Predicting clinical variables from neuroimages using fused sparse group lasso

Predictive models in which neuroimage features serve as predictors and a clinical variable is modeled as the outcome are good candidates for clinical application because (1) they can exploit dependencies between predictor variables and thus potentially explain more variability in the outcome than a mass univariate approach, and (2) they allow inference at the individual level, such that a prediction can be obtained for a new individual whose data was not used to train the model. This dissertation proposes methods for neuroimaging prediction models that not only aim for predictive accuracy, but also seek interpretability and potential insight into the underlying pathophysiology of neuropsychiatric disorders. In the first part of this dissertation we propose the fused sparse group lasso penalty, which encourages structured, sparse, interpretable solutions by incorporating prior information about spatial and group structure among voxels. We derive optimization steps for fused sparse group lasso penalized regression using the alternating direction method of multipliers algorithm. With simulation studies, we demonstrate conditions under which fusion and group penalties together outperform either of them alone. We then use fused sparse group lasso to predict continuous measures from resting state magnetic resonance imaging data using the Autism Brain Imaging Data Exchange dataset. In the second part of this dissertation we use fused sparse group lasso to predict age from multimodal neuroimaging data in a sample of cognitively normal adults aged 65 and older. In general, we show how the incorporation of prior information via the fused sparse group lasso penalty can enhance the interpretability of neuroimaging predictive models while also yielding good predictive performance. Public health significance: Psychiatric disorders and neurological diseases such as Alzheimer's present a large public health burden. As of yet, there have been relatively few translations of basic neuroscience findings to clinical applications in psychiatry. Prediction models using neuroimaging data can potentially help clinicians with diagnosis and prediction of prognosis and treatment response. Establishing interpretable neuroimaging-based biomarkers can improve our understanding of the neurobiological mechanisms underlying neuropsychiatric disorders and suggest approaches for prevention and treatment

The Impairment of Macrophage-to-Feces Reverse Cholesterol Transport during Inflammation Does Not Depend on Serum Amyloid A

Studies suggest that inflammation impairs reverse cholesterol transport (RCT). We investigated whether serum amyloid A (SAA) contributes to this impairment using an established macrophage-to-feces RCT model. Wild-type (WT) mice and mice deficient in SAA1.1 and SAA2.1 (SAAKO) were injected intraperitoneally with 3H-cholesterol-labeled J774 macrophages 4 hr after administration of LPS or buffered saline. 3H-cholesterol in plasma 4 hr after macrophage injection was significantly reduced in both WT and SAAKO mice injected with LPS, but this was not associated with a reduced capacity of serum from LPS-injected mice to promote macrophage cholesterol efflux in vitro. Hepatic accumulation of 3H-cholesterol was unaltered in either WT or SAAKO mice by LPS treatment. Radioactivity present in bile and feces of LPS-injected WT mice 24 hr after macrophage injection was reduced by 36% (P \u3c 0.05) and 80% (P \u3c 0.001), respectively. In contrast, in SAAKO mice, LPS did not significantly reduce macrophage-derived 3H-cholesterol in bile, and fecal excretion was reduced by only 45% (P \u3c 0.05). Injection of cholesterol-loaded allogeneic J774 cells, but not syngeneic bone-marrow-derived macrophages, transiently induced SAA in C57BL/6 mice. Our study confirms reports that acute inflammation impairs steps in the RCT pathway and establishes that SAA plays only a minor role in this impairment

Impact of Individual Acute Phase Serum Amyloid A Isoforms on HDL Metabolism in Mice

The acute phase (AP) reactant serum amyloid A (SAA), an HDL apolipoprotein, exhibits pro-inflammatory activities, but its physiological function(s) are poorly understood. Functional differences between SAA1.1 and SAA2.1, the two major SAA isoforms, are unclear. Mice deficient in either isoform were used to investigate plasma isoform effects on HDL structure, composition, and apolipoprotein catabolism. Lack of either isoform did not affect the size of HDL, normally enlarged in the AP, and did not significantly change HDL composition. Plasma clearance rates of HDL apolipoproteins were determined using native HDL particles. The fractional clearance rates (FCRs) of apoA-I, apoA-II, and SAA were distinct, indicating that HDL is not cleared as intact particles. The FCRs of SAA1.1 and SAA2.1 in AP mice were similar, suggesting that the selective deposition of SAA1.1 in amyloid plaques is not associated with a difference in the rates of plasma clearance of the isoforms. Although the clearance rate of SAA was reduced in the absence of the HDL receptor, scavenger receptor class B type I (SR-BI), it remained significantly faster compared with that of apoA-I and apoA-II, indicating a relatively minor role of SR-BI in SAA’s rapid clearance. These studies enhance our understanding of SAA metabolism and SAA’s effects on AP-HDL composition and catabolism

Facing homelessness

In facing homelessness we face the other, and in facing the other, we face ourselves. This book contributes to an emerging body of knowledge on street homelessness in the South African context. It is meant for researchers and scholars who are committed to finding solutions for street homelessness. It offers conceptual frameworks and practical guidelines for a liberative and transformative response to homelessness. It brings together authors from a wide range of disciplines, fusing the rigour of researchers, the vision of activists and the lived experience of practitioners. In this volume, the causes of street homelessness in South Africa today, and its different faces, are traced. It critiques singular solutions, and interrogates the political, institutional and moral failures that contribute to the systemic exclusion of homeless persons and other vulnerable populations from society. It proposes rights-based interventions as part of a radical re-imagination of how street homelessness can be ended, one person and one neighbourhood at a time. The analysis by the authors steer in the direction of new ways of doing and being that could demonstrate concrete, viable and sustainable alternatives to the exclusionary realities faced by homeless persons. It argues for solution-based approaches, aimed at radical forms of social inclusion and achieved through broad-based and creative collaborations by all spheres of society. In the face and presence of street homelessness – as one expression of urban vulnerability and deep socio-economic inequality – society is confronted with a clear political, institutional, moral and personal obligation. This volume calls for a reclamation of community in its most inclusionary, life-affirming and interdependent sense, asserting that we truly are well because of others, and we are unwell if others are. It is a call to reclaim our common humanity in the context of inclusive communities where all are equally welcome and bestowed with dignity and honour

Investigation of antihypertensive class, dementia, and cognitive decline: A meta-analysis

Objective High blood pressure is one of the main modifiable risk factors for dementia. However, there is conflicting evidence regarding the best antihypertensive class for optimizing cognition. Our objective was to determine whether any particular antihypertensive class was associated with a reduced risk of cognitive decline or dementia using comprehensive meta-analysis including reanalysis of original participant data. Methods To identify suitable studies, MEDLINE, Embase, and PsycINFO and preexisting study consortia were searched from inception to December 2017. Authors of prospective longitudinal human studies or trials of antihypertensives were contacted for data sharing and collaboration. Outcome measures were incident dementia or incident cognitive decline (classified using the reliable change index method). Data were separated into mid and late-life (>65 years) and each antihypertensive class was compared to no treatment and to treatment with other antihypertensives. Meta-analysis was used to synthesize data. Results Over 50,000 participants from 27 studies were included. Among those aged >65 years, with the exception of diuretics, we found no relationship by class with incident cognitive decline or dementia. Diuretic use was suggestive of benefit in some analyses but results were not consistent across follow-up time, comparator group, and outcome. Limited data precluded meaningful analyses in those ≤65 years of age. Conclusion Our findings, drawn from the current evidence base, support clinical freedom in the selection of antihypertensive regimens to achieve blood pressure goals. Clinical trials registration The review was registered with the international prospective register of systematic reviews (PROSPERO), registration number CRD42016045454.The corresponding author is funded by the Australian National Health and Medical Research Council, National Institute for Dementia Research, and Dementia Centre for Research Collaboration (NHMRC NNIDR DCRC)

Facing homelessness

In facing homelessness we face the other, and in facing the other, we face ourselves. This book contributes to an emerging body of knowledge on street homelessness in the South African context. It is meant for researchers and scholars who are committed to finding solutions for street homelessness. It offers conceptual frameworks and practical guidelines for a liberative and transformative response to homelessness. It brings together authors from a wide range of disciplines, fusing the rigour of researchers, the vision of activists and the lived experience of practitioners. In this volume, the causes of street homelessness in South Africa today, and its different faces, are traced. It critiques singular solutions, and interrogates the political, institutional and moral failures that contribute to the systemic exclusion of homeless persons and other vulnerable populations from society. It proposes rights-based interventions as part of a radical re-imagination of how street homelessness can be ended, one person and one neighbourhood at a time. The analysis by the authors steer in the direction of new ways of doing and being that could demonstrate concrete, viable and sustainable alternatives to the exclusionary realities faced by homeless persons. It argues for solution-based approaches, aimed at radical forms of social inclusion and achieved through broad-based and creative collaborations by all spheres of society. In the face and presence of street homelessness – as one expression of urban vulnerability and deep socio-economic inequality – society is confronted with a clear political, institutional, moral and personal obligation. This volume calls for a reclamation of community in its most inclusionary, life-affirming and interdependent sense, asserting that we truly are well because of others, and we are unwell if others are. It is a call to reclaim our common humanity in the context of inclusive communities where all are equally welcome and bestowed with dignity and honour

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant