The NHS Bowel Cancer Screening Program: current perspectives on strategies for improvement

Colorectal cancer (CRC) is the third most common cancer in the UK. The English National Health Service (NHS) Bowel Cancer Screening Program (BCSP) was introduced in 2006 to improve CRC mortality by earlier detection of CRC. It is now offered to patients aged 60-74 years and involves a home-based guaiac fecal occult blood test (gFOBt) biennially, and if positive, patients are offered a colonoscopy. This has been associated with a 15% reduction in mortality. In 2013, an additional arm to BCSP was introduced, Bowelscope. This offers patients aged 55 years a one-off flexible sigmoidoscopy, and if several adenomas are found, the patients are offered a completion colonoscopy. BCSP has been associated with a significant stage shift in CRC diagnosis; however, the uptake of bowel cancer screening remains lower than that for other screening programs. Further work is required to understand the reasons for nonparticipation of patients to ensure optimal uptake. A change of gFOBt kit to the fecal immunochemical tests (FIT) in the English BCSP may further increase patient participation. This, in addition to increased yield of neoplasia and cancers with the FIT kit, is likely to further improve CRC outcomes in the screened population

The Newcastle ENDOPREM™: a validated patient reported experience measure for gastrointestinal endoscopy

OBJECTIVES: Measuring patient experience of gastrointestinal (GI) procedures is a key component of evaluation of quality of care. Current measures of patient experience within GI endoscopy are largely clinician derived and measured; however, these do not fully represent the experiences of patients themselves. It is important to measure the entirety of experience and not just experience directly during the procedure. We aimed to develop a patient-reported experience measure (PREM) for GI procedures. DESIGN: Phase 1: semi-structured interviews were conducted in patients who had recently undergone GI endoscopy or CT colonography (CTC) (included as a comparator). Thematic analysis identified the aspects of experience important to patients. Phase 2: a question bank was developed from phase 1 findings, and iteratively refined through rounds of cognitive interviews with patients who had undergone GI procedures, resulting in a pilot PREM. Phase 3: patients who had attended for GI endoscopy or CTC were invited to complete the PREM. Psychometric properties were investigated. Phase 4 involved item reduction and refinement. RESULTS: Phase 1: interviews with 35 patients identified six overarching themes: anxiety, expectations, information & communication, embarrassment & dignity, choice & control and comfort. Phase 2: cognitive interviews refined questionnaire items and response options. Phase 3: the PREM was distributed to 1650 patients with 799 completing (48%). Psychometric properties were found to be robust. Phase 4: final questionnaire refined including 54 questions assessing patient experience across five temporal procedural stages. CONCLUSION: This manuscript gives an overview of the development and validation of the Newcastle ENDOPREM™, which assesses all aspects of the GI procedure experience from the patient perspective. It may be used to measure patient experience in clinical care and, in research, to compare patients' experiences of different endoscopic interventions

Role of the mesoamygdaloid dopamine projection in emotional learning

Amygdala dopamine is crucially involved in the acquisition of Pavlovian associations, as measured via conditioned approach to the location of the unconditioned stimulus (US). However, learning begins before skeletomotor output, so this study assessed whether amygdala dopamine is also involved in earlier 'emotional' learning. A variant of the conditioned reinforcement (CR) procedure was validated where training was restricted to curtail the development of selective conditioned approach to the US location, and effects of amygdala dopamine manipulations before training or later CR testing assessed. Experiment 1a presented a light paired (CS+ group) or unpaired (CS- group) with a US. There were 1, 2 or 10 sessions, 4 trials per session. Then, the US was removed, and two novel levers presented. One lever (CR+) presented the light, and lever pressing was recorded. Experiment 1b also included a tone stimulus. Experiment 2 applied intra-amygdala R(+) 7-OH-DPAT (10 nmol/1.0 A mu l/side) before two training sessions (Experiment 2a) or a CR session (Experiment 2b). For Experiments 1a and 1b, the CS+ group preferred the CR+ lever across all sessions. Conditioned alcove approach during 1 or 2 training sessions or associated CR tests was low and nonspecific. In Experiment 2a, R(+) 7-OH-DPAT before training greatly diminished lever pressing during a subsequent CR test, preferentially on the CR+ lever. For Experiment 2b, R(+) 7-OH-DPAT infusions before the CR test also reduced lever pressing. Manipulations of amygdala dopamine impact the earliest stage of learning in which emotional reactions may be most prevalent

A Bio-Logical Theory of Animal Learning

This article provides the foundation for a new predictive theory of animal learning that is based upon a simple logical model. The knowledge of experimental subjects at a given time is described using logical equations. These logical equations are then used to predict a subject’s response when presented with a known or a previously unknown situation. This new theory suc- cessfully anticipates phenomena that existing theories predict, as well as phenomena that they cannot. It provides a theoretical account for phenomena that are beyond the domain of existing models, such as extinction and the detection of novelty, from which “external inhibition” can be explained. Examples of the methods applied to make predictions are given using previously published results. The present theory proposes a new way to envision the minimal functions of the nervous system, and provides possible new insights into the way that brains ultimately create and use knowledge about the world

Quantitative Genetics, Pleiotropy, and Morphological Integration in the Dentition of Papio hamadryas

Variation in the mammalian dentition is highly informative of adaptations and evolutionary relationships, and consequently has been the focus of considerable research. Much of the current research exploring the genetic underpinnings of dental variation can trace its roots to Olson and Miller's 1958 book Morphological Integration. These authors explored patterns of correlation in the post-canine dentitions of the owl monkey and Hyopsodus, an extinct condylarth from the Eocene. Their results were difficult to interpret, as was even noted by the authors, due to a lack of genetic information through which to view the patterns of correlation. Following in the spirit of Olson and Miller's research, we present a quantitative genetic analysis of dental variation in a pedigreed population of baboons. We identify patterns of genetic correlations that provide insight to the genetic architecture of the baboon dentition. This genetic architecture indicates the presence of at least three modules: an incisor module that is genetically independent of the post-canine dentition, and a premolar module that demonstrates incomplete pleiotropy with the molar module. We then compare this matrix of genetic correlations to matrices of phenotypic correlations between the same measurements made on museum specimens of another baboon subspecies and the Southeast Asian colobine Presbytis. We observe moderate significant correlations between the matrices from these three primate taxa. From these observations we infer similarity in modularity and hypothesize a common pattern of genetic integration across the dental arcade in the Cercopithecoidea

LHC Discovery Potential for Non-Standard Higgs Bosons in the 3b Channel

In a variety of well motivated models, such as two Higgs Doublet Models (2HDMs) and the Minimal Supersymmetric Standard Model (MSSM), there are neutral Higgs bosons that have significantly enhanced couplings to b-quarks and tau leptons in comparison to those of the SM Higgs. These so called non-standard Higgs bosons could be copiously produced at the LHC in association with b quarks, and subsequently decay into b-quark pairs. However, this production channel suffers from large irreducible QCD backgrounds. We propose a new search strategy for non-standard neutral Higgs bosons at the 7 TeV LHC in the 3b's final state topology. We perform a simulation of the signal and backgrounds, using state of the art tools and methods for different sets of selection cuts, and conclude that neutral Higgs bosons with couplings to b-quarks of about 0.3 or larger, and masses up to 400 GeV, could be seen with a luminosity of 30 fb^{-1}. In the case of the MSSM we also discuss the complementarity between the 3b channel and the inclusive tau pair channel in exploring the supersymmetric parameter space.Comment: 14 pages, 3 figures, 4 tables, references added, published versio

A 125 GeV SM-like Higgs in the MSSM and the γγ\gamma \gamma rate

We consider the possibility of a Standard Model (SM)-like Higgs in the context of the Minimal Supersymmetric Standard Model (MSSM), with a mass of about 125 GeV and with a production times decay rate into two photons which is similar or somewhat larger than the SM one. The relatively large value of the SM-like Higgs mass demands stops in the several hundred GeV mass range with somewhat large mixing, or a large hierarchy between the two stop masses in the case that one of the two stops is light. We find that, in general, if the heaviest stop mass is smaller than a few TeV, the rate of gluon fusion production of Higgs bosons decaying into two photons tends to be somewhat suppressed with respect to the SM one in this region of parameters. However, we show that an enhancement of the photon decay rate may be obtained for light third generation sleptons with large mixing, which can be naturally obtained for large values of $\tan\beta$ and sizable values of the Higgsino mass parameter.Comment: 14 pages, 4 figures. Corrected small typos and added reference

Master equation approach to the conjugate pairing rule of Lyapunov spectra for many-particle thermostatted systems

The master equation approach to Lyapunov spectra for many-particle systems is applied to non-equilibrium thermostatted systems to discuss the conjugate pairing rule. We consider iso-kinetic thermostatted systems with a shear flow sustained by an external restriction, in which particle interactions are expressed as a Gaussian white randomness. Positive Lyapunov exponents are calculated by using the Fokker-Planck equation to describe the tangent vector dynamics. We introduce another Fokker-Planck equation to describe the time-reversed tangent vector dynamics, which allows us to calculate the negative Lyapunov exponents. Using the Lyapunov exponents provided by these two Fokker-Planck equations we show the conjugate pairing rule is satisfied for thermostatted systems with a shear flow in the thermodynamic limit. We also give an explicit form to connect the Lyapunov exponents with the time-correlation of the interaction matrix in a thermostatted system with a color field.Comment: 10 page

Anatomical Network Comparison of Human Upper and Lower, Newborn and Adult, and Normal and Abnormal Limbs, with Notes on Development, Pathology and Limb Serial Homology vs. Homoplasy

How do the various anatomical parts (modules) of the animal body evolve into very different integrated forms (integration) yet still function properly without decreasing the individual's survival? This long-standing question remains unanswered for multiple reasons, including lack of consensus about conceptual definitions and approaches, as well as a reasonable bias toward the study of hard tissues over soft tissues. A major difficulty concerns the non-trivial technical hurdles of addressing this problem, specifically the lack of quantitative tools to quantify and compare variation across multiple disparate anatomical parts and tissue types. In this paper we apply for the first time a powerful new quantitative tool, Anatomical Network Analysis (AnNA), to examine and compare in detail the musculoskeletal modularity and integration of normal and abnormal human upper and lower limbs. In contrast to other morphological methods, the strength of AnNA is that it allows efficient and direct empirical comparisons among body parts with even vastly different architectures (e.g. upper and lower limbs) and diverse or complex tissue composition (e.g. bones, cartilages and muscles), by quantifying the spatial organization of these parts-their topological patterns relative to each other-using tools borrowed from network theory. Our results reveal similarities between the skeletal networks of the normal newborn/adult upper limb vs. lower limb, with exception to the shoulder vs. pelvis. However, when muscles are included, the overall musculoskeletal network organization of the upper limb is strikingly different from that of the lower limb, particularly that of the more proximal structures of each limb. Importantly, the obtained data provide further evidence to be added to the vast amount of paleontological, gross anatomical, developmental, molecular and embryological data recently obtained that contradicts the long-standing dogma that the upper and lower limbs are serial homologues. In addition, the AnNA of the limbs of a trisomy 18 human fetus strongly supports Pere Alberch's ill-named "logic of monsters" hypothesis, and contradicts the commonly accepted idea that birth defects often lead to lower integration (i.e. more parcellation) of anatomical structures

Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway

In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10−5 M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding – differential affinity, rapid ligand exchange and conformational flexibility