A Role of Early Life Stress on Subsequent Brain and Behavioral Development

The prevalence of pediatric neuropsychiatric disorders has risen dramatically during the past two decades. A study surveying the years 1997-2008 verified that one in six children have a developmental disability – a number on the rise. Along similar lines, studies show higher incidents of criminal activity, substance use disorders, and the emergence of psychopathologies in early adolescence and young adulthood, which are particularly sensitive periods of brain and behavioral maturation. While developmental trajectories that may lead to adverse outcomes in youth are the result of a mix of genetics and environmental exposure, it is becoming clearer that they do not start at the time of the diagnosis or problem behaviors; rather, these developmental trajectories start at the earliest periods of life. The ability of children to achieve their full physical, academic, and social potential is tightly related to early life events, some of which may occur even before birth. The science is now amassed with investigators and research targeting the role of Early Life Stress and its interaction with biological systems in impacting the development of the brain and complex behaviors across all stages of development

Fraud on Any Market

Claims of securities fraud had historically failed because investors seldom rely on false or misleading statements when transacting securities. To bolster confidence in securities markets, the U.S. Supreme Court adopted a doctrine called “fraud-on-the-market” so that duped investors can show detrimental reliance without ever encountering the fraudulent statements. The doctrine assumes that a stock’s price reflects all material information, meaning that an investor who bought tainted stock has constructively relied on the fraud. Fraud-on-the-market is not only unavailable in other markets but is also embattled within securities law. The doctrine has endured volleys of criticisms about whether markets actually absorb information, leading critics to believe that the Supreme Court would eliminate it in 2014. The Court did not. In light of persistent questions about whether the doctrine reflects reality or has outlived its purpose, our empirical research tests fraud-on-the-market’s viability by investigating sports gambling: we find that the doctrine provides a sound remedy for investors in any market. The sports wagering market operates like others in which defrauded individuals have historically failed to support their fraud claims due to a lack of reliance. We show that securities and gambling markets suffer from many of the same frailties. Chief among them is that both investors and bettors place money in markets where they lack information about deception, cheating, and fraud. And like investors rely on prices affected by fraud, gamblers reference wagering information based on the playing field: if deception enables a team to fare better or worse, this skews the betting lines on which gamblers rely. The difference between these markets, though, is that investors enjoy a body of securities law to condemn fraud. We first argue that fraud-on-the-market would benefit most types of investable markets like sports gambling and support the doctrine in the securities context. Despite criticisms of the doctrine, our analysis shows that fraud creates the presumption of distorted prices. Second, the money wagered via sports betting and daily fantasy sports (DFS) would generate damages such that leagues would better maintain a competitive environment, boosting sports integrity akin to how securities regulations provide market protections. Also, our argument recognizes the inequity of denying sports bettors and DFS users a remedy. Whereas the leagues had traditionally benefited from gambling indirectly, today, the NFL, NHL, MLB, and NBA have partnered with DFS and other gambling industry companies. Since the leagues now benefit directly from gambling, and lucratively so, they should owe their fans a truly competitive landscape

Economic and Historical Perspectives on Stationarity, Structural Change and the Uncertainty of Outcome Hypothesis in Long-Term North American Professional Sports Attendance.

The following work extends the breakpoint literature regarding annual attendance and the impact of outcome uncertainty at the aggregate level to the National Basketball Association, National Football League, and National Hockey League as well as at the team level in these three leagues and Major League Baseball. Attendance series for each league under consideration are not stationary overall but are stationary with breakpoints. However, evidence for the presence of a unit root—with or without breaks—is mixed across teams within and between North American leagues. Break points correspond in believable ways to historical occurrences in these leagues and the cities in which many of the franchises reside. Ultimately, the impact of competitive balance varies across both leagues and teams with respect to the time path of stadium attendance, with mixed evidence for Rottenberg’s uncertainty of outcome hypothesis. I present implications of breaks and balance effects and suggest future research on attendance estimation in North American professional sports, including further econometric treatment for a fully specified model of long-term stadium attendance that may be censored due to sellouts.PHDKinesiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/94017/1/bmmillsy_1.pd

Adaptation of the Child - Parent Relationship Therapy Model for Use With Senior Citizen Volunteers in School Settings: A Pilot Study

This study provides a proposal for crucial volunteer services to fill the gap for overburdened school counselors when parents are unable to engage in Child-Parent Relationship Therapy (CPRT), a highly effective intervention for childhood problems. CPRT has been successfully adapted for use with individuals other than the child’s parents. The researcher in this pilot study adapted CPRT for use with senior citizen volunteers who often possess untapped abilities and talents. Seniors received several weeks of training, and then met with children for 1/2 hour supervised, video-taped play sessions for several weeks. Childhood adjustment problems were assessed before and after the intervention using the Child Behavior Checklist (CBCL) and Teacher Report Form (TRF). Seniors’ responses were measured before and after with the Older Adult Self-Report and qualitative interviews. Although no significant differences were noted on pre versus posttest measures for the children (CBCL and TRF), anecdotal reports suggest potential effectiveness of this volunteer intervention for school counselors to utilize. In addition, senior citizens reported their own benefits from working with the children. Suggestions for future research in this area are offered

Cardiometabolic effects of a novel SIRT1 activator, SRT2104, in people with type 2 diabetes mellitus

Background: The cardiometabolic effects of SRT2104, a novel SIRT1 activator, were investigated in people with type 2 diabetes mellitus (T2DM). Methods: Fifteen adults with T2DM underwent a randomised, double-blind, placebo-controlled cross-over trial and received 28 days of oral SRT2104 (2.0 g/day) or placebo. Forearm vasodilatation (measured during intrabrachial bradykinin, acetylcholine and sodium nitroprusside infusions) as well as markers of glycaemic control, lipid profile, plasma fibrinolytic factors, and markers of platelet-monocyte activation, were measured at baseline and at the end of each treatment period. Results: Lipid profile and platelet-monocyte activation were similar in both treatment arms (p>0.05 for all). Forearm vasodilatation was similar on exposure to acetylcholine and sodium nitroprusside (p>0.05,respectively). Bradykinin-induced vasodilatation was less during treatment with SRT2104 versus placebo (7.753vs9.044, respectively, mean difference=−1.291,(95% CI −2.296 to −0.285, p=0.012)). Estimated net plasminogen activator inhibitor type 1 antigen release was reduced in the SRT2104 arm versus placebo (mean difference=−38.89 ng/100mL tissue/ min, (95%CI −75.47, to –2.305, p=0.038)). There were no differences in other plasma fibrinolytic factors (p>0.05 for all). After 28 days, SRT2104 exposure was associated with weight reduction (−0.93 kg (95% CI −1.72 to −0.15), p=0.0236), and a rise in glycated haemoglobin (5 mmol/ mol or 0.48% (0.26 to 0.70), p=0.004) Conclusions: In people with T2DM, SRT2104 had inconsistent, predominantly neutral effects on endothelial and fibrinolytic function, and no discernible effect on lipids or platelet function. In contrast, weight loss was induced along with deterioration in glycaemic control, suggestive of potentially important metabolic effects. Clinical trial registration: NCT01031108; Results

Cross-sectional assessment of patient attitudes towards participation in clinical trials: does making results publicly available matter?

Previous studies have shown that a majority of patients cite altruistic motives, such as contributing to generalisable medical knowledge, as factors motivating clinical trial participation. We sought to examine the impact of making trial results publicly available on patients' willingness to participate in clinical research

Protection and mechanism of action of a novel human respiratory syncytial virus vaccine candidate based on the extracellular domain of small hydrophobic protein

Infections with human respiratory syncytial virus (HRSV) occur globally in all age groups and can have devastating consequences in young infants. We demonstrate that a vaccine based on the extracellular domain (SHe) of the small hydrophobic (SH) protein of HRSV, reduced viral replication in challenged laboratory mice and in cotton rats. We show that this suppression of viral replication can be transferred by serum and depends on a functional IgG receptor compartment with a major contribution of FcRI and FcRIII. Using a conditional cell depletion method, we provide evidence that alveolar macrophages are involved in the protection by SHe-specific antibodies. HRSV-infected cells abundantly express SH on the cell surface and are likely the prime target of the humoral immune response elicited by SHe-based vaccination. Finally, natural infection of humans and experimental infection of mice or cotton rats does not induce a strong immune response against HRSV SHe. Using SHe as a vaccine antigen induces immune protection against HRSV by a mechanism that differs from the natural immune response and from other HRSV vaccination strategies explored to date. Hence, HRSV vaccine candidates that aim at inducing protective neutralizing antibodies or T-cell responses could be complemented with a SHe-based antigen to further improve immune protection

Comparative effectiveness of dual-action versus single-action antidepressants for the treatment of depression in people living with HIV/AIDS

Background Depression is the most common psychiatric comorbidity among people living with HIV/AIDS (PLWHA). Little is known about the comparative effectiveness between different types of antidepressants used to treat depression in this population. We compared the effectiveness of dual-action and single-action antidepressants in PLWHA for achieving remission from depression. Methods We used data from the Centers for AIDS Research Network of Integrated Clinic Systems to identify 1175 new user dual-action or single-action antidepressant treatment episodes occurring from 2005 to 2014 for PLWHA diagnosed with depression. The primary outcome was remission from depression defined as a Patient Health Questionnaire-9 (PHQ-9) score <5. Mean difference in PHQ-9 depressive symptom severity was a secondary outcome. The main approach was an intent-to-treat (ITT) evaluation complemented with a per protocol (PP) sensitivity analysis. Generalized linear models were fitted to estimate treatment effects. Results In ITT analysis, 32% of the episodes ended in remission for both dual-action and single-action antidepressants. The odds ratio (OR) of remission was 1.02 (95%CI=0.63,1.67). In PP analysis, 40% of dual-action episodes ended in remission compared to 32% in single-action episodes. Dual-action episodes had 1.33 times the odds of remission (95%CI=0.55,3.21), however the result was not statistically significant. Non-significant differences were also observed for depressive symptom severity. Limitations Missing data was common but was addressed with inverse probability weights. Conclusions Results suggest that single-action and dual-action antidepressants are equally effective in PLWHA. Remission was uncommon highlighting the need to identify health service delivery strategies that aid HIV providers in achieving full remission of their patients’ depression

Caspase-11 regulates the tumour suppressor function of STAT1 in a murine model of colitis-associated carcinogenesis

Murine inflammatory caspase-11 has an important role in intestinal epithelial inflammation and barrier function. Activation of the non-canonical inflammasome, mediated by caspase-11, serves as a regulatory pathway for the production of the proinflammatory cytokines IL-1β and IL-18, and has a key role in pyroptotic cell death. We have previously demonstrated a protective role for caspase-11 during dextran sulphate sodium (DSS)-induced colitis, however the importance of caspase-11 during colorectal tumour development remains unclear. Here, we show that Casp11−/− mice are highly susceptible to the azoxymethane (AOM)-DSS model of colitis-associated cancer (CAC), compared to their wild type (WT) littermates. We show that deficient IL-18 production occurs at initial inflammation stages of disease, and that IL-1β production is more significantly impaired in Casp11−/− colons during established CAC. We identify defective STAT1 activation in Casp11−/− colons during disease progression, and show that IL-1β signalling induces caspase-11 expression and STAT1 activation in primary murine macrophages and intestinal epithelial cells. These findings uncover an anti-tumour role for the caspase-11 and the non-canonical inflammasome during CAC, and suggest a critical role for caspase-11, linking IL-1β and STAT1 signalling pathways