1. The two-year relapse rates were 14% (IC95%: 4–23%) in arm A, 40% (IC95%: 28–51%) in arm B, and 10% (IC95%: 2–18%) in arm C (p=0.0003 arm B vs arm A and <0.0001 arm B vs arm C) (figure 1). The time spent in remission was 1.91 yrs (IC95%: 1.83–1.99), 1.89 yrs (IC95%: 1.82–1.96) and 1.93 yrs (IC95%: 1.86–2.00) in arm A, B and C, respectively. Out of the 39 relapsers, 28 were retreated/optimized. Remission was achieved in 1/2 retreated patients in arm A, 22/23 in arm B and 2/3 in arm C. Treatment failure was observed in 4/67, 4/71 and 3/67 patients, in these three arms, respectively. No malignancy was observed, one tuberculosis in arm C and two severe infections (pneumonia and viral pericarditis) in arm B.

Conclusion

Infliximab withdrawal, but not antimetabolite withdrawal, was associated with a significantly higher risk of relapse than continuation of combination therapy. Almost all patients who stopped IFX achieved rapid remission when resuming treatment. The time spent in remission over 2 years was similar across groups.
OP18 Efficacy and safety of filgotinib for the treatment of perianal fistulizing Crohn’s Disease: Results from the phase 2 DIVERGENCE 2 study
Authors: Reinisch W , Colombel J F , D’Haens G R , Rimola J , DeHaas-Amatsaleh A , McKevitt M , Ren X , Serone A , Schwartz D A , Gecse K B
Published: January 2022

Background

Treatment of perianal fistulizing Crohn’s disease (PFCD) is a major unmet need. Filgotinib (FIL) is a once-daily, oral, preferential Janus kinase 1 inhibitor in development for the treatment of inflammatory bowel diseases. The efficacy and safety of FIL for the treatment of PFCD was evaluated in the phase 2, double-blind, randomized, placebo (PBO)-controlled DIVERGENCE 2 study (NCT03077412).

Methods

Patients (18–75 years old) with PFCD (documented diagnosis of CD for at least 3 months and 1–3 external openings [EOs] with drainage [spontaneous or on compression] for ≥ 4 weeks before screening) previously treated with antibiotics, immunomodulators and/or tumour necrosis factor inhibitors (TNFi) were randomized (2:2:1) to receive FIL 200 mg, FIL 100 mg or PBO once daily for up to 24 weeks. Active luminal CD was permitted providing that the Crohn’s Disease Activity Index score was ≤ 300 at screening. The primary endpoint was combined fistula response (reduction of ≥ 1 from baseline in the number of draining EOs determined by investigator assessment and no fluid collections > 1 cm on centrally read pelvic magnetic resonance imaging [MRI]) at Week 24. Combined fistula remission (closure of all draining EOs present at baseline and no fluid collections > 1 cm) at Week 24 was a key secondary endpoint. The study was not powered for statistical comparisons and was prematurely terminated owing to low recruitment rates during the COVID-19 pandemic.

Results

Baseline characteristics were broadly similar across the treatment groups (Table 1). Overall, 91.2% of patients had complex perianal fistulae and TNFi treatment had previously failed in 64.9% of patients. A lower proportion of patients randomized to receive FIL 200 mg discontinued the study compared with those who received PBO (Table 2). The proportion of patients who achieved a combined fistula response at Week 24 was numerically higher in the FIL 200 mg group (47.1%; 90% confidence interval [CI]: 26.0–68.9) than in the PBO group (25.0%; 90% CI: 7.2–52.7) (Figure 1), with similar results observed for combined fistula remission (FIL 200 mg [47.1%; CI: 26.0–68.9] versus PBO [16.7%; CI: 3.0–43.8]) (Figure 2). Treatment-emergent severe adverse events were highest in the FIL 200 mg group (Table 2). Adverse event rates were otherwise similar across treatment groups.

Conclusion

In this phase 2 study, numerically higher fistula response and remission rates were observed after 24 weeks of treatment with FIL 200 mg versus PBO in patients with active PFCD and a history of multiple medical treatment failures. FIL was well tolerated overall. Further studies of FIL for the treatment of PFCD are warranted.
DOP15 Fluorescent labelled vedolizumab for real-time visualization and quantification of local drug distribution and pharmacodynamics in Inflammatory Bowel Diseases during endoscopy
Authors: Gabriëls R Y , Linssen M , van der Waaij A , Volkmer P , Hooghiemstra W , Kats-Ugurlu G , Robinson D , Dijkstra G , Nagengast W
Published: January 2022

Background

Vedolizumab is a monoclonal antibody which blocks integrin α4β7 inhibiting trafficking of T-lymphocytes into the gut. Unfortunately, up to 60% of vedolizumab patients experience non-response. The mechanism of action of vedolizumab is not elucidated, predictors of response are unknown and data for local drug distribution in the gut are lacking. In this clinical trial, we investigated the feasibility of assessing local distribution of fluorescently labelled vedolizumab in the gut mucosa of inflammatory bowel diseases (IBD) patients to finally enable prediction of therapy response in individual patients.

Methods

Vedolizumab (Entyvio, Takeda Pharma) was labelled to IRDye 800CW under cGMP conditions to yield clinical grade vedolizumab-800CW. In this dose-escalation trial, vedolizumab naïve IBD patients and IBD patients treated with vedolizumab for at least 14 weeks were included. Patients received an intravenous dose of fluorescently labelled vedolizumab of either 0 mg, 4.5 mg, 15 mg or 15 mg + 75 mg unlabelled vedolizumab 3 days prior colonoscopy. In vivo fluorescence imaging was assessed by fibre-based wide-field fluorescence molecular endoscopy (FME) and quantified by spectroscopy in healthy, mildly inflamed and severely inflamed tissue. All assessed tissue was biopsied for ex vivo examination of the fluorescent signal, fluorescence microscopy and spectroscopy.

Results

Up to submission 34 patients completed tracer injection and FME. An interim analysis was performed after 20 patients (5 in each dose group), which showed in severely inflamed tissue an 8 fold higher fluorescent signal in the 15 mg dose group (0.049 Q*μfa,x [mm-1]) compared to the control group (0.006 μfa,x [mm-1]) (p<0.05). Furthermore, the fluorescent signal within the 15 mg dose group was also 2.5 fold higher compared to healthy tissue (0.019 Q*μfa,x [mm-1]) (p<0.05).The addition of unlabelled vedolizumab gave similar results to the 15 mg group (p>0.99), suggesting that the drug target was still not saturated. The optimal dosage group of 15 mg was expanded up to 18 IBD patients, amongst them 6 IBD patients after 14 weeks of treatment regimen. Fluorescence microscopy showed clustering of fluorescent signals especially in inflamed mucosa. Additional experiments to detect vedolizumab target cells are ongoing.

Conclusion

In vivo visualization of fluorescent vedolizumab revealed a clear dose-dependent correlation between mucosal drug concentrations and the severity of mucosal inflammation. Fluorescence molecular endoscopy is a promising novel tool to get insight in drug distribution in IBD, detect target cells, assess target engagement and possibly predict therapy response in individual patients.
DOP54 Identification and development of a 1st in class naturally-derived protein that drives mucosal healing and is orally delivered by an engineered cellular therapy targeting the gastro-intestinal tract
Authors: Shilova I , La Chat C , Nigatu E , Messner E , Desnoyer J , Willcoxon M , Banas S , Ravichandar D , Narayan N , DeSantis T , Dabbagh K , Yamamoto L
Published: January 2022

Background

In Inflammatory Bowel Disease (IBD), intestinal barrier dysfunction and epithelial cell injury are believed to be associated with activation of the immune system to drive disease-associated inflammation, which together constitute key features of active disease. Existing drugs used to treat IBD induce endoscopic remission and improvements in mucosal healing in only a minor proportion of patients, driving a critical need for therapies which lead directly to mucosal healing. Furthermore, predicting patients who may benefit from therapeutics that address specific mechanisms of mucosal healing may augment response rates.

Methods

We screened proteins, identified from a meta-analysis of healthy human microbiome, in cellular assays and animal models related to mucosal injury, with the goal of identifying novel therapeutics that have the potential to directly induce mucosal healing. The proteins identified were further optimized by protein engineering to increase their stability as well as gastro-intestinal (GI) targeting via oral administration. For this, therapeutic proteins were expressed using a probiotic, Lactococcus lactis (L.lactis), engineered to display the recombinant proteins on the cell surface, and evaluated for activity in DSS- and DNBS-induced models of colitis in mice. Mechanism of action studies using computational and laboratory based methods to analyze gene expression and direct molecular interactions with human proteins, enabled the identification of pathways modulated by the candidate molecules. These pathways were further evaluated for their ability to identify biomarkers in specific patients most suitable for treatment in a precision medicine approach.

Results

We have identified a novel, healthy microbiome-derived protein that demonstrated robust activity in human epithelial injury assays in vitro. The protein reduced intestinal injury related pathology in mice when orally administered to target directly the GI tract. SG-5-00455, the product based on an L.lactis strain expressing the candidate therapeutic protein, reduced pathology scores, inflammation and barrier function related LPS-binding protein levels to levels comparable to those obtained glucagon-like peptide 2 (GLP-2), as well as improving dysregulated tissue repair and fibrosis-associated gene expression and proteins levels. SG-5-0455 treatment did not result in systemic exposure, driving its therapeutic activity in a GI-localized manner by targeting pathways related to tissue injury and fibrinolysis.

Conclusion

SG-5-00455, through its novel mechanism of action and oral delivery to directly target tissue repair pathways in the GI-tract, offers the potential to address a large critical need in IBD.
DOP85 Efficacy of risankizumab rescue therapy in patients with moderately to severely active Crohn’s Disease and inadequate response to risankizumab maintenance therapy
Authors: Baert F J , Atreya R , Kakuta Y , Long M , Roblin X , Neimark E , Song A , Wallace K , Kingys K , Mallick M , Liao X , Lim A
Published: January 2022

Background

The efficacy and safety of 12 weeks of induction and 52 weeks of maintenance treatment with risankizumab (RZB), an interleukin 23 p19 inhibitor, in patients with moderately to severely active Crohn’s disease (CD) was previously demonstrated in 3 phase 3 trials (ADVANCE, MOTIVATE, and FORTIFY). We investigated outcomes in patients with inadequate response to subcutaneous (SC) RZB or SC placebo (PBO) treatment and required RZB rescue therapy during maintenance.

Methods

In FORTIFY, a phase 3, double-blind, re-randomised responder withdrawal, maintenance study (NCT03105102), patients that responded to 12 weeks of RZB IV induction received RZB 180 mg SC, RZB 360 mg SC, or PBO (ie, withdrawal) every 8 weeks for 52 weeks. Starting at week 16, patients with inadequate response, defined as average daily stool frequency [SF] ≥ 3.3 and/or average daily abdominal pain score [APS] ≥ 1.5 as well as high-sensitivity C-reactive protein ≥ 5 mg/L and/or faecal calprotectin ≥ 250 μg/g; or Simple Endoscopic Score for CD (SES-CD) ≥ 6 (≥ 4 for isolated ileal disease), excluding the narrowing component as scored by the site Investigator, were eligible to receive open-label rescue therapy (1 dose of intravenous [IV] RZB 1200 mg, followed by RZB 360 mg SC every 8 weeks). Up to 2 rescue therapy visits ≥ 16 weeks apart were permitted. Efficacy at week 52 was assessed in the intent-to-treat population using nonresponder imputation for missing data. Patients were also considered nonresponders when maximum equivalent steroid dose exceeded the dose used at baseline or if patients initiated any new steroids. Safety was assessed throughout the study.

Results

In the maintenance study, a greater proportion of patients in the withdrawal (PBO SC) arm (40.2% [66/164]) were administered RZB rescue therapy vs RZB 180 mg SC (24.2% [38/157]) and RZB 360 mg SC (21.3% [30/141]; Figure A); most patients (71.1%–81.8%) required 1 rescue visit, and 16.7%–26.3% required 2 visits. Median time to first RZB rescue therapy was 178 days for the withdrawal (PBO SC) group, 179 days for the RZB 180 mg SC group, and 154 days for the RZB 360 mg SC group. At week 52, 52.5%–75.0% of patients who received RZB rescue therapy achieved SF/APS clinical response (Figure B), and 20.0–36.4% of patients who received rescue therapy achieved clinical remission (per CDAI or SF/APS) and/or endoscopic response (Figures C-E). The safety profile of RZB in CD has previously been reported.

Conclusion

RZB rescue therapy (one dose of RZB 1200 mg IV followed by RZB 360 mg SC every 8 weeks) may be beneficial to patients with moderately to severely active CD experiencing inadequate response to or interruption in RZB maintenance treatment.
P010 Adherent-Invasive Escherichia Coli strain O83:H1 induces inflammatory response in Crohn’s disease
Authors: Iaquinto G C , Mazzarella G , Rotondi Aufiero V
Published: January 2022

Background

Several studies suggest that Adherent-Invasive Escherichia Coli (AIEC) colonize the ileal mucosa of patients with Crohn’s disease (CD). This strain is able to adhere to and invade intestinal epithelial cells, and survive within macrophages, prompting an inflammatory response.

The aim of this study was to investigate, by using an organ culture model, the ability of AIEC strain O83:H1 to colonize intestinal epithelial cells of CD patients, inducing chronic inflammation.

Methods

An organ culture model conducted with colonic biopsies derived from CD patients was set up to evaluate the ability of AIEC strain 083:H1, compared to a non-pathogenic (NP) E. Coli strain, to upregulate CEACAM 6 (CarcinoEmbryonic Antigen-related Cellular Adhesion Molecule 6), LAMP-1 (Lysosome Associated Membrane Protein 1), ICAM-1 (Intracellular Adhesion Molecule) and HLA-DR antigen expression, by immunohistochemistry, and to induce IFN-γ, TNF-α and IL-8 production, by RT-qPCR.

The staining of epithelial cells that expressed CEACAM6 and LAMP1 as well as the expression of ICAM1 on blood vessels was evaluated in terms of staining intensity. The number of LAMP1 and HLA-DR lamina propria mononuclear cells (LPMNC) was evaluated within a total area of 1 mm2 of lamina propria.

Results

Expression of CEACAM6 on intestinal epithelial cells, and the expression of LAMP-1 either on epithelium as well as in the LPMNCs, were significantly increased (P<0,05) in the biopsies cultured with the AIEC strain O83:H1 compared to the biopsies cultured with NP strain. ICAM-1 and HLA-DR were significantly increased (P<0,05) on blood vessels and on LPMNCs, respectively, in presence of AIEC strain O83:H1 as compared with NP strain.

Moreover we observed a higher level of IFN-γ, TNF-α and IL-8 mRNA trascripts in biopsies cultured with AIEC strain 083:H1 than in biopsies cultured with NP strain.

Conclusion

Our data suggest that AIEC strain O83:H1 in CD is able to adhere to and invade the intestinal epithelial cells, and to play an important role in activating chronic inflammatory responses observed in CD patients.
P072 Melanocortin MC3 and MC5 receptors expression is different according to colonic disease activity in Crohn’s Disease and Ulcerative Colitis biopsies: results from an immunohistochemical observational study
Authors: Gravina MD A G , Panarese I , Trotta M C , D’Amico M , Pellegrino R , Ferraraccio F , Galdiero M , Alfano R , Loguercio C , Romano M , Grieco P , Federico A
Published: January 2022

Background

MC3-R and MC5-R receptors belong to the complex melanocortin system, which has shown a strong immunomodulatory activity in several studies. Data on the role of these receptors in relation to inflammatory bowel disease are still missing and not fully elucidated. In this observational study we wanted to evaluate the expression profile of them in the colonic mucosa of Crohn’s Disease and Ulcerative Colitis patients both in the tracts directly affected by the disease activity and in the tracts spared.

Methods

We conducted on colonic biopsies of patients with histological diagnosis of inflammatory bowel disease immunohistochemical analyses in order to assess the degree of expression of MC3-R and MC5-R. Biopsies were performed on both the traits with macroscopic signs of inflammation and the macroscopically normal traits to assess whether the expression of the two receptors was different in relation to disease activity.

Results

In both Crohn’s disease and ulcerative colitis diseased tracts MC3-R (CD: +7.7 fold vs normal mucosa, P < 0.01; UC: +5.6 fold vs normal mucosa, P < 0.01) and MC5-R (CD: +5.5 fold vs normal mucosa, P < 0.01; UC: +8.1 fold vs normal mucosa, P < 0.01) were significantly increased compared to healthy mucosa.

Conclusion

MC3-R and MC5-R are expressed in the colon of patients with Crohn’s Disease and Ulcerative Colitis. In addition, expression is different with a higher degree of expression in the traits most affected by disease activity in both Crohn’s Disease and Ulcerative Colitis providing a potential use of these receptors in inflammatory bowel diseases pharmacology.
P182 Twisted Pouch Syndrome: A Rare, Difficult to Diagnose Mechanical Complication of Ileal Pouch-Anal Anastomosis Amenable to Redo Pouch Salvage Surgery
Authors: Holubar MD- MS S , Qazi T , Savage E , Ream J , Lightner A , Rieder F , Gordon I , Baker M , Hull T , Steele S
Published: January 2022

Background

Ileal pouch-anal anastomosis (IPAA) is a technically demanding procedure. Intraoperatively, great care must be taken to assure a straight superior mesenteric axis. Rarely, twisted pouches are inadvertently constructed, resulting in deviations of expected pouch function. Herein we describe our quaternary pouch referral center experience with twisted pouch syndrome (TPS).

Methods

We performed a retrospective review of our prospectively maintained pouch registry from 1995 – 2020. Patients were identified using free-text search of redo IPAA operative reports for variations of the term “twist”. We defined twisted pouch syndrome as intraoperative findings of twisting of the pouch around its mesenteric axis which could not be reduced without disconnection from the anus. Data represent frequency (proportion) or median (range).

Results

Over 25-years, we identified 31 patients with confirmed TPS who underwent a redo pouch procedure by 11 surgeons: 67% were female, median BMI 21.2 (16.9 – 29.5) kg/m2. The duration from the index IPAA to redo procedure was 5 (0.5 – 21) years; all (100%) were referral cases constructed elsewhere. Original diagnoses included: ulcerative colitis 28 (90%), FAP 2 (6.5%). All patients presented with symptoms of pouch dysfunction including erratic bowel habits 28 (93%) with urgency and frequency, abdominal/pelvic/rectal pain 26 (87%), and obstructive symptoms 28 (93%) i.e. obstructed defecation and incomplete evacuation. Most had (75%) been treated for chronic pouchitis with medical therapy, and 48% had undergone previous surgery. Prior to redo IPAA procedure patients underwent a thorough workup: 100% pouchoscopy, 94% pouchogram, 87% underwent EUA, 87% MRI/CT, 71% manometry, and 39% defecography. TPS was diagnosed in 16% by pouchoscopy, in 13% by imaging, and in 71% was diagnosed intra-operatively at re-diversion (20%) or revision/redo IPAA (51%). In terms of surgical intervention, 81% were initially re-diverted. A total of 18 (60%) underwent pouch revision, and 12 (40%) required neo-IPAA. Short-term outcomes: LOS 8 (3 – 32) days, any complication 48%, readmission 11%, reoperation 3.4%, zero mortalities. After a median follow-up 52.5 (1 – 206) months, there were 4 failures: 2 never had loop ileostomy closure, 1 pouch excision, 1 Kock pouch, yielding an overall pouch survival rate of 87%.

Conclusion

Twisted pouch syndrome presents with pouch dysfunction manifest by the triad of erratic bowel habits, unexplained pain, and obstructive (defecation) symptoms. This syndrome may also mimic chronic pouchitis. Despite a thorough workup suggesting a mechanical problem, many patient are not diagnosed until time of redo pouch surgery. Redo surgery for twisted pouch syndrome results in long-term pouch survival for the majority.
P458 Safety and Potential Efficacy of Escalating Dose of Ustekinumab in Pediatric Crohn’s disease (the SPEED-UP study) - A multi-center study from the paediatric IBD Porto group of ESPGHAN
Authors: Yerushalmy-Feler A , Pujol-Muncunill G , Martin-de-Carpi J , Kolho K L , Levine A , Olbjørn C , Granot M , Bramuzzo M , Jonsson Rolandsdotter H , Mouratidou N , Hradsky O , Scarallo L , Matar M , Magen Rimon R , Rinawi F , Shalem T , Najajra H , de Meij T , Aloi M , Velasco Rodríguez-Belvís M , Alvisi P , Schneider A M , van Rheenen P , Navas-López V M , Kiparissi F , Barrio J , Turner D , Cohen S
Published: January 2022

Background

Ustekinumab (UST) is an effective therapy for induction and maintenance of remission in Crohn’s disease (CD). Intensification of UST maintenance dosage has shown effectiveness in some adult patients, but no similar data are available in children. The aim of the study was to evaluate the effectiveness and safety of dose escalation of UST in paediatric CD.

Methods

This was a retrospective multicenter study from 25 centers affiliated to the IBD Interest and Porto groups of ESPGHAN. We included children with CD who initiated UST at a standard dosing and subsequently underwent dose escalation to intervals shorter than 8 weeks, or re-induction due to active disease. Demographic, clinical, laboratory, endoscopic and imaging data were collected at escalation and during a 12 months follow-up. Clinical remission was defined as weighted Paediatric Crohn’s Disease Activity Index (wPCDAI)<12.5 and clinical response as a decline in >17.5 points. Adverse events were explicitly recorded.

Results

Sixty-nine children, with a median age of 15.8 (IQR 13.8–16.9) years and disease duration of 4.3 (2.9–6.3) years were included. Sixty-eight (98.6%) and 59 (86.8%) children were biologic and immunomodulators experienced, respectively. UST dose was escalated after a median of 6 (3.6–12) months of therapy. Clinical response and remission were observed in 46 (67%) and 29 (42%) children at 3 months, respectively. The strongest predictor of clinical remission was lower wPCDAI at escalation (p=0.001). The median serum levels of C-reactive protein decreased from 14 (3–28.03) to 5 (1.1–20.5) mg/L at 3 months (p=0.012), and fecal calprotectin from 1110 (499–2300) to 248 (118–1159) mcg/g at 12 months (p=0.05). Endoscopic and transmural healing were achieved in 3/19 (16%) and 2/15 (13%) patients, respectively, of those with available tests. Overall, 13 patients (19%) discontinued therapy due to active disease, at a median of 3 (3–4.5) months. No serious adverse events were reported.

Conclusion

Two-thirds of children with active CD achieved response following dose escalation of UST.
P557 Robotic surgery significantly improves outcomes for patients with inflammatory bowel disease
Authors: Karategos A , Yassin N
Published: January 2022

Background

Patients with Inflammatory Bowel Disease (IBD) have a high likelihood of both surgical treatment at a young age and repetitive operative interventions. Therefore, development of novel surgical techniques to minimize operative trauma are crucial for this group of patients. Robotic Surgery represents the newest minimally invasive technology available to reduce the impact of surgery, but has mostly been used for colorectal cancer rather than for benign conditions. The purpose of this study was to assess the feasibility and clinical outcomes of robotic surgery for patients with IBD.

Methods

This is a single-institution prospective study evaluating all IBD patients undergoing robotic surgery between October 2020 to November 2021 at our trust. Demographic data, perioperative and 30-day postoperative outcomes were assessed. The feasibility of the techniques and clinical outcomes were documented and data were analysed.

Results

A total of ninety robotic cases were performed from October 2020 to November 2021. Of these, 20 were IBD (75% Crohn’s disease). The M:F ratio was 1:1; median age was 41 (18–79) years, BMI of 25 (16–37) kg/m2. Eighty-four per cent of patients were treated with a biologic agent in the preceding 60 days. The 2 most commonly performed procedures were Right Hemicolectomy with intracorporeal anastomosis (44%) and subtotal colectomy with end ileostomy (22%). There were no conversions to open surgery. Return of gut function, as defined by tolerating oral diet and passing flatus, was noted within 48 hours in 85% of the patients (n=17). There was minimal blood loss and all patients were discharged on their baseline Hb with no need for iron replacement therapy or blood transfusion. The median length of hospital stay was 4.5 days (3–10). There was no reported mortality. The 30-day readmission rate was 5% (n=1).

Conclusion

Robotic surgery for patients with IBD is feasible, safe and improves clinical and surgical outcomes. This novel approach ensures that surgery remains minimally invasive, leading to a significant reduction in length of hospital stay, a rapid postoperative recovery and an earlier return of gut function.
Chromosome restructuring and number change during the evolution of Morus notabilis and Morus alba
Authors: Xuan Yahui , Ma Bi , Li Dong , Tian Yu , Zeng Qiwei , He Ningjia
Published: January 2022

Mulberry (Morus spp.) is an economically important plant as the main food plant used for rearing domesticated silkworm and it has multiple uses in traditional Chinese medicine. Two basic chromosome numbers (Morus notabilis, n = 7, and Morus alba, n = 14) have been reported in the genus Morus, but the evolutionary history and relationship between them remain unclear. In the present study, a 335-Mb high-quality chromosome-scale genome was assembled for the wild mulberry species M. notabilis. Comparative genomic analyses indicated high chromosomal synteny between the 14 chromosomes of cultivated M. alba and the six chromosomes of wild M. notabilis. These results were successfully verified by fluorescence in situ hybridization. Chromosomal fission/fusion events played crucial roles in the chromosome restructuring process between M. notabilis and M. alba. The activity of the centromere was another key factor that ensured the stable inheritance of chromosomes. Our results also revealed that long terminal repeat retrotransposons were a major driver of the genome divergence and evolution of the mulberry genomes after they diverged from each other. This study provides important insights and a solid foundation for studying the evolution of mulberry, allowing the accelerated genetic improvement of cultivated mulberry species.
“It’s Not My Freedom or Free”: The Big Box and Toni Morrison’s Meditations on Violence, Justice, and Power
Authors: Brown Lauren M
Published: January 2022

Toni Morrison’s 1999 book The Big Box, coauthored with her son, Slade Morrison, depicts three children who are locked up because they “just can’t handle [their] freedom.” Ostensibly written for children, the text nonetheless engages issues of sociopolitical power, authority, and justice which affect readers of all ages, challenging them to reconsider the terms of freedom by which we operate. In this way, the book channels issues and themes central to Morrison’s oeuvre, including the many works of nonfiction in which she explores the dynamics of violence and power in the United States and our global community. Indeed, the book’s prescient central refrain is particularly relevant to our contemporary moment as we confront the persisting dis-ease concerning Black and brown bodies in the United States and our ongoing struggle to ensure “freedom and justice for all”.

This essay positions The Big Box as a lens through which we may read Morrison’s nonfiction meditations on the tensions between freedom, authority, justice, and power in the United States. Combining various essays in recent publications such as The Source of Self-Regard (2019) and The Origin of Others (2017) with other pieces of Morrison’s nonfiction, this essay explores how The Big Box channels Morrison’s broader concerns about freedom and justice in the United States that continue to resonate today.
Death of a Patriarch
Authors: Reynolds Daniel
Published: January 2022

This chapter focuses on a singular, highly public event set in the volatile world of tenth-century Jerusalem: the murder of the Melkite patriarch during the urban Eastern liturgy of 966. By analyzing the murder itself, the groups and individuals involved, as well as the way the event and the main actors were subsequently described in narrative histories, this case study demonstrates how the complex inter-religious relations in Palestine affected the treatment of the Christian community in the city, while also analyzing the way different identities were politicized to serve the needs of local powerbrokers in their dealings with overarching imperial interests.
Diversity and Convergence
Authors: Esders Stefan , Reimitz Helmut
Published: January 2022

This chapter is based on the paradox that whereas the Carolingians used an imagined Frankish identity upon which to build their empire, the very expedient of highlighting this ethnic identity catalyzed the fragmentation of the empire as a whole. As the core was strengthened, more peripheral communities used those same mechanisms to find a voice of their own. During the rise of the Carolingian Empire, the new ruling dynasty dealt with the reality of Frankish and other identities within their realm by reinforcing a legal pluralism that had grown out of the Roman Empire and that had been further developed under their Merovingian predecessors. In this process, acts of legislation came to be much less legitimated by central authority or office. They were agreements between rulers and groups through which authority was acknowledged in exchange for the confirmation or grants of rights and privileges. The resulting interdependence of claims to ethnic identity and legal status, however, intensified in the context of the Carolingian rise to power. But the increasing politicization of ethnic traditions and communities, their legal rights and claims, also worked against the political integration of Carolingian rule. Regional elites emphasized their own customs and rights vis-à-vis the new Frankish kings. The imperial framework allowed for accommodation of all these different claims along with the variety of Frankish ones in a Christian-imperial framework.
From the Sublime to the Ridiculous
Authors: Webb Peter
Published: January 2022

This chapter looks at various expressions of identity and identification within a community that encompassed various groups vying for power and influence. It starts from a polemic launched by members of a Yemeni (“Southerner”) faction in the centers of Abbasid power against northern Arabs, which was only loosely connected to whatever being Yemeni in South Arabia might mean. Analyzing the multivalent uses of “Yemeni” identity, especially in poetry composed around the Abbasid court, the chapter shows that it was precisely the rich history attached to this name that made it a flexible tool in the hands of authors commenting on the world around them. Polemical strategies of identification could be employed for a serious competition for political influence but also for courtly entertainment. In the end, it is argued that in a society where everybody was aware of the layers of meaning underlying such markers of identification, no single definition encompasses any of them, and no source should be taken for granted. The chapter includes a translation of selected Arabic poems.
Concluding Thoughts
Authors: Wickham Chris
Published: January 2022

This chapter concludes the volume and draws together many of the common themes addressed in the other chapters. It highlights the difficulties involved in comparing “empires” and their perceived successes and failures by stressing the variety of sources and the complexities inherent in the historical record, prompting the question of whether we are comparing sources, events, or modern attitudes. Moreover, it raises the question if and how comparing “empires” differs from comparing different “communities” within said empires: what, then, is the factor deciding along which axes a comparison may be succesful? Additionally, it presents alternative viewpoints and suggests ways of going forward with this particular kind of comparative research in a Mediterranean, but also in a global setting.
Urban Island or Node in a Network?
Authors: Raja Rubina
Published: January 2022

This chapter explores the importance of Palmyra as a city at the center of a network. While Palmyra was an oasis city in the desert, it was by no means isolated; rather, it had huge strategic and political importance. Here, the focus is on Palmyra as a living city and on its inhabitants in the first three centuries CE. The chapter begins by providing an overview of the social structure within Palmyra, looking at the roles of men and women at different ranks of society, as well as trade and the importance of the Palmyrene Tax Tariff. The next focus is the tribal structure said to underpin Palmyrene society. The chapter then shifts to archeological remains, examining the city’s monuments and questioning the extent to which Palmyra was ever a Hellenized city, before exploring the evidence for religious practice and the city’s many temples. Finally, attention is on the city’s infrastructure and buildings, and the role that many Palmyrenes must have played in a wider regional and international network.
Cutting Ties
Authors: Raja Rubina
Published: January 2022

Palmyra’s role as a site of historical and cultural importance is explored through an in-depth and careful analysis. Here the earliest archeological digs are first assessed, with a careful and considered discussion of cultural heritage, followed by an examination of nineteenth- and early twentieth-century trends for antiquities to be removed from their country of origin and placed in galleries and museums around the world. The focus of the chapter then moves to the Syrian civil war, which broke out in 2011, with a nuanced discussion about Palmyra’s importance as a political symbol to many on opposing sides, as well as the damage done to cultural heritage, the problems created by looting, and what can be done to prevent such destruction. Here, the idea of networks is once again introduced as ties between Palmyra and the outside world have in many ways been “cut” as a result of the civil war. The themes at play are often contentious but are here sympathetically and sensitively handled. The chapter ends with a discussion of preservation work and a call for greater protection for sites of cultural heritage around the world.
Prologue
Authors: Lee Michael J. , Atchison R. Jarrod
Published: January 2022

We Are Not One People is about groups of Americans, some eccentric, some thoughtful, all audacious, from 1776 to the present who gave up, moved on, and opted out, people who tried to bring forth on this continent or another a new nation. Groups both marginal and mainstream have used a common political language to withdraw from American laws, American politics, American culture, and the American public and whatever subjugation, norms, practices, obligations, customs, or laws they thought citizenship entailed. Invoking the hallmark moments and national heroes of the nation’s history, they withdrew as Americans. They cited the nation to undo it. Secession’s broad appeal as a symbolic action in America comes into full view when it is considered not singularly but as the endpoint of a spectrum of political disengagement. What we call the separatist spectrum spans targeted, temporary, and issue-specific acts of political exit all the way to the total, formal, and public political withdrawal of one group from a larger group. All told, secession and separatism hold primary positions in the nation’s history among disparate groups of people spread widely over two and a half centuries, tremendous geographical terrain, extreme power differences, and vast ideological territory.
White Devils and Black Separatists
Authors: Lee Michael J. , Atchison R. Jarrod
Published: January 2022

Black nationalism is a multicentury story of a search for Black space within or beyond America. This chapter highlights the fulsomeness of the Black nationalist vocabulary by examining influential nationalist books and speeches ranging from proto-nationalists in the antebellum period to Black power advocates in 1960s and 1970. It focuses on how Black separatists specifically and nationalists generally consecrated physical space. The full nationalist rhetorical spectrum includes advocates who urged the creation of separate Black styles of dress, modes of speech, organizations, rifle clubs, schools, stores, churches, neighborhoods, cities, states, nation-states, and polities generally, all “alternatives to the oppressive social institutions” that “dominated” Black life in America. The nations imagined served as both strategic goals and comforting dreams for the vast number of individuals and organizations who concluded that America was always and forever a racist nation and, therefore, that new possibilities for Black people required a new beginning.
Plug-in Cultures
Authors: D'Errico Mike
Published: January 2022

The global rise of electronic dance music (EDM) in the 2010s coincided with a renaissance in music software development and the entertainment industries more broadly. Like so many technologies throughout the history of the music products industry, the widespread use of software such as Image-Line’s FL Studio sparked renewed conversations about how the perceived financial accessibility and the user-friendly nature of music software has revolutionized how music gets produced and distributed. This chapter details the relationship between the design of FL Studio, neoliberal capitalism, and the toxic masculinity that permeated EDM in the early twenty-first century. It contextualizes the aesthetic desire among producers to integrate a vast array of media and technologies into their creative workflow within the broader consumerist milieu of digital maximalism—a philosophy that says that the more connected you are, the better.
Economic Rationality and Moral Constraints
Authors: Gauthier David
Published: January 2022

This early essay characterizes the economic conception of rationality and focuses on its implications for behaviour in two important contexts—under the conditions of perfect competition, and in the presence of externalities. This account of economic rationality provides a framework for the discussion of three moral theories: utilitarianism, natural rights, and contractarianism. These theories are thought of as proposing constraints on either the contexts or on the unimpeded exercise of economically rational behaviour. This interpretation will suggest how far these moral theories should be viewed as opposing alternatives, and how far they may be considered as complementary. The argument is made that contrary to expectations of many, contractarian morality is most, and utilitarian morality least, akin to the spirit of the rational economic individual.
Economic Man and the Rational Reasoner
Authors: Gauthier David
Published: January 2022

The orthodox economic understanding of rationality ties an agent’s reasons for action directly to his or her preferences over outcomes. We are to choose to evaluate actions one by one by their (likely) realization of our favoured outcomes. This chapter argues that in contexts of interpersonal action as well as those affected by preference change, rational reasoners will not link preference and action so tightly but will appreciate the importance of sequences of actions, of plans. In these contexts, the focus will be on the (likely) outcomes of the plans.
Rethinking the Toxin Puzzle
Authors: Gauthier David
Published: January 2022

This chapter considers Gregory Kavka’s well-known “toxin puzzle” and argues that it can be rational to drink the toxin. It grants that drinking the toxin does not have the best consequences. So one does not have an outcome-oriented reason to drink it. But drinking the toxin can be part of the best course of action—in terms of its consequences—that one embraces as a whole. This resolution of the toxin puzzle may occasion unease. Can it really be rational to drink the toxin when all that one accomplishes by drinking it is to make oneself ill? Yes, indeed it can, in the unusual circumstances in which the question whether to drink arises. Deliberation about the formation of the intention to drink the toxin, and about the subsequent execution of the intention, may be accommodated in a more general account of deliberation about future-directed intentions. This more general account has a pragmatic rationale in the role that deliberation plays in directing persons to act in ways that best fulfil their overall concerns. Good deliberators should drink up!