Investigating intratumour heterogeneity analysis methods and their application in GBM

Glioblastoma (GBM) is an incurable cancer with a median survival of 15 months. Despite debulking surgery, cancer cells are inevitably left behind in the surrounding brain, with a minority able to resist subsequent chemoradiotherapy and eventually form a recurrent tumour. This resistance is likely influenced by the cells’ genotypes, which show high variability (intratumour heterogeneity), as a result of tumour evolution. Characterising changes in the genetic architecture of tumours through therapy, may allow us to understand the effect that different mutations and pathways have on cell survival, and potentially identify novel targets for counteracting resistance in GBM. Such analyses involve detection of mutations from bulk tumour samples, and then delineating them into individual genetically distinct ‘subclones’, through subclonal deconvolution. This is a complex process, with no reliable guidelines for the best pipelines to use. I therefore developed methods to allow simulation and in silico sequencing of genomes from realistically complex, artificial tumour samples, so that I could benchmark such pipelines. This revealed that no tested pipelines, using single bulk samples, showed a high level of accuracy, though mutation calling with Mutect2 and FACETS, followed by subclonal deconvolution with Ccube, showed the best results. I then used alternative approaches with the largest longitudinal GBM dataset investigated to date. I found that evidence of strong subclonal selection is absent in many samples, and not associated with therapy. Nonetheless, this does not negate the possibility of smaller, or less frequent, pockets of altered fitness. Using pathway analysis combined with variants that are informative of tumour progression, I identified processes that may confer increased resistance, or sensitisation to therapy, and which warrant further investigation. Lastly, I apply subclonal deconvolution to investigate mouse-specific evolution in GBM patient-derived orthotopic xenografts and found no clear evidence to suggest these models are unsuitable for investigations relevant to humans

The mindful path to compassion in an adult mental health group

A naturalistic study was undertaken within an NHS setting to explore the effectiveness and satisfaction with a Mindfulness-Based Cognitive Therapy and Mindful Self-Compassion group programme in an adult mental health population. Outcome measures and qualitative feedback suggested beneficial effects and high levels of satisfaction

The impact of COVID-19 on the mental wellbeing of health and social care workers in Scotland

Background: Recent studies published during the COVID-19 pandemic have reported that the mental wellbeing of health and social care workers (HSCWs) has been adversely impacted. Research has yet to explore what factors may help HSCWs positively adapt in the face of the adversities endured during the pandemic. Methods: The study consisted of a cross-sectional online survey exploring the impact of COVID-19 on the mental wellbeing of HSCWs (n= 1300+). The survey included both closed and open-ended questions exploring COVID-19 perceived risks, stress, burnout and mental wellbeing as well as coping and team resilience. Both quantitative and qualitative content analysis of the online survey data was conducted. Expected results: Data collection began in December 2020 and data collection and analysis is due for completion in June 2021. Preliminary analysis suggested that access to PPE, psychological input and increased perceived team resilience and peer support helped mitigate against the adverse impact that COVID-19 related stressors have on HSCW's mental wellbeing. Visible leadership was also found to be essential in helping staff gain access to current and accurate information on COVID-19 and in helping workers adapt to constant change. Discussion: The implications of these findings are discussed, emphasising the importance of access to PPE as well as peer and team-based support in alleviating the negative impact that COVID-19 has on HSCW's mental wellbeing. The results of this study also highlight the urgency of offering psychological input for HSCWs who need it. The importance of supportive, adaptive and visible leadership is highlighted. Cogan N 1 , MacIntyre G University of Strathclyde , Kennedy C University of Strathclyde , Beck Z University of Strathclyde , McInnes L University of Strathclyde , Tanner G NHS Lanarkshire , Morton L University of Glasgow , Kolacz J Kinsey Institute 1 University Of Strathclyde, GLASGOW Lanarkshire, Scotlan

Asylsuchende und Flüchtlinge in der medizinischen Poliklinik: Ein Vergleich zwischen den Polikliniken Basel, Bern und Genf

Zusammenfassung: Die vorliegende Querschnittsstudie beschreibt den Gesundheitszustand und die Gesundheitsversorgung von Asylsuchenden und Flüchtlingen aus der sicht der in den medizinischen Polikliniken Basel, Bern und Genf tätigen Ärzte. Durch den Vergleich von Polikliniken unterschiedlicher Struktur wird die Identifikation positiver und negativer Determinanten der Gesundheitsbetreuung unterstützt. Die Ergebnisse der Studie beruhen auf der Auswertung von Fragebogen, Monatsstatistiken und semi-strukturierten Interviews. Der Fragebogen wurde von allen in diesen Polikliniken tätigen Ärzten ausgefüllt (Basel: 10, Bern: 1, Genf: 36) Alle Konsultationen von Asylsuchenden und Flüchtlingen wurden während eines definierten Zeitraumes dokumentiert (Basel: 42, Bern: 93, Genf: 187). Mit den drei an den jeweiligen Polikliniken für die Studienkoordination zuständigen Ärzten wurden Interviews durchgeführt. Im Zeitraum der Studie waren hauptsächlich Asylsuchende und Flüchtlinge aus Ex-Jugoslawien, der Türkei, Sri Lanka, Somalia, Angola und Zaire in Behandlung. Das untersuchte Patientenklientel zeichnete sich durch eine hohe Diversität bezüglich Herkunftsländer, Sprachen, Kommunikationsvermögen sowie Schul-und Berufsausbildung aus. Niedrige Konsultationsfrequenzen pro Arzt könnten zahlreiche der beobachteten Probleme erklären: mangelnde Erfahrung in spezifischen Betreuungsformen, administrative Probleme und Schwierigkeiten hinsichtlich der Organisation von Übersetzerdiensten. Die wesentliche Voraussetzung für die Verbesserung der institutionellen gesundheitlichen Versorgung wird in der Betreuung durch kleine Ärzteteams gesehen. Auf diese Weise kann der einzelne Arzt genügend Erfahrung sammeln und organisatorische Fragen rationeller behandeln. Ausbildungs- und Forschungsansätze, die sich aus den Ergebnissen dieser Studie ergeben, werden diskutier

Observation-based modeling of ozone chemistry in the Seoul metropolitan area during the Korea-United States Air Quality Study (KORUS-AQ)

The Seoul Metropolitan Area (SMA) has a population of 24 million and frequently experiences unhealthy levels of ozone (O3). In this work, measurements taken during the Korea-United States Air Quality Study (KORUS-AQ, 2016) are used to explore regional gradients in O3 and its chemical precursors, and an observationally-constrained 0-D photochemical box model is used to quantify key aspects of O3 production including its sensitivity to precursor gases. Box model performance was evaluated by comparing modeled concentrations of select secondary species to airborne measurements. These comparisons indicate that the steady state assumption used in 0-D box models cannot describe select intermediate species, highlighting the importance of having a broad suite of trace gases as model constraints. When fully constrained, aggregated statistics of modeled O3 production rates agreed with observed changes in O3, indicating that the box model was able to represent the majority of O3 chemistry. Comparison of airborne observations between urban Seoul and a downwind receptor site reveal a positive gradient in O3 coinciding with a negative gradient in NOx, no gradient in CH2O, and a slight positive gradient in modeled rates of O3 production. Together, these observations indicate a radical-limited (VOC-limited) O3 production environment in the SMA. Zero-out simulations identified C7+ aromatics as the dominant VOC contributors to O3 production, with isoprene and anthropogenic alkenes making smaller but appreciable contributions. Simulations of model sensitivity to decreases in NOx produced results that were not spatially uniform, with large increases in O3 production predicted for urban Seoul and decreases in O3 production predicted for far-outlying areas. The policy implications of this work are clear: Effective O3 mitigation strategies in the SMA must focus on reducing local emissions of C7+ aromatics, while reductions in NOx emissions may increase O3 in some areas but generally decrease the regional extent of O3 exposure

Sources and characteristics of summertime organic aerosol in the Colorado Front Range: perspective from measurements and WRF-Chem modeling

Abstract. The evolution of organic aerosols (OAs) and their precursors in the boundary layer (BL) of the Colorado Front Range during the Front Range Air Pollution and Photochemistry Éxperiment (FRAPPÉ, July–August 2014) was analyzed by in situ measurements and chemical transport modeling. Measurements indicated significant production of secondary OA (SOA), with enhancement ratio of OA with respect to carbon monoxide (CO) reaching 0.085±0.003 µg m−3 ppbv−1. At background mixing ratios of CO, up to  ∼  1.8 µg m−3 background OA was observed, suggesting significant non-combustion contribution to OA in the Front Range. The mean concentration of OA in plumes with a high influence of oil and natural gas (O&G) emissions was  ∼  40 % higher than in urban-influenced plumes. Positive matrix factorization (PMF) confirmed a dominant contribution of secondary, oxygenated OA (OOA) in the boundary layer instead of fresh, hydrocarbon-like OA (HOA). Combinations of primary OA (POA) volatility assumptions, aging of semi-volatile species, and different emission estimates from the O&G sector were used in the Weather Research and Forecasting model coupled with Chemistry (WRF-Chem) simulation scenarios. The assumption of semi-volatile POA resulted in greater than a factor of 10 lower POA concentrations compared to PMF-resolved HOA. Including top-down modified O&G emissions resulted in substantially better agreements in modeled ethane, toluene, hydroxyl radical, and ozone compared to measurements in the high-O&G-influenced plumes. By including emissions from the O&G sector using the top-down approach, it was estimated that the O&G sector contributed to  <  5 % of total OA, but up to 38 % of anthropogenic SOA (aSOA) in the region. The best agreement between the measured and simulated median OA was achieved by limiting the extent of biogenic hydrocarbon aging and consequently biogenic SOA (bSOA) production. Despite a lower production of bSOA in this scenario, contribution of bSOA to total SOA remained high at 40–54 %. Future studies aiming at a better emissions characterization of POA and intermediate-volatility organic compounds (IVOCs) from the O&G sector are valuable