Opening the doors of precision medicine: novel tools to assess intestinal barrier in inflammatory bowel disease and colitis-associated neoplasia.

Mounting evidence underscores the pivotal role of the intestinal barrier and its convoluted network with diet and intestinal microbiome in the pathogenesis of inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CRC). Moreover, the bidirectional association of the intestinal barrier with the liver and brain, known as the gut-brain axis, plays a crucial role in developing complications, including extraintestinal manifestations of IBD and CRC metastasis. Consequently, barrier healing represents a crucial therapeutic target in these inflammatory-dependent disorders, with barrier assessment predicting disease outcomes, response to therapy and extraintestinal manifestations.New advanced technologies are revolutionising our understanding of the barrier paradigm, enabling the accurate assessment of the intestinal barrier and aiding in unravelling the complexity of the gut-brain axis. Cutting-edge endoscopic imaging techniques, such as ultra-high magnification endocytoscopy and probe-based confocal laser endomicroscopy, are new technologies allowing real-time exploration of the 'cellular' intestinal barrier. Additionally, novel advanced spatial imaging technology platforms, including multispectral imaging, upconversion nanoparticles, digital spatial profiling, optical spectroscopy and mass cytometry, enable a deep and comprehensive assessment of the 'molecular' and 'ultrastructural' barrier. In this promising landscape, artificial intelligence plays a pivotal role in standardising and integrating these novel tools, thereby contributing to barrier assessment and prediction of outcomes.Looking ahead, this integrated and comprehensive approach holds the promise of uncovering new therapeutic targets, breaking the therapeutic ceiling in IBD. Novel molecules, dietary interventions and microbiome modulation strategies aim to restore, reinforce, or modulate the gut-brain axis. These advancements have the potential for transformative and personalised approaches to managing IBD.

Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Safety was also assessed. RESULTS: In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Elevated liver aminotransferase levels were more common with ozanimod. CONCLUSIONS: Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992.).

Evolution of Symptoms After Ustekinumab Induction Therapy in Patients With Crohn's Disease.

BACKGROUND & AIMS: Ustekinumab is an effective treatment of Crohn's disease (CD). Of interest to patients is knowing how soon symptoms may improve. We analyzed ustekinumab response dynamics from the ustekinumab CD trials. METHODS: Patients with CD received intravenous induction with ustekinumab ∼6 mg/kg (n = 458) or placebo (n = 457). Week 8 ustekinumab responders received subcutaneous ustekinumab 90 mg as the first maintenance dose or as an extended induction dose for nonresponders. Patient-reported symptom changes (stool frequency, abdominal pain, general well-being) within the first 14 days and clinical outcomes through week 44 were evaluated using the CD Activity Index. RESULTS: After ustekinumab infusion, stool frequency improvement was significantly (P < .05) greater than placebo on day 1 and for all patient-reported symptoms by day 10. In patients with no history of biologic failure or intolerance, cumulative clinical remission rates increased from 23.0% at week 3 to 55.5% at week 16 after the subcutaneous dose at week 8. Corresponding cumulative rates for patients with a history of biologic failure or intolerance increased from 12.9% to 24.1%. Neither change from baseline in CD Activity Index score nor week 8 ustekinumab pharmacokinetics were associated with week 16 response. Among all patients who received subcutaneous ustekinumab 90 mg q8w, up to 66.7% were in clinical response at week 44. CONCLUSIONS: Ustekinumab induction provided symptom relief by day 1 post-infusion. Following ustekinumab infusion and a subcutaneous 90 mg injection, clinical outcomes continued to increase through week 16 and up to week 44. Regardless of week 8 clinical status or ustekinumab pharmacokinetics, patients should receive additional treatment at week 8. CLINICALTRIALS: gov numbers, NCT01369329, NCT01369342, and NCT01369355.

Ozanimod in Patients With Moderate to Severe Ulcerative Colitis Naive to Advanced Therapies.

BACKGROUND & AIMS: The pivotal phase 3 True North (TN) study demonstrated the efficacy and safety of ozanimod in patients with moderately to severely active ulcerative colitis. This analysis assessed ozanimod during TN and the ongoing open-label extension (OLE) in patients with active disease who were naive to advanced therapies (ATs). METHODS: TN was a randomized, double-blind, placebo-controlled trial consisting of 10-week induction period and 42-week maintenance period. Eligible patients could enter the OLE. Symptomatic efficacy was evaluated from induction through the OLE. Clinical, endoscopic, and mucosal outcomes were evaluated at the end of induction (Week [W] 10) and maintenance (W52) and at predefined OLE timepoints (OLE W46 and W94). Safety during TN was reported. RESULTS: This analysis included 616 AT-naive patients. Numerically greater proportions of patients receiving ozanimod than placebo achieved symptomatic response (39% vs 29%, 95% confidence interval, -0.1 to 18.8) by W2, with significant differences (56% vs 39%, 95% confidence interval, 6.3-26.3) achieved by W4. Patients receiving ozanimod showed significant improvements across efficacy outcomes versus placebo at W10 and W52 (P < .05, all endpoints). In patients on continuous ozanimod who entered the OLE in clinical response at W52, 91% maintained clinical response through OLE W94, and 74% achieved endoscopic improvement and 57% achieved mucosal healing at OLE W94. In ozanimod-treated patients without clinical response by W10 who received extended induction in the OLE, 62% achieved symptomatic response by OLE W10. Safety outcomes in AT-naive patients were consistent with the total TN population. CONCLUSIONS: Ozanimod is an effective, durable, and well-tolerated oral therapy for AT-naive ulcerative colitis patients. CLINICALTRIALS: gov, numbers NCT02435992 and NCT02531126.

Artificial Intelligence Enabled Histological Prediction of Remission or Activity and Clinical Outcomes in Ulcerative Colitis.

BACKGROUND & AIMS: Microscopic inflammation has significant prognostic value in ulcerative colitis (UC); however, its assessment is complex with high interobserver variability. We aimed to develop and validate an artificial intelligence (AI) computer-aided diagnosis system to evaluate UC biopsies and predict prognosis. METHODS: A total of 535 digitalized biopsies (273 patients) were graded according to the PICaSSO Histologic Remission Index (PHRI), Robarts, and Nancy Histological Index. A convolutional neural network classifier was trained to distinguish remission from activity on a subset of 118 biopsies, calibrated on 42 and tested on 375. The model was additionally tested to predict the corresponding endoscopic assessment and occurrence of flares at 12 months. The system output was compared with human assessment. Diagnostic performance was reported as sensitivity, specificity, prognostic prediction through Kaplan-Meier, and hazard ratios of flares between active and remission groups. We externally validated the model in 154 biopsies (58 patients) with similar characteristics but more histologically active patients. RESULTS: The system distinguished histological activity/remission with sensitivity and specificity of 89% and 85% (PHRI), 94% and 76% (Robarts Histological Index), and 89% and 79% (Nancy Histological Index). The model predicted the corresponding endoscopic remission/activity with 79% and 82% accuracy for UC endoscopic index of severity and Paddington International virtual ChromoendoScopy ScOre, respectively. The hazard ratio for disease flare-up between histological activity/remission groups according to pathologist-assessed PHRI was 3.56, and 4.64 for AI-assessed PHRI. Both histology and outcome prediction were confirmed in the external validation cohort. CONCLUSION: We developed and validated an AI model that distinguishes histologic remission/activity in biopsies of UC and predicts flare-ups. This can expedite, standardize, and enhance histologic assessment in practice and trials.

Interface and Morphology Engineered Amorphous Si for Ultrafast Electrochemical Lithium Storage.

Ultrafast high-capacity lithium-ion batteries are extremely desirable for portable electronic devices, where Si is the most promising alternative to the conventional graphite anode due to its very high theoretical capacity. However, the low electronic conductivity and poor Li-diffusivity limit its rate capability. Moreover, high volume expansion/contraction upon Li-intake/uptake causes severe pulverization of the electrode, leading to drastic capacity fading. Here, interface and morphology-engineered amorphous Si matrix is being reported utilizing a few-layer vertical graphene (VG) buffer layer to retain high capacity at both slow and fast (dis)charging rates. The flexible mechanical support of VG due to the van-der-Waals interaction between the graphene layers, the weak adhesion between Si and graphene, and the highly porous geometry mitigated stress, while the three-dimensional mass loading enhanced specific capacity. Additionally, the high electronic conductivity of VG boosted rate-capability, resulting in a reversible gravimetric capacity of ≈1270 mAh g-1 (areal capacity of ≈37 µAh cm-2 ) even after 100 cycles at an ultrafast cycling rate of 20C, which provides a fascinating way for conductivity and stress management to obtain high-performance storage devices.

Sterically Crowded Donor-Rich Imidazole Systems as Hole Transport Materials for Solution-Processed OLEDs.

Imidazole, being an interesting dinitrogenic five-membered heterocyclic core, has been widely explored during the last several decades for developing various fascinating materials. Among the different domains where imidazole-based materials find wide applications, the area of optoelectronics has seen an overwhelming growth of functional imidazole derivatives developed through remarkable design and synthesis strategies. The present work reports a design approach for integrating bulky donor units at the four terminals of an imidazole core, leading to the development of sterically populated imidazole-based molecular platforms with interesting structural features. Rationally chosen starting substrates led to the incorporation of a bulky donor at the four terminals of the imidazole core. In addition, homo- and cofunctional molecular systems were synthesized through a suitable combination of initial ingredients. Our approach was extended to develop a series of four molecular systems, i.e., Cz3PhI, Cz4I, Cz3PzI, and TPA3CzI, containing carbazole, phenothiazine, and triphenylamine as known efficient donors at the periphery. Given their interesting structural features, three sterically crowded molecules (Cz4I, Cz3PzI, and TPA3CzI) were screened by using DFT and TD-DFT calculations to investigate their potential as hole transport materials (HTMs) for optoelectronic devices. The theoretical studies on several aspects including hole reorganization and exciton binding energies, ionization potential, etc., revealed their potential as possible candidates for the hole transport layer of OLEDs. Single-crystal analysis of Cz3PhI and Cz3PzI established interesting structural features including twisted geometries, which may help attain high triplet energy. Finally, the importance of theoretical predictions was established by fabricating two solution-process green phosphorescent OLED devices using TPA3CzI and Cz3PzI as HTMs. The fabricated devices exhibited good EQE/PE and CE of ∼15%/56 lm/W/58 cd/A and ∼13%/47 lm/W/50 cd/A, respectively, at 100 cd/m2.

Indolo[3,2-a]carbazoles as Engineered Materials for Optoelectronic Applications: Synthesis, Structural Insights, and Computational Screening.

The biological and medicinal importance of indolocarbazoles has been known for the past several decades. However, in recent times, these compounds have been emerging as potential candidates for optoelectronic applications, although several challenges are associated with their synthesis. We report here a Pd(II)-catalyzed process for the synthesis of indolo[3,2-a]carbazoles. The reaction proceeded under neat conditions and in the presence of aqueous nonmetallic oxidant TBHP, and the products were purified directly after the completion of the reaction. Also, the possibility of employing the present method for reaction with gram-scale feed was investigated. A detailed single-crystal analysis of several indolo[3,2-a]carbazoles revealed how the molecular arrangement can be tuned by altering the functionalization. Finally, the developed molecules were screened computationally to assess their potential for possible use as hole transport materials (HTMs) for organic light-emitting diodes (OLEDs).

Epidemiological and clinical burden of Clostridioides difficile infections and recurrences between 2015 - 2019: the RECUR Germany study.

BACKGROUND: This real-world study assessed the epidemiology and clinical complications of Clostridioides difficile infections (CDIs) and recurrences (rCDIs) in hospital and community settings in Germany from 2015 - 2019. METHODS: An observational retrospective cohort study was conducted among adult patients diagnosed with CDI in hospital and community settings using statutory health insurance claims data from the BKK database. A cross-sectional approach was used to estimate the annual incidence rate of CDI and rCDI episodes per 100,000 insurants. Patients' demographic and clinical characteristics were described at the time of first CDI episode. Kaplan-Meier method was used to estimate the time to rCDIs and time to complications (colonic perforation, colectomy, loop ileostomy, toxic megacolon, ulcerative colitis, peritonitis, and sepsis). A Cox model was used to assess the risk of developing complications, with the number of rCDIs as a time-dependent covariate. RESULTS: A total of 15,402 CDI episodes were recorded among 11,884 patients. The overall incidence of CDI episodes declined by 38% from 2015 to 2019. Most patients (77%) were aged ≥ 65 years. Around 19% of CDI patients experienced at least one rCDI. The median time between index CDI episode to a rCDI was 20 days. The most frequent complication within 12-months of follow-up after the index CDI episode was sepsis (7.57%), followed by colectomy (3.20%). The rate of complications increased with the number of rCDIs. The risk of any complication increased by 31% with each subsequent rCDI (adjusted hazard ratio [HR]: 1.31, 95% confidence interval: 1.17;1.46). CONCLUSIONS: CDI remains a public health concern in Germany despite a decline in the incidence over recent years. A substantial proportion of CDI patients experience rCDIs, which increase the risk of severe clinical complications. The results highlight an increasing need of improved therapeutic management of CDI, particularly efforts to prevent rCDI.

Estimating excess mortality and economic burden of Clostridioides difficile infections and recurrences during 2015-2019: the RECUR Germany study.

BACKGROUND: Clostridioides difficile infections (CDIs) and recurrences (rCDIs) remain a major public health challenge due to substantial mortality and associated costs. This study aims to generate real-world evidence on the mortality and economic burden of CDI in Germany using claims data between 2015 and 2019. METHODS: A longitudinal and matched cohort study using retrospective data from Statutory Health Insurance (SHI) was conducted in Germany with the BKK database. Adults diagnosed with CDI in hospital and community settings between 2015 and 2018 were included in the study. Patients had a minimum follow-up of 12-months. All-cause mortality was described at 6-, 12-, and 24-months. Healthcare resource usage (HCRU) and associated costs were assessed at 12-months of follow-up. A cohort of non-CDI patients matched by demographic and clinical characteristics was used to assess excess mortality and incremental costs of HCRU. Up to three non-CDI patients were matched to each CDI patient. RESULTS: A total of 9,977 CDI patients were included in the longitudinal cohort. All-cause mortality was 32%, 39% and 48% at 6-, 12-, and 24-months, respectively, with minor variations by number of rCDIs. When comparing matched CDI (n = 5,618) and non-CDI patients (n = 16,845), CDI patients had an excess mortality of 2.17, 1.35, and 0.94 deaths per 100 patient-months, respectively. HCRU and associated costs were consistently higher in CDI patients compared to non-CDI patients and increased with recurrences. Total mean and median HCRU cost per patient during follow-up was €12,893.56 and €6,050 in CDI patients, respectively, with hospitalisations representing the highest proportion of costs. A total mean incremental cost per patient of €4,101 was estimated in CDI patients compared to non-CDI patients, increasing to €13,291 in patients with ≥ 3 rCDIs. CONCLUSIONS: In this real-world study conducted in Germany, CDI was associated with increased risk of death and substantial costs to health systems due to higher HCRU, especially hospitalisations. HCRU and associated costs were exacerbated by rCDIs.

Self-assembled molecular network with waterwheel-like architecture: experimental and theoretical evaluation toward electron transport capabilities for optoelectronic devices.

In recent times, self-assembled electron transport materials for optoelectronic devices, both solar cells and organic light-emitting diodes (OLEDs), have been gaining much interest as they help in fabricating high-efficiency devices. However, designing organic small molecular materials with star-shaped self-assembled networks is a challenge. To achieve this sort of target, we chose triazine and benzene-1,3,5-tricarbonyl cores for developing such architecture, and we developed four molecular systems, vizTCpCN, TCmCN, TmCN, and TpCN. Successful isolation of single crystals followed by structural analysis of TmCN revealed interesting molecular arrangements in the solid state resulting in the formation of a waterwheel type architecture with an extended network bearing characteristic voids. Theoretical calculations was carried out to check their electron transportability. The natural transition orbital calculation helped in understanding the locally excited and charge transfer excited states. The low electron reorganization energies of these molecules indicated that these materials may have potential to be used in electron transport layers of optoelectronic devices, particularly in OLEDs. Moreover, the assembled networks have a relatively wide surface area and linked structures, which are advantageous for the conduction of carriers with poor electron recombination inside the ETL, and these may offer a straightforward channel for electron conduction to the emissive layer. Finally, the fabricated electron-only device indicated that the synthesized materials may be used as ETMs in the electron transport layer of optoelectronic devices.

Ozanimod Differentially Impacts Circulating Lymphocyte Subsets in Patients with Moderately to Severely Active Crohn's Disease.

BACKGROUND: Ozanimod showed efficacy and safety in the phase 2 STEPSTONE study conducted in patients with moderately to severely active Crohn's disease. AIMS: This analysis assessed the effects of ozanimod on circulating lymphocytes in Crohn's disease. METHODS: Patients received ozanimod 0.92 mg for 12 weeks. Lymphocyte subtypes were evaluated using multicolor flow analysis on blood samples collected before treatment and on Week 12. Absolute lymphocyte count changes were analyzed by Wilcoxon signed rank tests. Disease activity changes and efficacy outcomes were evaluated at Week 12, and associations with lymphocyte subtype levels were assessed using Spearman's correlation and logistic regression. RESULTS: Reductions in median total T, Th, and cytotoxic T cells occurred at Week 12 (45.4%-76.8%), with reductions in most subtypes of 47.5% to 91.3% (P < 0.001). CD8+ terminally differentiated effector memory cells were largely unaffected (median change, - 19%; P = 0.44). Reductions in median total B cells occurred at Week 12 (76.7%), with reductions in subtypes of 71.4% to 81.7% (P < 0.001). Natural killer and monocyte cell counts were unchanged. Greater baseline levels and changes in nonswitched memory B cells were significantly associated with clinical, endoscopic, and histologic efficacy (P < 0.05, all comparisons). CONCLUSIONS: Ozanimod reduced circulating levels of all B-cell and most T-cell subsets but not monocytes or natural killer cells. Key subsets relevant to immune surveillance were not reduced, supporting the low risk of infection and malignancy with ozanimod in chronic inflammatory diseases. Levels of nonswitched memory B cells were associated with efficacy, providing a potential marker for ozanimod response. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02531113, EudraCT: 2015-002025-19.

Kisspeptin stimulates oestradiol biosynthesis by upregulating steroidogenic transcripts and proliferation markers in the bubaline granulosa cells in vitro.

Kisspeptin (Kp), an upstream regulator of GnRH release, is essential for the development and function of reproductive axis. Previously, we demonstrated the localization of Kp and its receptor (Kiss1r) in the active follicle in the bubaline ovary. Present study aimed to determine the effect of Kp on granulosa cell (GCs) functions, especially oestradiol (E2 ) and progesterone (P4 ) production, and differential expression of genes regulating the proliferation, apoptosis and steroidogenesis in the buffalo. The ovaries with 6-10 mm size follicles obtained from the cyclic buffaloes after slaughtering were used for isolation of GCs for in vitro study. The primary GCs culture was treated with Kp (0, 10, 50 and 100 nM) and incubated for 48 h. Production of E2 and P4 was estimated in the culture supernatant by ELISA. The expression of gonadotropin receptors (FSHR and LHR), steroidogenic genes (STAR, 3ß-HSD, CYP19A1), proliferation marker (PCNA), apoptotic factors (CASP3 and BCL2) and Kp signalling molecule (extracellular signal-regulated kinase 1/2, ERK1/2 and p-ERK1/2) was studied in the GCs by qPCR. Significant E2 production was found in the Kp 50 and 100 nM groups (p < .05), whereas P4 production was reduced in Kp 100 nM group (p < .05). There was concomitant upregulation of FSHR, ERK1/2, STAR and CYP19A1 in the Kp 100 nM treated GCs. In addition, Kp at 100 nM stimulated the proliferation of GCs by upregulating the expression of BCL2 (5.0 fold) and PCNA (94.9 fold). Further, high immunoreactivity of p-ERK1/2 was observed in the Kp-treated GCs. It was concluded that Kp at 100 nM concentration stimulated E2 production by upregulating the steroidogenic pathway through ERK1/2, STAR and CYP19A1 and modulating PCNA and BCL2 expressions in the GCs. Further experiments are warranted using Kp antagonist in different combinations to establish the signalling pathway in Kp-mediated steroidogenesis in the GCs for developing strategies to control ovarian functions.

Present and future of endoscopy precision for inflammatory bowel disease.

Several advanced imaging techniques are now available for endoscopists managing inflammatory bowel disease (IBD) patients. These tools, including dye-based and virtual chromoendoscopy, probe-based confocal laser endomicroscopy and endocytoscopy, are increasingly innovative applications in clinical practice. They allow for a more in-depth and refined evaluation of the mucosal and vascular bowel surface, getting closer to histology. They have demonstrated a remarkable ability in assessing intestinal inflammation, histologic remission, and predicting relapse and favorable long-term outcomes. In addition, the future application of molecular endoscopy to predict biological drug responses has yielded preliminary but encouraging results. Furthermore, these techniques are crucial in detecting and characterizing IBD-related dysplasia, assisting endoscopic mucosal resection and submucosal dissection towards a surgery-sparing approach. Artificial intelligence (AI) holds great potential in this promising landscape, as it can provide an objective and reproducible assessment of inflammation and dysplasia. Moreover, it can improve the prediction of outcomes and aid in subsequent therapeutic decision-making. This review aims to summarize the promising role of state-of-the-art advanced endoscopic techniques and related AI-enabled models for managing IBD, paving the way for precision medicine.

Design, synthesis, and biological evaluation of a small molecule oral agonist of the glucagon-like-peptide-1 receptor.

An absolute or relative deficiency of pancreatic ß-cells mass and functionality is a crucial pathological feature common to type 1 diabetes mellitus and type 2 diabetes mellitus. Glucagon-like-peptide-1 receptor (GLP1R) agonists have been the focus of considerable research attention for their ability to protect ß-cell mass and augment insulin secretion with no risk of hypoglycemia. Presently commercially available GLP1R agonists are peptides that limit their use due to cost, stability, and mode of administration. To address this drawback, strategically designed distinct sets of small molecules were docked on GLP1R ectodomain and compared with previously known small molecule GLP1R agonists. One of the small molecule PK2 (6-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-6H-indolo[2,3-b]quinoxaline) displays stable binding with GLP1R ectodomain and induces GLP1R internalization and increasing cAMP levels. PK2 also increases insulin secretion in the INS-1 cells. The oral administration of PK2 protects against diabetes induced by multiple low-dose streptozotocin administration by lowering high blood glucose levels. Similar to GLP1R peptidic agonists, treatment of PK2 induces ß-cell replication and attenuate ß-cell apoptosis in STZ-treated mice. Mechanistically, this protection was associated with decreased thioredoxin-interacting protein expression, a potent inducer of diabetic ß-cell apoptosis and dysfunction. Together, this report describes a small molecule, PK2, as an orally active nonpeptidic GLP1R agonist that has efficacy to preserve or restore functional ß-cell mass.

Identifying, Understanding, and Managing Fecal Urgency in Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Fecal urgency, which is defined by the sudden need to rush to the bathroom to empty one's bowel, is one of the common and distressing symptoms experienced by patients with inflammatory bowel disease. METHODS: We performed a narrative review to investigate the definition, pathophysiology, and therapeutic management of fecal urgency. RESULTS: Definitions of fecal urgency in inflammatory bowel disease, but also in irritable bowel syndrome, oncology, nononcologic surgery, obstetrics and gynecology, and in proctology, are empirical and heterogenous, lacking standardization. In the majority of these studies, nonvalidated questionnaires were used. When nonpharmacologic measures (dietary regimen, cognitive behavioral program) fail, medications such as loperamide, tricyclic antidepressants, or biofeedback therapy may become necessary. Medical management of fecal urgency may be challenging, in part because only limited data are available regarding the treatment of this symptom in randomized clinical trials of biologics in patients with inflammatory bowel disease. CONCLUSIONS: There is an urgent need for a systematic approach to assessment of fecal urgency in inflammatory bowel disease. It is time to consider fecal urgency as an outcome in clinical trials to remedy this disabling symptom.

Emergence of a Non-Van der Waals Magnetic Phase in a Van der Waals Ferromagnet.

Manipulation of long-range order in 2D van der Waals (vdW) magnetic materials (e.g., CrI3 , CrSiTe3 ,etc.), exfoliated in few-atomic layer, can be achieved via application of electric field, mechanical-constraint, interface engineering, or even by chemical substitution/doping. Usually, active surface oxidation due to the exposure in the ambient condition and hydrolysis in the presence of water/moisture causes degradation in magnetic nanosheets that, in turn, affects the nanoelectronic /spintronic device performance. Counterintuitively, the current study reveals that exposure to the air at ambient atmosphere results in advent of a stable nonlayered secondary ferromagnetic phase in the form of Cr2 Te3 (TC2 ≈160 K) in the parent vdW magnetic semiconductor Cr2 Ge2 Te6 (TC1 ≈69 K). The coexistence of the two ferromagnetic phases in the time elapsed bulk crystal is confirmed through systematic investigation of crystal structure along with detailed dc/ac magnetic susceptibility, specific heat, and magneto-transport measurement. To capture the concurrence of the two ferromagnetic phases in a single material, Ginzburg-Landau theory with two independent order parameters (as magnetization) with a coupling term can be introduced. In contrast to the rather common poor environmental stability of the vdW magnets, the results open possibilities of finding air-stable novel materials having multiple magnetic phases.

In Search of Hosts for Blue OLEDs: Computational Design and Experimental Validation.

Considering the difficulties associated with the conventional 'trial and error' method for a complete analysis of a giant molecular space, we took the aid of computational pathway (DFT) in screening a large space search of 780 (12×13×5) molecules to search for a host for the blue emitter. The selection process was completed in three Tiers with the conditions of highest theoretical triplet energy (>2.81 eV), aligned HOMO/LUMO levels w.r.t blue dopant (FIrpic), and position of substituents to meet the optimal requirements as host materials. Tier 1 screened twelve different imidazole heterocycle derivatives as base space groups which resulted in the selection of 4,5-diphenyl-1H-imidazole. Tier 2 process converged the search to mCN-CZ having the highest triplet energy and appropriate HOMO/LUMO level relative to FIrpic and ETL. Further, the carbazole of mCN-CZ was replaced with different aromatic hydrocarbons to find the other best compound in terms of triplet energy and HOMO/LUMO. Tier 3 resulted in another promising candidate (mCN-FL) as possible host materials. The band alignment with guest predicted mCN-FL and mCN-CZ to have optimal device performances compared to CZ-CZ and the experimentally observed device performance was in accordance with virtual screening results when TAPC was utilized as the hole transporter. The device results of mCN-CZ and mCN-FL were better than the reference host TCTA. The obtained results thus proved that a virtual screening process will be a useful tool for synthetic chemists in designing task-specific materials.

Validation of a new optical diagnosis training module to improve dysplasia characterization in inflammatory bowel disease: a multicenter international study.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) increases risk of dysplasia and colorectal cancer. Advanced endoscopic techniques allow for the detection and characterization of IBD dysplastic lesions, but specialized training is not widely available. We aimed to develop and validate an online training platform to improve the detection and characterization of colonic lesions in IBD: OPtical diagnosis Training to Improve dysplasia Characterization in Inflammatory Bowel Disease (OPTIC-IBD). METHODS: We designed a web-based learning module that includes surveillance principles, optical diagnostic methods, approach to characterization, and classifications of colonic lesions using still images and videos. We invited gastroenterologists from Canada, Italy, and the United Kingdom with a wide range of experience. Participants reviewed 24 educational videos of IBD colonic lesions, predicted histology, and rated their confidence. The primary endpoint was to improve accuracy in detecting dysplastic lesions after training on the platform. Furthermore, participants were randomized 1:1 to get additional training or not, with a final assessment occurring after 60 days. Diagnostic performance for dysplasia and rater confidence were measured. RESULTS: A total of 117 participants completed the study and were assessed for the primary endpoint. Diagnostic accuracy improved from 70.8% to 75.0% (P = .002) after training, with the greatest improvements seen in less experienced endoscopists. Improvements in both accuracy and confidence were sustained after 2 months of assessment, although the group randomized to receive additional training did not improve further. Similarly, participants' confidence in characterizing lesions significantly improved between before and after the course (P < .001), and it was sustained after 2 months of assessment. CONCLUSIONS: The OPTIC-IBD training module demonstrated that an online platform could improve participants' accuracy and confidence in the optical diagnosis of dysplasia in patients with IBD. The training platform can be widely available and improve endoscopic care for people with IBD. (Clinical trial registration number: NCT04924543.).

A virtual chromoendoscopy artificial intelligence system to detect endoscopic and histologic activity/remission and predict clinical outcomes in ulcerative colitis.

BACKGROUND: Endoscopic and histological remission (ER, HR) are therapeutic targets in ulcerative colitis (UC). Virtual chromoendoscopy (VCE) improves endoscopic assessment and the prediction of histology; however, interobserver variability limits standardized endoscopic assessment. We aimed to develop an artificial intelligence (AI) tool to distinguish ER/activity, and predict histology and risk of flare from white-light endoscopy (WLE) and VCE videos. METHODS: 1090 endoscopic videos (67 280 frames) from 283 patients were used to develop a convolutional neural network (CNN). UC endoscopic activity was graded by experts using the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and Paddington International virtual ChromoendoScopy ScOre (PICaSSO). The CNN was trained to distinguish ER/activity on endoscopy videos, and retrained to predict HR/activity, defined according to multiple indices, and predict outcome; CNN and human agreement was measured. RESULTS: The AI system detected ER (UCEIS ≤ 1) in WLE videos with 72 % sensitivity, 87 % specificity, and an area under the receiver operating characteristic curve (AUROC) of 0.85; for detection of ER in VCE videos (PICaSSO ≤ 3), the sensitivity was 79 %, specificity 95 %, and the AUROC 0.94. The prediction of HR was similar between WLE and VCE videos (accuracies ranging from 80 % to 85 %). The model's stratification of risk of flare was similar to that of physician-assessed endoscopy scores. CONCLUSIONS: Our system accurately distinguished ER/activity and predicted HR and clinical outcome from colonoscopy videos. This is the first computer model developed to detect inflammation/healing on VCE using the PICaSSO and the first computer tool to provide endoscopic, histologic, and clinical assessment.