Potential for medical error: Incorrectly completed request forms for thyroid function tests limit pathologists’ advice to clinicians

Background. Various publications have highlighted the significance of laboratory errors in the pre- and post-analytical phases and their impact on results. Thyroid-stimulating hormone (TSH) is a first-line thyroid function test and, if abnormal, reflex thyroxine (T4) or tri-iodothyronine (T3) testing is requested, depending on clinical and medication data provided. Interpretative comments are added to all TFTresults.Objectives. In view of the paucity of articles describing such errors, we audited laboratory request forms requesting thyroid function tests (TFT), received from primary care clinics and regional hospitals at our laboratory.Design. We assessed 482 laboratory request forms for TFT from primary health care clinics for specific parameters. Results. A total of 482 forms were analysed. Medication/s used by the patient (74.5%) and doctor’s contact number (65.1%) were the most commonly incomplete parameters. Of the 123 patients with medication details, 62 (50.4%) were on thyroxine.Conclusions. There are few studies examining the frequencyand impact of incomplete laboratory forms on laboratory errors, and even fewer studies examining interpretative comments accompanying clinical biochemistry results. We studied how pre-analytical errors in completing request forms may lead to incorrect interpretative comments and inappropriate reflex testing, and so influence the quality of the post-analytical phase

New Constraints (and Motivations) for Abelian Gauge Bosons in the MeV-TeV Mass Range

We survey the phenomenological constraints on abelian gauge bosons having masses in the MeV to multi-GeV mass range (using precision electroweak measurements, neutrino-electron and neutrino-nucleon scattering, electron and muon anomalous magnetic moments, upsilon decay, beam dump experiments, atomic parity violation, low-energy neutron scattering and primordial nucleosynthesis). We compute their implications for the three parameters that in general describe the low-energy properties of such bosons: their mass and their two possible types of dimensionless couplings (direct couplings to ordinary fermions and kinetic mixing with Standard Model hypercharge). We argue that gauge bosons with very small couplings to ordinary fermions in this mass range are natural in string compactifications and are likely to be generic in theories for which the gravity scale is systematically smaller than the Planck mass - such as in extra-dimensional models - because of the necessity to suppress proton decay. Furthermore, because its couplings are weak, in the low-energy theory relevant to experiments at and below TeV scales the charge gauged by the new boson can appear to be broken, both by classical effects and by anomalies. In particular, if the new gauge charge appears to be anomalous, anomaly cancellation does not also require the introduction of new light fermions in the low-energy theory. Furthermore, the charge can appear to be conserved in the low-energy theory, despite the corresponding gauge boson having a mass. Our results reduce to those of other authors in the special cases where there is no kinetic mixing or there is no direct coupling to ordinary fermions, such as for recently proposed dark-matter scenarios.Comment: 49 pages + appendix, 21 figures. This is the final version which appears in JHE

Investigating causality in associations between smoking initiation and schizophrenia using Mendelian randomization

Smoking is strongly associated with schizophrenia. Although it has been widely assumed that this reflects self-medication, recent studies suggest that smoking may be a risk factor for schizophrenia. We performed two-sample bi-directional Mendelian randomization using summary level genomewide association data from the Tobacco And Genetics Consortium and Psychiatric Genomics Consortium. Variants associated with smoking initiation and schizophrenia were combined using an inverse-variance weighted fixed-effects approach. We found evidence consistent with a causal effect of smoking initiation on schizophrenia risk (OR 1.73, 95% CI 1.30-2.25, p < 0.001). However, after relaxing the p-value threshold to include variants from more than one gene and minimize the potential impact of pleiotropy, the association was attenuated (OR 1.03, 95% CI 0.97-1.09, p = 0.32). There was little evidence in support of a causal effect of schizophrenia on smoking initiation (OR 1.01, 95% CI 0.98-1.04, p = 0.32). MR Egger regression sensitivity analysis indicated no evidence for pleiotropy in the effect of schizophrenia on smoking initiation (intercept OR 1.01, 95% CI 0.99-1.02, p = 0.49). Our findings provide little evidence of a causal association between smoking initiation and schizophrenia, in either direction. However, we cannot rule out a causal effect of smoking on schizophrenia related to heavier, lifetime exposure, rather than initiation.Funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, and the National Institute for Health Research, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. Support from the Medical Research Council (MC_UU_12013/6, MR/M006727/1) is also gratefully acknowledged. Stephen Burgess is supported by a fellowship from the Wellcome Trust (100114)

Ovarian cancer symptom awareness and anticipated delayed presentation in a population sample

Background: While ovarian cancer is recognised as having identifiable early symptoms, understanding of the key determinants of symptom awareness and early presentation is limited. A population-based survey of ovarian cancer awareness and anticipated delayed presentation with symptoms was conducted as part of the International Cancer Benchmarking Partnership (ICBP). Methods: Women aged over 50 years were recruited using random probability sampling (n = 1043). Computer-assisted telephone interviews were used to administer measures including ovarian cancer symptom recognition, anticipated time to presentation with ovarian symptoms, health beliefs (perceived risk, perceived benefits/barriers to early presentation, confidence in symptom detection, ovarian cancer worry), and demographic variables. Logistic regression analysis was used to identify the contribution of independent variables to anticipated presentation (categorised as < 3 weeks or ≥ 3 weeks). Results: The most well-recognised symptoms of ovarian cancer were post-menopausal bleeding (87.4%), and persistent pelvic (79.0%) and abdominal (85.0%) pain. Symptoms associated with eating difficulties and changes in bladder/bowel habits were recognised by less than half the sample. Lower symptom awareness was significantly associated with older age (p ≤ 0.001), being single (p ≤ 0.001), lower education (p ≤ 0.01), and lack of personal experience of ovarian cancer (p ≤ 0.01). The odds of anticipating a delay in time to presentation of ≥ 3 weeks were significantly increased in women educated to degree level (OR = 2.64, 95% CI 1.61 – 4.33, p ≤ 0.001), women who reported more practical barriers (OR = 1.60, 95% CI 1.34 – 1.91, p ≤ 0.001) and more emotional barriers (OR = 1.21, 95% CI 1.06 – 1.40, p ≤ 0.01), and those less confident in symptom detection (OR = 0.56, 95% CI 0.42 – 0.73, p ≤ 0.001), but not in those who reported lower symptom awareness (OR = 0.99, 95% CI 0.91 – 1.07, p = 0.74). Conclusions: Many symptoms of ovarian cancer are not well-recognised by women in the general population. Evidence-based interventions are needed not only to improve public awareness but also to overcome the barriers to recognising and acting on ovarian symptoms, if delays in presentation are to be minimised

Risk factors for delay in symptomatic presentation: a survey of cancer patients

Background: Delay in symptomatic presentation leading to advanced stage at diagnosis may contribute to poor cancer survival. To inform public health approaches to promoting early symptomatic presentation, we aimed to identify risk factors for delay in presentation across several cancers. Methods: We surveyed 2371 patients with 15 cancers about nature and duration of symptoms using a postal questionnaire. We calculated relative risks for delay in presentation (time from symptom onset to first presentation >3 months) by cancer, symptoms leading to diagnosis and reasons for putting off going to the doctor, controlling for age, sex and deprivation group. Results: Among 1999 cancer patients reporting symptoms, 21% delayed presentation for >3 months. Delay was associated with greater socioeconomic deprivation but not age or sex. Patients with prostate (44%) and rectal cancer (37%) were most likely to delay and patients with breast cancer least likely to delay (8%). Urinary difficulties, change of bowel habit, systemic symptoms (fatigue, weight loss and loss of appetite) and skin symptoms were all common and associated with delay. Overall, patients with bleeding symptoms were no more likely to delay presentation than patients who did not have bleeding symptoms. However, within the group of patients with bleeding symptoms, there were significant differences in risk of delay by source of bleeding: 35% of patients with rectal bleeding delayed presentation, but only 9% of patients with urinary bleeding. A lump was a common symptom but not associated with delay in presentation. Twenty-eight percent had not recognised their symptoms as serious and this was associated with a doubling in risk of delay. Embarrassment, worry about what the doctor might find, being too busy to go to the doctor and worry about wasting the doctor’s time were also strong risk factors for delay, but were much less commonly reported (<6%). Interpretation: Approaches to promote early presentation should aim to increase awareness of the significance of cancer symptoms and should be designed to work for people of the lowest socioeconomic status. In particular, awareness that rectal bleeding is a possible symptom of cancer should be raised

The mu problem and sneutrino inflation

We consider sneutrino inflation and post-inflation cosmology in the singlet extension of the MSSM with approximate Peccei-Quinn(PQ) symmetry, assuming that supersymmetry breaking is mediated by gauge interaction. The PQ symmetry is broken by the intermediate-scale VEVs of two flaton fields, which are determined by the interplay between radiative flaton soft masses and higher order terms. Then, from the flaton VEVs, we obtain the correct mu term and the right-handed(RH) neutrino masses for see-saw mechanism. We show that the RH sneutrino with non-minimal gravity coupling drives inflation, thanks to the same flaton coupling giving rise to the RH neutrino mass. After inflation, extra vector-like states, that are responsible for the radiative breaking of the PQ symmetry, results in thermal inflation with the flaton field, solving the gravitino problem caused by high reheating temperature. Our model predicts the spectral index to be n_s\simeq 0.96 due to the additional efoldings from thermal inflation. We show that a right dark matter abundance comes from the gravitino of 100 keV mass and a successful baryogenesis is possible via Affleck-Dine leptogenesis.Comment: 27 pages, no figures, To appear in JHE

A bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomes

Attachment of ubiquitin to lysine 119 of Histone 2A (H2AK119Ub) is an epigenetic mark characteristic of repressed developmental genes, which is removed by the Polycomb Repressive-Deubiquitinase (PR-DUB) complex. Here we report the crystal structure of the Drosophila PR-DUB, revealing that the deubiquitinase Calypso and its activating partner ASX form a 2:2 complex. The bidentate Calypso–ASX complex is generated by dimerisation of two activated Calypso proteins through their coiled-coil regions. Disrupting the Calypso dimer interface does not affect inherent catalytic activity, but inhibits removal of H2AK119Ub as a consequence of impaired recruitment to nucleosomes. Mutating the equivalent surface on the human counterpart, BAP1, also compromises activity on nucleosomes. Together, this suggests that high local concentrations drive assembly of bidentate PR-DUB complexes on chromatin—providing a mechanistic basis for enhanced PR-DUB activity at specific genomic foci, and the impact of distinct classes of PR-DUB mutations in tumorigenesis

Cancer symptom awareness and barriers to symptomatic presentation in England – Are we clear on cancer?

Background: Low cancer awareness may contribute to delayed diagnosis and poor cancer survival. We aimed to quantify socio-demographic differences in cancer symptom awareness and barriers to symptomatic presentation in the English population. Methods: Using a uniquely large data set (n=49?270), we examined the association of cancer symptom awareness and barriers to presentation with age, gender, marital status and socio-economic position (SEP), using logistic regression models to control for confounders. Results: The youngest and oldest, the single and participants with the lowest SEP recognised the fewest cancer symptoms, and reported most barriers to presentation. Recognition of nine common cancer symptoms was significantly lower, and embarrassment, fear and difficulties in arranging transport to the doctor’s surgery were significantly more common in participants living in the most deprived areas than in the most affluent areas. Women were significantly more likely than men to both recognise common cancer symptoms and to report barriers. Women were much more likely compared with men to report that fear would put them off from going to the doctor. Conclusions: Large and robust socio-demographic differences in recognition of some cancer symptoms, and perception of some barriers to presentation, highlight the need for targeted campaigns to encourage early presentation and improve cancer outcomes

Developmental changes in the role of different metalinguistic awareness skills in Chinese reading acquisition from preschool to third grade

Copyright @ 2014 Wei et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The present study investigated the relationship between Chinese reading skills and metalinguistic awareness skills such as phonological, morphological, and orthographic awareness for 101 Preschool, 94 Grade-1, 98 Grade-2, and 98 Grade-3 children from two primary schools in Mainland China. The aim of the study was to examine how each of these metalinguistic awareness skills would exert their influence on the success of reading in Chinese with age. The results showed that all three metalinguistic awareness skills significantly predicted reading success. It further revealed that orthographic awareness played a dominant role in the early stages of reading acquisition, and its influence decreased with age, while the opposite was true for the contribution of morphological awareness. The results were in stark contrast with studies in English, where phonological awareness is typically shown as the single most potent metalinguistic awareness factor in literacy acquisition. In order to account for the current data, a three-stage model of reading acquisition in Chinese is discussed.National Natural Science Foundation of China and Knowledge Innovation Program of the Chinese Academy of Sciences

Estimating Marginal Healthcare Costs Using Genetic Variants as Instrumental Variables: Mendelian Randomization in Economic Evaluation

Accurate measurement of the marginal healthcare costs associated with different diseases and health conditions is important, especially for increasingly prevalent conditions such as obesity. However, existing observational study designs cannot identify the causal impact of disease on healthcare costs. This paper explores the possibilities for causal inference offered by Mendelian Randomization, a form of instrumental variable analysis that uses genetic variation as a proxy for modifiable risk exposures, to estimate the effect of health conditions on cost. Well-conducted genome-wide association studies provide robust evidence of the associations of genetic variants with health conditions or disease risk factors. The subsequent causal effects of these health conditions on cost can be estimated by using genetic variants as instruments for the health conditions. This is because the approximately random allocation of genotypes at conception means that many genetic variants are orthogonal to observable and unobservable confounders. Datasets with linked genotypic and resource use information obtained from electronic medical records or from routinely collected administrative data are now becoming available, and will facilitate this form of analysis. We describe some of the methodological issues that arise in this type of analysis, which we illustrate by considering how Mendelian Randomization could be used to estimate the causal impact of obesity, a complex trait, on healthcare costs. We describe some of the data sources that could be used for this type of analysis. We conclude by considering the challenges and opportunities offered by Mendelian Randomization for economic evaluation