A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial.

BACKGROUND: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. METHODS: PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 µg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 µg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). FINDINGS: Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight). INTERPRETATION: Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. FUNDING: Wellcome and PredictImmune Ltd.

Metal-Free Organic Chromophores Featuring an Ethynyl-Thienothiophene Linker with an n-Hexyl Chain for Translucent Dye-Sensitized Solar Cells.

We report the simple synthesis of two organic chromophores featuring an ethynyl-thienothiophene linker with an n-hexyl chain (CSD-03 and CSD-04), their optical and electrochemical properties, and their use as photosensitizers in dye-sensitized solar cells (DSSCs). Our theoretical and experimental studies show that adding the second thienothiophene allows for narrowing the bandgap of the molecule and thus ensuring more light harvesting in the visible region. The efficiencies of both CSD-03 (5.46 ± 0.03%) and CSD-04 (5.20 ± 0.03%) are comparable to that of N719 (5.92 ± 0.01%) in translucent DSSCs fabricated with 5 µm-thick TiO2 photoanodes.

Coplanar Donor-π-Acceptor Dyes Featuring a Furylethynyl Spacer for Dye-Sensitized Solar Cells.

Coplanar metal-free organic dyes featuring a furylethynyl spacer with different donor residues (MeO-, MeS-, and Me2N-) have been synthesized. Density functional theory (DFT) calculations predicted that the Me2N- residue would facilitate more effective charge transfer from donor to acceptor than the MeO- and MeS- residues. In agreement with DFT calculations, the dye-sensitized solar cells (DSSCs) fabricated with the Me2N- functionalized dye exhibited the best power conversion efficiency (η), 2.88%. Furthermore, the effect of the furan spacer on the photophysical properties and DSSC parameters are discussed in comparison to a previously reported thiophene counterpart.

Triptycene as a Supramolecular Additive in PTB7:PCBM Blends and Its Influence on Photovoltaic Properties.

Additives play an important role in modifying the morphology and phase separation of donor and acceptor molecules in bulk heterojunction (BHJ) solar cells. Here, we report triptycene (TPC) as a small-molecule additive for supramolecular control of phase separation and concomitant improvement of the power conversion efficiency (PCE) of PTB7 donor and fullerene acceptor-based BHJ polymer solar cells. An overall 60% improvement in PCE is observed for both PTB7:PC61BM and PTB7:PC71BM blends. The improved photovoltaic (PV) performance can be attributed to three factors: (a) TPC-induced supramolecular interactions with donor:acceptor components in the blends to realize a nanoscale phase-separated morphology; (b) an increase in the charge transfer state energy that lowers the driving force for electron transfer from donor to acceptor molecules; and (c) an increase in the charge carrier mobility. An improvement in efficiency using TPC as a supramolecular additive has also been demonstrated for other BHJ blends such as PBDB-T:PC71BM and P3HT:PCBM, implying the wide applicability of this new additive molecule. A comparison of the photostability of TPC as an additive for PTB7:PCBM solar cells to that of the widely used 1,8-diiodooctane additive shows ∼30% higher retention of PV performance for the TPC-added solar cells after 34 h of AM 1.5G illumination. The results obtained suggest that the approach of using additives that can promote supramolecular interactions to modify the length scale of phase separation between donor and acceptor is very promising and can lead to the development of highly efficient and stable organic photovoltaics.

Redox-mediated reactions of vinylferrocene: toward redox auxiliaries.

Chemical redox reactions have been exploited to transform unreactive vinylferrocene into a powerful dienophile for the Diels-Alder reaction and reactive substrate for thiol addition reactions upon conversion to its ferrocenium state. We have further investigated the ability of these reactions to facilitate redox-auxiliary-like reactivity by further hydrogenolyisis of the Diels-Alder adduct to the corresponding cyclopentane derivative.

Bilateral Pneumothorax and Subcutaneous Emphysema following Endoscopic Retrograde Cholangiopancreatography: A Rare Complication.

Endoscopic Retrograde Cholangiopancreatography (ERCP) is a widely used diagnostic and therapeutic modality in the management of biliary and pancreatic disease. Some of the complications of the procedure, although rare, may carry significant morbidity and mortality risks. We describe the case of a 68-year-old female who underwent elective ERCP for ductal stone clearance. Immediately postprocedure, the patient developed subcutaneous emphysema and bilateral pneumothoraces. Further imaging revealed the presence of free intra-abdominal air. The patient made a very quick recovery after bilateral chest drain insertion and no further intervention was required. We propose that pneumothorax, pneumomediastinum, and subcutaneous emphysema during ERCP, in the absence of duodenal perforation may be explained by leakage of air from a site of low resistance such as the sphincterotomy site, or as a result of copious Valsalva manoeuvres performed by a patient tolerating the procedure poorly.

Recent advances in the management of intestinal failure-associated liver disease.

PURPOSE OF REVIEW: To summarize the current management of intestinal failure-associated liver disease (IFALD) by reviewing recent advances in our understanding of the condition and the effects of different therapeutic approaches. RECENT FINDINGS: The importance of gastrointestinal length and continuity in the aetiology and treatment of IFALD has been demonstrated in both retrospective and interventional cohorts. A mechanism for the cholestatic effect of soy-based lipid has been described, and the clinical use of alternative lipid sources has demonstrated benefit. Prevention of IFALD has been shown with the use of erythromycin in neonates, and reversal of established IFALD has been demonstrated with isolated intestinal transplantation. SUMMARY: A greater understanding of the mechanisms of IFALD has led to promising interventions to prevent and treat the condition. Other possible therapeutic targets require more formal evaluation, and further work is required to develop noninvasive tools for the assessment and prognosis of IFALD that will guide treatment and help in the selection of patients and timing of transplantation.