Nationally Automated Colonoscopy Performance Feedback Increases Polyp Detection: The NED APRIQOT Randomized Controlled Trial.

BACKGROUND & AIMS: Postcolonoscopy colorectal cancer incidence and mortality rates are higher for endoscopists with low polyp detection rates. Using the UK's National Endoscopy Database (NED), which automatically captures real-time data, we assessed if providing feedback of case-mix-adjusted mean number of polyps (aMNP), as a key performance indicator, improved endoscopists' performance. Feedback was delivered via a theory-informed, evidence-based audit and feedback intervention. METHODS: This multicenter, prospective, NED Automated Performance Reports to Improve Quality Outcomes Trial randomized National Health Service endoscopy centers to intervention or control. Intervention-arm endoscopists were e-mailed tailored monthly reports automatically generated within NED, informed by qualitative interviews and behavior change theory. The primary outcome was endoscopists' aMNP during the 9-month intervention. RESULTS: From November 2020 to July 2021, 541 endoscopists across 36 centers (19 intervention; 17 control) performed 54,770 procedures during the intervention, and 15,960 procedures during the 3-month postintervention period. Comparing the intervention arm with the control arm, endoscopists during the intervention period: aMNP was nonsignificantly higher (7%; 95% CI, -1% to 14%; P = .08). The unadjusted MNP (10%; 95% CI, 1%-20%) and polyp detection rate (10%; 95% CI, 4%-16%) were significantly higher. Differences were not maintained in the postintervention period. In the intervention arm, endoscopists accessing NED Automated Performance Reports to Improve Quality Outcomes Trial webpages had a higher aMNP than those who did not (aMNP, 118 vs 102; P = .03). CONCLUSIONS: Although our automated feedback intervention did not increase aMNP significantly in the intervention period, MNP and polyp detection rate did improve significantly. Engaged endoscopists benefited most and improvements were not maintained postintervention; future work should address engagement in feedback and consider the effectiveness of continuous feedback. CLINICAL TRIALS REGISTRY:  www.isrctn.org ISRCTN11126923 .

Ibuprofen, Flurbiprofen, Etoricoxib or Paracetamol Do Not Influence ACE2 Expression and Activity In Vitro or in Mice and Do Not Exacerbate In-Vitro SARS-CoV-2 Infection.

SARS-CoV-2 uses the human cell surface protein angiotensin converting enzyme 2 (ACE2) as the receptor by which it gains access into lung and other tissue. Early in the pandemic, there was speculation that a number of commonly used medications-including ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDs)-have the potential to upregulate ACE2, thereby possibly facilitating viral entry and increasing the severity of COVID-19. We investigated the influence of the NSAIDS with a range of cyclooxygenase (COX)1 and COX2 selectivity (ibuprofen, flurbiprofen, etoricoxib) and paracetamol on the level of ACE2 mRNA/protein expression and activity as well as their influence on SARS-CoV-2 infection levels in a Caco-2 cell model. We also analysed the ACE2 mRNA/protein levels and activity in lung, heart and aorta in ibuprofen treated mice. The drugs had no effect on ACE2 mRNA/protein expression and activity in the Caco-2 cell model. There was no up-regulation of ACE2 mRNA/protein expression and activity in lung, heart and aorta tissue in ibuprofen-treated mice in comparison to untreated mice. Viral load was significantly reduced by both flurbiprofen and ibuprofen at high concentrations. Ibuprofen, flurbiprofen, etoricoxib and paracetamol demonstrated no effects on ACE2 expression or activity in vitro or in vivo. Higher concentrations of ibuprofen and flurbiprofen reduced SARS-CoV-2 replication in vitro.

Inhibition of capsaicin-induced increase in dermal blood flow by the oral CGRP receptor antagonist, telcagepant (MK-0974).

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Calcitonin gene-related peptide (CGRP) was first described as a potent vasodilator. * CGRP is also increasingly recognized as a key player in the pathophysiology of migraine, and CGRP receptor antagonists potentially offer a new approach for treating migraine. * A novel pharmacodynamic assay to measure CGRP receptor antagonist activity non-invasively in humans has been developed, which involves measuring the increase in dermal blood flow induced by topical application of capsaicin on the forearm. WHAT THIS STUDY ADDS: * This study shows that the novel oral CGRP receptor antagonist, telcagepant, inhibits the increases in dermal blood flow induced by the topical application of capsaicin on the human forearm. * This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists. AIMS: To evaluate inhibition of capsaicin-induced increase in dermal blood flow (DBF) following telcagepant (MK-0974), a potent and selective orally bioavailable calcitonin gene-related peptide (CGRP) receptor antagonist being developed for the acute treatment of migraine. METHODS: A three-period crossover study in 12 healthy adult men. Each subject received a single oral dose of telcagepant 300 mg, telcagepant 800 mg or placebo at 0 h, followed 0.5 and 3.5 h later by two topical doses of 300 and 1000 microg capsaicin per 20 microl water-ethanol mixture. Capsaicin was applied at two sites on the volar surface of the subjects' left and right forearms. DBF was assessed by laser Doppler perfusion imaging immediately before ('baseline'), and 0.5 h after each capsaicin application at 1 and 4 h. Plasma samples to determine telcagepant concentrations were collected immediately after laser Doppler perfusion imaging. A pharmacodynamic model was developed to explore the relationship between plasma concentration and inhibition of capsaicin-induced increase in DBF. RESULTS: Geometric mean plasma concentrations after dosing with 300 mg and 800 mg telcagepant were 720 and 1146 nm, respectively, at 1 h, vs. 582 and 2548 nm, respectively, at 4 h. The pharmacodynamic model suggested that the EC(90) for telcagepant inhibition of capsaicin-induced increases in DBF was 909 nm. CONCLUSIONS: Telcagepant inhibits the increases in DBF induced by the topical application of capsaicin on the human forearm. This experimental medicine model may have utility to assist in dose selection for the development of CGRP receptor antagonists.

The release of excitatory amino acids, dopamine, and potassium following transplantation of embryonic mesencephalic dopaminergic grafts to the rat striatum, and their effects on dopaminergic neuronal survival in vitro.

A major limitation to the effectiveness of grafts of fetal ventral mesencephalic tissue for parkinsonism is that about 90-95% of grafted dopaminergic neurones die. In rats, many of the cells are dead within 1 day and most cell death is complete within 1 week. Our previous results suggest that a major cause of this cell death is the release of toxins from the injured CNS tissue surrounding the graft, and that many of these toxins have dissipated within 1 h of inserting the grafting cannula. In the present experiments we measured the change over time in the concentration of several potential toxins around an acutely implanted grafting cannula. We also measured the additional effect of injecting suspensions of embryonic mesencephalon, latex microspheres, or vehicle on these concentrations. Measurements of glutamate, aspartate, and dopamine by microdialysis showed elevated levels during the first 20-60 min, which then declined to baseline. In the first 20 min glutamate levels were 10.7 times, aspartate levels 5 times, and dopamine levels 24.3 times baseline. Potassium levels increased to a peak of 33 +/- 10.6 mM 4-5 min after cannula insertion, returning to baseline of <5 mM by 30 min. Injection of cell suspension, latex microspheres, or vehicle had no significant effect on these levels. We then assayed the effect of high concentrations of glutamate, aspartate, dopamine, and potassium on dopaminergic neuronal survival in E14 ventral mesencephalic cultures. In monolayer cultures only dopamine at 200 microM showed toxicity. In three-dimensional cultures only the combination of raised potassium, dopamine, glutamate, and aspartate together decreased dopaminergic neuronal survival. We conclude that toxins other than the ones measured are the main cause of dopaminergic cell death after transplantation, or the effects of the toxins measured are enhanced by anoxia and metabolic challenges affecting newly inserted grafts.

Single- and multiple-dose pharmacokinetics and tolerability of telcagepant, an oral calcitonin gene-related peptide receptor antagonist, in adults.

Telcagepant is a novel, orally active, and selective calcitonin gene-related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half-life was approximately 6 hours. A greater than dose-proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice-daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily.

Evidence-based medicine: a new ritual in medical teaching.

Western medicine is a diverse social and cultural system which responds in different ways to internal and external pressures. The Evidence-Based Medicine (EBM) movement has, despite some resistance from the rofession, led to the introduction of EBM into many areas of medicine, including medical training. Using material from teaching sessions for junior psychiatrists in England, I argue that EBM's novelty and potential challenge to established medical practice has been absorbed and accommodated within ordinary professional life by ritualizing EBM teaching in the familiar form of a traditional teaching ward round, with the difference that a published paper is 'presented' rather than a patient. These ritual occasions have the further effects of preventing any debate about EBM (partly because of the lack of immediate clinical application) and of limiting thought outside the paradigm of EBM and, indeed, of Western medicine itself.