Improving the management of lung cancer using mass spectrometry and spectroscopy techniques

Lung cancer is a worldwide health problem associated with poor prognosis. The survival at 5 years remains between 5% and 15% in spite of the development of new drugs. One of the main reasons for this is the disease being diagnosed in late stages when curative treatments might not be available. Therefore, some of the most important factors within improving prognosis are both refining diagnostic techniques for early detection, and better assessing tumour response to treatment. Here lies a need for novel diagnostic tools for lung cancer. Spectroscopic and spectrometric analysis of the molecular underpinnings of the disease may provide biochemical signatures for use in diagnostics. Selected Ion Flow Tube – Mass Spectrometry (SIFT-MS) and Fourier Transform Infrared (FTIR) Spectroscopy may provide the gold standard of diagnostic assessment that is needed. Given both techniques previous contributions and technological advancements, their clinical requirements are being increasingly met. This is leading towards the opportunity for the study of lung cancer to benefit from the rapid, non-destructive and sensitive qualities they have to offer. In this thesis, both techniques have been used with the aim of improving the diagnosis and management of lung cancer

A comparative analysis of pharmaceutical workforce development needs across the commonwealth

Background Increasing demographic healthcare challenges, such as increased life expectancy coupled with increased use of medicines for complex morbidities, point to the need for globally applicable transformative policies in health workforce development. The International Pharmaceutical Federation (FIP) has established a set of 21 Global Development Goals (FIP DGs) to strengthen pharmacy workforce and benchmark professional developmental needs. Objective This study aimed to identify policy directions and factors affecting pharmacy workforce development across the Commonwealth, and to examine country progress made towards implementing workforce oriented FIP DGs. Methods The study involved a literature review and a global survey of commonwealth countries professional leadership bodies. The literature database search included PubMed/Medline, CINAHL, Scopus and PsychINFO databases as well as the websites of the respective national pharmacy organisations of Commonwealth countries. A global survey was also conducted to assess country-level alignment with the workforce component of FIP DGs. Results Thirty-one articles representing 21 Commonwealth countries were included in the literature overview. The development needs identified were workforce shortages and inequitable distribution across practice areas and geographical regions, low workforce supply capacity, workforce feminisation, lack of professional recognition, limited training opportunities, low job satisfaction, high workload and attrition. The survey showed disparities in country-level progress and alignment with the FIP DGs. High-income countries in the survey sample reported alignment with most of the FIP DGs, while the low-income countries reported alignment with fewer DGs. More than two-thirds of the countries showed alignment with the FIP DGs related to academic capacity, early career training, quality assurance and advancing integrated services. About half reported alignment with the FIP DGs related to competency and leadership development, respectively, while only a third aligned with the equity and equality DG. Conclusion This study identified realistic pharmacy workforce developmental needs across a range of Commonwealth countries. Addressing these needs through appropriate policy interventions will be essential for increasing the pharmacy workforce capacity and assuring the delivery of high-quality pharmaceutical care and medicines expertise in these countries

Beliefs about antibiotics, perceptions of antimicrobial resistance, and antibiotic use: initial findings from a multi-country survey

OBJECTIVES: To examine public beliefs about antibiotics, AMR, and knowledge of antibiotic use, and how these relate to self-reported antibiotic use. METHODS: Two hundred and fifty participants from 23 countries completed a cross-sectional, online survey assessing beliefs about antibiotics and AMR, knowledge of antibiotics, and antibiotic use. Descriptive statistics, Mann-Whitney U tests and Spearman's ρ correlations were used to understand relationships between outcomes. KEY FINDINGS: Respondents generally viewed antibiotics positively, with particularly strong beliefs regarding their benefit (M = 16.48 out of 20, SD = 2.62) and few concerns regarding their harm (M = 3.98 out of 10, SD = 1.82). Greater benefit beliefs about antibiotics were associated with fewer concerns about their overuse (P < .0001) and harm (P < .0001). Stronger perceived importance of AMR was associated with greater beliefs about the benefits of antibiotics (P = .006), greater concerns about their overuse (P = .009), and increased knowledge of appropriate use (P = .006). Those who reported inappropriately using their last antibiotics had greater concerns about overuse (P = .12) and less knowledge regarding appropriate use (P = .015), compared to those who did not. CONCLUSIONS: Generally, the public tends to view antibiotics as having strong benefits and have few concerns about their harm, which may have implications for inappropriate use. These initial findings highlight beliefs that could be targeted in messages to reduce inappropriate demand for antibiotics

Impact of measured and simulated tundra snowpack properties on heat transfer

Snowpack microstructure controls the transfer of heat to, as well as the temperature of, the underlying soils. In situ measurements of snow and soil properties from four field campaigns during two winters (March and November 2018, January and March 2019) were compared to an ensemble of CLM5.0 (Community Land Model) simulations, at Trail Valley Creek, Northwest Territories, Canada. Snow micropenetrometer profiles allowed for snowpack density and thermal conductivity to be derived at higher vertical resolution (1.25 mm) and a larger sample size (n=1050) compared to traditional snowpit observations (3 cm vertical resolution; n=115). Comparing measurements with simulations shows CLM overestimated snow thermal conductivity by a factor of 3, leading to a cold bias in wintertime soil temperatures (RMSE=5.8 ∘C). Two different approaches were taken to reduce this bias: alternative parameterisations of snow thermal conductivity and the application of a correction factor. All the evaluated parameterisations of snow thermal conductivity improved simulations of wintertime soil temperatures, with that of Sturm et al. (1997) having the greatest impact (RMSE=2.5 ∘C). The required correction factor is strongly related to snow depth () and thus differs between the two snow seasons, limiting the applicability of such an approach. Improving simulated snow properties and the corresponding heat flux is important, as wintertime soil temperatures are an important control on subnivean soil respiration and hence impact Arctic winter carbon fluxes and budgets

Simulating net ecosystem exchange under seasonal snow cover at an Arctic tundra site

Estimates of winter (snow-covered non-growing season) CO2 fluxes across the Arctic region vary by a factor of 3.5, with considerable variation between measured and simulated fluxes. Measurements of snow properties, soil temperatures, and net ecosystem exchange (NEE) at Trail Valley Creek, NWT, Canada, allowed for the evaluation of simulated winter NEE in a tundra environment with the Community Land Model (CLM5.0). Default CLM5.0 parameterisations did not adequately simulate winter NEE in this tundra environment, with near-zero NEE (< 0.01 gCm^-2d^-1) simulated between November and mid-May. In contrast, measured NEE was broadly positive (indicating net CO2 release) from snow-cover onset until late April. Changes to the parameterisation of snow thermal conductivity, required to correct for a cold soil temperature bias, reduced the duration for which no NEE was simulated. Parameter sensitivity analysis revealed the critical role of the minimum soil moisture threshold of decomposition (Ψmin) in regulating winter soil respiration. The default value of this parameter (Ψmin) was too high, preventing simulation of soil respiration for the vast majority of the snow-covered season. In addition, the default rate of change of soil respiration with temperature (Q10) was too low, further contributing to poor model performance during winter. As Ψmin and Q10 had opposing effects on the magnitude of simulated winter soil respiration, larger negative values of Ψmin and larger positive values of Q10 are required to simulate wintertime NEE more adequately.Natural Environment Research CouncilPeer Reviewe

Obsidian exchange networks and highland-lowland interaction in the Lesser Caucasus Borderlands

Obsidian sourcing studies have a long history in the Near East, but relatively few have focused on obsidian exchange after the Early Bronze Age. Here, we present a multi-technique analysis of an assemblage of 111 obsidian artifacts from excavated Late Bronze and Early Iron Age (LBA-EIA; c. 15th-6th c BCE) contexts at Mtsvane Gora, southern Georgia. Because the site is situated in the lowland Kura Valley and the nearest obsidian sources are in the highlands to the south and west, obsidian provenance can serve as a proxy for mapping highland-lowland interactions. Chemical compositions analyzed via portable X-ray fluorescence spectrometry (pXRF), electron microprobe analysis (EMPA), and laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS), were compared with existing geological datasets of chemical analyses to identify the source of all but one of the artifacts analyzed. The results show that Chikiani, a source in the highlands of southern Georgia, was the geological origin of >90% of the objects analyzed. While acknowledging that obsidian exchange is just one aspect of highland-lowland interaction, this finding implies that Mtsvane Gora’s connections with the adjacent highlands were skewed towards greater engagement with some highland areas relative to others. More generally, the research suggests that geographic adjacency of highlands and lowlands does not necessarily mean that they were highly interconnected.Fieldwork at Mtsvane Gora was funded by the American Research Institute of the South Caucasus, the Rust Family Foundation, a Spatial Archaeometry Research Collaborations (SPARC) Grant, the Harvard University Davis Center for Russian and Eurasian Studies, and the Harvard Department of Anthropology. The authors would like to thank Project ARKK team members for their support during fieldwork. Paul Albert is supported by a UKRI FLF (MR/S035478) Note: guessed MRC by grant number but this could be overarching UKRI as it is a Future Leaders Fellowships award. Paul Albert is not a CU researcher

Contamination within trials of community based public health interventions : lessons from the HENRY feasibility study

Introduction Contamination occurs when participants allocated to trial control arms receive elements of the active intervention. Randomisation at cluster level, rather than individual level, may reduce or eliminate contamination, avoiding the dilution of intervention effectiveness that it may cause. However, cluster randomisation can result in selection bias and may not be feasible to deliver. We explored the extent of contamination in a qualitative study nested within a feasibility study of HENRY (Health, Exercise and Nutrition for the Really Young); a UK community-based child obesity prevention programme. We aimed to determine the nature and impact of contamination to inform a larger planned trial and other trials in community based public health settings. Method We invited participants to take part in the nested qualitative study who were already involved in the HENRY feasibility study. Semi-structured interviews/focus groups were conducted with children’s centre managers (n=7), children’s centre staff (n=15), and parents (n=29). Data were transcribed and analysed using an integrative approach. First, deductively organised using a framework guided by the topic guide and then organised using inductive thematic analysis. Results Potential for contamination between treatment arms was recognised by all stakeholder groups. Staff within the intervention centres presented the greatest risk of contamination, predominantly because they were often asked to work in other children centre’s (including control group centres). ‘Sharing of best practice’ by staff was reported to be a common and desirable phenomenon within community based settings. Parental sharing of HENRY messages was reported inconsistently; though some parents indicated a high degree of knowledge transfer within their immediate circles. Conclusions The extent of contamination identified has influenced the design of a future effectiveness trial of HENRY which will be clustered at the centre level (with geographically distinct clusters). The common practice of knowledge sharing amongst community teams means that this clustering approach is also likely to be most suitable for other trials based within these settings. We provide recommendations (e.g. cluster randomisation, training intervention facilitators on implications of contamination) to help reduce the impact of contamination in public health intervention trials with or without clustering, whilst enabling transfer of knowledge where appropriate. Trial registration ClinicalTrials.gov Identifier NCT03333733 registered 6th November 201

National pharmacy associations in the commonwealth: current scenario and future needs to maximise effective contributions of the pharmacy profession towards universal health coverage

BackgroundThe Commonwealth Pharmacists Association (CPA) is a charity representing pharmacists across the Commonwealth, with the vision of empowering and collaboratively develop the profession and fully utilise the potential of pharmacists to strengthen health systems through supporting better access to, quality and use of medicines and related services. Commonwealth comprises predominantly of low- and middle-income countries, where limited data often exists in pharmacy practice. There is a recognised need across the Commonwealth to focus on developing, implementing and fully utilising pharmacy professional services to progress universal health coverage and achieve the sustainable development goals, particularly in low and middle-income countries; however, currently a knowledge gap exists in understanding the national priorities in Commonwealth nations. CPA is ideally positioned to access to these nations. The aim of this study was thus to explore the priorities and focus areas of NPAs across the Commonwealth and create evidence for a needs-based approach to inform the support that the Commonwealth pharmacists association can collaboratively and strategically provide to its members to progress towards shared goals.MethodsData were collected virtually on Zoom by conducting interviews using a semi-structured interview guide developed for this study with CPA councillors representing NPAs or their equivalents if no official body existed. An inductive, reflexive, thematic analysis was performed for data analysis.ResultsIn total, 30 councillors were interviewed from 30 low- and medium-income countries. The three main overarching priority areas identified across respective Commonwealth nations developing extended pharmacy services, improving pharmacy education, and developing and redefining the role of NPAs.ConclusionsThis novel study highlights the collective priorities for the pharmacy profession across the low and middle-income countries of the Commonwealth and the urgent need for supporting NPAs around the three identified overarching priority areas. The mapped-out priorities will inform an evidence-based approach for the CPA to better support NPAs in their mission through advocacy and practitioner development, to fully harness pharmacists’ unique skill set and maximise their contribution to progressing universal health coverage

Ligand-Specific Factors Influencing GLP-1 Receptor Post-Endocytic Trafficking and Degradation in Pancreatic Beta Cells.

The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of blood glucose homeostasis. Ligand-specific differences in membrane trafficking of the GLP-1R influence its signalling properties and therapeutic potential in type 2 diabetes. Here, we have evaluated how different factors combine to control the post-endocytic trafficking of GLP-1R to recycling versus degradative pathways. Experiments were performed in primary islet cells, INS-1 832/3 clonal beta cells and HEK293 cells, using biorthogonal labelling of GLP-1R to determine its localisation and degradation after treatment with GLP-1, exendin-4 and several further GLP-1R agonist peptides. We also characterised the effect of a rare GLP1R coding variant, T149M, and the role of endosomal peptidase endothelin-converting enzyme-1 (ECE-1), in GLP1R trafficking. Our data reveal how treatment with GLP-1 versus exendin-4 is associated with preferential GLP-1R targeting towards a recycling pathway. GLP-1, but not exendin-4, is a substrate for ECE-1, and the resultant propensity to intra-endosomal degradation, in conjunction with differences in binding affinity, contributes to alterations in GLP-1R trafficking behaviours and degradation. The T149M GLP-1R variant shows reduced signalling and internalisation responses, which is likely to be due to disruption of the cytoplasmic region that couples to intracellular effectors. These observations provide insights into how ligand- and genotype-specific factors can influence GLP-1R trafficking