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.

Geodetic Observations of Weak Determinism in Rupture Evolution of Large Earthquakes.

The moment evolution of large earthquakes is a subject of fundamental interest to both basic and applied seismology. Specifically, an open problem is when in the rupture process a large earthquake exhibits features dissimilar from those of a lesser magnitude event. The answer to this question is of importance for rapid, reliable estimation of earthquake magnitude, a major priority of earthquake and tsunami early warning systems. Much effort has been made to test whether earthquakes are deterministic, meaning that observations in the first few seconds of rupture can be used to predict the final rupture extent. However, results have been inconclusive, especially for large earthquakes greater than M w 7. Traditional seismic methods struggle to rapidly distinguish the size of large-magnitude events, in particular near the source, even after rupture completion, making them insufficient to resolve the question of predictive rupture behavior. Displacements derived from Global Navigation Satellite System data can accurately estimate magnitude in real time, even for the largest earthquakes. We employ a combination of seismic and geodetic (Global Navigation Satellite System) data to investigate early rupture metrics, to determine whether observational data support deterministic rupture behavior. We find that while the earliest metrics (~5 s of data) are not enough to infer final earthquake magnitude, accurate estimates are possible within the first tens of seconds, prior to rupture completion, suggesting a weak determinism. We discuss the implications for earthquake source physics and rupture evolution and address recommendations for earthquake and tsunami early warning.

Intrahepatic sources of biliary-like micelles.

To study the hepatocellular origins of biliary lipids, bile acid-lipid micelles were isolated from rat liver subfractions in vitro by Sephadex G-100 column chromatography, using 10 mM sodium taurocholate in the column eluant. Micelles of similar size to biliary micelles were obtained from microsome suspensions and from Golgi content that had been isolated in 5 mM sodium taurocholate-containing subcellular fractionation media. The phospholipid composition of these "biliary-like' micelles was similar but not identical to that of biliary micelles; cholesterol was detected in the micelles from Golgi content but not microsomes. 'Biliary-like' micelles could not be isolated from plasma membranes (including highly purified canalicular membranes), Golgi membranes or liver cytosol. These data suggest that biliary lipid micelles (or micelle precursors) may originate from the endoplasmic reticulum and Golgi apparatus.

Effect of an exogenous succinyl-CoA-generating system on the measurement of delta-aminolevulinic acid synthase activity in rat liver tissue by a radiochemical assay.

Rat liver tissue was used to examine the effect of an exogenous succinyl-CoA-generating system on the radiochemical assay for delta-aminolevulinic acid synthase (succinyl-CoA:glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37) activity developed by Ebert et al. (Ebert, P.S., Tschudy, D.P., Choudry, J.N. and Chirigos, M.A. (1970) Biochim. Biophys. Acta 208, 236--250). In the absence of exogenous succinate thiokinase, 34--62% (average 55%) of the radioactivity in the final column eluate could be attributed to delta-amino-[4-14C]levulinic acid, as assessed by conversion of delta-aminolevulinic acid in the eluate to a pyrrole. The addition of succinate thiokinase markedly enhanced the formation of the contaminant(s), as succinyl-CoA was metabolized to a compound or compounds that eluted chromatographically with delta-amino-levulinic acid. This effect was abolished by 10 mM EDTA, probably because the generation of succinyl-CoA was suppressed due to the chelation of Mg2+. These observations indicate that this radiochemical assay should be carefully examined for each set of assay conditions employed.

Serum bile acids in primary biliary cirrhosis.

Fasting serum bile acid levels were measured by gas-liquid chromatography in 56 patients with primary biliary cirrhosis. Of these, 52 (93%) had increased levels (greater than 2mug/ml), including 14 of the 18 with normal serum bilirubin concentrations. The four patients with normal bile acid levels had early lesions as judged by histological and clinical criteria. With progression of the disease, as indicated by the histological features of the lesions, total bile acid levels increased, and the ratio of serum cholic-to-chenodeoxycholic acid decreased. Ratios of serum cholic-to-chenodeoxycholic acid below 1 occurred predominantly in patients with advanced or terminal disease. These studies suggest that serial measurement of serum bile acids may aid in the evaluation of primary biliary cirrhosis.

Palliative treatment of tardive dyskinesia with combination of amantadine-neuroleptic administration.

The author presents six cases which suggest a palliative effect of combination amantadine/neuroleptic in tardive dyskinesia. The six patients all met criteria for definite tardive dyskinesia, and did not have coexistent pseudoparkinsonism. Serial addition and subtraction of amantadine with fixed low-dose neuroleptic points to a specific amantadine effect. Previous studies are reviewed and speculation about the mechanism of action of the combination is discussed.

Pseudodementia and ECT.

The author presents six cases of pseudodementia of varying degrees of severity that illustrate the difficulty in making purely clinical diagnoses of pseudodementia and demonstrate the usefulness of ECT in this condition in treatment-resistant patients. In addition, issues of cerebral laterality are raised by one case in which the patient paradoxically regressed to a preference for an acquired language (English) while pseudodemented and reverted to her native tongue (Spanish) after remission, with preservation of her ability to speak English.

Phencyclidine-induced psychosis.

During a 13-month period, 9 patients with phencyclidine-induced psychosis were admitted to Darnall Army Hospital. They exhibited hostility agitation, and tangentiality and had delusions of influence and religious grandiosity. Six subjects reported auditory hallucinations, and 4 were disoriented in at least 1 sphere. Despite treatment with antipsychotic medication, the psychotic episodes often persisted for more than 30 days. Our clinical finding of prolonged psychotic reactions, together with previous reports of the effects of phencyclidine, suggests that phenycyclidine provides an intriguing drug model for schizophrenia.

Diagnosing ventilator-associated pneumonia: the role of bronchoscopy.

OBJECTIVE: To discuss the two diagnostic procedures used most frequently to obtain uncontaminated lower airway secretions during bronchoscopy. DESIGN: This article reviews the contributing risk factors of ventilator-associated pneumonia (VAP) and the recent studies that have assessed the usefulness of the protected specimen brush (PSB) and bronchoalveolar lavage (BAL) in the nonimmunocompromised host. RESULTS: A prompt, accurate diagnosis of VAP, including specific identification of the bacterial pathogen, remains a common challenge in the intensive-care unit. Standard clinical criteria are of suboptimal specificity for making decisions, including selecting antibiotic therapy. Bronchoscopic techniques of lung secretion sampling can be used in the intensive-care unit in an effort to overcome the effects of oropharyngeal contamination. The PSB and BAL, used appropriately, can help intensive-care clinicians formulate specific antimicrobial therapy. Evaluation of intracellular bacteria obtained by BAL has been reported to be useful in guiding empiric antibiotic therapy while the final results of cultures obtained with the PSB are pending. Prior antibiotic therapy, however, may confound the interpretation and clinical utility of results. CONCLUSION: Currently, for a patient taking antibiotic therapy, no reliable technique nor quantitative culture threshold exists to help in diagnosing suspected VAP or in guiding antibiotic therapy. If the clinical situation allows, antibiotic therapy should be discontinued for 48 hours; then, the PSB, BAL, protected BAL, or endobronchial aspiration should be used. These contemporary modalities, however, necessitate further clinical trials before widespread use is warranted.

Attenuation of drug-induced anxiety dreams and pavor nocturnus by benzodiazepines.

Anxiety dreams and night terrors have been reported as complications of single-dose bedtime administration of both tricyclic antidepressants and neuroleptics. Five cases are presented that demonstrate the effectiveness of diazepam and its close relative clorazepate in controlling this problem. The clinical usefulness and possible mechanisms of action of these agents in treating sleep disorder are discussed.

Delirium associated with combined fluphenazine-clonidine therapy.

The authors report a case of acute organic brain syndrome in a patient being treated with clonidine and fluphenazine that cleared when clonidine was discontinued. Theoretical considerations of dopamine-norephinephrine interactions are discussed in the context of the drug-drug interaction.

Role of morphine maintenance dose in the development of tolerance and its attenuation by an NMDA receptor antagonist.

RATIONALE: Current research shows that N-methyl-d-aspartate (NMDA) receptor antagonists attenuate the development of morphine tolerance in rodent antinociceptive assays. OBJECTIVE: The purpose of this study was to determine the role of morphine maintenance dose in the attenuation of morphine tolerance by the competitive NMDA receptor antagonist, LY235959. METHODS: A rat warm-water tail-withdrawal procedure was used to measure the antinociceptive effects of morphine and LY235959. In this procedure, the distal 8 cm of each rat's tail is immersed in 40 degrees (non-noxious) and 55 degrees C (noxious) water, and the latency to remove the tail is recorded. RESULTS: Morphine (0.3-10 mg/kg, SC) produced dose-dependent increases in tail-withdrawal latencies from the 55 degrees C water. Following determination of the morphine dose-effect curves, rats were administered chronically one of three doses of morphine (10, 20, or 40 mg/kg) either alone or in combination with LY235959 (1.0, 3.0, or 5.6 mg/kg, SC) twice daily for 7 days. Chronic administration of 10, 20, and 40 mg/kg morphine produced rightward shifts in the morphine dose-effect curves of approximately 3-, 6-, and 12-fold, respectively. When LY235959 (1.0-5.6 mg/kg) was co-administered with 10 mg/kg morphine, the development of morphine tolerance was attenuated in a dose-dependent manner, with complete prevention observed following 3.0 mg/kg LY235959. LY235959 (1.0, 3.0 mg/kg) also attenuated the development of tolerance to 20 and 40 mg/kg morphine; however, tolerance was not completely prevented. Administering 3.0 mg/kg LY235959 along with 20 and 40 mg/kg morphine was functionally equivalent to treating rats with half the amount of morphine. CONCLUSION: These data suggest that the maintenance dose of morphine, and thus the magnitude of tolerance, can determine the effectiveness of an NMDA receptor antagonist to attenuate morphine tolerance.

The competitive NMDA receptor antagonist LY235959 modulates the progression of morphine tolerance in rats.

A rat warm-water tail-withdrawal procedure was used to examine the effects of chronic administration of the competitive NMDA receptor antagonist LY235959 in morphine tolerant rats. Morphine dose-dependently increased tail-withdrawal latencies from 55 degree C water. When morphine (10 mg/kg) was administered twice-daily for 7 days, the morphine dose-effect curves shifted 0.3-0.5 log unit to the right. When morphine was administered for an additional 7 days, the morphine dose-effect curve shifted 0.4 log unit further to the right. Co-administration of LY235959 (1, 3, 10 mg/kg) along with morphine prevented the development of tolerance observed during the second week of chronic morphine administration. Although the highest dose of LY235959 (10 mg/kg) partially reversed tolerance in five of seven rats, tolerance was not reversed by lower doses of LY235959. These data suggest that NMDA receptor antagonists may effectively prevent the progressive development of morphine tolerance at doses that are not sufficient to reverse pre-established morphine tolerance.

Amantadine reduces haloperidol-induced dopamine receptor hypersensitivity in the striatum.

In this report evidence is presented that amantadine hydrochloride greatly reduced the development of dopaminergic receptor hypersensitivity in the striatum, which normally results following chronic haloperidol administration using both a stereotyped behavior bioassay and a [3H]spiroperidol receptor binding assay. Amantadine prophylaxis reduced maximal ligand binding to near control levels and also significantly reduced apomorphine induced stereotypy. These results clearly demonstrate that amantadine greatly reduced haloperidol-induced striatal dopamine receptor hypersensitivity and support the hypothesis that amantadine given concurrently with neuroleptic agents might serve to prevent the development of human tardive dyskinesia.

A district general hospital's method of post-operative infection surveillance including post-discharge follow-up, developed over a five-year period.

We report on a post-operative infection surveillance system which includes post-discharge follow-up, developed over five years in a district general hospital in the West Midlands, UK. The methods used for following up 667 patients undergoing one of five representative surgical procedures are described. Emergency, elective and day-case procedures are included. A combination of healthcare worker questionnaire, telephone calls and patient questionnaire gave a follow-up rate of 92.7%. The system took infection control staff an average of 40 min per patient (30 min inpatient assessment, 10 min post-discharge). Almost half (48%) of surgical site infections were diagnosed after discharge from hospital. The system worked equally well when conducted as part of the UK Nosocomial Infection National Surveillance Scheme (NINSS), or as in-house projects. It is likely that the system could be used in other areas with similar population characteristics and support from local general practitioners working in the community.

Opioids and rate of positively reinforced behavior: III. Antagonism by the long-lasting kappa antagonist norbinaltorphimine.

Various opioid compounds were examined before and after administration of a 40µg (i.c.v.) dose of norbinaltorphimine (nor-BNI) in rats responding under a fixed ratio 20 schedule of food presentation. At time points ranging from 1 to 133 days after administration of nor-BNI, the dose-effect curve for the kappa opioid bremazocine was shifted to the right of that obtained prior to the administration of nor-BNI. The magnitude of these rightward shifts were somewhat larger at day 14 than day 1, remained unchanged between days 14 and 49, and then declined between days 70 and 133. Nor-BNI also produced large rightward shifts in the dose-effect curves for the kappa opioids U50,488, spiradoline and U69,593, and a small rightward shift in the curve for ethylketocyclazocine. In contrast, nor-BNI did not alter the dose-effect curves for (-)-n-allylnormetazocine, (-)-cyclazocine, nalorphine and the mu opioid morphine. The present findings indicate that the rate-decreasing effects of bremazocine, U50,488, U69,593, spiradoline and ethylketocyclazocine are mediated by agonist activity at the kappa opioid receptor(s). These findings also indicate that nor-BNI is a long-lasting and kappa opioid-selective antagonist that offers a number of advantages over naloxone and naltrexone as a pharmacological tool for examining the kappa opioid-mediated activity of opioid compounds.

The use of homologous and heterologous 125I-radioligands in the radioimmunoassay of progesterone.

Eight homologous and heterologous 125I-radioligand systems for the radioimmunoassay of progesterone were examined. Using an antiserum raised to 11alpha-hydroxyprogesterone 11-succinyl-bovine serum albumin, standard curves were set up with the homologous radioligands, 11alpha-hydroxyprogesterone 11-succinyl-[125I]-iodotyramine, -[125I]-iodohistamine and -[125I]-iodotyrosine methyl ester. Heterologous bridge systems were represented by progesterone-11alpha-oxycarbonyl-[125I]-iodotyrosine methyl ester and 11alpha-hydroxyprogesterone 11-phthalyl-[125I]-iodotyrosine methyl ester, and heterologous site systems by progesterone-3-(O-carboxymethyl)oxime-[125I]-iodotyramine, progesterone-12-(O-carboxymethyl)oxime-[125I]-iodotyramine, and progesterone-20-(O-carboxymethyl)oxime-[125I]-iodohistamine. The preparation of the steroid derivatives and iodination by a two-phase method are described. The curves obtained from the homologous radioligands were relatively insensitive compared with a tritiated system, with the tyrosine methyl ester derivative providing a more sensitive assay than the corresponding tyramine or histamine analogues. The heterologous bridge systems gave more sensitive curves than the homologous tracers whilst the 3- and 12-(O-carboxymethyl)oxime derivatives of progesterone furnished curves as sensitive as the tritiated reference. Progesterone-20-(O-carboxymethyl)oxime-[125I]-iodohistamine was not bound by the antibody.

Effects of neuropeptide Y on the discriminative stimulus and antinociceptive properties of morphine.

Previous research indicates that opioid receptor blockade diminishes the effects of neuropeptide Y (NPY) on feeding and memory. Conversely, NPY attenuates naloxone-precipitated morphine withdrawal. The present study evaluated the effects of NPY on the discriminative stimulus and antinociceptive effects produced by the prototypical mu opioid, morphine. Rats were trained to discriminate 5.6 mg/kg morphine (IP) from saline using a standard two-lever, food-reinforced, drug discrimination procedure. Across a range of doses (3.0, 5.0, and 10 microg), intracerebroventricular (ICV) injection of NPY failed to substitute for, antagonize, or potentiate the discriminative stimulus effects of morphine. A warm-water tail-withdrawal procedure was used to examine the antinociceptive effects of morphine and NPY, alone and in combination. NPY (3.0 and 10 microg, ICV) failed to alter tail-withdrawal latencies from 52 degrees and 56 degrees C water, whereas morphine (1.0-30 mg/kg, IP) produced a dose-related increase in latencies at both water temperatures. A 10-microg dose of NPY also failed to alter the antinociceptive effects of morphine. This study does not support the idea that the discriminative stimulus and antinociceptive effects of morphine are dependent on an NPYergic pathway.

A reliable and valid asthma general knowledge questionnaire useful in the training of asthma educators.

Using the responses of 115 adults attending an asthma educator training course, the Asthma General Knowledge Questionnaire for Adults (AGKQA) was found to be an acceptably valid and reliable measure for assessing knowledge related to the management of asthma by adults. Content and face validity: expert assessors considered the AGKQA to be a relevant and plausible test of the asthma general knowledge content of the programme. Criterion-related validity: the pretraining scores of educators were significantly higher (P < 0.001) than those of adults with no experience of asthma; total scores for the AGKQA and an asthma knowledge questionnaire developed for parents of children with asthma correlated strongly, 0.72. Test-retest reproducibility: the Spearman rank correlation for the test-retest score was 0.72 (P < 0.02), kappas for concordance of item responses were moderate to very good for two thirds of the items. Internal consistency for the total scale was also acceptable, KR20 0.66.

Tranquilizers and sedative/hypnotics: appropriate use in the elderly.

In treating the elderly patient, it is generally true that the fewer pharmacologic agents needed, the less the potential for drug interactions and puzzling toxic reactions. Nevertheless, sedative/hypnotics and anxiolytic drugs (mostly the benzodiazepines) are safe and effective therapy for the older patient, when the appropriate indications and dosages are observed. On the other hand, the toxic potential of nonbenzodiazepines (eg, barbiturates and pseudobarbiturates) and of even the relatively safe alternatives (eg, chloral hydrate, diphenhydramine, and hydroxyzine) render them less useful for the treatment of sleep disturbances. A final nonpharmacologic note: the physician should bear in mind that a balanced medical and psychological approach to sleep disturbance and anxiety in the elderly often yields success. This includes establishing a bedtime routine and using behavioral techniques, such as relaxation training, biofeedback, and even self-hypnosis. Patients can often be referred to a center where these approaches are employed.