Human Equivalent Dose Modeling for Omega-3 Fatty Acid Supplementation in C57BL/6J Mice

The rodent model is often used to study the impact of dietary n-3 fatty acids on a variety of biological endpoints, and the results of these studies have been used to explain anticipated effects of n-3 fatty acid intake in humans. However, supplemental levels of n-3 fatty acids that are commonly used in rodent studies do not represent reasonable human intake, by comparison. Currently there is no standard method for the addition of n-3 fatty acids to rodent diets. We tested a mathematical model for dosing supplemental levels of α-linolenic acid (ALA) and eicosapentaenoic acid (EPA) to rodent diets on the basis of energy%. C57BI/6J mice were fed a background diet that modeled typical Western intake in both macronutrient and fatty acid composition. Three levels of ALA and EPA (0.3, 0.8, and 1.4 energy%) were supplemented to either a normal-ALA control diet (0.6 energy% ALA) or a high-ALA control diet (1.2 energy% ALA). Plasma and erythrocyte phospholipid fatty acid changes were determined and compared to archival human n-3 fatty acid supplementation studies reporting the same tissue endpoints. In mice, supplemental EPA had a greater effect than supplemental ALA on both plasma and erythrocyte phospholipid EPA. Docosahexaenoic acid (DHA) levels in mice were only minimally changed by either ALA or EPA supplementation. Use of the high- ALA control diet resulted in attenuated phospholipid fatty acid changes in both tissues compared to the normal-ALA control diet for both supplemented fatty acids. At each supplemented dose of ALA or EPA, changes in murine plasma or erythrocyte phospholipid EPA exceeded changes observed in the same human tissues by 2-4 fold when compared to equivalent human supplemental doses in energy%. Tissue changes observed using the high-ALA control diet better modeled the results observed in humans at the same supplemental energy% for both ALA and EPA in plasma and erythrocyte phospholipids. This is the first study to use pharmacodynamic modeling to compare the effect of supplemental n-3 doses on mouse and human endpoints. The addition of n-3 fatty acids to rodent diets on the basis of energy% represents a reasonable improvement to current dosing strategies. This data is useful both as a guideline for n-3 fatty acid dosing in rodent studies and as a reference point for future calculated refinements in dosing

Evaluating multiagency interventions for children living with intimate partner violence in Birmingham

This research endeavour was born out of the need for a systematic evaluation of the efficacy of the multiagency Domestic Abuse Risk Assessment tool, which necessitates that all incidents of ‘domestic abuse’ (any incident within the family domain) reported to West Midlands Police, where a child or unborn child resides within that home, are scrutinised by Police and Social Care (and partners from Health, Education and the voluntary sector where possible) using a joint protocol. The primary purpose of the protocol is to promote safeguarding and provide a timely and appropriate response to children at risk following domestic abuse. The protocol incorporates the Banardos’ Multiagency Domestic Violence Risk Identification Threshold Scales (MDVRITS), which aids decision making about appropriate interventions based on predicted risk to children using a four level scale

Determinants of pubertal development in an urban South African cohort

Age at the initiation of puberty and at menarche are key maturational indicators. They reflect health both within and between populations; in that a declining average age is associated with improving health, nutrition, and socio-economic conditions. Knowledge of the timing of pubertal development and menarche is important as earlier development within a population, in particular, has been linked with an increased risk of negative sequelae including overweight and obesity, development of risk factors for non-communicable diseases such as hypertension and insulin resistance, and engagement in risk behaviours such as early sexual debut and substance abuse. The main aims of this study were to investigate the timing of, and the early life factors (such as body composition and growth velocities) associated with pubertal development and age at menarche in Black and White urban South African adolescents. Mixed-longitudinal data (n = 401) from the Birth to Twenty (Bt20) birth-cohort study, initiated in 1990 and set in SowetoJohannesburg, South Africa were used. Median age at the initation of puberty and at menarche was derived by fitting logistic curves to cumulative frequency plots. Logistic regression models were constructed to examine the early life predictors of the timing of puberty and menarche. Data were also collected from adolescents and Bt20 staff (n = 72) using focus groups to explore views on the pubertal development questionnaire used in the Bt20 study. Median age at the initiation of genitalia development was 10.4 years (95% Cl = 8.4, 12.4) for Black boys and 9.8 years (95% Cl = 9.4, 10.2) for White boys. Median age for the initiation of pubic hair development for Black males was 10.8 years (95% Cl = 9.6, 12.0) compared to White males, which was 10.2 years (95% Cl = 8.4, 12.0). Median age at the initiation of breast development in Black females was 10.1 years (95% Cl = 9.3, 10.9) compared to White females which was 10.2 years (95% Cl = 8.2, 12.2). Median age for the initiation of pubic hair was 10.3 years (95% Cl = 9.3, 11.3) and 10.5 years (95% Cl = 8.7, 12.3) for Black and White girls, respectively. Results from logistic regression showed that a greater weight and height velocity in late childhood significantly increased the odds of achieving early breasU genitalia development. Furthermore, a low socio-economic status (SES) index at 9/10 years significantly reduced the odds of achieving early breasUgenitalia development. A greater weight, height, body mass index (BM I), and growth rate during infancy and childhood significantly increased the odds of achieving early pubic hair development. Median age at menarche for Black females was 12.4 years (95% Cl = 12.2, 12.6) and 12.5 . years (95% Cl = 11.7,13.3) for White females. Average menarcheal age for Black girls has declined by 0.56 years per decade and 0.32 years for White girls in South Africa, when comparing the current study findings with those from previous studies. Results from logistic regression showed that being taller, fatter and heavier in late childhood significantly increased the odds of achieving earlier menarche. The focus groups provided a range of opinions relating to the Bt20 pubertal development questionnaire and procedure. The majority of views were positive and included the ease of understanding and completion of the tool. Negative views revolved around the language used and privacy issues. These qualitative results provided a unique insight into the way in which pubertal development data are assessed and how these methods can potentially be improved to enhance the reliability and accuracy of pubertal development data collection. The results from this study provide the most recent estimates of age at the. initiation of puberty and age at menarche for urban Black and White South African adolescents. This is particularly important given the social, nutritional, and economic transition currently occurring in this country as these key maturity indicators reflect population health. This study has also added to our knowledge of the factors that are associated with pubertal development, showing that proximate rather than distal factors are the most sensitive indicators in this urban transitioning environment. In addition, the results from the focus groups provided a unique insight into how pubertal development data are assessed and how these methods could be improved. The negative health outcomes which have been associated with earlier pubertal development and age at menarche are major public health concerns, particularly in the South African context given the HIV/AIDS epidemic and rising levels of obesity. This study highlights the need for renewed research and resources for intervention strategies and policy programmes which target appropriate sex and obesity education in urban South African children.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Restriction of HIV-1 Genotypes in Breast Milk Does Not Account for the Population Transmission Genetic Bottleneck That Occurs following Transmission

BACKGROUND. Breast milk transmission of HIV-1 remains a major route of pediatric infection. Defining the characteristics of viral variants to which breastfeeding infants are exposed is important for understanding the genetic bottleneck that occurs in the majority of mother-to-child transmissions. The blood-milk epithelial barrier markedly restricts the quantity of HIV-1 in breast milk, even in the absence of antiretroviral drugs. The basis of this restriction and the genetic relationship between breast milk and blood variants are not well established. METHODOLOGY/PRINCIPAL FINDINGS. We compared 356 HIV-1 subtype C gp160 envelope (env) gene sequences from the plasma and breast milk of 13 breastfeeding women. A trend towards lower viral population diversity and divergence in breast milk was observed, potentially indicative of clonal expansion within the breast. No differences in potential N-linked glycosylation site numbers or in gp160 variable loop amino acid lengths were identified. Genetic compartmentalization was evident in only one out of six subjects in whom contemporaneously obtained samples were studied. However, in samples that were collected 10 or more days apart, six of seven subjects were classified as having compartmentalized viral populations, highlighting the necessity of contemporaneous sampling for genetic compartmentalization studies. We found evidence of CXCR4 co-receptor using viruses in breast milk and blood in nine out of the thirteen subjects, but no evidence of preferential localization of these variants in either tissue. CONCLUSIONS/SIGNIFICANCE. Despite marked restriction of HIV-1 quantities in milk, our data indicate intermixing of virus between blood and breast milk. Thus, we found no evidence that a restriction in viral genotype diversity in breast milk accounts for the genetic bottleneck observed following transmission. In addition, our results highlight the rapidity of HIV-1 env evolution and the importance of sample timing in analyses of gene flow.National Institute of Child Health and Human Development; National Institutes of Health (R01 HD 39611, R01 HD 40777); International Maternal Pediatric Adolescent AIDS Clinical Trials Group (U01 AI068632-01); National Institutes of Health Cellular, Biochemical; Molecular Sciences Training Program Grant (T 32 067587

4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms

Human antibody 4E10 targets the highly conserved membrane-proximal external region (MPER) of the HIV-1 transmembrane glycoprotein, gp41, and has extraordinarily broad neutralizing activity. It is considered by many to be a prototype for vaccine development. In this study, we describe four subjects infected with viruses carrying rare MPER polymorphisms associated with resistance to 4E10 neutralization. In one case resistant virus carrying a W680G substitution was transmitted from mother to infant. We used site-directed mutagenesis to demonstrate that the W680G substitution is necessary for conferring the 4E10-resistant phenotype, but that it is not sufficient to transfer the phenotype to a 4E10-sensitive Env. Our third subject carried Envs with a W680R substitution causing variable resistance to 4E10, indicating that residues outside the MPER are required to confer the phenotype. A fourth subject possessed a F673L substitution previously associated with 4E10 resistance. For all three subjects with W680 polymorphisms, we observed additional residues in the MPER that co-varied with position 680 and preserved charged distributions across this region. Our data provide important caveats for vaccine development targeting the MPER. Naturally occurring Env variants described in our study also represent unique tools for probing the structure-function of HIV-1 envelope

Lung Cancer Screening Practices in North Carolina CT Facilities

The burden of lung cancer in the United States is staggering, with more Americans dying from lung cancer than the next four most common cancers combined. With endorsement of lung cancer screening by the United States Preventive Services Task Force and reimbursement by the Centers for Medicare and Medicaid Services (CMS), the number screened for lung cancer with low-dose computed tomography (LDCT) is anticipated to rise in the near future

Comorbid health conditions and their impact on social isolation, loneliness, quality of life, and well-being in people with dementia: longitudinal findings from the IDEAL programme

BackgroundMost people with dementia have multiple health conditions. This study explores (1) number and type of health condition(s) in people with dementia overall and in relation to age, sex, dementia type, and cognition; (2) change in number of health conditions over two years; and (3) whether over time the number of health conditions at baseline is related to social isolation, loneliness, quality of life, and/or well-being.MethodsLongitudinal data from the IDEAL (Improving the experience of Dementia and Enhancing Active Life) cohort were used. Participants comprised people with dementia (n = 1490) living in the community (at baseline) in Great Britain. Health conditions using the Charlson Comorbidity Index, cognition, social isolation, loneliness, quality of life, and well-being were assessed over two years. Mixed effects modelling was used.ResultsOn average participants had 1.8 health conditions at baseline, excluding dementia; increasing to 2.5 conditions over two years. Those with vascular dementia or mixed (Alzheimer’s and vascular) dementia had more health conditions than those with Alzheimer’s disease. People aged ≥ 80 had more health conditions than those aged < 65 years. At baseline having more health conditions was associated with increased loneliness, poorer quality of life, and poorer well-being, but was either minimally or not associated with cognition, sex, and social isolation. Number of health conditions had either minimal or no influence on these variables over time.ConclusionsPeople with dementia in IDEAL generally had multiple health conditions and those with more health conditions were lonelier, had poorer quality of life, and poorer well-being