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Autotransporter proteins are bacterial outer membrane proteins that display passenger domains with various functions through a β-barrel shaped translocation domain. YeeJ is an autotransporter protein from E. coli MG1655. In contrast to most other autotransporter proteins, its passenger domain is located at the C-terminus of the translocation domain. Due to this inverted domain organization, YeeJ belongs to autotransporter proteins of type Ve. To investigate the assembly of YeeJ, the fluorescence of a heterologous mCherry passenger domain was measured to quantify its assembly. Based on AlphaFold2 models of 119 sequences similar to YeeJ, a sequence conservation logo for the β 1 - and the β 12 -strand of type Ve autotransporter proteins was generated. Then, the effect of mutations in these strands on the assembly of YeeJ were analyzed. Mutations of the N-terminal aromatic amino acid of the β 1 -strand did not affect the assembly of the translocation domain and the display of the passenger domain. Likewise, exchange of the β 1 -strand with the β 3 -strand did not impair the assembly of the autotransporter fusion protein. Mutation of the C-terminal aromatic amino acid of the β 12 -strand strongly impaired surface display of the mCherry passenger domain. This amino acid has been shown before as an essential feature of the β-signals of classical autotransporter proteins and outer membrane β-barrel proteins in general. We therefore propose that the β 12 -strand of YeeJ acts as its β-signal and that the assembly of the YeeJ β-barrel is driven by its C-terminal β-strand, like in most other autotransporter proteins, despite its inverted domain organization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Pharmacokinetic non-inferiority of subcutaneous (SC) to intravenous (IV) CT-P13 maintenance therapy was demonstrated in a randomized trial (NCT02883452). This post hoc analysis evaluated longitudinal clinical outcomes with the two infliximab treatment strategies., Methods: Patients with Crohn's disease or ulcerative colitis received CT‑P13 IV loading doses (5 mg/kg; Week [W] 0 and W2) before randomization (1:1) to receive CT-P13 SC (body weight-based dosing every 2 weeks [Q2W]; W6-54; 'SC maintenance group') or CT‑P13 IV (5 mg/kg Q8W; W6-22) then CT-P13 SC (Q2W; W30-54; 'IV-to-SC switch group'). Paired W30/W54 patient-level data were analyzed., Results: Fifty-three (IV-to-SC switch) and fifty-nine (SC maintenance) patients were analyzed. Median trough serum CT-P13 concentrations were significantly higher at W54 versus W30 in the IV-to-SC switch group (20.4 versus 2.3 µg/mL; p < 0.00001), while remaining consistent in the SC maintenance group. Statistically significant improvements in pharmacokinetics, efficacy, fecal calprotectin levels, and quality of life were seen following switch to SC administration at W30 in the IV-to-SC switch group; safety findings were similar pre- and post-switch., Conclusion: Formulation switching from IV to SC infliximab maintenance therapy was well tolerated and may provide additional clinical improvements. Findings require confirmation in larger prospective studies., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Intestinal involvement in Behçet's disease (BD) is associated with poor prognosis and is more prevalent in East Asian than in Mediterranean populations. Identifying the genetic causes of intestinal BD is important for understanding the pathogenesis and for appropriate treatment of BD patients., Methods: We performed genome-wide association studies (GWAS) and imputation/replication genotyping of human leukocyte antigen (HLA) alleles for 1,689 Korean and Turkish patients with BD (including 379 patients with intestinal BD) and 2,327 healthy controls, followed by replication using 593 Japanese patients with BD (101 patients with intestinal BD) and 737 healthy controls. Stratified cross-phenotype analyses were performed for 1) overall BD, 2) intestinal BD, and 3) intestinal BD without association of overall BD., Results: We identified three novel genome-wide significant susceptibility loci including NPHP4 (rs74566205; P=1.36 × 10 -8 ), TYW1-AUTS2 (rs60021986; P=1.14 × 10 -9 ), and SEMA6D (rs4143322; P=5.54 × 10 -9 ) for overall BD, and a new association with HLA-B*46:01 for intestinal BD (P=1.67 × 10 -8 ) but not for BD without intestinal involvement. HLA peptide binding analysis revealed that Mycobacterial peptides, have a stronger binding affinity to HLA-B*46:01 compared to the known risk allele HLA-B*51:01., Conclusions: HLA-B*46:01 is associated with the development of intestinal BD; NPHP4, TYW1-AUTS2, and SEMA6D are susceptibility loci for overall BD., Competing Interests: Conflicts of interest No potential conflict of interest relevant to this article was reported., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Collagen type XVIII (COL18) is an abundant heparan sulfate proteoglycan in vascular basement membranes. Here, we asked (i) if the loss of COL18 would result in blood-brain barrier (BBB) breakdown, pathological alterations of small arteries and capillaries and neuroinflammation as found in cerebral small vessel disease (CSVD) and (ii) if such changes may be associated with remodeling of synapses and neural extracellular matrix (ECM). We found that 5-month-old Col18a1 -/- mice had elevated BBB permeability for mouse IgG in the deep gray matter, and intravascular erythrocyte accumulations were observed brain-wide in capillaries and arterioles. BBB permeability increased with age and affected cortical regions and the hippocampus in 12-month-old Col18a1 -/- mice. None of the Col18a1 -/- mice displayed hallmarks of advanced CSVD, such as hemorrhages, and did not show perivascular space enlargement. Col18a1 deficiency-induced BBB leakage was accompanied by activation of microglia and astrocytes, a loss of aggrecan in the ECM of perineuronal nets associated with fast-spiking inhibitory interneurons and accumulation of the perisynaptic ECM proteoglycan brevican and the microglial complement protein C1q at excitatory synapses. As the pathway underlying these regulations, we found increased signaling through the TGF-ß1/Smad3/TIMP-3 cascade. We verified the pivotal role of COL18 for small vessel wall structure in CSVD by demonstrating the protein's involvement in vascular remodeling in autopsy brains from patients with cerebral hypertensive arteriopathy. Our study highlights an association between the alterations of perivascular ECM, extracellular proteolysis, and perineuronal/perisynaptic ECM, as a possible substrate of synaptic and cognitive alterations in CSVD., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Topographic maps form a critical feature of cortical organization, yet are poorly described with respect to their microstructure in the living aging brain. We acquired quantitative structural and functional 7T-MRI data from younger and older adults to characterize layer-wise topographic maps of the primary motor cortex (M1). Using parcellation-inspired techniques, we show that quantitative T1 and Quantitative Susceptibility Maps values of the hand, face, and foot areas differ significantly, revealing microstructurally distinct cortical fields in M1. We show that these fields are distinct in older adults and that myelin borders between them do not degenerate. We further show that the output layer 5 of M1 shows a particular vulnerability to age-related increased iron, while layer 5 and the superficial layer show increased diamagnetic substance, likely reflecting calcifications. Taken together, we provide a novel 3D model of M1 microstructure, where body parts form distinct structural units, but layers show specific vulnerability toward increased iron and calcium in older adults. Our findings have implications for understanding sensorimotor organization and aging, in addition to topographic disease spread., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The Indian River Lagoon (IRL) spans approximately one-third of the east coast of Florida and, in recent years, has faced frequent harmful algal blooms (HABs). Blooms of the potentially toxic diatom, Pseudo-nitzschia, occur throughout the lagoon and were reported primarily from the northern IRL. The goal of this study was to identify species of Pseudo-nitzschia and characterize their bloom dynamics in the southern IRL system where monitoring has been less frequent. Surface water samples collected from five locations between October 2018 and May 2020 had Pseudo-nitzschia spp. present in 87% of samples at cell concentrations up to 1.9×10 3 cells mL -1 . Concurrent environmental data showed Pseudo-nitzschia spp. were associated with relatively high salinity waters and cool temperatures. Six species of Pseudo-nitzschia were isolated, cultured, and characterized through 18S Sanger sequencing and scanning electron microscopy. All isolates demonstrated toxicity and domoic acid (DA) was present in 47% of surface water samples. We report the first known occurrence of P. micropora and P. fraudulenta in the IRL, and the first known DA production from P. micropora., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P 2,3 , is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis., Methods: In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively., Findings: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported., Interpretation: Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis., Funding: Arena Pharmaceuticals., Competing Interests: Declaration of interests WJS reports research grants from AbbVie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Gilead Sciences, GSK, Janssen, Lilly, Pfizer, Prometheus Laboratories, Seres Therapeutics, Shire Pharmaceuticals, Takeda, and Theravance Biopharma; consulting fees from AbbVie, Abivax, Alfasigma, Alimentiv (previously Robarts Clinical Trials, owned by Alimentiv Health Trust), Allakos, Amgen, Arena Pharmaceuticals, AstraZeneca, Atlantic Pharmaceuticals, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, ClostraBio, Forbion, Galapagos, Genentech (Roche), GSK, Gossamer Bio, Index Pharmaceuticals, Iota Biosciences, Janssen, Lilly, Morphic Therapeutics, Novartis, Oppilan Pharma (now Ventyx Biosciences), Pfizer, Pharm Olam, Polpharma, Progenity, Prometheus Biosciences, Protagonist Therapeutics, PTM Therapeutics, Seres Therapeutics, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Vedanta Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivreon Gastrosciences, Xencor, and Zealand Pharmaceuticals; stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma (now Ventyx Biosciences), Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonists Therapeutics, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, and Vivreon Gastrosciences; and is Chief Medical Officer at Ventyx Biosciences. SV reports grants from AbbVie, J&J, Pfizer, Galapagos, and Takeda; and has received consulting or speaking fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, IMIDomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MRM Health, Mundipharma, MSD, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts Pharma AG, and Zealand Pharma. LP-B reports consulting fees from AbbVie, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharma, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia, and Abivax; grants from Takeda, Fresenius Kabi, and Celltrion; and lecture or speaker fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Lilly, Gilead, Viatris, and Medac. MCD reports consulting fees from AbbVie, Arena, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, Gilead, Janssen, Pfizer, Prometheus Labs, and Takeda; and is founder and a shareholder of Trellus Health. JP reports consulting fees from AbbVie, Arena Pharmaceuticals, Athos, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Genentech, GSK, Janssen, Mirum, Morphic, Nestle, Origo, Pandion, Progenity, Pfizer, Revolo, Robarts, Roche, Takeda, Theravance, and Wassermann; speaker fees from AbbVie, Biogen, Ferring, Janssen, Pfizer, and Takeda; and research funding from AbbVie and Pfizer. AY reports consulting fees from Takeda, Prometheus Labs, Arena Pharmaceuticals, and Bristol Myers Squibb; and speaker bureau fees from Bristol Myers Squibb. TR served on advisory boards or speaker panels for Gilead, AbbVie, Arena Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Gossamer, Intercept, Janssen, Eli Lilly, Pfizer, Prometheus, and Takeda. FB reports grant or research support from AbbVie, Amgen, Janssen, and Takeda; honoraria from AbbVie, Amgen, Arena Pharmaceuticals, Celgene, Celltrion, Ferring, Fresenius Kabi, Janssen, MSD, Pfizer, Sandoz, and Takeda; and was on speakers bureaus for AbbVie, Arena Pharmaceuticals, Ferring, Galapagos, Janssen, MSD, Pfizer, and Takeda. SSc has been a consultant for AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Dr Falk Pharma, Ferring, Fresenius, Galapagos, Genentech, GSK, Gilead, I-MAB Biopharma, Janssen, Lilly, Merck, Novartis-Sandoz, Pfizer, Protagonist, Takeda, and Theravance. FC was a previous employee and stockholder of Arena Pharmaceuticals at the time of research. SSl, KS, CJR, and MG are employees and stockholders of Arena Pharmaceuticals, a wholly-owned subsidiary of Pfizer Inc. MC has been a speaker for AbbVie, Janssen, Medtronic, Pfizer, Bristol Myers Squibb, and Takeda; and has served as a consultant for AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Medtronic, Pfizer, Lilly, Prometheus, and Takeda. DCW has received consulting or speaker honoraria from AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Janssen, Lilly, Pfizer, and Takeda. BES reports consulting fees from Abivax, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion Healthcare, ClostraBio, Entera, Evommune, Galapagos, Genentech, Gilead Sciences, GSK, Gossamer Bio, Index Pharmaceuticals, Inotrem, Innovation Therapeutics, Ironwood Pharmaceuticals, Janssen, Kaleido, Kallyope, Lilly, Miro Bio, Morphic Therapeutics, MRM Health, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Q32 Bio, Surrozen, Takeda, Teva, TLL Pharmaceutical, USWM Enterprises, and Viela Bio; speaking fees from Abivax, Bristol Myers Squibb, Janssen, Pfizer, and Takeda; and grant or research support from Janssen. GD has been a consultant for AbbVie, AgomAb, AstraZeneca, AM Pharma, AMT, Arena Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Index Pharmaceuticals, Kaleido, Roche, Gilead, GSK, Gossamer Bio, Pfizer, Immunic, J&J, Origo, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, and Protagonist; and has received speakers bureau fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, Pfizer, Bristol Myers Squibb, and Takeda. SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, J&J, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor; and payment for expert testimony from AbbVie, Amgen, Ferring Pharmaceuticals, Gilead, Janssen, Mylan, Pfizer, and Takeda. BGF has been a consultant for AbbVie, Admirx, AgomAb Therapeutics, Applied Molecular Transport, Arena Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Ferring, Galapagos, Galen Atlantica, Genentech-Roche, Gilead, Gossamer Pharma, GSK, F Hoffmann-La Roche, Janssen, Morphic Therapeutics, OM Pharma, Pandion Therapeutics, Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Sanofi, Seres Therapeutics, Surrozen, Takeda, Theravance, TiGenix, Tillotts, and Zealand Pharma; has received speaker bureau fees from AbbVie, Janssen, and Takeda; served on the scientific advisory board for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Bristol Myers Squibb, Genentech, Roche, Janssen, Novartis, Origo BioPharma, Pfizer, Prometheus, Takeda, Tillotts Pharma, Teva, Progenity, Index, and GSK; is a stockholder of Gossamer Pharma; and is an employee of Western University and Alimentiv., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Ozanimod, an oral sphingosine 1-phosphate receptor modulator currently approved for the treatment of moderately to severely active ulcerative colitis and relapsing multiple sclerosis, showed clinical, endoscopic, and histological benefit in the phase 2 STEPSTONE trial for Crohn's disease (CD). We aim to describe the trial design of the YELLOWSTONE phase 3 program evaluating the safety and efficacy of ozanimod in patients with moderately to severely active CD., Methods: The YELLOWSTONE program consists of phase 3, randomized, double-blind, placebo-controlled induction (NCT03440372 and NCT03440385) and maintenance (NCT03464097) trials and an open-label extension (OLE) study (NCT03467958). Patients with inadequate response or intolerance to ≥1 CD treatment are randomized to receive daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo for 12 weeks during induction. Those who respond to ozanimod are rerandomized to continue ozanimod or placebo maintenance therapy for 52 weeks. Patients who do not meet criteria for maintenance, experience relapse during maintenance, or complete maintenance or ≥ 1 year of STEPSTONE are eligible for open-label treatment for up to 234 weeks. Efficacy endpoints include clinical, endoscopic, and histologic outcomes., Results: Expected 2023 (induction studies), 2024 (maintenance study), and 2026 (OLE)., Conclusion: YELLOWSTONE will provide pivotal phase 3 data on the safety and efficacy of ozanimod in patients with moderately to severely active CD using state-of-the-art methods, including centrally read endoscopic and histologic measurements, along with subjective assessments of symptom control based on the Crohn's Disease Activity Index. These studies could enable approval of ozanimod as a new CD therapy., Clinical Trial Registration Numbers: NCT03440372, NCT03440385, NCT03464097, NCT03467958., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Brian G. Feagan has consulted for AbbVie, ActoGeniX, Albireo, Amgen, AstraZeneca, Avaxia Biologics, Baxter, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Calypso, Celgene, Elan, enGene, Ferring Pharma, Roche/Genentech, gIcare Pharma, Gilead, Given Imaging, GSK, Ironwood, Janssen, Johnson & Johnson, Lexicon, Lilly, Merck, Millennium, Nektar, Novo Nordisk, Pfizer, Prometheus Laboratories, Protagonist, Sanofi, and UCB, and is a director at Robarts Clinical Trials. Stefan Schreiber has received personal fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Fresenius, Galapagos/Gilead, I-Mab, Janssen, MSD, Mylan, Pfizer, Protagonist, ProventionBio, Takeda, and Theravance Biopharma. Anita Afzali has served as a consultant for AbbVie, Takeda, Janssen, Pfizer, Bristol Myers Squibb, Eli Lilly, Gilead, TLL Pharmaceuticals, Arena Pharmaceuticals, and DiaSorin, and has received speaker fees from AbbVie, Takeda, Janssen, Pfizer, and Bristol Myers Squibb. Florian Rieder has consulted for Adnovate, AgomAb, Allergan, AbbVie, Arena, Boehringer Ingelheim, Celgene/Bristol Myers Squibb, CDISC, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, GuidePoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Janssen, Koutif, Mestag Therapeutics, Metacrine, Morphic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, Redx Pharma, Roche, Samsung, Surmodics, Surrozen, Takeda, TechLab, Theravance, Thetis, UCB, Ysios Capital, and 89bio. Jeffrey Hyams served on advisory boards for Janssen, Pfizer, and Boehringer Ingelheim and as a consultant to Takeda, Bristol Myers Squibb, Thetis, and Eli Lilly. Kanthi Kollengode, Jared Pearlman, Vladimir Son, and Cecilia Marta are employees of Bristol Myers Squibb. Douglas C. Wolf has received honoraria as a speaker, consultant, and/or advisory board member from AbbVie, Arena, Celgene/Bristol Myers Squibb, Janssen, Pfizer, Prometheus, Takeda, and UCB. Geert G. D'Haens has consulted for AbbVie, Cellceutix, Celgene, Endo, Ferring, Gilead, Janssen Ortho Biotech, Eli Lilly, American Regent, Merck, Morphic, Pfizer, Prometheus Laboratories, Romark, Salix Pharmaceuticals/Valeant, Shire Pharmaceuticals, Takeda, and UCB; conducted research for UCB, Janssen Ortho Biotech; editor (honorarium) Gastroenterology and Hepatology (Gastro-Hep Communications), Springer Science and Business Media; received book royalties from SLACK, Inc., and Professional Communications, Inc., (Copyright © 2022. Published by Elsevier Inc.)

Objective: The current study investigated the oscillatory brain activity of PTSD patients during directed and imaginal exposure to the traumatic memory using magnetoencephalography (MEG), in a paradigm resembling exposure therapy., Methods: Brain activity of healthy trauma-exposed controls and PTSD participants was measured with MEG as they listened to individualized trauma narratives as well as to a neutral narrative and as they imagined the narrative in detail. Source localization analysis by frequency bands was conducted in order to map neural generators of oscillatory activity., Results: Elicitation of traumatic memories resulted in a distinct neural pattern in PTSD patients compared to healthy trauma-exposed individuals. In response to trauma scripts PTSD patients showed increases in high-gamma band power in visual areas, increased frontal and temporal theta as well as prefrontal alpha and medial temporal beta power relative to neutral scripts., Conclusions: Results suggest that when recollecting and imagining traumatic memories PTSD patients attempt to engage control or inhibition mechanisms. However, these are either not successfully recruited or inefficient leading to heightened responses and recollection., Significance: Investigating the oscillatory neural dynamics of PTSD patients can help us better understand the processes underlying trauma re-experiencing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Declaration of Competing Interest None., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease., Methods: ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete., Findings: Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12-29; 152/336) with risankizumab 600 mg and 42% (17%, 8-25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14-30; 146/336) with risankizumab 600 mg and 41% (19%, 11-27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21-35; 135/336) with risankizumab 600 mg and 32% (20%, 14-27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13-31; 80/191) with risankizumab 600 mg and 40% (21%, 12-29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6-24; 66/191) with risankizumab 600 mg and 40% (20%, 12-29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10-25; 55/191) with risankizumab 600 mg and 34% (23%, 15-31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug., Interpretation: Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease., Funding: AbbVie., Competing Interests: Declaration of interests GD’H reports being a consultant or speaker for AbbVie, ActoGeniX, AIM, Allergan, Amgen, Arena, Boehringer Ingelheim, Celgene (formerly Receptos), Celltrion, Cosmo Technologies, Elan, Eli Lilly, enGene, Dr Falk Pharma, Ferring, Galapagos, Genentech, Gilead Sciences, Giuliani, Given Imaging, GlaxoSmithKline (GSK), Gossamer Bio, Janssen Biologics, Merck, Sharp & Dohme (MSD), Neovacs, Norgine, Novo Nordisk, Otsuka, PDL BioPharma, Prometheus Laboratories, Progenity, Pfizer, Alimentiv (formerly Robarts Clinical Trials), Salix, Seres and Nestle, Schering-Plough, SetPoint, Shire, Takeda, Tillotts, Tramedico, UCB, Versant, and Vifor; and reports research grants from AbbVie, Dr Falk Pharma, Given Imaging, Janssen, MSD, and PhotoPill. RP reports being a consultant or speaker for AI4GI, AbbVie, Arena, Amgen, Atlantic Healthcare, BioBalance, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Celgene, Coronado Biosciences, Cosmo Technologies, Eagle, Eisai Medical Research, Elan, Eli Lilly, EnGene, Ferring, Genentech, Gilead, Given Imaging, GSK, Janssen, Lycera, Meda, Merck & Co, Merck Research, Merck Serono, Novo Nordisk, PDL Biopharma, Pfizer, Prometheus, Protagonist, Celgene, Alimentiv, Salix, Soz, Sanofi Genzyme, Shire, Sigmoid, Sublimity, Takeda, and Theravance. FB reports being a consultant or speaker for AbbVie, Arena, Celltrion, Falk, Ferring, Janssen, Mundipharma, MSD, Pfizer, Sandoz, Takeda, Vifor; and received research grants from AbbVie, Amgen, Chiesi, Ipsen, Janssen, and MSD. PB has received financial support for research from AbbVie, Amgen, Janssen, Mundipharma, Mylan, and Pfizer; lecture fees from AbbVie, Celltrion, Janssen, Pfizer, and Takeda; and advisory board fees from AbbVie, Arena Pharmaceuticals, BMS, Hospira, Janssen, Lilly, Merck, Mundipharma, Pentax Medical, Pfizer, PSI CRO, Roche, Sandoz, and Takeda. J-FC reports research grants from AbbVie, Janssen Pharmaceuticals, and Takeda; received payment for lectures from AbbVie, Amgen, Allergan, Ferring Pharmaceuticals, Shire, and Takeda; received consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, GSK, Janssen, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microba, Novartis, PBM Capital, Pfizer, Sanofi, Takeda, TiGenix, Vifor; and holds stock options in Intestinal Biotech Development. SD reports research grants from AbbVie, Alimentiv, Amgen, Genentech, Gilead, Janssen, Pfizer, Celgene, Seres Therapeutics, Takeda, and UCB; and has been a consultant for AbbVie, Allergan, Amgen, BMS, Celgene, Celltrion, Janssen, Lilly, Pfizer, Takeda, and UCB. MD reports being a consultant for AbbVie, Arena, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Gilead, Janssen, Merck, Pfizer, Prometheus Laboratories, Takeda, and UCB; and received research grants from Janssen, AbbVie, and Prometheus Laboratories. BGF reports grants or research support from AbbVie, Amgen, AstraZeneca (MedImmune), Atlantic Pharmaceuticals, Boehringer Ingelheim, Celgene, Celltech, Genentech (subsidiary of Roche), Gilead Sciences, GSK, Janssen Research & Development, Pfizer, Celgene (Receptos), Sanofi, Santarus, Takeda Development Center Americas, Tillotts Pharma, and UCB; being a consultant for Abbott (AbbVie), AgomAB Therapeutics, Allakos, Allergan, Amgen, Applied Molecular Transport, Aptevo Therapeutics, AstraZeneca, Atlantic Pharma, BioMx Israel, Boehringer Ingelheim, BMS, Calypso Biotech, Celgene, Connect BioPharma, Everest Clinical Research, Galapagos, Galen Atlantica, Genentech (Roche), Gilead, Gossamer Pharma, GSK, Roche, Index Pharma, ImmunExt, Janssen, Kaleido Biosciences, Kyowa Kakko Kirin, Lilly, Lument AB, Merck, Millenium, Mylan, Nestles, Nextbiotix, Origo BioPharma, Pandion Therapeutics, ParImmune, Parvus Therapeutics, Pfizer, Prometheus Laboratories, Progenity, Protagonist, Qu Biologics, Rebiotix, Celgene, Salix Pharma, Sandoz, Sanofi, Shire, Surrozen, Takeda, Tillotts, UCB Pharma, VHsquared, Ysios, and Zealand Pharma; being on speakers bureau for AbbVie, Janssen, and Takeda; scientific advisory board membership with AbbVie, Allergan, Amgen, Astra Zeneca, Boehringer Ingelheim, BMS, Celgene, Genentech (Roche), Janssen, Novartis, Origo BioPharma, Pfizer, Prometheus Laboratories, Protagonist, Takeda, Tillotts Pharma; board of directors membership with Alimentiv; and being a shareholder of stock with Gossamer Pharma. TH reports speaker or consultant fees from Mitsubishi Tanabe Pharma Corporation, EA Pharma, AbbVie, JIMRO, Zeria Pharmaceutical, Kyorin Pharmaceutical, Takeda, Pfizer Japan, Mochida Pharmaceutical, Celgene, Janssen, and Nichi-Iko Pharmaceutical; and reports research grants from Alfresa Pharma, EA pharma, Mitsubishi Tanabe Pharma Corporation, AbbVie, JIMRO, Zeria Pharmaceutical, Daiichi-Sankyo, Kyorin Pharmaceutical, Nippon Kayaku, Takeda, Pfizer, and Mochida Pharmaceutical. AL reports being a consultant, speaker, or stockholder with AbbVie, Takeda, Janssen, and Ferring; and reports research grants from AbbVie, Takeda, Janssen, and Eli Lilly. JOL reports advisory board membership or speaker fees from AbbVie, Allergan, BMS, Celgene, Celtrion, Ferring, Gilead, GSK, Janssen, MSD, Napp, Pfizer, and Takeda; and research grants from AbbVie, Gilead, Takeda, and Pfizer. EVL reports being a consultant for AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Calibr, Celgene, Genentech, Gilead, Gossamer Bio, Iterative Scopes, Janssen, Lilly, Morphic, Ono Pharmaceutical, Pfizer, Protagonist, Scipher Medicine, Sun Pharma, Surrozen, Takeda, and UCB; research support from Alimentiv (Robarts Clinical Trials); and research grants from AbbVie, Amgen, BMS, Genentech, Gilead, Gossamer Bio, Janssen, Pfizer, Celgene (Receptos), Takeda, Theravance, and UCB. JP reports being a consultant or speaker for AbbVie, Arena, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Genentech, GSK, Janssen, Nestle, Origo, Pandion, Pfizer, Progenity, Alimentiv, Roche, Shire, Takeda, Theravance, and Wasserman; and research grants from AbbVie and Pfizer. LP-B reports personal fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Inotrem, Allergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSE Immunotherapeutics, Enthera, Theravance, Pandion Therapeutics, Gossamer Bio, Viatris, and Thermo Fisher Scientific; grants from AbbVie, MSD, Takeda, and Fresenius Kabi; and holds stock options in Clinical Trials Mobile Application. DTR reports speaker or consultant fees from AbbVie, Abgenomics, Allergan, Arena Pharmaceuticals, Bellatrix Pharmaceuticals, Boehringer Ingelheim, BMS, CDx Diagnostics, Syneos, Check-Cap, Dizal Pharmaceuticals, Genentech (Roche), Gilead Sciences, Ichnos Sciences (formerly Glenmark Pharmaceuticals), InDex Pharmaceuticals, Iterative Scopes, Janssen, Lilly, Materia Prima, Narrow River Management, Pfizer, Prometheus Laboratories, Reistone, Takeda, and Techlab; and research grants from Takeda. WJS reports research grants from AbbVie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, GSK, Janssen, Lilly, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, Theravance Biopharma; consulting fees from AbbVie, Abivax, Admirx, Alfasigma, Alimentiv (Robarts Clinical Trials), Alivio Therapeutics, Allakos, Allergan, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Avexegen Therapeutics, Salix (subsidiary of Bausch Health), Beigene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, BMS, Celgene, Celltrion, Cellularity, Conatus, Cosmo Pharmaceuticals, Escalier Biosciences, Ferring, Forbion, Equillium, Genentech (Roche), Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic Therapeutics (formerly Vital Therapies), Incyte, Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyowa Kirin Pharmaceutical Research, Kyverna Therapeutics, Landos Biopharma, Lilly, Miraca Life Sciences, Nivalis Therapeutics, Novartis, Nutrition Science Partners, Oppilan Pharma (acquired by Ventyx Biosciences), Otsuka, Pandion Therapeutics, Paul Hastings, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Ritter Pharmaceuticals, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tigenix, Tillotts Pharma, UCB Pharma, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, Zealand Pharma; stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma (acquired by Ventyx Biosciences), Prometheus Biosciences, Prometheus Laboratories, Progenity, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivreon Biosciences; and employment at Shoreline Biosciences. SS reports consultant or speaker fees from AbbVie, Allergosan, Amgen, Arena, BMS, Celltrion, Falk Pharma, Ferring, Galapagos, Gilead, Genentech (Roche), GSK, IMAB, Janssen, Lilly, MSD, Pfizer, Shire, Takeda, and Viatris. MF reports being a consultant or speaker for AbbVie, Amgen, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Dr Falk, Ferring, Janssen-Cilag, Lamepro, Eli Lilly, Medtronic, MSD, Mylan, Pfizer, Regeneron, Samsung Bioepis, Sandoz, Takeda, Thermo Fisher Scientific, Truvion Healthcare; and research grants from AbbVie, Amgen, Biogen, Janssen, Pfizer, and Takeda. EN, AS, KK, YP, VP, SB, WRD, BH, JK, XL, AR, and KW are full-time employees of AbbVie, and own AbbVie stock. ZR declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: There is a great unmet need for new therapeutics with novel mechanisms of action for patients with Crohn's disease. The ADVANCE and MOTIVATE studies showed that intravenous risankizumab, a selective p19 anti-interleukin (IL)-23 antibody, was efficacious and well tolerated as induction therapy. Here, we report the efficacy and safety of subcutaneous risankizumab as maintenance therapy., Methods: FORTIFY is a phase 3, multicentre, randomised, double-blind, placebo-controlled, maintenance withdrawal study across 273 clinical centres in 44 countries across North and South America, Europe, Oceania, Africa, and the Asia-Pacific region that enrolled participants with clinical response to risankizumab in the ADVANCE or MOTIVATE induction studies. Patients in ADVANCE or MOTIVATE were aged 16-80 years with moderately to severely active Crohn's disease. Patients in the FORTIFY substudy 1 were randomly assigned again (1:1:1) to receive either subcutaneous risankizumab 180 mg, subcutaneous risankizumab 360 mg, or withdrawal from risankizumab to receive subcutaneous placebo (herein referred to as withdrawal [subcutaneous placebo]). Treatment was given every 8 weeks. Patients were stratified by induction dose, post-induction endoscopic response, and clinical remission status. Patients, investigators, and study personnel were masked to treatment assignments. Week 52 co-primary endpoints were clinical remission (Crohn's disease activity index [CDAI] in the US protocol, or stool frequency and abdominal pain score in the non-US protocol) and endoscopic response in patients who received at least one dose of study drug during the 52-week maintenance period. Safety was assessed in patients receiving at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03105102., Findings: 712 patients were initially assessed and, between April 9, 2018, and April 24, 2020, 542 patients were randomly assigned to either the risankizumab 180 mg group (n=179), the risankizumab 360 mg group (n=179), or the placebo group (n=184). Greater clinical remission and endoscopic response rates were reached with 360 mg risankizumab versus placebo (CDAI clinical remission was reached in 74 (52%) of 141 patients vs 67 (41%) of 164 patients, adjusted difference 15% [95% CI 5-24]; stool frequency and abdominal pain score clinical remission was reached in 73 (52%) of 141 vs 65 (40%) of 164, adjusted difference 15% [5-25]; endoscopic response 66 (47%) of 141 patients vs 36 (22%) of 164 patients, adjusted difference 28% [19-37]). Higher rates of CDAI clinical remission and endoscopic response (but not stool frequency and abdominal pain score clinical remission [p=0·124]) were also reached with risankizumab 180 mg versus withdrawal (subcutaneous placebo; CDAI clinical remission reached in 87 [55%] of 157 patients, adjusted difference 15% [95% CI 5-24]; endoscopic response 74 [47%] of 157, adjusted difference 26% [17-35]). Results for more stringent endoscopic and composite endpoints and inflammatory biomarkers were consistent with a dose-response relationship. Maintenance treatment was well tolerated. Adverse event rates were similar among groups, and the most frequently reported adverse events in all treatment groups were worsening Crohn's disease, arthralgia, and headache., Interpretation: Subcutaneous risankizumab is a safe and efficacious treatment for maintenance of remission in patients with moderately to severely active Crohn's disease and offers a new therapeutic option for a broad range of patients by meeting endpoints that might change the future course of disease., Funding: AbbVie., Competing Interests: Declaration of interests MF reports being a consultant or speaker for AbbVie, Amgen, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Dr Falk, Ferring, Janssen-Cilag, Lamepro, Eli Lilly, Medtronic, Merck Sharp & Dohme (MSD), Mylan, Pfizer, Regeneron, Samsung Bioepis, Sandoz, Takeda, Thermo Fisher Scientific, and Truvion Healthcare; and research grants from AbbVie, Amgen, Biogen, Janssen, Pfizer, and Takeda. RP reports being a consultant or speaker for AI4GI, AbbVie, Arena, Amgen, Atlantic Healthcare, BioBalance, Boehringer Ingelheim, Bristol-Myers Squibb (BMS), Celgene, Coronado Biosciences, Cosmo Technologies, Eagle, Eisai Medical Research, Elan, Eli Lilly, EnGene, Ferring, Genentech, Gilead, Given Imaging, GlaxoSmithKline (GSK), Janssen, Lycera, Meda, Merck & Co, Merck Research, MerckSerono, Novo Nordisk, PDL Biopharma, Pfizer, Prometheus, Protagonist, Celgene, Alimentiv, Salix, Soz, Sanofi Genzyme, Shire, Sigmoid, Sublimity, Takeda, and Theravance. FB reports being a consultant or speaker for AbbVie, Arena, Celltrion, Falk, Ferring, Janssen, Mundipharma, MSD, Pfizer, Sandoz, Takeda, Vifor; and received research grants from AbbVie, Amgen, Chiesi, Ipsen, Janssen, and MSD. PB has received financial support for research from AbbVie, Amgen, Janssen, Mundipharma, Mylan, and Pfizer; lecture fees from AbbVie, Celltrion, Janssen, Pfizer, and Takeda; and advisory board fees from AbbVie, Arena Pharmaceuticals, BMS, Hospira, Janssen, Lilly, Merck, Mundipharma, Pentax Medical, Pfizer, PSI CRO, Roche, Sandoz, and Takeda. J-FC reports research grants from AbbVie, Janssen Pharmaceuticals, and Takeda; received payment for lectures from AbbVie, Amgen, Allergan, Ferring Pharmaceuticals, Shire, and Takeda; received consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, GSK, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microba, Novartis, PBM Capital, Pfizer, Sanofi, Takeda, TiGenix, and Vifor; and holds stock options in Intestinal Biotech Development. SD reports research grants from AbbVie, Alimentiv, Amgen, Genentech, Gilead, Janssen, Pfizer, Celgene, Seres Therapeutics, Takeda, and UCB; and has been a consultant for AbbVie, Allergan, Amgen, BMS, Celgene, Celltrion, Janssen, Lilly, Pfizer, Takeda, and UCB. MD reports being a consultant for AbbVie, Arena, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Gilead, Janssen, Merck, Pfizer, Prometheus Labs, Takeda, and UCB; and received research grants from Janssen, AbbVie, and Prometheus Labs. BGF reports grants or research support from AbbVie, Amgen, AstraZeneca (MedImmune), Atlantic Pharmaceuticals, Boehringer-Ingelheim, Celgene Corporation, Celltech, Genentech (subsidiary of Roche), Gilead Sciences, GSK, Janssen Research & Development, Pfizer, Celgene (Receptos), Sanofi, Santarus, Takeda Development Center Americas, Tillotts Pharma, and UCB; reports being a consultant for Abbott (AbbVie), AgomAB Therapeutics, Allakos, Allergan, Amgen, Applied Molecular Transport, Aptevo Therapeutics, Astra Zeneca, Atlantic Pharma, BioMx Israel, Boehringer-Ingelheim, BMS, Calypso Biotech, Celgene, Connect BioPharma, Everest Clinical Research, Galapagos, Galen Atlantica, Genentech (Roche), Gilead, Gossamer Pharma, GSK, Roche, Index Pharma, ImmunExt, Janssen, Kaleido Biosciences, Kyowa Kakko Kirin, Lilly, Lument AB, Merck, Millenium, Mylan, Nestle, Nextbiotix, Origo BioPharma, Pandion Therapeutics, ParImmune, Parvus Therapeutics, Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Qu Biologics, Rebiotix, Celgene, Salix Pharma, Sandoz, Sanofi, Shire, Surrozen, Takeda, Tillotts, UCB Pharma, VHsquared, Ysios, and Zealand Pharma; reports being on the speakers bureau for AbbVie, Janssen, and Takeda; reports scientific advisory board membership with AbbVie, Allergan, Amgen, Astra Zeneca, Boehringer-Ingelheim, BMS, Celgene, Genentech (Roche), Janssen, Novartis, Origo BioPharma, Pfizer, Prometheus, Protagonist, Takeda, and Tillotts Pharma; reports board of directors membership with Alimentiv; and reports being a shareholder of stock with Gossamer Pharma. TH reports speaker or consultant fees from Mitsubishi Tanabe Pharma Corporation, EA Pharma, AbbVie, JIMRO, Zeria Pharmaceutical, Kyorin Pharmaceutical, Takeda Pharmaceutical, Pfizer Japan, Mochida Pharmaceutical, Celgene, Janssen Pharmaceutical, and Nichi-Iko Pharmaceutical; and reports research grants from Alfresa Pharma, EA pharma, Mitsubishi Tanabe Pharma Corporation, AbbVie, JIMRO, Zeria Pharmaceutical, Daiichi-Sankyo, Kyorin Pharmaceutical, Nippon Kayaku, Takeda Pharmaceutical, Pfizer, and Mochida Pharmaceutical. AL reports being a consultant, speaker, or stockholder with AbbVie, Takeda, Janssen, and Ferring; and reports research grants from AbbVie, Takeda, Janssen, and Eli Lilly. JOL reports advisory board membership or speaker fees from AbbVie, Allergan, BMS, Celgene, Celtrion, Ferring, Gilead, GSK, Janssen, MSD, Napp, Pfizer, and Takeda; and research grants from AbbVie, Gilead, Takeda, and Pfizer. EVL reports being a consultant for AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Calibr, Celgene, Genentech, Gilead, Gossamer Bio, Iterative Scopes, Janssen, Lilly, Morphic, Ono Pharmaceutical, Pfizer, Protagonist, Scipher Medicine, Sun Pharma, Surrozen, Takeda, and UCB; research support from Alimentiv (Robarts Clinical Trials); and research grants from AbbVie, Amgen, BMS, Genentech, Gilead, Gossamer Bio, Janssen, Pfizer, Celgene (Receptos), Takeda, Theravance, and UCB. JP reports being a consultant or speaker for AbbVie, Arena, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Genentech, GSK, Janssen, Nestle, Origo, Pandion, Pfizer, Progenity, Alimentiv, Roche, Shire, Takeda, Theravance, and Wasserman; and research grants from AbbVie and Pfizer. LP-B reports personal fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Inotrem, Allergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSE Immunotherapeutics, Enthera, Theravance, Pandion Therapeutics, Gossamer Bio, Viatris, and Thermo Fisher Scientific; grants from AbbVie, MSD, Takeda, and Fresenius Kabi; and holds stock options in Clinical Trials Mobile Application. DTR reports speaker or consultant fees from AbbVie, Abgenomics, Allergan, Arena Pharmaceuticals, Bellatrix Pharmaceuticals, Boehringer Ingelheim, BMS, CDx Diagnostics, Syneos, Check-Cap, Dizal Pharmaceuticals, Genentech (Roche), Gilead Sciences, Ichnos Sciences (formerly Glenmark Pharmaceuticals), InDex Pharmaceuticals, Iterative Scopes, Janssen, Lilly, Materia Prima, Narrow River Management, Pfizer, Prometheus Laboratories, Reistone, Takeda, and Techlab; and research grants from Takeda. WJS reports research grants from Abbvie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, GSK, Janssen, Lilly, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, and Theravance Biopharma; consulting fees from Abbvie, Abivax, Admirx, Alfasigma, Alimentiv (Robarts Clinical Trials), Alivio Therapeutics, Allakos, Allergan, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Avexegen Therapeutics, Salix (subsidiary of Bausch Health), Beigene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, BMS, Celgene, Celltrion, Cellularity, Conatus, Cosmo Pharmaceuticals, Escalier Biosciences, Ferring, Forbion, Equillium, Genentech (Roche), Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic Therapeutics (formerly Vital Therapies), Incyte, Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyowa Kirin Pharmaceutical Research, Kyverna Therapeutics, Landos Biopharma, Lilly, Miraca Life Sciences, Nivalis Therapeutics, Novartis, Nutrition Science Partners, Oppilan Pharma (acquired by Ventyx Biosciences), Otsuka, Pandion Therapeutics, Paul Hastings, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Ritter Pharmaceuticals, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tigenix, Tillotts Pharma, UCB Pharma, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, and Zealand Pharma; stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma (acquired by Ventyx Biosciences), Prometheus Biosciences, Prometheus Laboratories, Progenity, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, and Vivreon Biosciences; and employment at Shoreline Biosciences. SS reports consultant or speaker fees from AbbVie, Allergosan, Amgen, Arena, BMS, Celltrion, Falk Pharma, Ferring, Galapagos, Gilead, Genentech (Roche), GSK, IMAB, Janssen, Lilly, MSD, Pfizer, Shire, Takeda, and Viatris. EN, AS, KK, YP, VP, SB, WRD, BH, JK, XL, AR, and KW are full-time employees of AbbVie, and might hold AbbVie stock or stock options. ZR declares no competing interests. GD’H reports being a consultant or speaker for AbbVie, ActoGeniX, AIM, Allergan, Amgen, Arena, Boehringer Ingelheim, Celgene (formerly Receptos), Celltrion, Cosmo Technologies, Elan, Eli Lilly, enGene, Dr Falk Pharma, Ferring, Galapagos, Genentech, Gilead Sciences, Giuliani, Given Imaging, GSK, Gossamer Bio, Janssen Biologics, MSD, Neovacs, Norgine, Novo Nordisk, Otsuka, PDL BioPharma, Prometheus, Progenity, Pfizer, Alimentiv (formerly Robarts Clinical Trials), Salix, Seres and Nestle, Schering-Plough, SetPoint, Shire, Takeda, Tillotts, Tramedico, UCB, Versant, and Vifor; and reports research grants from AbbVie, Dr Falk Pharma, Given Imaging, Janssen, MSD, and PhotoPill., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: The objective of the study was to investigate pregnancy outcome and placental pathology lesions among patients with gestational diabetes mellitus (GDM) versus patients with one abnormal value (OAV), in the oral glucose tolerance test (OGTT)., Methods: A prospective study was performed from 2016 to 2019. All participants performed an OGTT between 24 and 28 weeks. Included patients who delivered at term (>37 weeks) with the diagnosis of GDMA2 (treated with insulin), GDMA1 (controlled with diet) and those with OAV. Maternal characteristics, pregnancy outcomes, and placental histopathology reports were compared between the GDMA2, GDMA1, and OAV groups. Placental lesions were classified according to "Amsterdam" criteria to maternal and fetal vascular malperfusion (MVM, FVM) lesions, and inflammatory lesions., Results: The GDMA2 group (n = 59) was characterized by higher maternal BMI (p < 0.001), increased rate of chronic hypertension (p < 0.01), cesarean delivery (CD) (p < 0.001), adverse neonatal outcomes (p < 0.001) and prolonged hospitalization (p < 0.001) as compared to the GDMA1 (n = 73) and the OAV group (n = 124). Average placental weight in the GDMA2 group were higher (p = 0.004). There were no between groups differences in the rate of placental MVM or inflammatory lesions. The OAV and GDMA1 groups were characterized by an increased rate of FVM lesions, as compared to the GDMA2 group (p = 0.02)., Discussion: GDMA2 is associated with increased rate of CD and adverse neonatal outcome. The similar rate of placental MVM lesions among the study groups, and the increased rate of FVM lesions observed among the OAV group, implies of impaired placental function among the OAV group as in GDM pregnancies., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To assess the incidence of post-operative non-ischaemic cerebral complications as a pivotal outcome parameter with respect to size of cerebral infarction, timing of surgery, and peri-operative management in patients with symptomatic carotid stenosis who underwent carotid endarterectomy (CEA)., Methods: Retrospective analysis of prospectively collected single centre CEA registry data. Consecutive patients with symptomatic carotid stenosis were subjected to standard patch endarterectomy. Brain infarct size was measured from the axial slice of pre-operative computed tomography/magnetic resonance imaging demonstrating the largest infarct dimension and was categorised as large (> 4 cm 2 ), small (≤ 4 cm 2 ), or absent. CEA was performed early (within 14 days) or delayed (15 - 180 days) after the ischaemic event. Peri-operative antiplatelet regimen (none, single, dual) and mean arterial blood pressure during surgery and at post-operative stroke unit monitoring were registered. Non-ischaemic post-operative cerebral complications were recorded comprising haemorrhagic stroke and encephalopathy, i.e., prolonged unconsciousness, delirium, epileptic seizure, or headache., Results: 646 symptomatic patients were enrolled of whom 340 (52.6%) underwent early CEA; 367 patients (56.8%) demonstrated brain infarction corresponding to stenosis induced symptoms which was small in 266 (41.2%) and large in 101 (15.6%). Post-operative non-ischaemic cerebral complications occurred in 12 patients (1.9%; 10 encephalopathies, two haemorrhagic strokes) and were independently associated with large infarcts (adjusted odds ratio [OR] 6.839; 95% confidence interval [CI] 1.699 - 27.534) and median intra-operative mean arterial blood pressure in the upper quartile, i.e., above 120 mmHg (adjusted OR 13.318; 95% CI 2.749 - 64.519). Timing of CEA after the ischaemic event, pre-operative antiplatelet regimen, and post-operative blood pressure were not associated with non-ischaemic cerebral complications., Conclusion: Infarct size and unintended high peri-operative blood pressure may increase the risk of non-ischaemic complications at CEA independently of whether performed early or delayed., Competing Interests: Conflict of interest and funding None., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Preference for sweet-tasting foods, weight gain, and constipation characterize patients receiving methadone maintenance treatment (MMT). The prevalence of constipation in MMT and its relation to preference for sweet taste and body mass index (BMI) are undetermined., Methods: A random sample of 83 patients was interviewed for constipation with the Patient Assessment Constipation Quality of Life (PAC-QOL) questionnaire. They rated taste intensity and reward of sweet, salty, and sour solutions by means of a nine-point Likert scale. Data on their BMI, drugs in urine, methadone dose, and serum levels were analyzed., Results: Forty-two patients reported minimum to severe constipation. They characterized as having longer durations of opioid usage before MMT and worse sleep quality than non-constipated patients (logistic regression). Constipation intensity was inversely correlated with duration in MMT and linearly correlated with the Patient Assessment Constipation Quality of Life score. Patients with constipation rated reward to sweet taste significantly higher with no differences in taste intensity compared to non-constipated patients. Patients with high methadone serum levels (≥750 ng/mL) rated taste intensity significantly lower compared to those with normal methadone serum levels (<750 ng/mL), and the lowest rates were reported among patients with no constipation and high methadone serum levels., Conclusions: Constipation was highly prevalent among MMT patients and associated with poor sleep and lower quality of life. The relation to preference for sweets, as reflected by higher reward rating, strongly supports the need for nutritional intervention to alleviate constipation symptoms and improve quality of life and sleep., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The global prevalence of ulcerative colitis is increasing, and induction and maintenance of remission is a crucial therapeutic goal. We assessed the efficacy and safety of filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, for treatment of ulcerative colitis., Methods: This phase 2b/3, double-blind, randomised, placebo-controlled trial including two induction studies and one maintenance study was done in 341 study centres in 40 countries. Eligible patients were aged 18-75 years with moderately to severely active ulcerative colitis for at least 6 months before enrolment (induction study A: inadequate clinical response, loss of response to or intolerance to corticosteroids or immunosuppressants, naive to tumour necrosis factor [TNF] antagonists and vedolizumab [biologic-naive]; induction study B: inadequate clinical response, loss of response to or intolerance to any TNF antagonist or vedolizumab, no TNF antagonist or vedolizumab use within 8 weeks before screening [biologic-experienced]). Patients were randomly assigned 2:2:1 to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once per day for 11 weeks. Patients who had either clinical remission or a Mayo Clinic Score response at week 10 in either induction study entered the maintenance study. Patients who received induction filgotinib were rerandomised 2:1 to continue their induction filgotinib regimen or to placebo. Patients who received induction placebo continued receiving placebo. The primary endpoint was clinical remission by Mayo endoscopic, rectal bleeding, and stool frequency subscores at weeks 10 and 58. For the induction studies, efficacy was assessed in all randomised patients who received at least one dose of study drug or placebo within that study. For the maintenance study, efficacy was assessed in all patients randomised to any filgotinib treatment group in the induction studies who received at least one dose of study drug or placebo in the maintenance study. Patients who received placebo throughout the induction and maintenance study were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of the study drug or placebo within each study. This trial is registered with ClinicalTrials.gov, NCT02914522., Findings: Between Nov 14, 2016, and March 31, 2020, we screened 2040 patients for eligibility. 659 patients enrolled in induction study A were randomly assigned to receive filgotinib 100 mg (n=277), filgotinib 200 mg (n=245), or placebo (n=137). 689 patients enrolled into induction study B were randomly assigned to receive filgotinib 100 mg (n=285), filgotinib 200 mg (n=262), or placebo (n=142). 34 patients in induction study A and 54 patients in induction study B discontinued the study drug before week 10. After efficacy assessment at week 10, 664 patients entered the maintenance study (391 from induction study A, 273 from induction study B). 93 patients continued to receive placebo. 270 patients who had received filgotinib 100 mg in the induction study were randomly assigned to receive filgotinib 100 mg (n=179) or placebo (n=91). 301 patients who had received filgotinib 200 mg in the induction study were randomly assigned to receive filgotinib 200 mg (n=202) or placebo (n=99). 263 patients discontinued treatment in the maintenance study. At week 10, a greater proportion of patients given filgotinib 200 mg had clinical remission than those given placebo (induction study A 26·1% vs 15·3%, difference 10·8%; 95% CI 2·1-19·5, p=0·0157; induction study B 11·5% vs 4·2%, 7·2%; 1·6-12·8, p=0·0103). At week 58, 37·2% of patients given filgotinib 200 mg had clinical remission versus 11·2% in the respective placebo group (difference 26·0%, 95% CI 16·0-35·9; p<0·0001). Clinical remission was not significantly different between filgotinib 100 mg and placebo at week 10, but was significant by week 58 (23·8% vs 13·5%, 10·4%; 0·0-20·7, p=0·0420). The incidence of serious adverse events and adverse events of interest was similar between treatment groups. In the induction studies, serious adverse events occurred in 28 (5·0%) of 562 patients given filgotinib 100 mg, 22 (4·3%) of 507 patients given filgotinib 200 mg, and 13 (4·7%) of 279 patients given placebo. In the maintenance study, serious adverse events were reported in eight (4·5%) of 179 patients given filgotinib 100 mg, seven (7·7%) of 91 patients in the respective placebo group, nine (4·5%) of 202 patients in the filgotinib 200 mg group, and no patients in the respective placebo group. No deaths were reported during either induction study. Two patients died during the maintenance study; neither was related to treatment., Interpretation: Filgotinib 200 mg was well tolerated, and efficacious in inducing and maintaining clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis., Funding: Gilead Sciences., Competing Interests: Declaration of interests BGF reports grants and personal fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb (BMS), Janssen Biotech/Centocor, Johnson & Johnson (J&J)/Janssen, Pfizer, Receptos, and Takeda; personal fees from Ablynx, Actogenix, AdMIRx, Akebia Therapeutics, Allergan, Atlantic Pharma, Avaxia Biologics, Avir Pharma, Baxter Healthcare Corporation, Biogen Idec, BioMx Israel, Boehringer-Ingelheim, Boston Pharmaceuticals, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring, Galapagos, Genentech/Roche, GiCare Pharma, Gilead, Given Imaging, Gossamer Pharma, GSK, Inception IBD, Ironwood, Japan Tobacco Company, Kyowa Kakko Kirin, Lexicon, Lilly, Lycera Biotech, Merck, Mesoblast Pharma, Millennium, Nestles, NextBiotix, Novartis, Novo Nordisk, ParImmune, Progenity, Prometheus Therapeutics & Diagnostics, Protagonist, Qu Biologics, Salix, Shire, Sienna Biologics, Sigmoid Pharma, Synergy Pharma, Teva Pharma, TiGenix, Tillotts, UCB, Vertex, VHsquared, Vivelix Pharma, Wyeth, Zealand, and Zyngenia, outside the submitted work. BGF is Senior Scientific Director at Alimentiv and Professor of Medicine at Western University. SD reports personal fees from AbbVie, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ely Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen, J&J, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor outside the submitted work. EVL Jr reports grants and personal fees from Gilead during the conduct of the study; grants from Receptos, Robarts Clinical Trials, and Theravance; grants and personal fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Gilead, Janssen, Pfizer, and Takeda; and personal fees from Allergan, Boehringer Ingelheim, Celltrion Healthcare, Eli Lilly, Iterative Scopes, and Ono Pharma, outside the submitted work. SV reports grants from AbbVie, J&J, Pfizer, and Takeda; and consultancy fees from AbbVie, Arena Pharmaceuticals, Avaxia, Boehringer Ingelheim, Celgene, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, Hospira, Janssen, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Takeda, Theravance, and Tillots Pharma, outside the submitted work. SS reports personal fees from AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Dr Falk Pharma, Fresenius, Gilead, IMAB, Janssen, MSD, Mylan, Pfizer, Protagonist, ProventionBio, Takeda, and Theravance, outside the submitted work. TR reports personal fees from Gilead during the conduct of the study and personal fees from AbbVie, Arena Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Gossamer, Intercept, Janssen, Eli Lilly, Pfizer, Prometheus, and Takeda, outside the submitted work. SN reports grants from Gilead Sciences during the conduct of the study. RK reports grants from Janssen and Takeda outside the submitted work. RFi reports grants from Egis and personal fees from AbbVie, Ferring, MSD, and Takeda, outside the submitted work. US reports grants from AbbVie, Abivax, Index Pharmaceuticals, Lilly, Roche-Genentech, and Theravance; grants and personal fees from Takeda; grants, personal fees, and non-financial support from Janssen; and personal fees from Arena Pharmaceuticals, outside the submitted work. FS reports consultancy fees from AbbVie, Janssen, MSD, Pfizer, Takeda and Vifor, outside the submitted work. ILPB reports personal fees from Gilead and Pfizer and personal fees and non-financial support from AbbVie, Janssen, and Takeda, outside the submitted work. HJK reports consultancy fees from Celltrion and speaking fees from Pfizer and Takeda, outside the submitted work. JM, CY, SZ, XL, and C-HH are employees and shareholders of Gilead Sciences. CT is an employee of Galapagos. RB is an employee and shareholder of Galapagos. MW reports grants from Alfresa, Asahi Kasei Medical, Ayumi, Fujirebio, JIMRO, Kaken, Kyorin, Kyowa Hakko Kirin, Miyarisan, and Taiho; grants and personal fees from AbbVie, Astellas, EA, Gilead Sciences, Kissei, Mitsubishi Tanabe, Mochida, Nippon Kayaku, Pfizer Japan, Takeda, and Zeria; and personal fees from Celgene, Celltrion, Eli Lilly Japan, Gilead Sciences, and Janssen, outside the submitted work. WJS reports grants, personal fees, medical writing, and reimbursement of travel expenses from Gilead Sciences, during the conduct of the study; grants and stock options from Allakos; grants and personal fees from AbbVie, Abivax, Alimentiv (previously Robarts Clinical Trials), Arena, Boehringer Ingelheim, Celgene, Genentech/Roche, Gilead Sciences, GSK, Janssen, Eli Lilly, Pfizer, Seres Therapeutics, Shire, Surrozen, Takeda, and Theravance Biopharma; grants, personal fees, and stock and stock options from Prometheus Biosciences; stock and stock options from Ventyx Biosciences and Vimalan Biosciences; personal fees from Admirx, Alfasigma, Alivio Therapeutics, Allergan, Amgen, Applied Molecular Transport, Avexegen Therapeutics, Bausch Health (Salix), Bellatrix Pharmaceuticals, Boston Pharmaceuticals, BMS, Celltrion, Cellularity, Conatus, Cosmo Pharmaceuticals, Equillium, Escalier Biosciences, Ferring, Forbion, Glenmark, Immunic (Vital Therapies), Incyte, Index Pharmaceuticals, Intact Therapeutics, Kyowa Kirin Pharmaceutical Research, Kyverna Therapeutics, Landos Biopharma, Miraca Life Sciences, Nivalis Therapeutics, Novartis, Nutrition Science Partners, Otsuka, Pandion Therapeutics, Paul Hastings, Protagonist Therapeutics, Provention Bio, Reistone Biopharma, Ritter Pharmaceuticals, Shanghai Pharma Biotherapeutics, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Thetis Pharmaceuticals, Tigenix, Tillotts Pharma, UCB, Vendata Biosciences, Vivelix Pharmaceuticals, and Zealand; personal fees and stock from Beigene; and personal fees and stock options from Gossamer Bio, Oppilan Pharma, Progenity, Shoreline Biosciences, and Vivreon Biosciences, outside the submitted work. WJS reports that their spouse is a consultant and owns stock options for Iveric Bio and Oppilan Pharma; is an employee with stock and stock options for Prometheus Biosciences; has stock for Progenity; and has stock and stock options for Ventyx Biosciences and Vimalan Biosciences. GR reports personal fees from AbbVie, AstraZeneca, Augurix, BMS, Boehringer, Calypso, Celgene, Dr Falk Pharma, Ferring, Fisher, Genentech, Gilead, Janssen, MSD, Novartis, Pfizer, Phadia, Roche, Takeda, Tillots, UCB, Vifor, Vital Solutions, and Zeller; and grants from AbbVie, Ardeypharm, Augurix, Calypso, Dr Falk Pharma, Flamentera, MSD, Novartis, Pfizer, Roche, Takeda, Tillots, UCB, and Zeller, outside the submitted work. TH reports grants from Otuska Holdings; grants and personal fees from AbbVie, IMRO, Kyorin, Mitsubishi-Tanabe, Mochida, Takeda, and Zeria; and personal fees from Aspen Japan, BMS, Celltrion, EA, Eli Lilly, Ferring, Gilead Sciences, Janssen, Kisse Pharmaceutical, Nichi-Iko Pharmaceutical, Nippon Kayaku, and Pfizer, outside the submitted work. LP-B reports personal fees from AbbVie, Allergan, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Boerhinger Ingelheim, Celgene, Celltrion, Enterome, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Hikma, Index Pharmaceuticals, Inotrem, Janssen, Lilly, MSD, Mylan, Nestle, Norgine, Oppilan Pharma, OSE Immunotherapeutics, Pfizer, Pharmacosmos, Roche, Samsung Bioepis, Sandoz, Sterna, Sublimity Therapeutics, Takeda, Theravance, Tillots, and Vifor; grants from AbbVie, MSD, and Takeda; and stock options with CTMA. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Harmful algal blooms that can produce toxins are common in the Indian River Lagoon (IRL), which covers ~250 km of Florida's east coast. The current study assessed the dynamics of microcystins and saxitoxin in six segments of the IRL: Banana River Lagoon (BRL), Mosquito Lagoon (ML), Northern IRL (NIRL), Central IRL (CIRL), Southern IRL (SIRL), and the St. Lucie Estuary (SLE). Surface water samples (n = 40) collected during the 2018 wet and 2019 dry season were analyzed to determine associations between toxins and temperature, salinity, pH, oxygen saturation, concentrations of dissolved nutrients and chlorophyll-a, presence of biosynthetic genes for toxins, relative abundance of planktonic species, and composition of the microbial community. The potential toxicity of samples was assessed using multiple mammalian cell lines. Enzyme-Linked Immunosorbent Assays were used to determine concentrations of microcystins and saxitoxin. Overall, the microcystins concentration ranged between 0.01-85.70 µg/L, and saxitoxin concentrations ranged between 0.01-2.43 µg/L across the IRL. Microcystins concentrations were 65% below the limit of quantification (0.05 µg/L), and saxitoxin concentrations were 85% below the limit of detection (0.02 µg/L). Microcystins concentrations were higher in the SLE, while saxitoxin was elevated in the NIRL and BRL. Cytotoxicity related to the presence of microcystins was seen in the SLE during the wet season. No significant patterns between cytotoxicity and saxitoxin were identified. Dissolved nutrients were identified as the most highly related parameters, explaining 53% of microcystin and 47% of saxitoxin variability. Multivariate models suggested cyanobacteria, flagellates, ciliates, and diatoms as the subset of microorganisms whose abundances were maximally correlated with saxitoxin and microcystins concentrations. Lastly, biosynthetic genes for microcystins were detected in the SLE and for saxitoxin in the BRL and NIRL. These results highlight the synergistic roles environmental and biological parameters play in influencing the dynamics of toxin production by harmful algae in the IRL., (Copyright © 2021. Published by Elsevier B.V.)

Background: FGF-21 is described as a powerful metabolic regulator with beneficial effects including glucose-lowering and improvement of insulin sensitivity without hypoglycaemia. On the other hand, FGF-21 is activated when muscle and other tissues are stressed by external effects or internal cellular pathogens that lead to shortcomings in metabolic balance. Previous results suggested that FGF-21 could be a promising target to develop future metabolic therapeutics., Purpose: The present study was performed to gain deeper insight into the regulation of FGF-21 by protein metabolism in obese human subjects., Methods: FGF-21 serum concentrations were measured in a cohort of n = 246 obese humans ± type 2 diabetes mellitus (T2DM) (median age 53.0 [46.0; 60.0] years and BMI 40.43 [35.11; 47.24] kg/m 2 ) and related to the nutritional protein intake. In addition, the effect of a novel oligopeptide purified from a β-casein hydrolysate on FGF-21 was examined in vitro in liver cells and in vivo in a human intervention study with the main focus on metabolic inflammation including 40 mainly obese subjects (mean age 41.08 ± 9.76 years, mean BMI 38.29 ± 9.4 kg/m 2 ) in a randomized 20 weeks double-blind cross-over design., Main Findings: In the cohort analysis, FGF-21 serum concentrations were significant lower with higher protein intake in obese subjects without T2DM but not in obese subjects with T2DM. Furthermore, relative methionine intake was inversely related to FGF-21. While global protein intake in obesity was inversely associated with FGF-21, incubation of HepG2 cells with a β-casein oligopeptide increased FGF-21 expression in vitro. This stimulatory effect was also present in vivo, since in the clinical intervention study treatment of obese subjects with the β-casein oligopeptide for 8 weeks significantly increased FGF-21 serum levels from W0 = 23.86 pg/mL to W8 = 30.54 pg/mL (p < 0.001), while no increase was found for placebo., Conclusion: While the total nutritional protein intake is inversely associated with FGF-21 serum levels, a purified and well characterised oligopeptide is able to induce FGF-21 serum levels in humans. These findings suggest a differential role of various components of protein metabolism on FGF-21, rather than this factor being solely a sensor of total nutritional protein intake., Competing Interests: Conflicts of interest No potential conflicts of interest relevant to this article were reported., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Memory impairment in motor neuron disease (MND) is still an underrecognized feature and has traditionally been attributed to executive dysfunction. Here, we investigate the rate of memory impairment in a longitudinal cohort of MND patients, its relationship to other cognitive functions and the underlying neuroanatomical correlates. 142 patients with MND and 99 healthy controls (HC) underwent comprehensive neuropsychological testing and structural MRI at 3T up to four times over a period of 18 months. Linear-mixed effects models were fitted to identify changes at baseline and over time in episodic memory function (learning, immediate and delayed recall, recognition), composed cognitive scores (memory, verbal fluency, executive function), and memory-related structural brain regions (hippocampus, entorhinal cortex, parahippocampal gyrus). Associations between episodic memory performance and volumetric or cortical thickness changes of these regions were computed using Pearson's r. Learning, immediate and delayed recall, as well as recognition performance were significantly reduced in MND when compared to controls at baseline. Performances in these subtests improved over time although MND showed less improvement than controls. This relationship did not change when only "classical" ALS patients were considered. Patients with MND showed thinning of the right parahippocampal gyrus (PhG) in comparison to controls that was progressing over time. Bilateral hippocampal atrophy was observed in MND patients with memory impairment after splitting the group according to their overall episodic memory performance, with the right hippocampus shrinking over time. In MND patients, the bilateral hippocampal atrophy was associated with impairment in learning, recall, and recognition at baseline. In contrast, left PhG thinning was associated with a poorer learning performance. These results show that episodic memory impairment in MND is a frequent cognitive dysfunction. Since deficits are not clearly declining with disease course, an early involvement of this cognitive domain in the disease seems probable. The memory performance-dependent atrophy of the hippocampus and PhG provide evidence for a widespread involvement of these non-motor cortical areas in disease pathology., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate underlying cerebral small vessel disease (CSVD) in patients with mixed cerebral hemorrhages patterns and phenotype them according to the contribution of the two most common sporadic CSVD subtypes: cerebral amyloid angiopathy (CAA) vs. hypertensive arteriopathy (HA)., Methods: Brain MRIs of patients with intracerebral hemorrhages (ICHs) and/or cerebral microbleeds (CMBs) were assessed for the full spectrum of CSVD markers using validated scales: ICHs, CMBs, cortical superficial siderosis (cSS), white matter hyperintensities, MRI-visible perivascular spaces (PVS). PVS predominance pattern was grouped as centrum-semiovale (CSO)-PVS predominance, basal-ganglia (BG)-PVS predominance, CSO-PVS and BG-PVS equality. Patients with mixed cerebral hemorrhages were classified into mixed CAA-pattern or mixed HA-pattern according to the existence of cSS and/or a CSO-PVS predominance pattern and comparisons were performed., Results: We included 110 patients with CAA (strictly lobar ICHs/CMBs), 33 with HA (strictly deep ICHs/CMBs) and 97 with mixed lobar/deep ICHs/CMBs. Mixed patients were more similar to HA with respect to their MRI-CSVD markers, vascular risk profile and cerebrospinal fluid (CSF) measures. In the mixed patients, 33 (34%) had cSS, a CSO-PVS predominance pattern, or both, and were defined as mixed CAA-pattern cases. The mixed CAA-pattern patients were more alike CAA patients regarding their MRI-CSVD markers, CSF and genetic profile., Conclusion: Our findings suggest that the heterogeneous group of patients with mixed cerebral hemorrhages distribution can be further phenotyped according to the predominant underlying CSVD. cSS presence and a CSO-PVS predominance pattern could serve as strongly suggestive markers of a contribution from CAA among patients with mixed hemorrhages., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Metabolic alterations in cancer represent convergent effects of oncogenic mutations. We hypothesized that a metabolism-restricted genetic screen, comparing normal primary mouse hematopoietic cells and their malignant counterparts in an ex vivo system mimicking the bone marrow microenvironment, would define distinctive vulnerabilities in acute myeloid leukemia (AML). Leukemic cells, but not their normal myeloid counterparts, depended on the aldehyde dehydrogenase 3a2 (Aldh3a2) enzyme that oxidizes long-chain aliphatic aldehydes to prevent cellular oxidative damage. Aldehydes are by-products of increased oxidative phosphorylation and nucleotide synthesis in cancer and are generated from lipid peroxides underlying the non-caspase-dependent form of cell death, ferroptosis. Leukemic cell dependence on Aldh3a2 was seen across multiple mouse and human myeloid leukemias. Aldh3a2 inhibition was synthetically lethal with glutathione peroxidase-4 (GPX4) inhibition; GPX4 inhibition is a known trigger of ferroptosis that by itself minimally affects AML cells. Inhibiting Aldh3a2 provides a therapeutic opportunity and a unique synthetic lethality to exploit the distinctive metabolic state of malignant cells., (© 2020 by The American Society of Hematology.)

We systematically identified and reviewed 29 studies of peripheral nerve ultrasound or magnetic resonance imaging (MRN) in amyotrophic lateral sclerosis (ALS). The majority of the ultrasound studies reported smaller nerves and nerve roots in ALS compared to healthy controls, but there was a large overlap of the cross-sectional nerve area between ALS and controls. Most of the MRN studies confirmed nerve abnormalities demonstrating slight T2 hyperintensities and, sometimes, mild enlargement of more proximal nerve segments (plexus, roots) in ALS. The size of the proximal nerve segments, i.e. nerve roots, is thus somewhat incongruent between nerve ultrasound and MRN in ALS. Peripheral nerve ultrasound has the potential to differentiate between ALS and multifocal motor neuropathy (MMN) in that patients with MMN have significantly larger nerves. Conversely, there is an overlap of MRN abnormalities in ALS and MMN, restricting the techniques' utility in the clinical setting. A subgroup of patients with ALS seems to reveal a sonographic nerve pattern suggesting peripheral nerve inflammation. In the future, combined imaging with nerve ultrasound and MRN assessing parameters such as blood flow or textural markers may aid in the understanding of the deep nerve microstructure down to the fascicle level, and thus, in the classification of the nerve state as more degenerative or more inflammatory in ALS. This systematic review provides evidence that nerve imaging abnormalities are common in ALS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)