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Genome-wide analyses of variance in blood cell phenotypes provide new insights into complex trait biology and prediction
Get PDFBlood cell phenotypes are routinely tested in healthcare to inform clinical decisions. Genetic variants influencing mean blood cell phenotypes have been used to understand disease aetiology and improve prediction; however, additional information may be captured by genetic effects on observed variance. Here, we mapped variance quantitative trait loci (vQTL), i.e. genetic loci associated with trait variance, for 29 blood cell phenotypes from the UK Biobank (N ~ 408,111). We discovered 176 independent blood cell vQTLs, of which 147 were not found by additive QTL mapping. vQTLs displayed on average 1.8-fold stronger negative selection than additive QTL, highlighting that selection acts to reduce extreme blood cell phenotypes. Variance polygenic scores (vPGSs) were constructed to stratify individuals in the INTERVAL cohort (N ~ 40,466), where the genetically most variable individuals had increased conventional PGS accuracy (by ~19%) relative to the genetically least variable individuals. Genetic prediction of blood cell traits improved by ~10% on average combining PGS with vPGS. Using Mendelian randomisation and vPGS association analyses, we found that alcohol consumption significantly increased blood cell trait variances highlighting the utility of blood cell vQTLs and vPGSs to provide novel insight into phenotype aetiology as well as improve prediction
Call for new criteria for monitoring and registering Natura 2000 species data
Get PDFThe European Union’s Birds and Habitats Directives are intended to guarantee the persistence of species and natural habitats across member states. To achieve this laudable aim, the Natura 2000 network of protected areas was established in 1992. Since then, member states are required to regularly monitor species and habitats and report findings to the European Commission, which requires substantial investment from all countries. The Natura 2000 network is an invaluable example of a large-scale coordinated network developed to address major conservation issues. Based on our analysis of the 2020 Species Natura 2000 Database and on expert opinions by Natura 2000 executives, we found that the network is failing to adequately show biodiversity status and guide conservation because it does not allow cross-border comparisons of species’ and populations’ conservation status. The main contributing factor to this failure is that member states frequently fail to follow reporting EU guidelines, resulting in heterogeneity in criteria for monitoring and registering species among Natura 2000 areas. We advocate developing new unified and realistic criteria for monitoring and reporting species data that correctly allows crossborder comparisons and conservation diagnosis. We propose that monitoring protocols and current criteria be modified slightly by considering species’ life history strategies, distribution, and conservation status. We do not suggest a major overhaul of the directives; rather, we propose debate on how relatively small changes in guidelines could improve the utility of the huge amount of data collected from the Natura 2000 network
The role of MLH1, MSH2 and MSH6 in the development of colorectal cancer in Uganda
Get PDFIntroduction: In Uganda, colorectal cancer (CRC) is steadily increasing according to the Kampala Cancer Registry. In the West, microsatellite instability is detected in 90% of hereditary nonpolyposis colon cancers (HNPCC) which account for 1–2% of all CRC, and 15% of sporadic CRC. Germline mutations in MLH1 and MSH2 account for 90% of HNPCC in the West, whilst the remainder of cases are due to mutations in MSH6 and PMS2. The aim of this study was to determine the microsatellite instability (MSI) status and determine the proportions of MLH1, MSH2, and MSH6 pathological mutations in Ugandan CRC patients. Methodology: This was a cross-sectional study carried out between 1st January 2008 to 15th September 2021. Patients were recruited prospectively from 16th September 2019 to 16th September 2021, from Masaka Regional Referral Hospital, Mulago National Referral Hospital, Uganda Martyrs’ Hospital Lubaga and Mengo Hospital. From 1st January 2008 to 15th September 2019, CRC FFPE tissue blocks were obtained from the archives of the Department of Pathology, Makerere University. Data was abstracted from the medical case files for demographics, topography and stage. The histopathological subtype and grade of CRC were obtained by two consultant pathologists from the H&E slides. DNA was extracted from CRC formalin-fixed paraffin-embedded (FFPE) tissue blocks. Library preparation was completed using the Qiagen custom design panel. The custom panel represented 56 genes. The MLH-1, MSH2, MSH6, BRAF and KRAS genes were sequenced using the above library preparation and NGS sequencing. The MSI status was obtained if one of the MSI genes, MLH1, MSH2 or MSH6 was pathologically mutated. If none of the genes was pathologically mutated it was considered MSI negative, microsatellite stable (MSS). Immunohistochemistry was carried out to determine whether MLH1 and PMS2 was MMR proficient or deficient. Categorical data was summarized using frequencies and proportions corresponding to each of the three histopathological subtypes and MSI status subtypes. Continuous and categorical variables were analyzed using the chi-square and Fischer’s exact tests. A p -value ≤ 0.05 was considered statistically significant for all the analyses. Results: Out of 127 CRC patients, the mean(SD) age of MSI cases was 55.6(16.9) years and of MSS cases was 55.4(15.5) years. The majority were MSS, 75(59.06%) followed by MSI, 52(40.9%). There were 14(11.02%) MLH-1 mutations, 30(23.62%) MSH2 mutations, and 26(20.47%) MSH6 mutations. BRAF mutational analysis showed only 5(3.9%) having pathologic missense BRAF V600 mutations. KRAS mutations consisted of only 8(6.3%) having pathologic missense KRAS mutations. Conclusions: The high rate of MSI in Ugandan colorectal tumours was mainly associated with a lack of BRAF mutations and a high frequency of MSH2 and MSH6 MMR gene mutations. In CRC patients, identification of the causative mutation is recommended, however in a resource-limited setting, MSI testing and immunohistochemistry is more cost effective. In Ugandan CRC patients who meet at least one of the Bethesda criteria, MSI testing and immunohistochemistry may therefore be offered to obtain the MSI status of the tumour
Protectors and protected: regulating land and labour in the Nyasaland colonial protectorate
Get PDFIssues around land and labour are two of the most pervasive themes in British imperial history. Land was a contentious issue, with competing claims to its possession, access, and use permeating to the core of imperial orders. Similarly, labour issues regarding the abolition of slavery, labour migration and varying levels of unfreedom in labour arrangements reverberated throughout imperial contexts. In British colonial protectorates, where the Crown’s dominion did not extend, and inhabitants were protected persons rather than subjects of the Crown, these conflicts assumed a distinct degree of complexity. This thesis examines the nature of protection and colonial subjecthood in a colonial protectorate through an analysis of the legal regulation of land and labour from the gradual extension of extraterritorial jurisdiction in the late 19th century, to the heavy-handed governmental response to the African uprising of 1915.
This thesis (1) Illustrates the central role of jurisdictional concerns in establishing protection in the region and considers shifts in protectionist rhetoric from the military allegiances and security arrangements of missionaries to the protection of lives and property of British settlers in treaty arrangements, and finally to the governability of Africans and the maintenance of order once a protectorate was established. (2) Examines Commissioner Johnston’s land settlement programme (1892-1893) demonstrating his crude deployment of a pre-emption policy to deny Africans the authority to transfer land in a programme that evaluated settler claims to title and designated Crown land. (3) Argues that the regulation of labour on private estates took the acerbity of master and servant legislation to this rudimentary legal order and compounded it with a dependence on the land of the master and a racialised culture of fear and physical violence resulting in a distinctive form of labour unfreedom. (4) Argues that the colonial government’s heavy-handed response to the native uprising through treason trials, executions and collective punishment highlights the reality of British protected persons in a colonial protectorate facing full subjection and without the protections of the law
Connotative Congruency Effect Between Instrumental Timbre and Visual Design Features on Consumer Decision‐Making
Get PDFConducting online, controlled laboratory, and more realistic laboratory experiments, this study investigates how the connotative congruency between instrumental timbre and visual design affects consumer evaluation and choice behavior. The results demonstrate that consumers are more likely to respond positively to the target when the instrumental timbre of background music shares connotative meanings like bright, smooth, or heavy with a visual feature of the target. In addition, we identified that the connotative congruency effect is mediated by the sense of feeling right and excitement (i.e., high arousal positive emotion). A carefully‐controlled Study 3 and Study 5, which measured behavioral outcomes in a more realistic mock‐up corner drugstore, enhanced the ecological and external validity of the timbre‐vision connotative congruency effects. This is the first empirical marketing study on timbre‐vision congruency that covers comprehensive sets of connotative descriptions and reveals the mediating role of both feeling right and excitement
Urban power, black mayors: managing inequality in Kurt Schmoke's Baltimore (MD) 1987-1999
No full textThe late twentieth-century was an era of Black mayors: in 1967, two cities elected Black mayors, and by 1993, 67 cities with more than fifty thousand residents had elected Black mayors. Scholars conclude that these mayors inherited a “hollow prize:” a city in inexorable structural decline with little power to advance equity. Though the last thirty years of the 20th century did see urban decline, residents and city officials did not surrender. They contested, innovated, and organized, sometimes challenging inequality and other times unwittingly enabling it.
Urban Power, Black Mayors examines the mechanics of power—who wielded it, how and to what ends—during the tenure of Baltimore’s first elected Black mayor, Kurt Schmoke (1987-1999). This thesis conceptualizes the governance of Baltimore as “latticed.” Schmoke, as mayor, was a node of power in the network of Baltimore’s governance, and he influenced and was influenced by other nodes: universities, corporate actors, churches, civic leaders, the state, and the federal government. Drawing from interviews, newspaper articles, and the papers of local activists, the City of Baltimore, and corporate actors, Urban Power, Black Mayors studies contests over the control and distribution of critical goods: education, health, auto insurance, and housing. Specifically, this thesis focuses on the contests between equity-champions—those who fought for a more uniform distribution of a good—and adversaries—those who fought to maintain its unequal distribution.
Within the lattice, equity-champions—actors such as Schmoke, community organizations, and residents—sourced power from interdependence to challenge the ongoing concentration of wealth in an increasingly unequal economy. In response, diverse coalitions of adversaries—state legislatures, corporations, the federal government, Congress, and suburban leaders—each motivated to preserve their distinct advantages, coordinated to erode urban power. Schmoke’s “hollow prize” was further hollowed in response to the equity-champions’ challenges to inequality and racism. The autonomy of cities such as Baltimore was deliberately and systematically suppressed, a practice that persists today
Implementation, Processes and Outcomes of Advance Care Planning: A Culturally and Contextually Appropriate Programme Theory Developed in Chinese Long‐Term Care Facilities
Get PDFBackground: Despite advance care planning (ACP) being associated with positive outcomes for residents in long‐term care facilities (LTCFs), the causal pathways between ACP and these outcomes are context‐specific and less understood. This lack of clarity can hinder the cultural adaptation and evaluation of ACP interventions. This study aimed to develop a programme theory that outlines the causal pathways through which the ACP is hypothesised to achieve impacts in Chinese LTCFs, with a focus on understanding its implementation, processes and outcomes. Methods: Exploratory qualitative design incorporating Theory of Change (ToC) methodology. Two ToC workshops (one face‐to‐face and one online) were held with 37 participants experienced in caring for residents or older people. The process was informed by a realist review and primary qualitative study. A programme theory was developed through thematic analysis, generating a ToC map depicting implementation, processes and outcomes of ACP in LTCFs. Results: The programme theory was constructed to outline the causal pathways of ACP in LTCFs, populating five ‘precondition’ domains: (1) buy‐in from government and facility leadership, (2) availability of external and internal resource, (3) adequate training and awareness for public and facility, (4) identification of residents who are ready for ACP and (5) culturally sensitive communication. Nine intervention components were identified that target preconditions, such as raising ACP awareness and providing staff training and mentoring. The potential impacts of ACP were identified, for example, fostering public attitudes towards a ‘good death’ and increasing public awareness and acceptance of palliative care. Conclusions: Our mid‐range programme theory can serve as a heuristic tool, adaptable for context‐specific ACP interventions in other countries, enhancing the likelihood of achieving intended impacts. In particular, intervention components focused on family involvement can be transferable to East Asian regions, where relational autonomy and family‐centred decision‐making are emphasised. The programme theory is ready for feasibility testing for residents in Chinese LTCFs. Patient or Public Contributions: We were guided by patient and public involvement members including two residents and one family member of a resident throughout the study. They supported the overall development of programme theory, including reviewing the theory and interpreting findings
Microbial repair and ecological justice: A new paradigm for agriculture
Get PDFIn this paper, we put forward a case for repair by showing how food security, rural economic resilience, ecological restoration, and environmental justice can be achieved through a repaired agricultural microbiome. Microbial repair must reverse the damage done by legacies of agricultural intensification to restore the microbiome’s ability to deliver key agricultural and societal functions. This project demands collaboration from diverse food system actors building on different types of knowledge