Real-world Effectiveness and Safety of Vedolizumab for the Treatment of Inflammatory Bowel Disease: The Scottish Vedolizumab Cohort.

BACKGROUND & AIMS: Vedolizumab is an anti-a4b7 monoclonal antibody that is licensed for the treatment of moderate to severe Crohn's disease and ulcerative colitis. The aims of this study were to establish the real-world effectiveness and safety of vedolizumab for the treatment of inflammatory bowel disease. METHODS: This was a retrospective study involving seven NHS health boards in Scotland between June 2015 and November 2017. Inclusion criteria included: a diagnosis of ulcerative colitis or Crohn's disease with objective evidence of active inflammation at baseline (Harvey-Bradshaw Index[HBI] ≥5/Partial Mayo ≥2 plus C-reactive protein [CRP] >5 mg/L or faecal calprotectin ≥250 µg/g or inflammation on endoscopy/magnetic resonance imaging [MRI]); completion of induction; and at least one clinical follow-up by 12 months. Kaplan-Meier survival analysis was used to establish 12-month cumulative rates of clinical remission, mucosal healing, and deep remission [clinical remission plus mucosal healing]. Rates of serious adverse events were described quantitatively. RESULTS: Our cohort consisted of 180 patients with ulcerative colitis and 260 with Crohn's disease. Combined median follow-up was 52 weeks (interquartile range [IQR] 26-52 weeks). In ulcerative colitis, 12-month cumulative rates of clinical remission, mucosal healing, and deep remission were 57.4%, 47.3%, and 38.5%, respectively. In Crohn's disease, 12-month cumulative rates of clinical remission, mucosal healing, and deep remission were 58.4%, 38.9%, and 28.3% respectively. The serious adverse event rate was 15.6 per 100 patient-years of follow-up. CONCLUSIONS: Vedolizumab is a safe and effective treatment for achieving both clinical remission and mucosal healing in ulcerative colitis and Crohn's disease.

Pain catastrophizing and employment histories.

BACKGROUND: Studies examining pain catastrophizing and employment have had mixed findings. No study of pain catastrophizing has examined its relationship to lifetime employment status in a general clinical population. AIMS: To examine pain catastrophizing in relationship to lifetime employment functioning in a sample of US primary care patients (rather than injured workers). METHODS: A cross-sectional anonymous self-report survey of consecutive adults in a US internal medicine outpatient clinic. We assessed pain catastrophizing using the Pain Catastrophizing Scale and employment histories using a four-item author-developed measure. RESULTS: There were 239 participants and an initial participation rate of 70%. While pain catastrophizing was not related to the number of different full-time jobs held or the percentage of time employed in adulthood, pain catastrophizing was statistically significantly associated with ever having been paid 'under the table' [F(1,236) = 27.89, P < 0.001] and ever having been fired from a job [F(1,237) = 50.78, P < 0.001], as well as with not getting along with fellow employees [F(1,60) = 7.48, P < 0.01]. CONCLUSIONS: In this clinical sample, pain catastrophizing demonstrated varying relationships with different aspects of lifetime employment, rather than exerting an overall global effect on employment.

Efficacy and complications of adalimumab treatment for medically-refractory Crohn's disease: analysis of nationwide experience in Scotland (2004-2008).

BACKGROUND: Adalimumab is a second generation humanized anti-tumour necrosis factor (TNF) monoclonal antibody with established efficacy in Crohn's disease (CD). AIMS: To evaluate the efficacy and safety of adalimumab on a nationwide clinical setting. METHODS: We used the Scottish Society of Gastroenterology network to identify and follow up the clinical outcomes of patients with CD treated with adalimumab over a 4-year period (2004-2008). RESULTS: A total of 98 patients received adalimumab - 100.5 patient follow-up years were recorded (64.3% females; median age at diagnosis of 20.7 years; 88.8% treated with 80/40 mg induction regimen. Eighty eight (89.8%) had previous infliximab with 29 (32.9%) primary nonresponders; 32 (32.6%) were corticosteroid-dependent; 47 (47.9%) were intolerant/resistant to most immunosuppressive therapies (two or more). In all, 60% of patients were in clinical remission at 1-year follow-up, with 30% and 55% requiring dose escalation to weekly therapy at 1-and 2-year follow-up respectively. Overall, 29 (29.6%) patients developed complications with eight nonfatal serious (8.2%) adverse events and 2 (2.0%) case fatalities (sepsis following perforation and disseminated colorectal cancer, respectively). CONCLUSIONS: Adalimumab is efficacious in severe and refractory CD in the clinical setting, although there remain significant therapy- and disease-related risks of serious complications.

The genetic jigsaw of inflammatory bowel disease.

Following a prolonged period of relative inertia, real progress has been made in the past few years in understanding the pathogenesis of the chronic inflammatory bowel diseases, Crohn's disease and ulcerative colitis. Clinical experience, epidemiological studies, and molecular genetics have provided strong evidence that both genetic and environmental factors are important in disease pathogenesis, and gene-environmental interaction determines disease susceptibility and behaviour.

Reflux symptom relief with omeprazole in patients without unequivocal oesophagitis.

BACKGROUND: As many as 50% of patients with reflux symptoms have no endoscopic evidence of oesophagitis. This multicentre study was designed to assess symptom relief after omeprazole 20 mg once daily in patients with symptoms typical of gastro-oesophageal reflux disease but without endoscopic evidence of oesophagitis. METHODS: Patients (n = 209) were randomized in a double-blind study to receive either omeprazole 20 mg once daily (n = 98) or placebo (n = 111) for 4 weeks. Symptoms were assessed at clinic visits and using daily diary cards, with patient-completed questionnaires providing additional data on symptoms and on psychological disturbance. RESULTS: On completion, symptom relief favoured omeprazole: 57% of patients on omeprazole were free of heartburn (vs. 19% on placebo), 75% were free of regurgitation (47%) and 43% were completely asymptomatic (14%), each with P < 0.0001. Fewer patients in the omeprazole group required alginate/antacid relief medication (P < 0.05). Symptom relief (time to first heartburn-free day) was more rapid with omeprazole (2 vs. 5 days on placebo; P < 0.01). A greater reduction in anxiety occurred in the omeprazole group (P < 0.05). CONCLUSION: Omeprazole 20 mg once daily is effective in providing relief of the symptoms typical of gastro-oesophageal reflux disease in patients with essentially normal oesophageal mucosa.

Split skin grafting using topical local anaesthesia (EMLA): a comparison with infiltrated anaesthesia.

The analgesic efficacy of EMLA cream was compared with that produced by infiltration of lignocaine solution when used to provide anaesthesia for cutting of skin grafts. The study was performed as an open parallel group comparison in 80 patients. Pain felt during administration of the anaesthetic and during cutting of the graft was assessed using visual analogue and verbal rating scales. During graft cutting, the anaesthesia produced by EMLA was at least as effective as infiltration. On administration, infiltration produced varying amounts of pain in all patients, but in contrast EMLA produced no discomfort. In view of this lack of discomfort and the consequent greater freedom afforded regarding the area of donor site anaesthetised, EMLA can be considered the treatment of choice when skin grafts are harvested under local anaesthetic.

Myoglobin interspecies structural differences: effects on autoxidation and oxygenation.

Thermodynamic and kinetic parameters of the oxygenation and autoxidation reactions were determined for yellowfin tuna (Thunnus albacares), Pacific green sea turtle (Chelonia mydas caranigra), and sperm whale myoglobin. These proteins have quite similar heme contact residues, but vary in residues which are involved in globin stabilization and in postulated ligand paths to the heme iron. Oxygen equilibria measurements from 10 to 40 degrees C reveal that green sea turtle myoglobin has a lower oxygen affinity and lower enthalpy and entropy for oxygen-binding than the other proteins. Yellowfin tuna myoglobin has the most rapid oxygen dissociation rate and the highest susceptibility to autoxidation under all conditions studied. However, the dependence of the autoxidation rate on ionic strength is the same for the three proteins, despite substantial differences in their dynamic stabilities. These results suggest that the autoxidation reaction is more dependent on ligand accessibility than on the dynamic stability of the myoglobin.

The primary structure of myoglobin from pacific green sea turtle (Chelonia mydas caranigra).

The amino acid sequence of the main component myoglobin from skeletal muscle of Pacific green sea turtle (Chelonia mydas caranigra) has been determined. The globin is 153 residues in length and has a free amino-terminus. The heme-binding and internal residues are as found in mammalian myoglobins. Ten substitutions are observed between this myoglobin and that from map turtle. About 38, 52, 47 and 86 substitutions are noted in comparison with the myoglobins of other reptiles, mammals, birds and fish, respectively. The inferred pattern of structural stabilization and conservation of two loci are typical of tetrapod myoglobin.

The primary structure of myoglobin from yellowfin tuna (Thunnus albacares).

The amino acid sequence of myoglobin from yellowfin tuna (Thunnus albacares) has been determined. The globin is an aminoacetylated chain containing 146 residues and having deletions, with respect to mammalian and avian myoglobins, at the NH2 terminus and two internal locations. From 79 to 85 amino acid substitutions are observed between this myoglobin and those of mammals, birds, and shark. Two external regions containing 6 and 7 residues, which are highly conserved in mammalian and avian myoglobins, are greatly or totally altered in the tuna sequence. Significant differences are apparent in the extent of electrostatic bonding in the myoglobins of fish and in those of mammals or birds.

Sequences of the soluble tryptic peptides from myoglobin of yellowfin tuna (Thunnus albacares).

1. Amino acid sequences of the soluble tryptic peptides of yellowfin tuna myoglobin, comprising 60% of the total residues, are presented. 2. The amino terminus is acetylated as shown by Fourier transform nuclear magnetic resonance spectroscopy of an N-terminal dipeptide. 3. Comparison of peptide sequences from yellowfin tuna myoglobin with corresponding regions of mammalian myoglobins shows obvious homology around the heme-attachment site and the carboxyl terminus, but marked dissimilarity is evident at other locations, such as the amino terminal region.