Incidence and prevalence of inflammatory bowel disease in UK primary care: a population-based cohort study

OBJECTIVES: We describe temporal trends in the recorded incidence of inflammatory bowel disease (IBD) in UK primary care patients between 2000 and 2018. DESIGN: A cohort study. SETTING: The IQVIA Medical Research data (IMRD) primary care database. PARTICIPANTS: All individuals registered with general practices contributing to IMRD during the period 01 January 2000-31 December 2018. MAIN OUTCOME MEASURES: The primary outcome was the recorded diagnosis of IBD. RESULTS: 11 325 025 individuals were included and 65 700 IBD cases were identified, of which 22 560 were incident diagnoses made during the study period. Overall, there were 8077 incident cases of Crohn's disease (CD) and 12 369 incident cases of ulcerative colitis (UC). Crude incidence estimates of 'IBD overall', CD and UC were 28.6 (28.2 to 28.9), 10.2 (10.0 to 10.5) and 15.7 (15.4 to 15.9)/100 000 person years, respectively. No change in IBD incidence was observed for adults aged 17-40 years and children aged 0-9 years. However, for adults aged over 40 years, incidence fell from 37.8 (34.5 to 41.4) to 23.6 (21.3 to 26.0)/100 000 person years (average decrease 2.3% (1.9 to 2.7)/year (p<0.0001)). In adolescents aged 10-16 years, incidence rose from 13.1 (8.4 to 19.5) to 25.4 (19.5 to 32.4)/100 000 person years (average increase 3.0% (1.7 to 4.3)/year (p<0.0001)). Point prevalence estimates on 31 December 2018 for IBD overall, CD and UC were 725, 276 and 397 per 100 000 people, respectively. CONCLUSIONS: This is one of the largest studies ever undertaken to investigate trends in IBD epidemiology. Although we observed stable or falling incidence of IBD in adults, our results are consistent with some of the highest reported global incidence and prevalence rates for IBD, with a 94% rise in incidence in adolescents. Further investigation is required to understand the aetiological drivers

Identification and functional characterisation of CRK12:CYC9, a novel cyclin-dependent kinase (CDK)-cyclin complex in Trypanosoma brucei

The protozoan parasite, Trypanosoma brucei, is spread by the tsetse fly and causes trypanosomiasis in humans and animals. Both the life cycle and cell cycle of the parasite are complex. Trypanosomes have eleven cdc2-related kinases (CRKs) and ten cyclins, an unusually large number for a single celled organism. To date, relatively little is known about the function of many of the CRKs and cyclins, and only CRK3 has previously been shown to be cyclin-dependent in vivo. Here we report the identification of a previously uncharacterised CRK:cyclin complex between CRK12 and the putative transcriptional cyclin, CYC9. CRK12:CYC9 interact to form an active protein kinase complex in procyclic and bloodstream T. brucei. Both CRK12 and CYC9 are essential for the proliferation of bloodstream trypanosomes in vitro, and we show that CRK12 is also essential for survival of T. brucei in a mouse model, providing genetic validation of CRK12:CYC9 as a novel drug target for trypanosomiasis. Further, functional characterisation of CRK12 and CYC9 using RNA interference reveals roles for these proteins in endocytosis and cytokinesis, respectively

Mechanisms for the Evolution of a Derived Function in the Ancestral Glucocorticoid Receptor

Understanding the genetic, structural, and biophysical mechanisms that caused protein functions to evolve is a central goal of molecular evolutionary studies. Ancestral sequence reconstruction (ASR) offers an experimental approach to these questions. Here we use ASR to shed light on the earliest functions and evolution of the glucocorticoid receptor (GR), a steroid-activated transcription factor that plays a key role in the regulation of vertebrate physiology. Prior work showed that GR and its paralog, the mineralocorticoid receptor (MR), duplicated from a common ancestor roughly 450 million years ago; the ancestral functions were largely conserved in the MR lineage, but the functions of GRs—reduced sensitivity to all hormones and increased selectivity for glucocorticoids—are derived. Although the mechanisms for the evolution of glucocorticoid specificity have been identified, how reduced sensitivity evolved has not yet been studied. Here we report on the reconstruction of the deepest ancestor in the GR lineage (AncGR1) and demonstrate that GR's reduced sensitivity evolved before the acquisition of restricted hormone specificity, shortly after the GR–MR split. Using site-directed mutagenesis, X-ray crystallography, and computational analyses of protein stability to recapitulate and determine the effects of historical mutations, we show that AncGR1's reduced ligand sensitivity evolved primarily due to three key substitutions. Two large-effect mutations weakened hydrogen bonds and van der Waals interactions within the ancestral protein, reducing its stability. The degenerative effect of these two mutations is extremely strong, but a third permissive substitution, which has no apparent effect on function in the ancestral background and is likely to have occurred first, buffered the effects of the destabilizing mutations. Taken together, our results highlight the potentially creative role of substitutions that partially degrade protein structure and function and reinforce the importance of permissive mutations in protein evolution

Measurement of Rapidity Distribution for High Mass Drell-Yan ee Pairs at CDF

We report on the first measurement of the rapidity distribution dsigma/dy over nearly the entire kinematic region of rapidity for e^+e^- pairs in the Z-boson region of 66116 GeV/c^2. The data sample consists of 108 pb^{-1} of ppbar collisions at \sqrt{s}=1.8 TeV taken by the Collider Detector at Fermilab during 1992--1995. The total cross section in the $Z$-boson region is measured to be 252 +- 11 pb. The measured total cross section and d\sigma/dy are compared with quantum chromodynamics calculations in leading and higher orders.Comment: 7 pages, 3 figures. Submitted to Physical Review Letter

Measurement of Branching Fractions and Rate Asymmetries in the Rare Decays B -> K(*) l+ l-

In a sample of 471 million BB events collected with the BABAR detector at the PEP-II e+e- collider we study the rare decays B -> K(*) l+ l-, where l+ l- is either e+e- or mu+mu-. We report results on partial branching fractions and isospin asymmetries in seven bins of di-lepton mass-squared. We further present CP and lepton-flavor asymmetries for di-lepton masses below and above the J/psi resonance. We find no evidence for CP or lepton-flavor violation. The partial branching fractions and isospin asymmetries are consistent with the Standard Model predictions and with results from other experiments.Comment: 16 pages, 14 figures, accepted by Phys. Rev.

Inclusive Search for Anomalous Production of High-pT Like-Sign Lepton Pairs in Proton-Antiproton Collisions at sqrt{s}=1.8 TeV

We report on a search for anomalous production of events with at least two charged, isolated, like-sign leptons with pT > 11 GeV/c using a 107 pb^-1 sample of 1.8 TeV ppbar collisions collected by the CDF detector. We define a signal region containing low background from Standard Model processes. To avoid bias, we fix the final cuts before examining the event yield in the signal region using control regions to test the Monte Carlo predictions. We observe no events in the signal region, consistent with an expectation of 0.63^(+0.84)_(-0.07) events. We present 95% confidence level limits on new physics processes in both a signature-based context as well as within a representative minimal supergravity (tanbeta = 3) model.Comment: 15 pages, 4 figures. Minor textual changes, cosmetic improvements to figures and updated and expanded reference

Search for Narrow Diphoton Resonances and for gamma-gamma+W/Z Signatures in p\bar p Collisions at sqrt(s)=1.8 TeV

We present results of searches for diphoton resonances produced both inclusively and also in association with a vector boson (W or Z) using 100 pb^{-1} of p\bar p collisions using the CDF detector. We set upper limits on the product of cross section times branching ratio for both p\bar p\to\gamma\gamma + X and p\bar p\to\gamma\gamma + W/Z. Comparing the inclusive production to the expectations from heavy sgoldstinos we derive limits on the supersymmetry-breaking scale sqrt{F} in the TeV range, depending on the sgoldstino mass and the choice of other parameters. Also, using a NLO prediction for the associated production of a Higgs boson with a W or Z boson, we set an upper limit on the branching ratio for H\to\gamma\gamma. Finally, we set a lower limit on the mass of a `bosophilic' Higgs boson (e.g. one which couples only to \gamma, W, and Z$ bosons with standard model couplings) of 82 GeV/c^2 at 95% confidence level.Comment: 30 pages, 11 figure

Limits on Gravitino Production and New Processes with Large Missing Transverse Energy in p-pbar Collisions at sqrt(s)=1.8 TeV

Events collected by the Collider Detector at Fermilab (CDF) with an energetic jet plus large missing transverse energy can be used to search for physics beyond the Standard Model. We see no deviations from the expected background and set upper limits on the production of new processes. We consider in addition the production of light gravitinos within the framework of the Gauge Mediated Supersymmetry Breaking models and set a limit at 95% confidence level on the breaking scale sqrt(F) >= 217 GeV, which excludes gravitino masses smaller than 1.1x10^-5 eV/c^2.Comment: 13 pages, 4 figures. Submitted to Physical Review Letter