bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug Testing in Blood: Validated Negative-Ion Chemical Ionization Gas Chromatographic–Mass Spectrometric Assay for Determination of Amphetamine and Methamphetamine Enantiomers and Its Application to Toxicology Cases
Authors: Peters Frank T , Kraemer Thomas , Maurer Hans H 
Published: January 2020

Abstract
Background: Enantioselective analysis of amphetamine (AM) or methamphetamine (MA) in urine is already a well-established tool for differentiation of illicit from therapeutic ingestion of AM or MA derivatives. However, because of the increasing importance of plasma or serum in analytical toxicology, a method for enantioselective analysis of AM and MA in these matrices is needed.
Methods: AM and/or MA were extracted from 0.2 mL of blood plasma or serum by mixed-mode solid-phase extraction. After derivatization with S-(−)-heptafluorobutyrylprolyl chloride, the resulting diastereomers were separated by gas chromatography on a HP-5MS column during a 15-min program and detected by mass spectrometry in the negative-ion chemical ionization mode (NICI-GC-MS). The method was fully validated and applied to &gt;50 samples from authentic toxicology cases.
Results: The derivatized AM and MA enantiomers were well separated and sensitively detected. The method was linear from 5 to 250 μg/L per enantiomer with analytical recoveries, accuracy, and within- and between-run precision well within required limits. Extraction yields were 88.9–98.6%. Implications of concentrations and enantiomeric composition of AM and MA in the authentic samples were considered.
Conclusions: This sensitive, reliable, rapid NICI-GC-MS assay is suitable for enantioselective determination of AM and MA in blood plasma or serum samples.
Persistent Müllerian duct syndrome due to anti-Müllerian hormone receptor 2 microdeletions: a diagnostic challenge
Authors: Tosca L , Giltay J C , Bouvattier C , Klijn A J , Bouligand J , Lambert A S , Lecerf L , Josso N , Tachdjian G , Picard J Y 
Published: January 2020

Abstract
The persistent Müllerian duct syndrome (PMDS) is defined by the persistence of Müllerian derivatives in an otherwise normally virilized 46,XY male. It is usually caused by mutations in either the anti-Müllerian hormone (AMH) or AMH receptor type 2 (AMHR2) genes. We report the first cases of PMDS resulting from a microdeletion of the chromosomal region 12q13.13, the locus of the gene for AMHR2. One case involved a homozygous microdeletion of five exons of the AMHR2 gene. In the second case, the whole AMHR2 gene was deleted from the maternally inherited chromosome. The patient’s paternal allele carried a stop mutation, which was initially thought to be homozygous by Sanger sequencing. Diagnostic methods are discussed, with an emphasis on comparative genomic hybridization and targeted massive parallel sequencing.
Interrogating the Gut-Brain Axis in the Context of Inflammatory Bowel Disease: A Translational Approach
Authors: Collins Stephen M 
Published: January 2020

Abstract
This review examines preclinical and clinical studies relevant to our understanding of how the bidirectional gut-brain axis influences the natural history of inflammatory bowel disease. Preclinical studies provide proof of concept that preexisting behavioral illness, such as depression, results in increased susceptibility to inflammatory stimuli and that commonly used classes of antidepressants protect against this vulnerability. However, clinical studies suggesting behavioral illness as a risk factor for IBD and a protective role for antidepressants have relied primarily on symptom-reporting rather than objective measurements of inflammation. In terms of gut-to-brain signaling, there is emerging evidence from preclinical and clinical observation that intestinal inflammation alters brain functions, including the induction of mood disorders, alteration of circadian rhythm both centrally and peripherally, and changes in appetitive behaviors. Furthermore, preclinical studies suggest that effective treatment of intestinal inflammation improves associated behavioral impairment. Taken together, the findings of this review encourage a holistic approach to the management of patients with IBD, accommodating lifestyle issues that include the avoidance of sleep deprivation, optimized nutrition, and the monitoring and appropriate management of behavioral disorders. The review also acknowledges the need for better-designed clinical studies evaluating the impact of behavioral disorders and their treatments on the natural history of IBD, utilizing hard end points to assess changes in the inflammatory process as opposed to reliance on symptom-based assessments. The findings of the review also encourage a better understanding of changes in brain function and circadian rhythm induced by intestinal inflammation.
Temporal Gut Microbial Changes Predict RecurrentClostridiodes DifficileInfection in Patients With and Without Ulcerative Colitis
Authors: Lee Allen A , Rao Krishna , Limsrivilai Julajak , Gillilland Merritt , Malamet Benjamin , Briggs Emily , Young Vincent B , Higgins Peter D R 
Published: January 2020

AbstractBackgroundUlcerative colitis (UC) carries an increased risk of primary and recurrent Clostridiodes difficile infection (rCDI), and CDI is associated with UC flares. We hypothesized that specific fecal microbial changes associate with UC flare and rCDI.MethodsWe conducted a prospective observational cohort study of 57 patients with UC and CDI, CDI only, and UC only. Stool samples were collected at baseline, at the end of antibiotic therapy, and after reconstitution for 16S rRNA sequencing. The primary outcomes were recurrent UC flare and rCDI. Logistic regression and Lasso models were constructed for analysis.ResultsThere were 21 (45.7%) patients with rCDI, whereas 11 (34.4%) developed UC flare. Patients with rCDI demonstrated significant interindividual (P = 0.008) and intraindividual differences (P = 0.004) in community structure by Jensen-Shannon distance (JSD) compared with non-rCDI. Two cross-validated Lasso regression models predicted risk of rCDI: a baseline model with female gender, hospitalization for UC in the past year, increased Ruminococcaceae and Verrucomicrobia, and decreased Eubacteriaceae, Enterobacteriaceae, Lachnospiraceae, and Veillonellaceae (AuROC, 0.94); and a model 14 days after completion of antibiotics with female gender, increased Shannon diversity, Ruminococcaceae and Enterobacteriaceae, and decreased community richness and Faecalibacterium (AuROC, 0.9). Adding JSD between baseline and post-treatment samples to the latter model improved fit (AuROC, 0.94). A baseline model including UC hospitalization in the past year and increased Bacteroidetes was associated with increased risk for UC flare (AuROC, 0.88).ConclusionFecal microbial features at baseline and after therapy predict rCDI risk in patients with and without UC. These results may help risk stratify patients to guide management.
P101 SARCOPENIA IS ASSOCIATED WITH INCREASED RISK OF INFECTION IN IBD PATIENTS OLDER THAN 50 YEARS STARTING BIOLOGIC MEDICATIONS
Authors: Campbell James , Teigen Levi , Feussom Ghislaine , Price Kathleen , Cogswell Rebecca , Colombel Jean-Frederic , Shmidt Eugenia 
Published: January 2020

Abstract

Background
The relationship between sarcopenia and clinical outcomes outside of the post-operative setting has not been well-studied in IBD patients. We aimed to characterize the prevalence of sarcopenia and its association with adverse events and clinical response in IBD patients starting on new biologic medications.

Methods
We identified a retrospective cohort of adult (≥18 years old) IBD patients at the University of Minnesota with an abdominal CT or MRI within 6 months prior to or one month after starting a new biologic medication. Baseline demographics, disease severity (based on Physician’s Global Assessment from GI encounters), laboratory values and clinical outcomes for one year after the start of medications were obtained from chart review. The primary endpoint was incidence of adverse events (defined as infection, need for surgery, or hospitalization) within one year after medication start. The secondary outcome was clinical response as assessed based on clinical, endoscopic, and radiographic follow-up. Skeletal muscle index (SMI) measures were obtained from CT/MRI images at the L3 vertebral level. Published cut-offs (SMI of 38.5 cm2/m2 for women and 52.4 cm2/m2 for men) were used to determine the presence of sarcopenia. Associations between sarcopenia and outcomes were analyzed using logistic regression and age stratification was performed.

Results
Ninety-four patients (74 CD, 20 UC, 47% male, mean age 38 years) were included in the analysis. The majority of patients had moderate disease severity or worse (83%) at the time of medication start, and 75% were started on anti-TNF medications. Overall prevalence of sarcopenia was 57% (57% CD, 60% UC). In the entire cohort, sarcopenia was not associated with increased rates of adverse events (OR = 0.516, 95% CI 0.217–1.225; p= 0.1334). However, in patients ≥ 50 years of age (n=23), those with sarcopenia had higher risk of infection at 1 year compared to those without sarcopenia (85% vs. 20%; OR = 21.99, 95% CI 3.086–262.515; p = 0.0051). The majority of infections were those that required antibiotics or antivirals, but not hospitalization. Examples included sinusitis, upper respiratory infections, periodontitis, urinary tract infection, herpes simplex, and two cases of C. difficile. Furthermore, when controlling for disease duration and concomitant steroid use, the association between sarcopenia and infection remained significant. In this age subgroup, there was no association between sarcopenia and clinical response to therapy.

Conclusions
In our cohort, sarcopenia was present in the majority of adult IBD patients starting new biologic medications. In patients ≥ 50 years old, sarcopenia was associated with an increased risk of infections. Further work is needed to validate these findings and to understand which patients may benefit from sarcopenia assessment prior to biologic start.
18 A HUMAN-DERIVED 5-MER PEPTIDE (MTADV), WHICH RESTRICTIVELY ALLEVIATES THE PRO-INFLAMMATORY ACTIVITY OF SERUM AMYLOID A (SAA), SUBSTANTIALLY AMELIORATES IBD PATHOLOGY: NEW POTENTIAL DRUG (MTADV) AND THERAPEUTIC TARGET CANDIDATE (SAA) FOR IBD
Authors: Naor David , Hemed-Shaked Maayan , Cowman Mary , Kim Jin , Armengol Jordi , Alemany Jorge , Kanduc Darja 
Published: January 2020

Abstract
A human anti-inflammatory 5-MER peptide MTADV (methionine-threonine-alanine-aspartic acid-valine) derived from a sequence of a pro-inflammatory CD44 variant was first described by us in Nedvetzki et al., J. Clin. Invest. 111,1211-1220, 2003. A NCBI BLAST RefSeq protein sequence database, that contains at present 81,347 human protein sequences, reveals that only one additional protein contains this unique MTADV sequence of alternating hydrophobic and hydrophilic amino acids. This human peptide displays an efficient anti-inflammatory effect in Inflammatory Bowel Disease (IBD), Rheumatoid Arthritis and Multiple sclerosis mouse models, all share amyloid proteins in the relevant target organs. We show here that the 5-MER peptide, administered after the onset of disease,either by SC injections or oral delivery, inhibited the pathological activity of two IBD models (TNBS and DSS), as indicated by histopathology analysis (Ameho’s score) or Bioluminescence Imaging, sensing the release of Reactive Oxdative Species (ROS), which reflect colon inflammation (Fig 1). The 5-MER MTADV peptide, while inhibiting chronic inflammation, neither interferes with normal immune responses nor induce neutralizing antibodies. A pull-down experiment with mass spectrometric analysis revealed that the 5-MER peptide specifically binds to serum amyloid A (SAA), a stress pro-inflammatory protein, which generates aggregated amyloid deposits in the IBD colon (de Villiers at al Cytokine 12:1337-1347,2000). Our studies further provide in vitro evidence, strengthened by in vivo experiments, that SAA is a significant target of this pentamer. To this end, the 5-MER peptide (but not the corresponding scrambled peptide) inhibits the release of the pro-inflammatory cytokines IL-6 and IL-1β from SAA-activated fibroblasts. Furthermore, the 5-MER peptide was found to retard the early stages of amyloid-type aggregation of SAA in solution (Fig 2). Adopting the β-sheet conformation, MTADV would display opposing hydrophobic and hydrophilic faces that could interact with the β-sheet-forming amyloidogenic sequences in SAA. This suggests that the mechanism of action for the 5-MER peptide in vivo may depend on its ability to slow the aggregation of SAA, thus reduce its contribution to chronic inflammation. Finally, using bioinformatics and qRT-PCR, we have found the pentamer up-regulates set of genes involved in resistance to chronic inflammations. Hence, our study provides both a new potential drug (MTADV) and a new therapeutic target candidate (SAA) for IBD.
P154 THE ANTI-INFLAMMATORY EFFECT OF A PLANT-BASED DIET IN DSS-INDUCED COLITIS
Authors: Basson Abigail , Kulpins Danielle , LaSalla Alexandria , Di Martino Luca , Rodriguez-Palacios Alexander , Cominelli Fabio 
Published: January 2020

Abstract

Background
Inflammatory Bowel Disease (IBD) results from an imbalanced immune response toward the gut microbiota. Disruptions in the gut microbiota are proposed as critical elements that could foster pro-inflammatory imbalances and cause active flares IBD. Diet has been shown to have a pro-inflammatory effect in Crohn’s disease (CD) but not much is known on the anti-inflammatory effect of a plant-based diet. Gut microbial modulation via diet is a needed strategy for the therapeutic management of CD; however, no specific recommendations exist for CD patients. We hypothesized that plant-based diet may have a protective effect on the severity of acute dextran sodium sulfate (DSS)-induced colitis.

Methods
20-wk old age-sex matched C57BL/6 mice were fed a plant-based diet or standard chow for 7 days. Mice were then administered 3% DSS for 7 days and sacrificed 2 days later. Mice were individually caged and maintained on Aspen bedding. A fecal homogenization protocol was performed prior to the start of the experiment. We monitored body weight, fecal myeloperoxidase activity, water and food intake in all mice. Epithelial permeability (FITC-dextran) and endoscopic assessment were performed before and after DSS treatment. Post mortem blood, mesenteric lymph node, colon and liver were collected. Colon morphology was evaluated using 3D-stereomicroscopy. Histological assessment was performed in a blinded manner. Analysis of samples by Illumina 16S protocols, real-time quantitative PCR (qPCR), flow cytometry.

Results
Mice fed the plant-based diet had decreased DSS-induced weight loss, myeloperoxidase activity and mortality compared to chow-fed mice (P&lt;0.05). Plant-fed mice also had significantly lower colonoscopy and histological scores, with colonoscopic images showing decreased transparency and increased presence of erosion and strictures in chow-fed mice. Compared to the chow-fed mice, the concentration of FITC-D in the plasma of plant-fed mice was significantly lower (Mann-Whitney P=0.004, power 0.98). Bacterial quantification qPCR CT-values (DNA copy abundance) revealed differences in the microbiota composition with increased abundance for Lactobacilli in the context of a generic/universal 16S bacterial primer and the host gut cell DNA copies using β-actin in the plant diet mice. Illumina 16S rRNA gene sequencing of fecal genomic DNA samples is in progress.

Conclusion
Our results show that a plant-based diet has a protective effect on DSS-induced colitis. Further studies are needed to investigate the potential underlying mechanisms. These findings may have great potential for therapeutic dietary interventions in individuals with IBD.
P067 IMPACT OF MIRIKIZUMAB TREATMENT ON HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH ULCERATIVE COLITIS: A PHASE 2 STUDY ANALYSIS USING THE SF-36 V2 STANDARD
Authors: Lichtenstein Gary , Feagan Brian , Tuttle Jay , Morris Nathan , Dong Yan , Arora Vipin , Naegeli April , Rubin David 
Published: January 2020

Abstract

Background
Mirikizumab (LY3074828) is a humanized monoclonal antibody directed against the p19 subunit of IL-23, and had demonstrated efficacy in psoriasis, ulcerative colitis (UC), and Crohn’s disease. The effect of miri on health-related quality of life (HRQoL) as measured by the 36-Item Short Form Health Survey v2 Standard (SF-36) was examined in a Phase 2, multicenter, randomized, parallel-arm, double-blind placebo (PBO)-controlled trial (NCT02891226) in patients with moderate to severely active UC.

Methods
Patients were randomized 1:1:1:1 to receive intravenous PBO, miri 50mg or 200mg with possibility of exposure-based (EB) dose increases, or fixed miri 600mg every 4 weeks (Q4W), with efficacy assessment at Week 12. Patients with clinical response to miri at Week 12 were re-randomized 1:1 to a double-blind maintenance treatment of miri 200mg subcutaneously (SC) Q4W or 12 weeks (Q12W) and were treated through Week 52. The SF-36, a 36-item patient-completed questionnaire with recall period past 4-weeks, that measures 8 domains (physical functioning, role-physical, role-emotional, bodily pain, vitality, social functioning, mental health, and general health) and two summary scores, physical component summary (PCS) and mental component summary (MCS), was assessed at baseline and at Weeks 4, 8, 12, 24, 32, and 52. Treatment comparisons were evaluated using mixed effects for repeated measures for mean improvement of PCS, MCS, and domain score changes with treatment, geographic region, and prior biologic UC therapy use as factors.

Results
The PCS was significantly higher in all miri doses at Week 12 (Least Squares Mean [LSM] ± SE; PBO: 45.4±0.8; miri 50mg: 48.2±0.9, p=0.011; 200mg: 48.0±0.8, p=0.022; 600mg: 49.0±0.9, p=0.002; Fig 1A), while the MCS was significantly higher in the miri 200mg and 600mg groups (PBO: 42.5±1.2; miri 50mg: 43.8±1.3; 200mg: 46.1±1.2, p=0.028; 600mg: 48.1±1.3, p&lt;0.001; Fig 1B). Of the 8 SF-36 domains, 7 (physical functioning, role-physical, role-emotional, social functioning, vitality, bodily pain, and mental health) showed statistically significant improvement at Week 12 in at least one miri dose group compared to PBO, while 1 (general health) demonstrated a numerical improvement (Fig 1C). Patients who continued onto randomized maintenance treatment sustained the improved scores through Week 52 (Fig 2). These results paralleled the observed treatment associated benefits on clinical response and remission rates at Weeks 12 and 521.

Conclusion
Mirikizumab treatment results in significant improvements in patient HRQoL demonstrated by significantly improved SF-36 scores after 12 weeks of induction treatment, which were sustained during an additional 40 weeks of maintenance treatment.
P069 ONTAMALIMAB, A FULLY HUMAN MONOCLONAL ANTIBODY AGAINST MUCOSAL ADDRESSIN CELL ADHESION MOLECULE-1, PROVIDES SUSTAINED EXPOSURE FOLLOWING LONG-TERM TREATMENT IN PATIENTS WITH ULCERATIVE COLITIS
Authors: Wang Yi , Marier J F , Kheibarshekan Leila , Kassir Nastya , Martin Patrick 
Published: January 2020

Abstract

Introduction
Ontamalimab is a fully human immunoglobulin G2 monoclonal antibody against mucosal addressin cell adhesion molecule-1 in development for the induction and maintenance of clinical remission in patients with ulcerative colitis (UC). This study aimed to assess the long-term pharmacokinetics (PK) of ontamalimab in patients with UC, and the effects of concomitant medications on PK parameters.

Methods
A 12-week induction study (TURANDOT; NCT01620255) was performed to assess the PK, efficacy and safety of ontamalimab (7.5, 22.5, 75 and 225 mg subcutaneous [s.c.] every four weeks [Q4W]) in patients with UC. Individuals who completed the induction study were eligible for enrollment in an open-label extension (OLE) study (TURANDOT II; NCT01771809) to assess the long-term PK, efficacy and safety of ontamalimab (75 or 225 mg s.c. Q4W up to week 72). Population PK analyses were performed using nonlinear mixed-effects modelling. Exposure-response analyses were performed to assess the relationships between minimum concentration (Cmin,ss) of ontamalimab and clinical response, clinical remission and mucosal healing. The effect of concomitant treatments (used for ≥20% of treatment duration) on PK parameters was also evaluated.

Results
The PK population included 130 (39.8%) women and 197 (60.2%) men, of median age of 40 years. A 1-compartment model with linear elimination adequately described the PK of ontamalimab. Population estimates of apparent clearance (CL/F) and volume of distribution (V/F) were 0.00917 L/h (0.22 L/day) and 7.44 L, respectively. Albumin had a significant effect on the variability of CL/F. Individuals with albumin levels of 30 g/L and 47 g/L are expected to have CL/F values 44% higher and 23% lower, respectively, than a typical patient with an albumin level of 39 g/L. Anti-inflammatory agents affected CL/F, such that CL/F is expected to be 14% higher in patients receiving than not receiving these agents. Other medications including immunosuppressants, steroids and treatments for peptic ulcers and gastroesophageal reflux disease had no effect on CL/F. Weight was the only covariate that significantly affected V/F. The half-life of ontamalimab was 23.4 days. Concentrations of ontamalimab over 72 weeks in the OLE study were consistent with those observed in the 12-week induction study. Ontamalimab Cmin,ss was related to efficacy, such that at week 16 (week 28 in total including induction), patients with higher Cmin,ss values were more likely to have clinical response, clinical remission and mucosal healing than those with lower Cmin,ss.

Conclusion
The exposure to ontamalimab was sustained following prolonged treatment in patients with UC for up to 72 weeks. Higher ontamalimab exposure was associated with a higher probability of clinical response.