Faculty Bibliography

Heavy metals such as cadmium, arsenic and nickel are classified as carcinogens. Although the precise mechanism of carcinogenesis is undefined, heavy metal exposure can contribute to genetic damage by inducing double strand breaks (DSBs) as well as inhibiting critical proteins from different DNA repair pathways. Here we take advantage of two previously published culture assay systems developed to address mechanistic aspects of DNA repair to evaluate the effects of heavy metal exposures on competing DNA repair outcomes. Our results demonstrate that exposure to heavy metals significantly alters how cells repair double strand breaks. The effects observed are both specific to the particular metal and dose dependent. Low doses of NiCl2 favored resolution of DSBs through homologous recombination (HR) and single strand annealing (SSA), which were inhibited by higher NiCl2 doses. In contrast, cells exposed to arsenic trioxide preferentially repaired using the "error prone" non-homologous end joining (alt-NHEJ) while inhibiting repair by HR. In addition, we determined that low doses of nickel and cadmium contributed to an increase in mutagenic recombination-mediated by Alu elements, the most numerous family of repetitive elements in humans. Sequence verification confirmed that the majority of the genetic deletions were the result of Alu-mediated non-allelic recombination events that predominantly arose from repair by SSA. All heavy metals showed a shift in the outcomes of alt-NHEJ repair with a significant increase of non-templated sequence insertions at the DSB repair site. Our data suggest that exposure to heavy metals will alter the choice of DNA repair pathway changing the genetic outcome of DSBs repair.

Substantial evidence supports the value of outdoor education programs for promoting healthy adolescent development, yet measurement of program outcomes often lacks rigor. Accurately assessing the impacts of programs that seek to promote positive youth development is critical for determining whether youth are benefitting as intended, identifying best practices and areas for improvement, and informing decisions about which programs to invest in. We generated brief, customized instruments for measuring three outcomes among youth participants in Baltimore City Outward Bound programs: conflict management, emotional self-efficacy, and problem solving confidence. Measures were validated through exploratory and confirmatory factor analyses of pilot-testing data from two groups of program participants. We describe our process of identifying outcomes for measurement, developing and adapting measurement instruments, and validating these instruments. The finalized measures support evaluations of outdoor education programs serving urban adolescent youth. Such evaluations enhance accountability by determining if youth are benefiting from programs as intended, and strengthen the case for investment in programs with demonstrated success.

Populations around the world are rapidly ageing and effective treatment for HIV means women living with HIV (WLHIV) can live longer, healthier lives. HIV testing and screening programmes and safer sex initiatives often exclude older sexually active WLHIV. Systematically reviewing the literature to inform World Health Organization guidelines on the sexual and reproductive health and rights (SRHR) of WLHIV, identified four studies examining healthy sexuality among older WLHIV. In Uganda, WLHIV reported lower rates of sexual activity and rated sex as less important than men. In the United States, HIV stigma, disclosure, and body image concerns, among other issues, were described as inhibiting relationship formation and safer sexual practices. Sexual activity declined similarly over time for all women, including for WLHIV who reported more protected sex, while a significant minority of WLHIV reported unprotected sex. A single intervention, the "ROADMAP" intervention, demonstrated significant increases in HIV knowledge and decreases in HIV stigma and high risk sexual behaviour. WLHIV face ageist discrimination and other barriers to remaining sexually active and maintaining healthy sexual relationships, including challenges procuring condoms and seeking advice on safe sex practices, reduced ability to negotiate safer sex, physical and social changes associated with menopause, and sexual health challenges due to disability and comorbidities. Normative guidance does not adequately address the SRHR of older WLHIV, and while this systematic review highlights the paucity of data, it also calls for additional research and attention to this important area.

BACKGROUND:Impairments in key neuropsychological domains (e.g. working memory, attention) and social cognitive deficits have been implicated as intermediate (endo) phenotypes for bipolar disorder (BD), and should therefore be evident in unaffected relatives. METHOD/METHODS:Neurocognitive and social cognitive ability was examined in 99 young people (age range 16-30 years) with a biological parent or sibling diagnosed with the disorder [thus deemed to be at risk (AR) of developing BD], compared with 78 healthy control (HC) subjects, and 52 people with a confirmed diagnosis of BD. RESULTS:Only verbal intelligence and affective response inhibition were significantly impaired in AR relative to HC participants; the BD participants showed significant deficits in attention tasks compared with HCs. Neither AR nor BD patients showed impairments in general intellectual ability, working memory, visuospatial or language ability, relative to HC participants. Analysis of BD-I and BD-II cases separately revealed deficits in attention and immediate memory in BD-I patients (only), relative to HCs. Only the BD (but not AR) participants showed impaired emotion recognition, relative to HCs. CONCLUSIONS:Selective cognitive deficits in the capacity to inhibit negative affective information, and general verbal ability may be intermediate markers of risk for BD; however, the extent and severity of impairment in this sample was less pronounced than has been reported in previous studies of older family members and BD cases. These findings highlight distinctions in the cognitive profiles of AR and BD participants, and provide limited support for progressive cognitive decline in association with illness development in BD.

OBJECTIVE:Medication nonadherence is a serious issue in clinical trials, especially in studies of substance abuse disorders. Measuring and confirming adherence is critical to ensuring that collected data is accurate and interpretable. This study evaluated the feasibility and success of a smartphone-based approach (Cellphone Assisted Remote Observation of Medication Adherence [CAROMA]) to visually confirm medication adherence in a clinical trial. METHOD:Medication adherence was confirmed visually via smartphones provided to participants in a double-blind, randomized, placebo-controlled trial for cannabis dependence. Every morning, subjects (n=20) were video-called by staff who observed consumption of study medication. Adherence was also assessed with weekly face-to-face visits, pill counts and plasma drug levels. Subjects were paid for completing daily CAROMA visits, and for returning the smartphone at study completion. RESULTS:CAROMA confirmed 96.04% adherence to medication. Concordance between expected and actual remaining study medication counted at weekly study visits was 87.69%. Subjects assigned to active study medication had detectable plasma drug levels, while those assigned to placebo did not. CAROMA was estimated to cost approximately $100 per subject per week - a total of $300.24 per subject for the 3-week outpatient portion of the trial. CONCLUSION:This pilot study demonstrates the feasibility, success and cost-effectiveness of CAROMA to facilitate and confirm medication adherence in a clinical trial. Preliminary findings support larger and longer studies, and possibly applying this approach to clinical care - especially in other populations with high rates of medication nonadherence.

BACKGROUND:R availability in cannabis-dependent (CD) subjects after short-term and intermediate-term abstinence has not been determined. METHODS:C]OMAR volume of distribution was measured in male CD subjects (n = 11) and matched healthy control (HC) subjects (n = 19). The CD subjects were scanned at baseline (while they were neither intoxicated nor in withdrawal) and after 2 days and 28 days of monitored abstinence. The HC subjects were scanned at baseline, and a subset (n = 4) was scanned again 28 days later. RESULTS:R availability in CD subjects after 28 days of abstinence. CONCLUSIONS:R downregulation, which begins to reverse rapidly on termination of cannabis use and may continue to increase over time.