Performance of AAV8 vectors expressing human factor IX from a hepatic-selective promoter following intravenous injection into rats

Background: Vectors based on adeno-associated virus-8 (AAV8) have shown efficiency and efficacy for liver-directed gene therapy protocols following intravascular injection, particularly in relation to haemophilia gene therapy. AAV8 has also been proposed for gene therapy targeted at skeletal and cardiac muscle, again via intravascular injection. It is important to assess vector targeting at the level of virion accumulation and transgene expression in multiple species to ascertain potential issues relating to species variation in infectivity profiles. Methods: We used AAV8 vectors expressing human factor IX (FIX) from the liver-specific LP-1 promoter and administered this virus via the intravascular route of injection into 12 week old Wistar Kyoto rats. We assessed FIX levels in serum by ELISA and transgene expression at sacrifice by immunohistochemistry using anti-FIX antibodies. Vector DNA levels in organs we determined by real time PCR. Results: Administration of 1 × 1011 or 5 × 1011 scAAV8-LP1-hFIX vector particles/rat resulted in efficient production of physiological hFIX levels, respectively in blood assessed 4 weeks post-injection. This was maintained for the 4 month duration of the study. At 4 months we observed liver persistence of vector with minimal non-hepatic distribution. Conclusion: Our results demonstrate that AAV8 is a robust vector for delivering therapeutic genes into rat liver following intravascular injection

Fitness and Adiposity Are Independently Associated with Cardiometabolic Risk in Youth

Purpose. The purpose of the study was to examine the independent associations of adiposity and cardiorespiratory fitness with clustered cardiometabolic risk. Methods. A cross-sectional sample of 192 adolescents (118 boys), aged 14–16 years, was recruited from a South Lanarkshire school in the West of Scotland. Anthropometry and blood pressure were measured, and blood samples were taken. The 20 m multistage fitness test was the indicator of cardiorespiratory fitness (CRF). A clustered cardiometabolic risk score was constructed from HDL-C (inverted), LDL-C, HOMA, systolic blood pressure, and triglycerides. Interleukin-6, C-reactive protein, and adiponectin were also measured and examined relative to the clustered cardiometabolic risk score, CRF, and adiposity. Results. Although significant, partial correlations between BMI and waist circumference (WC) and both CRF and adiponectin were negative and weak to moderate, while correlations between the BMI and WC and CRP were positive but weak to moderate. Weak to moderate negative associations were also evident for adiponectin with CRP, IL-6, and clustered cardiometabolic risk. WC was positively associated while CRF was negatively associated with clustered cardiometabolic risk. With the additional adjustment for either WC or CRF, the independent associations with cardiometabolic risk persisted. Conclusion. WC and CRF are independently associated with clustered cardiometabolic risk in Scottish adolescent

Factors Affecting Infant Feeding Practices Among Women With Severe Mental Illness

Background: The health benefits of breastfeeding are well-established but for mothers with severe mental illness (SMI), the decision to breastfeed can be complex. Very few prior studies have investigated the infant feeding choices of women with SMI, or the factors associated with this. Our aims were to examine antenatal infant feeding intentions and infant feeding outcomes in a cohort of women admitted for acute psychiatric care in the first postpartum year. We also aimed to examine whether demographic and clinical characteristics associated with breastfeeding were similar to those found in previous studies in the general population, including age, employment, education, BMI, mode of delivery, smoking status, and social support. Methods: This study was a mixed-methods secondary analysis of a national cohort study, ESMI-MBU (Examining the effectiveness and cost-effectiveness of perinatal mental health services). Participants had been admitted to acute care with SMI in the first postpartum year. Infant feeding outcomes were retrospectively self-reported by women during a 1-month post-discharge interview. Free-text responses to questions relating to infant feeding and experience of psychiatric services were also explored using thematic analysis. Results: 144 (66.1%) of 218 women reported breastfeeding (mix feeding and exclusive breastfeeding). Eighty five percentage of the cohort had intended to breastfeed and of these, 76.5% did so. Factors associated with breastfeeding included infant feeding intentions, employment and non-Caucasian ethnicity. Although very few women were taking psychotropic medication contraindicated for breastfeeding, over a quarter (n = 57, 26.15%) reported being advised against breastfeeding because of their medication. Women were given this advice by psychiatry practitioners (40% n = 22), maternity practitioners (32.73% n = 18) and postnatal primary care (27.27% n = 15). Most women stopped breastfeeding earlier than they had planned to as a result (81.1% n = 43). Twenty five women provided free text responses, most felt unsupported with infant feeding due to inconsistent information about medication when breastfeeding and that breastfeeding intentions were de-prioritized for mental health care. Conclusion: Women with SMI intend to breastfeed and for the majority, this intention is fulfilled. Contradictory and insufficient advice relating to breastfeeding and psychotropic medication indicates that further training is required for professionals caring for women at risk of perinatal SMI about how to manage infant feeding in this population. Further research is required to develop a more in-depth understanding of the unique infant feeding support needs of women with perinatal SMI

Utility of the hypertriglyceridemic waist phenotype in the cardiometabolic risk assessment of youth stratified by body mass index

Background: It is unclear whether the Hypertriglyceridemic Waist Phenotype can be used to identify those at most risk of cardiometabolic disorders. Objectives: The utility of the Hypertriglyceridemic Waist Phenotype (HTWP) as a useful predictor of cardiometabolic risk in youth stratified by body mass index (BMI) was assessed. Methods: Three hundred and eighty seven children (12-17.5 years) were used within this cross-sectional study. Participants were classified as normal weight or overweight/obese according to the IOTF criteria. The HTWP phenotype was defined as having a waist circumference ≥ 90th percentile for age and gender with concomitant triglyceride concentrations ≥ 1.24 mmol/L. Cardiometabolic risk profiles were compared using MANCOVA. Results: Normal weight participants with the HTWP had significantly higher levels of C-reactive protein 2.6 ± 0.4 vs. 1.6 ± 0.3 mg/L (P < 0.05) and cardiometabolic risk scores (1.3 ± 0.3 vs. -0.7 ± 0.2 and 2.1 ± 0.4 vs. -0.5 ± 0.2; both P < 0.05) compared to those of a normal weight without the HTWP. Overweight/obese participants with the HTWP had significantly higher C-reactive protein levels (3.5 ± 0.6 vs. 2.6 ± 0.5; P < 0.05) as well as both cardiometabolic risk scores (1.6 ± 0.6 vs. 0.9 ± 0.2 and 2.2 ± 0.6 vs. 0.8 ± 0.2; both P < 0.001) when compared to overweight/obese participants without the HTWP. Conclusions: The HTWP may serve as a simple and clinically useful approach to identify youth at increased cardiometabolic risk

The fallacy of enrolling only high-risk subjects in cancer prevention trials: Is there a "free lunch"?

BACKGROUND: There is a common belief that most cancer prevention trials should be restricted to high-risk subjects in order to increase statistical power. This strategy is appropriate if the ultimate target population is subjects at the same high-risk. However if the target population is the general population, three assumptions may underlie the decision to enroll high-risk subject instead of average-risk subjects from the general population: higher statistical power for the same sample size, lower costs for the same power and type I error, and a correct ratio of benefits to harms. We critically investigate the plausibility of these assumptions. METHODS: We considered each assumption in the context of a simple example. We investigated statistical power for fixed sample size when the investigators assume that relative risk is invariant over risk group, but when, in reality, risk difference is invariant over risk groups. We investigated possible costs when a trial of high-risk subjects has the same power and type I error as a larger trial of average-risk subjects from the general population. We investigated the ratios of benefit to harms when extrapolating from high-risk to average-risk subjects. RESULTS: Appearances here are misleading. First, the increase in statistical power with a trial of high-risk subjects rather than the same number of average-risk subjects from the general population assumes that the relative risk is the same for high-risk and average-risk subjects. However, if the absolute risk difference rather than the relative risk were the same, the power can be less with the high-risk subjects. In the analysis of data from a cancer prevention trial, we found that invariance of absolute risk difference over risk groups was nearly as plausible as invariance of relative risk over risk groups. Therefore a priori assumptions of constant relative risk across risk groups are not robust, limiting extrapolation of estimates of benefit to the general population. Second, a trial of high-risk subjects may cost more than a larger trial of average risk subjects with the same power and type I error because of additional recruitment and diagnostic testing to identify high-risk subjects. Third, the ratio of benefits to harms may be more favorable in high-risk persons than in average-risk persons in the general population, which means that extrapolating this ratio to the general population would be misleading. Thus there is no free lunch when using a trial of high-risk subjects to extrapolate results to the general population. CONCLUSION: Unless the intervention is targeted to only high-risk subjects, cancer prevention trials should be implemented in the general population

Peramorphosis, an evolutionary developmental mechanism in neotropical bat skull diversity

Background The neotropical leaf‐nosed bats (Chiroptera, Phyllostomidae) are an ecologically diverse group of mammals with distinctive morphological adaptations associated with specialized modes of feeding. The dramatic skull shape changes between related species result from changes in the craniofacial development process, which brings into focus the nature of the underlying evolutionary developmental processes. Results In this study, we use three‐dimensional geometric morphometrics to describe, quantify, and compare morphological modifications unfolding during evolution and development of phyllostomid bats. We examine how changes in development of the cranium may contribute to the evolution of the bat craniofacial skeleton. Comparisons of ontogenetic trajectories to evolutionary trajectories reveal two separate evolutionary developmental growth processes contributing to modifications in skull morphogenesis: acceleration and hypermorphosis. Conclusion These findings are consistent with a role for peramorphosis, a form of heterochrony, in the evolution of bat dietary specialists

Socio-economic status influences the relationship between obesity and antenatal depression: Data from a prospective cohort study

Background Obesity has been associated with increased risk of antenatal depression, but little is known about this relationship. This study tested whether socio-economic status (SES) influences the relationship between obesity and antenatal depression. Methods Data were taken from the Screening for Pregnancy Endpoints (SCOPE) cohort. BMI was calculated from measured height and weight at 15±1 weeks' gestation. Underweight women were excluded. SES was indicated by self-reported household income (dichotomised around the median: low SES ≤£45,000; high SES >£45,000). Antenatal depression was defined as scoring ≥13 on the Edinburgh Postnatal Depression Scale at both 15±1 and 20±1 weeks' gestation, to identify persistently elevated symptoms of depression. Results Five thousand five hundred and twenty two women were included in these analyses and 5.5% had persistently elevated antenatal depression symptoms. There was a significant interaction between SES and BMI on the risk of antenatal depression (p=0.042). Among high SES women, obese women had approximately double the odds of antenatal depression than normal weight controls (AOR 2.11, 95%CI 1.16–3.83, p=0.014, adjusted for confounders). Among low SES women there was no association between obesity and antenatal depression. The interaction effect was robust to alternative indicators of SES in sensitivity analyses. Limitations 1) Antenatal depression was assessed with a self-reported screening measure; and 2) potential mediators such as stigma and poor body-image could not be examined. Conclusions Obesity was only associated with increased risk of antenatal depression among high SES women in this sample. Healthcare professionals should be aware that antenatal depression is more common among low SES women, regardless of BMI category

Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis

PMCID: PMC379391