Modelling the photopolarimetric variability of AA Tau

We present Monte Carlo scattered light models of a warped disc that reproduce the observed photopolarimetric variability of the classical T Tauri star, AA Tauri. For a system inclination of 75° and using an analytic description for a warped inner disc, we find that the shape and amplitude of the photopolarimetric variability are reproduced with a warp that occults the star, located at 0.07 au, amplitude 0.016 au, extending over radial and azimuthal ranges 0.0084 au and 145°. We also show a time sequence of high spatial resolution scattered light images, showing a dark shadow cast by the warp sweeping round the disc. Using a modified smooth particle hydrodynamics code, we find that a stellar dipole magnetic field of strength 5.2 kG, inclined at 30° to the stellar rotation axis can reproduce the required disc warping to explain the photopolarimetric variability of AA Ta

Indoor Particulate Air Pollution from Open Fires and the Cognitive Function of Older People

Exposure to indoor air pollution is known to affect respiratory and cardiovascular health, but little is known about its effects on cognitive function. We measured the concentrations and magnetite content of airborne particulate matter (PM) in the indoor environment arising from burning peat, wood or coal in residential open fires. Highest indoor PM2.5 concentrations (60 µg/m3, i.e. 2.4 times the WHO-recommended 24-hour mean) occurred when peat was burned, followed by burning of coal (30 µg/m3) and wood (17 µg/m3). Conversely, highest concentrations of coarser PM (PM10-2.5) were associated with coal burning (20 µg/m3), with lower concentrations emitted during burning of wood (10 µg/m3) and peat (8 µg/m3). The magnetic content of the emitted PM, greatest (for both PM size fractions) when coal was burned, is similar to that of roadside airborne PM. Exposure to PM, and to strongly magnetic airborne PM, can be greater for individuals spending ~5 hours/day indoors with a coal-burning open fire for 6 months/year compared to those commuting via heavily-trafficked roads for 1 hour/day for 12 months/year. Given these high indoor PM and magnetite concentrations, and the reported associations between (outdoor) PM and impaired neurological health, we used individual-level data from The Irish Longitudinal Study on Ageing (TILDA) to examine the association between the usage of open fires and the cognitive function of older people. Using a sample of nearly seven thousand older people, we estimated multi-variate models of the association between cognitive function and open fire usage, in order to account for relevant confounders such as socio-economic status. We found a negative association between open fire usage and cognitive function as measured by widely-used cognitive tests such as word recall and verbal fluency tests. The negative association was largest and statistically strongest among women, a finding explained by the greater exposure of women to open fires in the home because they spent more time at home than men. Our findings were also robust to stratifying the sample between old and young, rich and poor, and urban and rural

Oral tolerance to cancer can be abrogated by T regulatory cell inhibition

Oral administration of tumour cells induces an immune hypo-responsiveness known as oral tolerance. We have previously shown that oral tolerance to a cancer is tumour antigen specific, non-cross-reactive and confers a tumour growth advantage. We investigated the utilisation of regulatory T cell (Treg) depletion on oral tolerance to a cancer and its ability to control tumour growth. Balb/C mice were gavage fed homogenised tumour tissue – JBS fibrosarcoma (to induce oral tolerance to a cancer), or PBS as control. Growth of subcutaneous JBS tumours were measured; splenic tissue excised and flow cytometry used to quantify and compare systemic Tregs and T effector (Teff) cell populations. Prior to and/or following tumour feeding, mice were intraperitoneally administered anti-CD25, to inactivate systemic Tregs, or given isotype antibody as a control. Mice which were orally tolerised prior to subcutaneous tumour induction, displayed significantly higher systemic Treg levels (14% vs 6%) and faster tumour growth rates than controls (p<0.05). Complete regression of tumours were only seen after Treg inactivation and occurred in all groups - this was not inhibited by tumour feeding. The cure rates for Treg inactivation were 60% during tolerisation, 75% during tumour growth and 100% during inactivation for both tolerisation and tumour growth. Depletion of Tregs gave rise to an increased number of Teff cells. Treg depletion post-tolerisation and post-tumour induction led to the complete regression of all tumours on tumour bearing mice. Oral administration of tumour tissue, confers a tumour growth advantage and is accompanied by an increase in systemic Treg levels. The administration of anti-CD25 Ab decreased Treg numbers and caused an increase in Teffs. Most notably Treg cell inhibition overcame established oral tolerance with consequent tumor regression, especially relevant to foregut cancers where oral tolerance is likely to be induced by the shedding of tumour tissue into the gut

Cannabidiol Reduces Intestinal Inflammation through the Control of Neuroimmune Axis

Enteric glial cells (EGC) actively mediate acute and chronic inflammation in the gut; EGC proliferate and release neurotrophins, growth factors, and pro-inflammatory cytokines which, in turn, may amplify the immune response, representing a very important link between the nervous and immune systems in the intestine. Cannabidiol (CBD) is an interesting compound because of its ability to control reactive gliosis in the CNS, without any unwanted psychotropic effects. Therefore the rationale of our study was to investigate the effect of CBD on intestinal biopsies from patients with ulcerative colitis (UC) and from intestinal segments of mice with LPS-induced intestinal inflammation. CBD markedly counteracted reactive enteric gliosis in LPS-mice trough the massive reduction of astroglial signalling neurotrophin S100B. Histological, biochemical and immunohistochemical data demonstrated that S100B decrease was associated with a considerable decrease in mast cell and macrophages in the intestine of LPS-treated mice after CBD treatment. Moreover the treatment of LPS-mice with CBD reduced TNF-α expression and the presence of cleaved caspase-3. Similar results were obtained in ex vivo cultured human derived colonic biopsies. In biopsies of UC patients, both during active inflammation and in remission stimulated with LPS+INF-γ, an increased glial cell activation and intestinal damage were evidenced. CBD reduced the expression of S100B and iNOS proteins in the human biopsies confirming its well documented effect in septic mice. The activity of CBD is, at least partly, mediated via the selective PPAR-gamma receptor pathway. CBD targets enteric reactive gliosis, counteracts the inflammatory environment induced by LPS in mice and in human colonic cultures derived from UC patients. These actions lead to a reduction of intestinal damage mediated by PPARgamma receptor pathway. Our results therefore indicate that CBD indeed unravels a new therapeutic strategy to treat inflammatory bowel diseases

European Association of Nuclear Medicine Focus 5: Consensus on Molecular Imaging and Theranostics in Prostate Cancer

BACKGROUND In prostate cancer (PCa), questions remain on indications for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging and PSMA radioligand therapy, integration of advanced imaging in nomogram-based decision-making, dosimetry, and development of new theranostic applications. OBJECTIVE We aimed to critically review developments in molecular hybrid imaging and systemic radioligand therapy, to reach a multidisciplinary consensus on the current state of the art in PCa. DESIGN, SETTING, AND PARTICIPANTS The results of a systematic literature search informed a two-round Delphi process with a panel of 28 PCa experts in medical or radiation oncology, urology, radiology, medical physics, and nuclear medicine. The results were discussed and ratified in a consensus meeting. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Forty-eight statements were scored on a Likert agreement scale and six as ranking options. Agreement statements were analysed using the RAND appropriateness method. Ranking statements were analysed using weighted summed scores. RESULTS AND LIMITATIONS After two Delphi rounds, there was consensus on 42/48 (87.5%) of the statements. The expert panel recommends PSMA PET to be used for staging the majority of patients with unfavourable intermediate and high risk, and for restaging of suspected recurrent PCa. There was consensus that oligometastatic disease should be defined as up to five metastases, even using advanced imaging modalities. The group agreed that [$^{177}$Lu]Lu-PSMA should not be administered only after progression to cabazitaxel and that [$^{223}$Ra]RaCl$_{2}$ remains a valid therapeutic option in bone-only metastatic castration-resistant PCa. Uncertainty remains on various topics, including the need for concordant findings on both [$^{18F}$]FDG and PSMA PET prior to [$^{177}$Lu]Lu-PSMA therapy. CONCLUSIONS There was a high proportion of agreement among a panel of experts on the use of molecular imaging and theranostics in PCa. Although consensus statements cannot replace high-certainty evidence, these can aid in the interpretation and dissemination of best practice from centres of excellence to the wider clinical community. PATIENT SUMMARY There are situations when dealing with prostate cancer (PCa) where both the doctors who diagnose and track the disease development and response to treatment, and those who give treatments are unsure about what the best course of action is. Examples include what methods they should use to obtain images of the cancer and what to do when the cancer has returned or spread. We reviewed published research studies and provided a summary to a panel of experts in imaging and treating PCa. We also used the research summary to develop a questionnaire whereby we asked the experts to state whether or not they agreed with a list of statements. We used these results to provide guidance to other health care professionals on how best to image men with PCa and what treatments to give, when, and in what order, based on the information the images provide

European Association of Nuclear Medicine Focus 5:Consensus on Molecular Imaging and Theranostics in Prostate Cancer

BACKGROUND: In prostate cancer (PCa), questions remain on indications for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging and PSMA radioligand therapy, integration of advanced imaging in nomogram-based decision-making, dosimetry, and development of new theranostic applications.OBJECTIVE: We aimed to critically review developments in molecular hybrid imaging and systemic radioligand therapy, to reach a multidisciplinary consensus on the current state of the art in PCa.DESIGN, SETTING, AND PARTICIPANTS: The results of a systematic literature search informed a two-round Delphi process with a panel of 28 PCa experts in medical or radiation oncology, urology, radiology, medical physics, and nuclear medicine. The results were discussed and ratified in a consensus meeting.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Forty-eight statements were scored on a Likert agreement scale and six as ranking options. Agreement statements were analysed using the RAND appropriateness method. Ranking statements were analysed using weighted summed scores.RESULTS AND LIMITATIONS: After two Delphi rounds, there was consensus on 42/48 (87.5%) of the statements. The expert panel recommends PSMA PET to be used for staging the majority of patients with unfavourable intermediate and high risk, and for restaging of suspected recurrent PCa. There was consensus that oligometastatic disease should be defined as up to five metastases, even using advanced imaging modalities. The group agreed that [177Lu]Lu-PSMA should not be administered only after progression to cabazitaxel and that [223Ra]RaCl2 remains a valid therapeutic option in bone-only metastatic castration-resistant PCa. Uncertainty remains on various topics, including the need for concordant findings on both [18F]FDG and PSMA PET prior to [177Lu]Lu-PSMA therapy.CONCLUSIONS: There was a high proportion of agreement among a panel of experts on the use of molecular imaging and theranostics in PCa. Although consensus statements cannot replace high-certainty evidence, these can aid in the interpretation and dissemination of best practice from centres of excellence to the wider clinical community.PATIENT SUMMARY: There are situations when dealing with prostate cancer (PCa) where both the doctors who diagnose and track the disease development and response to treatment, and those who give treatments are unsure about what the best course of action is. Examples include what methods they should use to obtain images of the cancer and what to do when the cancer has returned or spread. We reviewed published research studies and provided a summary to a panel of experts in imaging and treating PCa. We also used the research summary to develop a questionnaire whereby we asked the experts to state whether or not they agreed with a list of statements. We used these results to provide guidance to other health care professionals on how best to image men with PCa and what treatments to give, when, and in what order, based on the information the images provide.</p

European Association of Nuclear Medicine Focus 5 : Consensus on Molecular Imaging and Theranostics in Prostate Cancer

Funding/Support and role of the sponsor: This research was funded by the EANM and supported by unrestricted grants from Advanced Accelerator Applications—a Novartis company, Monrol, Spectrum Dynamics Medical Ltd., Blue Earth Diagnostics, GE HealthCare, ITM Isotope Technologies Munich SE, Siemens Healthineers, and Telix Pharmaceuticals. These sponsors had no direct or indirect influence on the programme and content of the EANM Focus 5 meeting and the writing or content of this consensus statement. Acknowledgements: We would like to thank Evelyn Mansutti, Susanne Koebe, Andrea Csismazia, Jutta Peter, Petra Neubauer, Andreas Felser, and Henrik Silber (all from EANM) for project management. We also acknowledge all who participated in EANM Focus 5 meeting and especially the patients who participated in clinical and research projects, making it possible to inform expert opinion.Peer reviewe

Representational predicaments at three Hong Kong sites

Representational predicaments arise when a job incumbent believes that attributions and images assumed by dominant authorities unfavourably ignore, or disproportionately and unfavourably emphasize, aspects of the incumbent\u27s own work and social identity. This is likely to happen when the incumbent does not have a close relationship with a dominant authority, and when power asymmetries give the former relatively little control over which aspects of their work and social identity are made visible or invisible to the latter. We draw on critical incident interviews from three organizations to illustrate a typology of six types of representational predicament: invasive spotlighting, idiosyncratic spotlighting, embedded background work, paradoxical social visibility, standardization of work processes, and standardization of work outputs. We analyse responses to representational predicaments according to whether they entailed exit, voice, loyalty, or neglect. Incumbents tended to respond with loyalty if they felt able and willing to accommodate their work behaviour and/or social identity to the dominant representations, and if there were sufficient compensatory factors, such as intrinsic rewards from the work or solidarity with colleagues. Exit or neglect appeared to reflect the belief that it was impossible to accommodate. Power asymmetries appeared to deter voice. Individual employees with a close and cordial working relationship with a member of a dominant authority group, or who were relationally networked to one, appeared not to experience representational predicaments

Genome-wide association study identifies loci on 12q24 and 13q32 associated with Tetralogy of Fallot

We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P = 1.4 × 10−7) and replicated convincingly (P = 3.9 × 10−5) in 798 cases and 2931 controls [per allele odds ratio (OR) = 1.27 in replication cohort, P = 7.7 × 10−11 in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P = 1.7 × 10−7) and replicated convincingly (P = 1.2 × 10−5) in 789 cases and 2927 controls (per allele OR = 1.31 in replication cohort, P = 3.03 × 10−11 in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TO