Summary
Background
Crohn's disease recurs in the majority of patients after intestinal resection.
Aim
To compare the relative efficacy of thiopurines and anti‐TNF therapy in patients at high risk of ...disease recurrence.
Methods
As part of a larger study comparing post‐operative management strategies, patients at high risk of recurrence (smoker, perforating disease, ≥2nd operation) were treated after resection of all macroscopic disease with 3 months metronidazole together with either azathioprine 2 mg/kg/day or mercaptopurine 1.5 mg/kg/day. Thiopurine‐intolerant patients received adalimumab induction then 40 mg fortnightly. Patients underwent colonoscopy at 6 months with endoscopic recurrence assessed blind to treatment.
Results
A total of 101 patients 50% male; median (IQR) age 36 (25–46) years were included. There were no differences in disease history between thiopurine‐ and adalimumab‐treated patients. Fifteen patients withdrew prior to 6 months, five due to symptom recurrence (of whom four were colonoscoped). Endoscopic recurrence (Rutgeerts score i2–i4) occurred in 33 of 73 (45%) thiopurine vs. 6 of 28 (21%) adalimumab‐treated patients intention‐to‐treat (ITT); P = 0.028 or 24 of 62 (39%) vs. 3 of 24 (13%) respectively per‐protocol analysis (PPA); P = 0.020. Complete mucosal endoscopic normality (Rutgeerts i0) occurred in 17/73 (23%) vs. 15/28 (54%) (ITT; P = 0.003) and in 27% vs. 63% (PPA; P = 0.002). The most advanced disease (Rutgeerts i3 and i4) occurred in 8% vs. 4% (thiopurine vs. adalimumab).
Conclusions
In Crohn's disease patients at high risk of post‐operative recurrence adalimumab is superior to thiopurines in preventing early disease recurrence.
Aim Eighty per cent of patients with Crohn’s disease require surgery, of whom 70% will require a further operation. Recurrence occurs at the anastomosis. Although often recommended, the impact of ...postoperative colonoscopy and treatment adjustment is unknown.
Method Patients with a bowel resection over a 10‐year period were reviewed and comparison made between those who did and did not have a postoperative colonoscopy within 1 year of surgery, and those who did or did not have a step‐up in drug therapy.
Results Of 222 patients operated on, 136 (65 men, mean age 33 years, mean disease duration 8 years, median follow‐up 4 years) were studied. Of 70 patients with and 66 without postoperative colonoscopy, clinical recurrence occurred in 49% and 48% (NS) and further surgery in 9% and 5% (NS). Eighty‐nine per cent of colonoscoped patients had a decision based on the colonoscopic findings: of these, 24% had a step‐up of drug therapy antibiotics (n = 10), aminosalicylates (n = 2), thiopurine (n = 5), methotrexate (n = 1) and 76% had no step‐up in drug therapy. In colonoscoped patients clinical recurrence occurred in 9 (60%) of 15 patients with, and 23 (49%) of 47 without step‐up and surgical recurrence in 2 (13%) of 15 and 4 (9%) of 47 (NS).
Conclusion Clinical recurrence occurs in a majority of patients soon after surgery. In this cohort, there was no clinical benefit from colonoscopy or increased drug therapy within 1 year after operation. However, the response to the endoscopic findings was not standardized and immunosuppressive therapy was uncommon. Standardizing timing of colonoscopy and drug therapy, including more intense therapy, may improve outcome, although this remains to be proven.
A young man with known steroid refractory terminal ileal Crohn's disease developed torrential gastrointestinal bleeding necessitating an emergency ileal resection. Serology was indicative of primary ...cytomegalovirus (CMV) infection and this was confirmed with histopathology of the resected ileum. We highlight the difficulty in clinical practice of distinguishing between CMV infection and CMV disease as well as the different investigations available to aid in the diagnosis of pathogenic CMV disease.
Abstract
Background
The impact of pregnancy on vedolizumab (VDZ) and ustekinumab (UST) pharmacokinetics is not well defined. Similarly, the time to infant clearance and outcomes following in-utero ...exposure require elucidation. We aim to define the stability of UST and VDZ levels in pregnancy, placental drug transfer, and the time to and factors influencing infant drug clearance.
Methods
This multicentre prospective cohort study recruited women with IBD who were pregnant or planning pregnancy and receiving VDZ or UST. Trough drug levels, and clinical and biochemical data were documented pre-conception and in each trimester (T) of pregnancy. Maternal and infant drug levels were obtained at delivery and repeated in infants at intervals until clearance. Infant outcomes were assessed to 2 years of age. Drug levels were measured by ELISA (Theradiag) with a lower limit of detection of 0.25ug/mL (VDZ) and 0.4ug/mL (UST).
Results
97 women aged median 31 (IQR 29-34) y with 54 receiving VDZ (41,17 with Crohn’s disease respectively) were included. Clinical and biochemical disease remission was maintained in the majority (Table 1). Median VDZ levels decreased by 42% from T1 to T3 (p<0.001; Skilling’s Mack) without a corresponding increase in faecal calprotectin (p=0.65; Wilcoxon signed-rank), whilst UST levels were stable over the course of pregnancy (p=0.14) (Fig 1). 82% (VDZ) and 78% (UST) of participants continued drug into T3. Favourable delivery and infant outcomes were observed (Table 2). Infant:maternal drug level ratio was 1.74 (1.24-3.5, n=35) for UST and 0.71 (0.52-0.91, n=44) for VDZ. Delivery levels in infants correlated positively with concomitant maternal levels and gestation at time of final drug dose (Table 2). 67% UST and 90% VDZ exposed infants cleared drug by 15 weeks (p=0.06; two sided test of proportions), with a time to clearance of 13 (9-22) weeks for UST and 11 (8-13) weeks for VDZ (p=0.11; non-parametric comparison of medians). Time to clearance correlated positively with infant delivery level (Table 2). There was no difference in the time to infant clearance between those receiving their last dose in T2 vs T3 (UST p=0.45 or VDZ p=0.44).
Conclusion
UST levels are stable over the course of pregnancy. VDZ levels fall but without a parallel increase in biochemical disease activity. Proactive dose adjustment and level monitoring during pregnancy is therefore not necessary. Differences in placental transfer of UST and VDZ were confirmed, with the infant:maternal drug level ratio at delivery lower for VDZ than UST. Both are cleared prior to 15 weeks in the majority, but the higher placental transfer of UST results in numerically fewer exposed infants clearing drug by this timepoint. No concerning infant outcomes were identified in this cohort.
Abstract
Background
Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were evaluated in randomised, ...placebo-controlled Phase (P)2 (NCT00787202) and P3 (NCT01465763; NCT01458951; NCT01458574) studies, an open-label, long-term extension (OLE) study (NCT01470612) and an ongoing P3b/4 study (NCT03281304). Ex-smokers have an increased risk of UC, but the response to therapy in these patients (pts) has not been previously evaluated. We assessed the impact of smoking status on the efficacy and safety of tofacitinib in the UC clinical programme.
Methods
Efficacy endpoints and adverse events (AEs) were evaluated by smoking status (ever smokers current and ex-smokers and never smokers) in P2 (safety only)/P3/OLE/P3b/4 studies. Efficacy endpoints were summarised by treatment allocation; pt characteristics and AEs were summarised by tofacitinib predominant dose.
Results
This analysis included 1156 pts (ever smokers, n=416 36.0%; current smokers, n=59 (5.1%); ex-smokers, n=357 (30.9%); never smokers, n=740 64.0%; Table 1). Compared with never smokers, ever smokers were older and more likely to have a prior history of myocardial infarction, diabetes mellitus, or ischaemic or coronary heart disease. The proportion of pts achieving efficacy endpoints was generally similar across tofacitinib treatment groups regardless of smoking status (Table 2). AEs were reported in 88.7% of ever smokers and 83.8% of never smokers. Overall, 60.6% of ever smokers had an infection, specifically 10.8% had herpes zoster (non-serious and serious), 12.0% had a Clostridioides difficile infection and 19.5% had a lower respiratory tract infection; corresponding values for each AE among never smokers were 53.1%, 6.8%, 8.5% and 11.4% (Table 1). Major adverse cardiovascular events were reported in 1.0% of ever smokers and 0.7% of never smokers; thromboembolic events were reported in 1.0% of ever smokers and 0.9% of never smokers. Malignancies (excl. non-melanoma skin cancer NMSC) occurred in 2.5% of ever smokers and 1.5% of never smokers; NMSC occurred in 3.7% and 1.0%, respectively. In total, 0.6% of never smokers had colorectal cancer and there were no cases in ever smokers.
Conclusion
The efficacy and safety of tofacitinib were generally similar in ever smokers and never smokers. This study is limited by the combined analysis of current and ex-smokers and unknown factors such as the degree of smoking and the time between smoking cessation and UC diagnosis. These data are consistent with previous reports in the general population and pts with UC.1,2
References
1. Meserve J et al. Clin Gastroenterol Hepatol 2019; 7: 1533–1540.
2. Rogers MA et al. PLoS One 2012; 7: e42091.
Introduction:
Patients with Crohn’s disease have poorer health-related quality of life HRQoL than healthy individuals, even when in remission. Although HRQoL improves in patients who achieve ...drug-induced or surgically induced remission, the effects of surgery overall have not been well characterised.
Methods:
In a randomised trial, patients undergoing intestinal resection of all macroscopically diseased bowel were treated with postoperative drug therapy to prevent disease recurrence. All patients were followed prospectively for 18 months. C-reactive protein CRP, Crohn’s Disease Activity Index CDAI, and faecal calprotectin FC were measured preoperatively and at 6, 12, and 18 months. HRQoL was assessed with a general SF36 and disease-specific IBDQ questionnaires at the same time points.
Results:
A total of 174 patients were included. HRQoL was poor preoperatively but improved significantly p < 0.001 at 6 months postoperatively. This improvement was sustained at 18 months. Females and smokers had a poorer HRQoL when compared with males and non-smokers, respectively. Persistent endoscopic remission, intensification of drug treatment at 6 months, and anti-tumour necrosis factor therapy were not associated with HRQoL outcomes different from those when these factors were not present. There was a significant inverse correlation between CDAI, but not endoscopic recurrence, CRP, or FC on HRQoL.
Conclusion:
Intestinal resection of all macroscopic Crohn’s disease in patients treated with postoperative prophylactic drug therapy is associated with significant and sustained improvement in HRQoL irrespective of type of drug treatment or endoscopic recurrence. HRQoL is lower in female patients and smokers. A higher CDAI, but not direct measures of active disease or type of drug therapy, is associated with a lower HRQoL.
This longitudinal study tested students in Grade 8 and again in Grade 10 on career (maturity, barriers, indecision, decision-making and self-efficacy), well-being (self-esteem, life satisfaction, and ...coping), and social (school achievement, paid work experience) variables. Students were allocated to decided or undecided conditions at T1, T2 and across T1-T2, based on self-reported global decidedness ratings. As predicted, the undecided students had poorer career, well-being, and social outcomes than the decided students at T1 and T2. The undecided group was also less likely to report having paid work experience at T1, and to be overrepresented by females at T2. Students who were undecided at T1 and T2 (i.e., continuously undecided) fared poorer than students who were decided at T1 and T2 (continuously decided) and students who changed decision status from T1 to T2 (i.e., developmentally undecided). Females were more likely to be continuously undecided, although continuously undecided males were more complacent and more likely to use maladaptive strategies than females. Implications of being temperamentally versus developmentally undecided are discussed.
The effect of domain knowledge on students' memory for vocabulary terms was investigated. Participants were 142 college students (94 education majors and 48 business majors). The measure of domain ...knowledge was the number of courses completed in the major. Students recalled three different lists (control, education, and business) of 20 words. Knowledge effects were estimated controlling for academic aptitude, academic achievement, and general memory ability. Domain-specific knowledge consistently predicted recall, above and beyond the effect of these control variables. Moreover, nonlinear models better represented the relation between knowledge and memory, with very similar functions predicting recall in both knowledge domains. Specifically, early in the majors more classes corresponded with increased memory performance, but a plateau period, when more classes did not result in higher recall, was evident for both majors. Longitudinal research is needed to explore at what point in learning novices' performance begins to resemble experts' performance.
Depuis que
deGroot (1966)
a comparé la mémoire des configurations de jeu des joueurs d'échecs experts à celle des débutants, voici près de 40 ans, nombre de chercheurs ont mis en regard la performance d'experts et celle de débutants dans un éventail de domaines. Leurs études, entre autres, montrent que les experts devancent les débutants par le volume de renseignements appris et retenu dans leur champ de connaissance (
Van Overschelde & Healy, 2001
). Par contre, les enquêtes expérimentales sur la relation entre la connaissance et la mémoire (voir à ce propos
DeMarie-Dreblow, 1991
;
Muir-Broaddus, Rorer, Braden & George, 1995
) n'ont pas prouvé l'existence d'un lien causal entre elles. En clair, la progression de la connaissance ne donne pas lieu dans tous les cas à l'amélioration de la mémoire. Trois limites des études sur les experts et les débutants sont susceptibles d'expliquer l'écart entre les enquêtes corrélationnelles et les enquêtes expérimentales. D'abord, le plus souvent, la performance des participants n'est évaluée que dans un seul domaine. Deuxièmement, la plupart des études ne comparent que des experts et des débutants (à l'exclusion d'individus qui possèdent une connaissance moyenne). Troisièmement, connaissance et intérêt sont normalement confondus, car ceux qui deviennent experts dans un domaine y portent normalement un grand intérêt. La présente étude 1) a porté sur des étudiants de premier cycle dont la connaissance se situait sur une vaste échelle (allant de nulle à l'étude du domaine durant, au plus, quatre ans) et a visé le savoir-faire dans deux domaines distincts; 2) a départagé les effets de l'intérêt de ceux de la connaissance en tenant compte de la situation de débutants qui portaient de l'intérêt au domaine (c'est-à-dire, qui avaient déclaré leur majeure mais n'avaient pas encore pris de cours dans le domaine); 3) a contrôlé l'habileté, la réalisation et la mémoire générale afin de constater si les effets de la connaissance étaient toujours observables. Le nombre de cours réussis par les étudiants dans leur majeure a servi à évaluer de façon continue leurs connaissances. Cette donnée était une mesure objective que confirmait un examen de leurs relevés de notes. La connaissance a également été évaluée sur la base du caractère familier des mots pour les étudiants. Aux fins de cette dernière mesure subjective, les étudiants devaient déclarer s'ils croyaient connaître ou ignorer le sens de chaque mot. Nous nous sommes reportés aux estimations fournies par les enseignants de la fréquence de l'utilisation des termes pendant les cours pour évaluer l'exposition des étudiants au vocabulaire. Nous avons pu ainsi valider l'enseignement continu du vocabulaire pendant les programmes d'études. Comme la connaissance était quantifiée par l'application d'échelles de mesure continues, nous avons pu vérifier l'existence de rapports non linéaires entre les mesures de la connaissance et les mesures de la mémoire. L'étude a porté sur 142 étudiants (dont 94 en sciences de l'éducation et 48 en gestion des affaires) d'un petit collège d'enseignement général. Ils étaient invités à se rappeler 20 mots sur chacune de trois listes distinctes (contrôle, éducation, affaires). Nous avons évalué les effets de la connaissance en contrôlant l'aptitude (soit l'écart réduit des résultats obtenus aux examens ACT ou SAT), les résultats d'études (la moyenne des notes obtenues) et la mémoire générale (la capacité à se rappeler les mots sur la liste de contrôle). La connaissance propre au domaine s'est révélée être un prédicteur constant de la remémoration, et les résultats s'y rapportant étaient sans cesse supérieurs à ceux qui concernaient les variables de contrôle. Qui plus est, les modèles non linéaires ont représenté, mieux que les autres, la relation entre la connaissance et la mémoire, et des fonctions étroitement comparables ont prédit la remémoration dans les deux champs de connaissance. Notamment, les étudiants qui avaient suivi un grand nombre de cours au début de leur programme majeur ont obtenu de meilleurs résultats que les autres à la remémoration, quoique l'atteinte d'un plateau ait été observée relativement aux deux majeures, soit au moment où l'augmentation du nombre de cours ne se traduisait plus par une remémoration améliorée. La constatation du plateau était intéressante, car le vocabulaire du domaine continuait à être enseigné au cours de la période, et les étudiants ont déclaré que les termes leur devenaient de plus en plus familiers à ce moment. L'existence du plateau pourrait éventuellement éclairer la relation incohérente observée à l'occasion entre la connaissance et la mémoire. Ainsi, si
DeMarie-Dreblow (1991)
et
Muir-Broaddus, Rorer, Braden et George (1995)
testaient et remaniaient la connaissance d'étudiants dont la plupart se situaient dans la moyenne, il est possible qu'ils les aient exposés à de nouvelles connaissances au cours d'une période dite « de plateau ». Lorsqu'un plateau est atteint, l'observateur est susceptible de constater une évolution de la connaissance à laquelle ne correspond aucun changement de la capacité de remémoration. Grâce à sa conception singulière, la présente étude a mis en lumière des aspects importants de la relation entre la connaissance et la mémoire. Il faudra effectuer des recherches longitudinales pour déceler le moment où le rendement du débutant en apprentissage commence à ressembler à celui de l'expert.
Experimental Linguistics Prideaux, Gary D; Derwing, Bruce L; Baker, William J
1980, 1980-01-01
eBook
In order to isolate the major perceptual dimensions involved in the recognition of selected English consonants, four experiments were conducted. The first experiment attempted to characterize the ...nature of the perceptual space for English consonants, while the second was a replication and extension of the first, with the results being analyzed using multidimensional scaling (MDS). The third experiment attempted to test the predictive validity of the original MDS interpretation. The fourth experiment was a preliminary investigation of the impact of the method of measuring perceptual proximity upon the scaling solution using a proximity measure derived from a number of verbal rating scales. Two major perceptual dimensions were clearly isolated, and a third dimension also appeared, although with less consistency than the first two.
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