Patient-doctor continuity and diagnosis of cancer: electronic medical records study in general practice

This is the final version of the article. Available from Royal College of General Practitioners via the DOI in this record.BACKGROUND: Continuity of care may affect the diagnostic process in cancer but there is little research. AIM: To estimate associations between patient-doctor continuity and time to diagnosis and referral of three common cancers. DESIGN AND SETTING: Retrospective cohort study in general practices in England. METHOD: This study used data from the General Practice Research Database for patients aged ≥40 years with a diagnosis of breast, colorectal, or lung cancer. Relevant cancer symptoms or signs were identified up to 12 months before diagnosis. Patient-doctor continuity (fraction-of-care index adjusted for number of consultations) was calculated up to 24 months before diagnosis. Time ratios (TRs) were estimated using accelerated failure time regression models. RESULTS: Patient-doctor continuity in the 24 months before diagnosis was associated with a slightly later diagnosis of colorectal (time ratio [TR] 1.01, 95% confidence interval [CI] =1.01 to 1.02) but not breast (TR = 1.00, 0.99 to 1.01) or lung cancer (TR = 1.00, 0.99 to 1.00). Secondary analyses suggested that for colorectal and lung cancer, continuity of doctor before the index consultation was associated with a later diagnosis but continuity after the index consultation was associated with an earlier diagnosis, with no such effects for breast cancer. For all three cancers, most of the delay to diagnosis occurred after referral. CONCLUSION: Any effect for patient-doctor continuity appears to be small. Future studies should compare investigations, referrals, and diagnoses in patients with and without cancer who present with possible cancer symptoms or signs; and focus on 'difficult to diagnose' types of cancer.This work was funded by Cancer Research UK (C41384/A13266)

Molecular brakes regulating mTORC1 activation in skeletal muscle following synergist ablation

The goal of the current work was to profile positive (mTORC1 activation, autocrine/paracrine growth factors) and negative [AMPK, unfolded protein response (UPR)] pathways that might regulate overload-induced mTORC1 (mTOR complex 1) activation with the hypothesis that a number of negative regulators of mTORC1 will be engaged during a supraphysiological model of hypertrophy. To achieve this, mTORC1- IRS-1/2 signaling, BiP/CHOP/IRE1, and AMPK activation were determined in rat plantaris muscle following synergist ablation (SA). SA resulted in significant increases in muscle mass of 4% per day throughout the 21 days of the experiment. The expression of the insulin-like growth factors (IGF) were high throughout the 21st day of overload. However, IGF signaling was limited, since IRS-1 and -2 were undetectable in the overloaded muscle from day 3 to day 9. The decreases in IRS-1/2 protein were paralleled by increases in GRB10 Ser501/503 and S6K1 Thr389 phosphorylation, two mTORC1 targets that can destabilize IRS proteins. PKB Ser473 phosphorylation was higher from 3– 6 days, and this was associated with increased TSC2 Thr939 phosphorylation. The phosphorylation of TSC2 Thr1345 (an AMPK site) was also elevated, whereas phosphorylation at the other PKB site, Thr1462, was unchanged at 6 days. In agreement with the phosphorylation of Thr1345, SA led to activation of AMPK1 during the initial growth phase, lasting the first 9 days before returning to baseline by day 12. The UPR markers CHOP and BiP were elevated over the first 12 days following ablation, whereas IRE1 levels decreased. These data suggest that during supraphysiological muscle loading at least three potential molecular brakes engage to downregulate mTORC1. m

NLO Higgs boson production via vector-boson fusion matched with shower in POWHEG

We present a next-to-leading order calculation of Higgs boson production in vector-boson fusion processes interfaced to shower Monte Carlo programs, implemented according to the POWHEG method.Comment: 16 pages, 9 figures. A few references and a new figure adde

Assessing connectivity between an overlying aquifer and a coal seam gas resource using methane isotopes, dissolved organic carbon and tritium

Coal seam gas (CSG) production can have an impact on groundwater quality and quantity in adjacent or overlying aquifers. To assess this impact we need to determine the background groundwater chemistry and to map geological pathways of hydraulic connectivity between aquifers. In south-east Queensland (Qld), Australia, a globally important CSG exploration and production province, we mapped hydraulic connectivity between the Walloon Coal Measures (WCM, the target formation for gas production) and the overlying Condamine River Alluvial Aquifer (CRAA), using groundwater methane (CH4) concentration and isotopic composition (δ13C-CH4), groundwater tritium (3H) and dissolved organic carbon (DOC) concentration. A continuous mobile CH4 survey adjacent to CSG developments was used to determine the source signature of CH4 derived from the WCM. Trends in groundwater δ13C-CH4 versus CH4 concentration, in association with DOC concentration and 3H analysis, identify locations where CH4 in the groundwater of the CRAA most likely originates from the WCM. The methodology is widely applicable in unconventional gas development regions worldwide for providing an early indicator of geological pathways of hydraulic connectivity

Dark-adapted red flash ERGs in healthy adults

Purpose: The x-wave of the dark-adapted (DA) ERG to a red flash reflects DA cone function. This exploratory study of healthy adults aimed to investigate changes in the DA red ERG with flash strength and during dark adaptation to optimise visualisation and therefore quantification of the x-wave. Methods: The effect of altering red flash strength was investigated in four subjects by recording ERGs after 20 minutes dark adaptation to red flashes (0.2–2.0 cd s m-2) using skin electrodes and natural pupils. The effect of dark adaptation duration was investigated in 16 subjects during 20 minutes in the dark, by recording DA 1.5 red ERGs at 1, 2, 3, 4, 5, 10, 15 and 20 minutes. Results: For a dark adaption period of 20 minutes, the x-wave was more clearly visualised to weaker (< 0.6 cd s m-2) red flash strengths: to stronger flashes it became obscured by the b-wave. For red flashes of 1.5 cd s m-2, the x-wave was most prominent in ERGs recorded after 1–5 minutes of dark adaptation: with longer dark-adaptation, it was subsumed into the b-wave’s rising edge. Conclusions: This small study suggests that x-wave visibility in healthy subjects after 20 minutes dark adaptation is improved by using flashes weaker than around 0.6 cd s m-2; for flash strengths of 1.5 cd s m-2, x-wave visibility is enhanced by recording after only around 5 minutes of dark adaptation. No evidence was found that interim red flash ERGs affecting the dark-adapted state of the normal retina

The Social context of motorcycle riding and the key determinants influencing rider behavior: A qualitative investigation

Objective: Given the increasing popularity of motorcycle riding and heightened risk of injury or death associated with being a rider, this study explored rider behaviour as a determinant of rider safety and, in particular, key beliefs and motivations which influence such behaviour. To enhance the effectiveness of future education and training interventions, it is important to understand riders’ own views about what influences how they ride. Specifically, this study sought to identify key determinants of riders’ behaviour in relation to the social context of riding including social and identity-related influences relating to the group (group norms and group identity) as well as the self (moral/personal norm and self-identity). ----- ----- Method: Qualitative research was undertaken via group discussions with motorcycle riders (n = 41). Results: The findings revealed that those in the group with which one rides represent an important source of social influence. Also, the motorcyclist (group) identity was associated with a range of beliefs, expectations, and behaviours considered to be normative. Exploration of the construct of personal norm revealed that riders were most cognizant of the “wrong things to do” when riding; among those issues raised was the importance of protective clothing (albeit for the protection of others and, in particular, pillion passengers). Finally, self-identity as a motorcyclist appeared to be important to a rider’s self-concept and was likely to influence their on-road behaviour. ----- ----- Conclusion: Overall, the insight provided by the current study may facilitate the development of interventions including rider training as well as public education and mass media messages. The findings suggest that these interventions should incorporate factors associated with the social nature of riding in order to best align it with some of the key beliefs and motivations underpinning riders’ on-road behaviours

Signalling Responses Following Varying Sequencing of Strength and Endurance Training in a Fed State.

The objective of this study was to compare anabolic signalling responses to differing sequences of concurrent strength and endurance training in a fed state.Eighteen resistance-trained males were randomly assigned to the following experimental conditions; i) strength training (ST), ii) strength followed by endurance training (ST-END) or iii) endurance followed by strength training (END-ST). Muscle tissue samples were taken from the vastus lateralis before each exercise protocol, upon cessation of exercise, and 1 h-post cessation of strength training. Tissue was analysed for total and phosphorylated (p-) signalling proteins linked to the mTOR and AMPK networks.Strength training performance was similar between ST, ST-END and END-ST. p-S6k1 was elevated from baseline 1 h post training in ST and ST-END (both p < 0.05). p-4E-BP1 was significantly lower than baseline post ST (p = 0.01), while 1 h post exercise in the ST-END condition p-4E-BP1 was significantly greater than post exercise (p = 0.04). p-ACC was elevated from baseline both post and 1 h post exercise (both p < 0.05) in the END-ST condition. AMPK, mTOR, p38, PKB, eEF2 responded similarly to the ST, ST-END and END-ST. Signalling responses to ST, ST-END and END were largely similar. As such it cannot be ascertained which sequence of concurrent strength and endurance training is most favourable in promoting anabolic signalling.These data indicate that in the case of the present study an acute bout of concurrent training of differing sequences elicited similar responses of the AMPK and mTOR networks

An Intact Kidney Slice Model to Investigate Vasa Recta Properties and Function in situ

Background: Medullary blood flow is via vasa recta capillaries, which possess contractile pericytes. In vitro studies using isolated descending vasa recta show that pericytes can constrict/dilate descending vasa recta when vasoactive substances are present. We describe a live kidney slice model in which pericyte-mediated vasa recta constriction/dilation can be visualized in situ. Methods: Confocal microscopy was used to image calcein, propidium iodide and Hoechst labelling in ‘live’ kidney slices, to determine tubular and vascular cell viability and morphology. DIC video-imaging of live kidney slices was employed to investigate pericyte-mediated real-time changes in vasa recta diameter. Results: Pericytes were identified on vasa recta and their morphology and density were characterized in the medulla. Pericyte-mediated changes in vasa recta diameter (10–30%) were evoked in response to bath application of vasoactive agents (norepinephrine, endothelin-1, angiotensin-II and prostaglandin E2) or by manipulating endogenous vasoactive signalling pathways (using tyramine, L-NAME, a cyclo-oxygenase (COX-1) inhibitor indomethacin, and ATP release). Conclusions: The live kidney slice model is a valid complementary technique for investigating vasa recta function in situ and the role of pericytes as regulators of vasa recta diameter. This technique may also be useful in exploring the role of tubulovascular crosstalk in regulation of medullary blood flow

Safety, Tolerability, and Pharmacokinetics of ARC-520 Injection, an RNA Interference-Based Therapeutic for the Treatment of Chronic Hepatitis B Virus Infection, in Healthy Volunteers

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