Complement receptor 1 in microglia: implications for Alzheimer's disease

Recent genome wide association studies in Alzheimer’s disease have highlighted the importance of the complement cascade in the pathogenesis of Alzheimer’s disease. However, the cellular and molecular roles of these complement proteins are not fully understood. Microglia express complement receptors and the activation of specific receptors may increase Aβ clearance and reduce/prevent neurodegeneration. The work presented in this thesis was aimed at investigating the contribution of Complement receptor 1 (CR1), the second most significant hit in GWAS studies, on microglia to neuronal damage. To explore the consequences of blocking CR1 to microglial-neuronal interactions, primary rat microglia were treated with a CR1 functional blocking antibody together with microglial activators for 24 h. It was found that microglia displaying an activated phenotype demonstrated an increase in CR1 expression. Activation of microglial CR1 was found to be detrimental to neurons and this correlated with an increase in microglial intracellular superoxide generation, nitric oxide (NO) production, tumor necrosis factor-α (TNFα) and interleukin-1 β (IL-1β) secretion. Amyloid-β 1-42 (Aβ1-42)-treated microglia displayed an increased ability to phagocytose dextran beads following antibody blockade of CR1 but a decreased capacity to phagocytose fluorescent-tagged Aβ1-42. CR1 immunoreactivity was investigated by immunohistochemistry in AD and control human post-mortem brain tissue. A higher level of CR1 immunoreactivity was found in areas of high Aβ plaque burden in AD brain tissue. A difference in CR1 expression on red blood cells between individuals was measured by flow cytometry. Together, these results indicate that microglial CR1 plays a role in the neuronal death observed in AD and investigating this further may provide a possible strategy to control neurotoxicity in the AD brain

Semiclassical transmission across transition states

It is shown that the probability of quantum-mechanical transmission across a phase space bottleneck can be compactly approximated using an operator derived from a complex Poincar\'e return map. This result uniformly incorporates tunnelling effects with classically-allowed transmission and generalises a result previously derived for a classically small region of phase space.Comment: To appear in Nonlinearit

Indirect impacts of the COVID-19 pandemic at two tertiary neonatal units in Zimbabwe and Malawi: an interrupted time series analysis.

OBJECTIVES: To examine indirect impacts of the COVID-19 pandemic on neonatal care in low-income and middle-income countries. DESIGN: Interrupted time series analysis. SETTING: Two tertiary neonatal units in Harare, Zimbabwe and Lilongwe, Malawi. PARTICIPANTS: We included a total of 6800 neonates who were admitted to either neonatal unit from 1 June 2019 to 25 September 2020 (Zimbabwe: 3450; Malawi: 3350). We applied no specific exclusion criteria. INTERVENTIONS: The first cases of COVID-19 in each country (Zimbabwe: 20 March 2020; Malawi: 3 April 2020). PRIMARY OUTCOME MEASURES: Changes in the number of admissions, gestational age and birth weight, source of admission referrals, prevalence of neonatal encephalopathy, and overall mortality before and after the first cases of COVID-19. RESULTS: Admission numbers in Zimbabwe did not initially change after the first case of COVID-19 but fell by 48% during a nurses' strike (relative risk (RR) 0.52, 95% CI 0.41 to 0.66, p0.05). CONCLUSIONS: The indirect impacts of COVID-19 are context-specific. While our study provides vital evidence to inform health providers and policy-makers, national data are required to ascertain the true impacts of the pandemic on newborn health

Small denominators, frequency operators, and Lie transforms for nearly integrable quantum spin systems

Based on the previously proposed notions of action operators and of quantum integrability, frequency operators are introduced in a fully quantum-mechanical setting. They are conceptually useful because another formulation can be given to unitary perturbation theory. When worked out for quantum spin systems, this variant is found to be formally equivalent to canonical perturbation theory applied to nearly integrable systems consisting of classical spins. In particular, it becomes possible to locate the quantum-mechanical operator-valued equivalent of the frequency denominators that may cause divergence of the classical perturbation series. The results that are established here link the concept of quantum-mechanical integrability to a technical question, namely, the behavior of specific perturbation series

Wigner's Dynamical Transition State Theory in Phase Space: Classical and Quantum

A quantum version of transition state theory based on a quantum normal form (QNF) expansion about a saddle-centre-...-centre equilibrium point is presented. A general algorithm is provided which allows one to explictly compute QNF to any desired order. This leads to an efficient procedure to compute quantum reaction rates and the associated Gamov-Siegert resonances. In the classical limit the QNF reduces to the classical normal form which leads to the recently developed phase space realisation of Wigner's transition state theory. It is shown that the phase space structures that govern the classical reaction d ynamicsform a skeleton for the quantum scattering and resonance wavefunctions which can also be computed from the QNF. Several examples are worked out explicitly to illustrate the efficiency of the procedure presented.Comment: 132 pages, 31 figures, corrected version, Nonlinearity, 21 (2008) R1-R11

Protocol for an intervention development and pilot implementation evaluation study of an e-health solution to improve newborn care quality and survival in two low-resource settings, Malawi and Zimbabwe: Neotree.

INTRODUCTION: Every year 2.4 million deaths occur worldwide in babies younger than 28 days. Approximately 70% of these deaths occur in low-resource settings because of failure to implement evidence-based interventions. Digital health technologies may offer an implementation solution. Since 2014, we have worked in Bangladesh, Malawi, Zimbabwe and the UK to develop and pilot Neotree: an android app with accompanying data visualisation, linkage and export. Its low-cost hardware and state-of-the-art software are used to improve bedside postnatal care and to provide insights into population health trends, to impact wider policy and practice. METHODS AND ANALYSIS: This is a mixed methods (1) intervention codevelopment and optimisation and (2) pilot implementation evaluation (including economic evaluation) study. Neotree will be implemented in two hospitals in Zimbabwe, and one in Malawi. Over the 2-year study period clinical and demographic newborn data will be collected via Neotree, in addition to behavioural science informed qualitative and quantitative implementation evaluation and measures of cost, newborn care quality and usability. Neotree clinical decision support algorithms will be optimised according to best available evidence and clinical validation studies. ETHICS AND DISSEMINATION: This is a Wellcome Trust funded project (215742_Z_19_Z). Research ethics approvals have been obtained: Malawi College of Medicine Research and Ethics Committee (P.01/20/2909; P.02/19/2613); UCL (17123/001, 6681/001, 5019/004); Medical Research Council Zimbabwe (MRCZ/A/2570), BRTI and JREC institutional review boards (AP155/2020; JREC/327/19), Sally Mugabe Hospital Ethics Committee (071119/64; 250418/48). Results will be disseminated via academic publications and public and policy engagement activities. In this study, the care for an estimated 15 000 babies across three sites will be impacted. TRIAL REGISTRATION NUMBER: NCT0512707; Pre-results

Talking South African fathers: a critical examination of men’s constructions and experiences of fatherhood and fatherlessness

The absence of biological fathers in South Africa has been constructed as a problem for children of both sexes but more so for boy-children. Arguably the dominant discourse in this respect has demonized non-nuclear, female-headed households. Fathers are constructed as either absent or ‘bad’. Thus it has become important to explore more closely how male care-givers have been experienced by groups of men in South Africa. This article examines discourses of fatherhood and fatherlessness by drawing on qualitative interviews with a group of 29 men who speak about their reported experiences and understandings of being fathered or growing up without biological fathers. Two major and intertwined subjugated discourses about adult men’s experiences of being fathered that counter- balance the prevailing discourses about meaning of fatherhood and fatherlessness became evident, namely, ‘being always there’ and ‘talking fatherhood’. The importance of the experience of fatherhood as ‘being there’, which relates to a quality of time and relationship between child and father rather than physical time together, is illustrated. It is not only biological fathers who can ‘be there’ for their sons but also social fathers, other significant male role models and father figures who step in at different times in participants’ lives when biological fathers are unavailable for whatever reason. Second, many positive experiences of fathers or father figures that resist a traditional role of authority and control and subscribe to more nurturant and non-violent forms of care, represented as ‘talking’ fathers, are underlined. If we are to better understand the impact of colonial and apartheid history and its legacy on family life in contemporary society, there is a need for more historically and contextually informed studies on the meaning of fatherhood and fatherlessness.Web of Scienc

Marital status and mortality among Japanese men and women: the Japan Collaborative Cohort Study

<p>Abstract</p> <p>Background</p> <p>Several studies have indicated a significant association between marital status and mortality risks. However, most of these studies have compared married and unmarried people without differentiating among single, divorced and widowed status. Moreover, gender differences in mortality rates associated with marital status have not been sufficiently clarified. With significant increases in the percentages of divorced and widowed people and a corresponding drop in the marriage rate in Japan during the past two or three decades, it can be expected that these changes will have a significant impact on mortality rates.</p> <p>Methods</p> <p>This investigation used a prospective study of a total of 94,062 Japanese men and women aged 40–79 who completed self-administered questionnaires at baseline and during a followed-up of 9.9-years.</p> <p>Results</p> <p>Compared with married men, never-married men showed higher risks of mortality from cardiovascular disease [relative risk (RR) = 3.05, 95% confidence interval (CI) 2.03–4.60], respiratory disease (RR = 2.43, 95%CI 1.27–4.63), external causes (RR = 2.18, 95%CI 1.05–4.54) and all causes (RR = 1.91, 95%CI 1.51–2.42) after adjustment for potentially confounding variables. For never-married women, there was a smaller but significantly higher risk of mortality from all causes (RR = 1.46, 95%CI 1.15–1.84). Divorced and widowed men showed moderately higher risks of mortality from cardiovascular disease, external causes and all causes compared with married men, but such a trend was not observed in women.</p> <p>Conclusion</p> <p>Single status was associated with a higher risk of mortality than was married status for both men and women. Divorce and widowhood were associated with elevated risk for men, but not for women. These findings suggest single, divorce and widowhood status constitute potentially adverse health effects.</p