The thymus: what's normal and what's not? Problem-solving with MRI.

Anterior mediastinal masses can be difficult to characterise on computed tomography (CT) due to the wide spectrum of normal appearances of thymic tissue as well as the challenge of differentiating between benign and malignant pathologies. Additionally, attenuation of cystic mediastinal lesions can be misinterpreted on CT due to varying attenuation values. Anecdotally, non-vascular magnetic resonance imaging (MRI) of the thorax is underutilised across radiology departments in the UK, but has been shown to improve diagnostic certainty and reduce unnecessary surgical intervention. T2-weighted MRI is useful in confirming the cystic nature of lesions, whereas chemical shift techniques can be utilised to document the presence of macroscopic and intra-cellular fat and thus help distinguish between benign and malignant pathologies. In this review article, we present a practical approach to using MRI for the characterisation of anterior mediastinal lesions based on our clinical experience in a UK district general hospital.

Influences on emergency department attendance among frail older people with deteriorating health: a multicentre prospective cohort study.

OBJECTIVES: To examine the patterns and influences on repeated emergency department attendance among frail older people with deteriorating health. STUDY DESIGN: Multicentre prospective cohort study (International Access Rights and Empowerment II study) with convergent mixed methods design. METHODS: Eligible patients were aged ≥65 years, with Clinical Frailty Score ≥5, and ≥1 hospital admission or ≥2 acute attendances in the previous 6 months. Questionnaires were administered to participants over 6 months and we extracted clinical data from the medical records. We conducted modified Poisson multivariable regression analysis to identify factors associated with repeated emergency department attendance (≥2 over 6 months) and thematic analysis of qualitative interviews. RESULTS: A total of 90 participants were recruited. The mean age was 84 years, and 63% were women. Of 87 participants, 21 experienced repeated emergency department attendance. Severe and/or overwhelming pain (adjusted prevalence ratio 2.44, 95% confidence interval 1.17-5.11), greater number of comorbidities (1.32, 1.08-1.62), ≥10 community nursing contacts (2.93, 1.31-6.56), and a total of ≥2 weeks spent in hospital during the previous 6 months (2.91, 1.24-6.84) were associated with repeated attendance. From 45 interviews, we identified influences on emergency department attendance: 1. inaccessibility of community healthcare; 2. perceived barriers to community healthcare seeking; 3. perceived benefits of hospital admission; 4. barriers to recovery during previous hospital admission (unsuitable food, inactivity); and 5. poorly coordinated transitions between settings. CONCLUSIONS: We identified missed opportunities to optimise older people's recovery during hospital admission, such as improved food and a timely and coordinated discharge, which may reduce reattendances. Proactive care in the community with systematic assessment of symptoms may be required, particularly for those with multimorbidity.

Processes of consent in research for adults with impaired mental capacity nearing the end of life: systematic review and transparent expert consultation (MORECare_Capacity statement).

BACKGROUND: Involving adults lacking capacity (ALC) in research on end of life care (EoLC) or serious illness is important, but often omitted. We aimed to develop evidence-based guidance on how best to include individuals with impaired capacity nearing the end of life in research, by identifying the challenges and solutions for processes of consent across the capacity spectrum. METHODS: Methods Of Researching End of Life Care_Capacity (MORECare_C) furthers the MORECare statement on research evaluating EoLC. We used simultaneous methods of systematic review and transparent expert consultation (TEC). The systematic review involved four electronic databases searches. The eligibility criteria identified studies involving adults with serious illness and impaired capacity, and methods for recruitment in research, implementing the research methods, and exploring public attitudes. The TEC involved stakeholder consultation to discuss and generate recommendations, and a Delphi survey and an expert 'think-tank' to explore consensus. We narratively synthesised the literature mapping processes of consent with recruitment outcomes, solutions, and challenges. We explored recommendation consensus using descriptive statistics. Synthesis of all the findings informed the guidance statement. RESULTS: Of the 5539 articles identified, 91 met eligibility. The studies encompassed people with dementia (27%) and in palliative care (18%). Seventy-five percent used observational designs. Studies on research methods (37 studies) focused on processes of proxy decision-making, advance consent, and deferred consent. Studies implementing research methods (30 studies) demonstrated the role of family members as both proxy decision-makers and supporting decision-making for the person with impaired capacity. The TEC involved 43 participants who generated 29 recommendations, with consensus that indicated. Key areas were the timeliness of the consent process and maximising an individual's decisional capacity. The think-tank (n = 19) refined equivocal recommendations including supporting proxy decision-makers, training practitioners, and incorporating legislative frameworks. CONCLUSIONS: The MORECare_C statement details 20 solutions to recruit ALC nearing the EoL in research. The statement provides much needed guidance to enrol individuals with serious illness in research. Key is involving family members early and designing study procedures to accommodate variable and changeable levels of capacity. The statement demonstrates the ethical imperative and processes of recruiting adults across the capacity spectrum in varying populations and settings.

Associations between prenatal, childhood, and adolescent stress and variations in white-matter properties in young men.

OBJECTIVE: Previous studies have shown that both pre- and post-natal adversities, the latter including exposures to stress during childhood and adolescence, explain variation in structural properties of white matter (WM) in the brain. While previous studies have examined effects of independent stress exposures within one developmental period, such as childhood, we examine effects of stress across development using data from a prospective longitudinal study. More specifically, we ask how stressful events during prenatal development, childhood, and adolescence relate to variation in WM properties in early adulthood in young men recruited from a birth cohort. METHOD: Using data from 393 mother-son pairs from a community-based birth cohort from England (Avon Longitudinal Study of Parents and Children), we examined how stressful life events relate to variation in different structural properties of WM in the corpus callosum and across the whole brain in early adulthood in men aged 18-21 years. We distinguish between stress occurring during three developmental periods: a) prenatal maternal stress, b) postnatal stress within the first four years of life, c) stress during adolescence (age 12-16 years). To obtain a comprehensive quantification of variation in WM, we assess structural properties of WM using four different measures, namely fractional anisotropy (FA), mean diffusivity (MD), magnetization transfer ratio (MTR) and myelin water fraction (MWF). RESULTS: The developmental model shows that prenatal stress is associated with lower MTR and MWF in the genu and/or splenium of the corpus callosum, and with lower MTR in global (lobar) WM. Stress during early childhood is associated with higher MTR in the splenium, and stress during adolescence is associated with higher MTR in the genu and lower MD in the splenium. We see no associations between postnatal stress and variation in global (lobar) WM. CONCLUSIONS: The current study found evidence for independent effects of stress on WM properties during distinct neurodevelopmental periods. We speculate that these independent effects are due to differences in the developmental processes unfolding at different developmental time points. We suggest that associations between prenatal stress and WM properties may relate to abnormalities in neurogenesis, affecting the number and density of axons, while postnatal stress may interfere with processes related to myelination or radial growth of axons. Potential consequences of prenatal glucocorticoid exposure should be considered in obstetric care.

How many people will need palliative care in 2040? Past trends, future projections and implications for services.

BACKGROUND: Current estimates suggest that approximately 75% of people approaching the end-of-life may benefit from palliative care. The growing numbers of older people and increasing prevalence of chronic illness in many countries mean that more people may benefit from palliative care in the future, but this has not been quantified. The present study aims to estimate future population palliative care need in two high-income countries. METHODS: We used mortality statistics for England and Wales from 2006 to 2014. Building on previous diagnosis-based approaches, we calculated age- and sex-specific proportions of deaths from defined chronic progressive illnesses to estimate the prevalence of palliative care need in the population. We calculated annual change over the 9-year period. Using explicit assumptions about change in disease prevalence over time, and official mortality forecasts, we modelled palliative care need up to 2040. We also undertook separate projections for dementia, cancer and organ failure. RESULTS: By 2040, annual deaths in England and Wales are projected to rise by 25.4% (from 501,424 in 2014 to 628,659). If age- and sex-specific proportions with palliative care needs remain the same as in 2014, the number of people requiring palliative care will grow by 25.0% (from 375,398 to 469,305 people/year). However, if the upward trend observed from 2006 to 2014 continues, the increase will be of 42.4% (161,842 more people/year, total 537,240). In addition, disease-specific projections show that dementia (increase from 59,199 to 219,409 deaths/year by 2040) and cancer (increase from 143,638 to 208,636 deaths by 2040) will be the main drivers of increased need. CONCLUSIONS: If recent mortality trends continue, 160,000 more people in England and Wales will need palliative care by 2040. Healthcare systems must now start to adapt to the age-related growth in deaths from chronic illness, by focusing on integration and boosting of palliative care across health and social care disciplines. Countries with similar demographic and disease changes will likely experience comparable rises in need.

Spectroscopic confirmation of a galaxy at redshift z = 8.6.

Galaxies had their most significant impact on the Universe when they assembled their first generations of stars. Energetic photons emitted by young, massive stars in primeval galaxies ionized the intergalactic medium surrounding their host galaxies, cleared sightlines along which the light of the young galaxies could escape, and fundamentally altered the physical state of the intergalactic gas in the Universe continuously until the present day. Observations of the cosmic microwave background, and of galaxies and quasars at the highest redshifts, suggest that the Universe was reionized through a complex process that was completed about a billion years after the Big Bang, by redshift z ≈ 6. Detecting ionizing Lyman-α photons from increasingly distant galaxies places important constraints on the timing, location and nature of the sources responsible for reionization. Here we report the detection of Lyα photons emitted less than 600 million years after the Big Bang. UDFy-38135539 (ref. 5) is at a redshift of z = 8.5549 ± 0.0002, which is greater than those of the previously known most distant objects, at z = 8.2 (refs 6 and 7) and z = 6.96 (ref. 8). We find that this single source is unlikely to provide enough photons to ionize the volume necessary for the emission line to escape, requiring a significant contribution from other, probably fainter galaxies nearby.

Improved precision in CHARMED assessment of white matter through sampling scheme optimization and model parsimony testing.

PURPOSE: The composite hindered and restricted model of diffusion provides microstructural indices that are potentially more specific than those from diffusion tensor imaging. However, in comparison to diffusion tensor imaging, the acquisition time is longer, limiting clinical applications. Moreover, the model requires several parameters to be estimated whose confidence intervals can be large. Here, the composite hindered and restricted model of diffusion acquisition and data processing pipelines are optimized to extend the utility of this approach. METHODS: A multishell sampling scheme was optimized using the electrostatic repulsion algorithm, combined with optimal ordering. The optimal protocol, using as few measurements as possible, was determined through leave-n-out analyses. Parsimonious model selection criteria were used to select between nested models, comprising up to three restricted compartments. The schemes were evaluated using both through Monte-Carlo simulations and in vivo data. RESULTS: The optimization/model selection procedure resulted in increased accuracy and precision on the estimated parameters, allowing for a reduction in acquisition time and marked improvements in data quality. The final protocol provided whole brain coverage data in only 12 min. CONCLUSION: Through careful optimization of the acquisition and analysis pipeline for the composite hindered and restricted model of diffusion, it is possible to reduce acquisition time for whole brain datasets to a time that is clinically applicable.

Incidence and risk factors for venous reflux in the general population: Edinburgh Vein Study.

OBJECTIVE/BACKGROUND: Chronic venous disease (CVD) is common, but the incidence of venous reflux, a precursor to this condition, is unknown. This study measured the incidence of venous reflux and associated risk factors, and examined the association between venous reflux and the incidence of CVD. METHODS: In the Edinburgh Vein Study, a random sample of 1566 men and women aged 18-64 years were examined at baseline. Eight hundred and eighty of these patients were followed up 13 years and underwent an examination comprising clinical classification of CVD and duplex scanning of the deep and superficial systems to measure venous reflux ≥0.5 s. RESULTS: The 13-year incidence of reflux was 12.7% (95% confidence interval [CI] 9.2-17.2), equivalent to an annual incidence of 0.9% (95% CI 0.7-1.3). The 13-year incidence of isolated superficial, isolated deep, and combined deep and superficial reflux was 8.8% (95% CI 5.6-12.0), 2.6% (95% CI 1.2-5.0), and 1.3% (95% CI 0.4-3.2), respectively. The highest incidence was in the great saphenous vein in the lower thigh (8.1%, 95% CI 5.4-11.8). There were no age or sex differences (p > .050). The risk of developing reflux was associated with being overweight (odds ratio [OR] 2.1, 95% CI 1.0-4.4) and with history of deep vein thrombosis (OR 11.3, 95% CI 1.0-132.3). Venous reflux at baseline was associated with new varicose veins at follow up (p < .001): the age- and sex-adjusted OR was 4.4 (95% CI 1.8-10.8) in those with isolated superficial reflux and 7.3 (95% CI 2.6-22.5) in those with combined deep and superficial reflux. CONCLUSION: For every year of follow-up, around 1% of this adult population developed venous reflux. In two thirds of cases, the superficial system was affected. Venous reflux increased the risk of developing varicose veins, especially when combined deep and superficial reflux was present.

RAPID: a routine assurance pipeline for imaging of diffusion.

Despite the widespread adoption of diffusion MRI techniques, there is still no consensus on a comprehensive quality assurance routine specific for diffusion acquisitions. We propose here a routine assurance pipeline for imaging of diffusion. The routine simply comprises diffusion-weighted acquisitions on a phantom; each repetition lasts less than 5 min and can be performed using a variety of isotropic test liquids. The proposed QA script checks for the linearity of G, the uniformity of Gmax across the field-of-view, the mutual agreement of gradient power across the three logical axes and the temporal stability. Optionally, the routine can correct for the mutual agreement of gradient power along the three axes, returning a set of gradient orientations to be used in data analysis. The effectiveness of the scheme in the presence of mismatched gradient amplitudes is reported using both simulations and in vivo data. The script is freely available online.

Validation study of the Self-Assessment Goal Achievement (SAGA) questionnaire for lower urinary tract symptoms.

BACKGROUND: Patients' treatment goals for overactive bladder (OAB) and other lower urinary tract symptoms (LUTS) may not be aligned with their healthcare provider's goals. Successful management of OAB symptoms is improved by individualised treatment plans with attainable treatment goals. Goal attainment setting may facilitate patient-provider interaction and the development of a personalised treatment plan based on realistic, individual goals, thereby increasing patient satisfaction and therapeutic outcomes. The purpose of this study was to validate the utility of the Self-Assessment Goal Achievement (SAGA) questionnaire for LUTS in helping patients identify and achieve realistic treatment goals. METHODS: The 2-module SAGA questionnaire consists of nine prespecified (fixed) items and five open-ended items for goal identification and ranking (baseline module) and goal achievement rating (follow-up module). Adult patients in the United States (n = 104) seeking treatment for LUTS, including symptoms of OAB, completed the SAGA baseline module, micturition diary, other patient-reported outcome measures (PROs), and discussed their urinary goals with a clinician at baseline. The SAGA follow-up module was completed 2-4 months later. SAGA was validated based on analyses of face, concurrent, known-groups, and convergent validity and item distribution. RESULTS: Among the nine fixed goals of SAGA, four were ranked as very important by > 50% of patients (i.e. reduce night-time frequency, daytime frequency, urine leakage, urgency). Most patients did not change the importance level of their goals after discussion with their healthcare provider. Pearson correlations between SAGA, diary variables and PRO scores were generally of low to moderate strength. The global mean (SD) follow-up SAGA T-score was 32.54 (12.54), indicating that overall goal attainment was not achieved after 3 months. The goal attainment score was significantly different between groups differing in symptom severity, health-related quality of life, bladder control and continence status. CONCLUSIONS: The results support the validity of SAGA as a measure of patients' goals and goal achievement for the treatment of LUTS, including symptoms of OAB. SAGA may improve healthcare provider-patient interactions and treatment outcomes in clinical practice.

Evidence against altered excitatory/inhibitory balance in the posteromedial cortex of young adult APOE E4 carriers: A resting state 1H-MRS study.

A strategy to gain insight into early changes that may predispose people to Alzheimer's disease (AD) is to study the brains of younger cognitively healthy people that are at increased genetic risk of AD. The Apolipoprotein (APOE) E4 allele is the strongest genetic risk factor for AD, and several neuroimaging studies comparing APOE E4 carriers with non-carriers at age ∼20-30 years have detected hyperactivity (or reduced deactivation) in posteromedial cortex (PMC), a key hub of the default network (DN), which has a high susceptibility to early amyloid deposition in AD. Transgenic mouse models suggest such early network activity alterations may result from altered excitatory/inhibitory (E/I) balance, but this is yet to be examined in humans. Here we test the hypothesis that PMC fMRI hyperactivity could be underpinned by altered levels of excitatory (glutamate) and/or inhibitory (GABA) neurotransmitters in this brain region. Forty-seven participants (20 APOE E4 carriers and 27 non-carriers) aged 18-25 years underwent resting-state proton magnetic resonance spectroscopy (1H-MRS), a non-invasive neuroimaging technique to measure glutamate and GABA in vivo. Metabolites were measured in a PMC voxel of interest and in a comparison voxel in the occipital cortex (OCC). There was no difference in either glutamate or GABA between the E4 carriers and non-carriers in either MRS voxel, or in the ratio of glutamate to GABA, a measure of E/I balance. Default Bayesian t-tests revealed evidence in support of this null finding. Our findings suggest that PMC hyperactivity in APOE E4 carriers is unlikely to be associated with, or possibly may precede, alterations in local resting-state PMC neurotransmitters, thus informing our understanding of the spatio-temporal sequence of early network alterations underlying APOE E4 related AD risk.

Preferential localization of a vesicular monoamine transporter to dense core vesicles in PC12 cells.

Neurons and endocrine cells have two types of secretory vesicle that undergo regulated exocytosis. Large dense core vesicles (LDCVs) store neural peptides whereas small clear synaptic vesicles store classical neurotransmitters such as acetylcholine, gamma-aminobutyric acid (GABA), glycine, and glutamate. However, monoamines differ from other classical transmitters and have been reported to appear in both LDCVs and smaller vesicles. To localize the transporter that packages monoamines into secretory vesicles, we have raised antibodies to a COOH-terminal sequence from the vesicular amine transporter expressed in the adrenal gland (VMAT1). Like synaptic vesicle proteins, the transporter occurs in endosomes of transfected CHO cells, accounting for the observed vesicular transport activity. In rat pheochromocytoma PC12 cells, the transporter occurs principally in LDCVs by both immunofluorescence and density gradient centrifugation. Synaptic-like microvesicles in PC12 cells contain relatively little VMAT1. The results appear to account for the storage of monoamines by LDCVs in the adrenal medulla and indicate that VMAT1 provides a novel membrane protein marker unique to LDCVs.

Identification of pro-opiomelanocortin-derived peptides in the human adrenal medulla.

Extracts from adult human adrenals contained high concentrations of immunoreactive beta-endorphin and alpha-melanotropin. Lower quantities of immunoreactive adrenocorticotropic hormone could also be detected. Distribution studies showed the presence of pro-opiomelanocortin fragments in the adrenal medulla. No alpha-melanotropin, beta-endorphin, or adrenocorticotropic hormone could be found in adrenal extracts from several other mammalian species. Analysis of the beta-endorphin-like immunoreactivity using region specific radioimmunoassays interfacing with gel filtration and reverse-phase high-performance liquid chromatography showed the majority of the beta-endorphin-like material to exist as nonacetylated beta-endorphin-(1-31) with a small percentage of lipotropin-sized molecules. The alpha-melanotropin-like immunoreactivity cochromatographed on gel filtration and reverse-phase high-performance liquid chromatography with desacetyl alpha-melanotropin. The data suggest that pro-opiomelanocortin is expressed in the adrenal medulla of humans but is not detectable in the adrenal glands of many other mammalian species.

Human chorionic gonadotropin secreted by preimplantation embryos cultured in vitro.

Human oocytes were collected by laparoscopy and fertilized and cultured in vitro. Human chorionic gonadotropin was detected in the medium surrounding two embryos cultured for more than 7 days after fertilization.

Cloning of a delta opioid receptor by functional expression.

Opiate drugs have potent analgesic and addictive properties. These drugs interact with receptors that also mediate the response to endogenous opioid peptide ligands. However, the receptors for opioids have eluded definitive molecular characterization. By transient expression in COS cells and screening with an iodinated analog of the opioid peptide enkephalin, a complementary DNA clone encoding a functional delta opioid receptor has been identified. The sequence shows homology to G protein-coupled receptors, in particular the receptors for somatostatin, angiotensin, and interleukin-8.

Novel peptide neuronal system in rat brain and pituitary.

Immunohistofluorescence studies of the rat central nervous system with antibodies to Phe-Met-Arg-Phe-NH2 (molluskan cardioexcitatory peptide) revealed a widespread neuronal system in the brain, spinal cord, and posterior pituitary. Immunoreactive axons and cell bodies were mainly located in cortical, limbic, and hypothalamic areas. Immunostaining of serial sections of the brain and pituitary showed that the Phe-Met-Arg-Phe-NH2 immunoreactive neurons were different from neurons labeled by antibodies to either Met-enkephalin or the putative Met-enkephalin precursor Tyr-Gly-Gly-Phe-Met-Arg-Phe, which is structurally related to Phe-Met-Arg-Phe-NH2. Control staining by antiserum absorption and radioimmunoassay indicated that the antibodies that caused the specific immunofluorescence recognized peptides with an amidated Arg-Phe sequence at the carboxyl terminus.

A mathematical model of doxorubicin penetration through multicellular layers.

Inadequate drug delivery to tumours is now recognised as a key factor that limits the efficacy of anticancer drugs. Extravasation and penetration of therapeutic agents through avascular tissue are critically important processes if sufficient drug is to be delivered to be therapeutic. The purpose of this study is to develop an in silico model that will simulate the transport of the clinically used cytotoxic drug doxorubicin across multicell layers (MCLs) in vitro. Three cell lines were employed: DLD1 (human colon carcinoma), MCF7 (human breast carcinoma) and NCI/ADR-Res (doxorubicin resistant and P-glycoprotein [Pgp] overexpressing ovarian cell line). Cells were cultured on transwell culture inserts to various thicknesses and doxorubicin at various concentrations (100 or 50 microM) was added to the top chamber. The concentration of drug appearing in the bottom chamber was determined as a function of time by HPLC-MS/MS. The rate of drug penetration was inversely proportional to the thickness of the MCL. The rate and extent of doxorubicin penetration was no different in the presence of NCI/ADR-Res cells expressing Pgp compared to MCF7 cells. A mathematical model based upon the premise that the transport of doxorubicin across cell membrane bilayers occurs by a passive "flip-flop" mechanism of the drug between two membrane leaflets was constructed. The mathematical model treats the transwell apparatus as a series of compartments and the MCL is treated as a series of cell layers, separated by small intercellular spaces. This model demonstrates good agreement between predicted and actual drug penetration in vitro and may be applied to the prediction of drug transport in vivo, potentially becoming a useful tool in the study of optimal chemotherapy regimes.

Malaysian participation in the IAEA/WHO postal TLD and postal ionisation chamber intercomparison programmes: analysis of results obtained during 1985-2008.

During the years 1985-2008, the Secondary Standards Dosimetry Laboratory of Malaysia (SSDL Malaysia) has participated 37 times in the IAEA/WHO intercomparison programmes. This paper reports an analysis of the intercomparison data and demonstrates that the quality of the SSDL calibration service is well within the limits required by IAEA.