Faculty Bibliography

BACKGROUND:Disability among women of reproductive age is common; many of these women desire children and do not have impaired fertility. OBJECTIVES/OBJECTIVE:To examine the epidemiological literature on perinatal health outcomes among women with physical disabilities. DATA SOURCES/METHODS:We searched Medline and CINAHL for articles published January 2009-April 2020 following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. STUDY SELECTION AND DATA EXTRACTION/METHODS:Eligible studies were observational, quantitative, and reported on physical disabilities in association with prenatal, perinatal, postpartum, and/or infant health outcomes. We included studies that grouped physical and non-physical disabilities, such as surveys that queried only about general daily life limitations. We excluded case reports, descriptive studies without comparison groups, and studies conducted in low- or middle-income countries. Data extraction was done using predefined data fields. SYNTHESIS/RESULTS:All authors were involved in screening activities, data extraction, and/or quality assessment (rating and areas for bias). RESULTS:A total of 2650 articles were evaluated, of which sixteen met inclusion criteria (8 cross-sectional studies and 8 retrospective cohort studies). Assessments of disability status and perinatal outcomes widely varied across studies. Studies were rated as poor (n = 8) or fair quality (n = 8). Findings suggested that women with physical disabilities were at risk of several adverse outcomes, including caesarean delivery, infections, preterm complications, and maternal post-delivery hospitalisations, while their infants may be at risk of low birthweight and small-for-gestational age. Women classified as having complex/severe disabilities were often observed to be at higher risk of adverse outcomes compared to women with less severe disabilities. CONCLUSIONS:Research assessing how physical, functional, and medical restrictions influence health outcomes among women with physical disabilities, from preconception through postpartum, is limited. Longitudinal studies with comprehensive data collection that accurately identify women with physical disabilities are critical to understanding their reproductive health risks and outcomes.

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene-environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene-environment studies.

OBJECTIVE:Recently, rational polypharmacy approaches have been proposed, regardless of the lower risk and cost of monotherapy. Considering monotherapy as first-line treatment and polypharmacy as rational treatment, a balanced attitude toward polypharmacy is recommended. However, the high prevalence of polypharmacy led the Japanese government to establish a polypharmacy reduction policy. Based on this, the association between the policy and psychiatrists' attitude toward polypharmacy has been under debate. METHODS:We developed an original questionnaire about Psychiatrists' attitudes toward polypharmacy (PAP). We compared the PAP scores with the treatment decision-making in clinical case vignettes. Multiple regression analyses were performed to quantify associations of explanatory variables including policy factors and PAP scores. The anonymous questionnaires were administered to psychiatrists worldwide. RESULTS:The study included 347 psychiatrists from 34 countries. Decision-making toward polypharmacy was associated with high PAP scores. Multiple regression analysis revealed that low PAP scores were associated with the policy factor (β=-0.20, p=0.004). The culture in Korea was associated with high PAP scores (β=0.34, p<0.001), whereas the culture in India and Nepal were associated with low scores (β=-0.15, p=0.01, and β=-0.17, p=0.006, respectively). CONCLUSION/CONCLUSIONS:Policy on polypharmacy may influence psychiatrists' decision-making. Thus, policies considering rational polypharmacy should be established.

Background PVSRIPO, a novel intratumoral viral immunotherapy, infects cells via CD155, which is widely expressed on solid tumors and antigen-presenting cells (APC). Infection is lethal in malignant cells, but a unique, activating, nonlethal infection of local APCs yields type-I/III interferon (IFN)-dominant inflammation with subsequent anti-tumor T-cell priming and activation resulting in anti-tumor efficacy. In preclinical models, PVSRIPO-dependent inflammation upregulated the PD-1/L1 pathway, and greater anti-tumor response was observed with PVSRIPO + anti-PD-1/L1 (aPD-1/L1). Promising clinical activity with PVSRIPO monotherapy was observed in patients with recurrent glioblastoma and advanced aPD-1- refractory melanoma.1 2 Collectively, these results warrant further clinical investigation of PVSRIPO +/- aPD-1/L1. Methods LUMINOS-103 (NCT04690699) is a phase (Ph) 1/2, open-label, multi-center, single-arm basket trial evaluating repeat administration of PVSRIPO +/- aPD-1/L1 in adults with solid tumors. Trial objectives are to assess the safety and tolerability of PVSRIPO monotherapy in each cohort in Ph 1 and the safety, tolerability, and antitumor efficacy of PVSRIPO + aPD-1/L1 in each cohort in Ph 2. The first two study cohorts include patients with muscle-invasive bladder cancer being treated in the neoadjuvant setting (A) and patients with metastatic bladder cancer being treated in the 1st/2nd line setting (B); these cohorts have been described previously.3 Cohort C includes patients with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC) being treated in the neoadjuvant setting; Cohort D includes patients with recurrent/ metastatic HNSCC with a PD-L1 Combined Positive Score >=1 being treated in the 1st line setting. Eligibility: HNSCC patients must have histologically or cytologically-proven SCC of the oral cavity, oropharynx, hypopharynx, or larynx. All patients must have prior and boosted PV immunization and tumors amenable to injection and biopsy. Key exclusion criteria: Requirement for oxygen supplementation, systemic or intratumoral therapy <=6 months prior to the first dose of study drug, CNS metastases requiring immediate treatment, systemic immunosuppressive medications <=4 weeks prior to the first dose of study drug, and severe active comorbidities. Patients who are HIV+, HBV+ or HCV+ are eligible provided they meet certain criteria. Primary endpoints include safety (all cohorts), tolerability (all cohorts), surgical complication rate (A, C), pathologic treatment effect/response (A, C), and objective response rate (B, D). Secondary endpoints include overall survival (all cohorts), pathologic downstaging and relapse-free survival (A, C), duration of response and progression- free survival (B, D), and assessment of tumor/blood biomarkers (all cohorts)

The high co-occurrence of intimate partner violence (IPV) and physical child abuse suggests that studying these forms of aggression simultaneously, bidirectionally, and longitudinally is critical. Guided by family systems theory, this study examined parent-child aggression (PCA) risk, IPV victimization, and child behavior problems as reported by mothers and fathers when their child was 18 months and at 4 years old, to evaluate whether negative processes can transmit across family subsystems (i.e., spillover hypothesis) and/or across individuals (i.e., crossover hypothesis). Results indicated that mothers' PCA risk predicted their subsequent IPV victimization and their reported child behavior problems (i.e., spillover effects) as well as fathers' reported IPV victimization (i.e., crossover effect). Maternal reports of child behavior problems also predicted mothers' reported IPV victimization and fathers' reported child behavior problems, indicating child-driven effects. Overall, mothers rather than fathers appear more vulnerable to harmful spillover effects. Findings underscore the need for early prevention and intervention given the complex, transactional nature of family violence.

Infant walking skill improves with practice-crudely estimated by elapsed time since walk onset. However, despite the robust relation between elapsed time (months walking) and skill, practice is likely constrained and facilitated by infants' home environments, sociodemographic influences, and spontaneous activity. Individual pathways are tremendously diverse in the timing of walk onset and the trajectory of improvement, and presumably, in the amount and type of practice. So, what factors affect the development of walking skill? We examined the role of months walking, walk onset age, spontaneous locomotor activity, body dimensions, and environmental factors on the development of walking skill in two sociodemographically distinct samples (ns = 38 and 44) of 13-, 15-, and 19-month-old infants. Months walking best predicted how well infants walked, but environmental factors and spontaneous activity explained additional variance in walking skill. Specifically, less crowded homes, a larger percentage of time in spontaneous walking, and a smaller percentage of short walking bouts predicted more mature walking. Walk onset age differed by sample but did not affect walking skill. Findings indicate that elapsed time since walk onset remains a robust predictor of walking skill, but environmental factors and spontaneous activity also contribute to infants' practice, thereby affecting walking skill.

Purpose: Although the intrahippocampal kainic acid (IHKA) model has been widely used to simulate temporal lobe epilepsy (TLE) in mice, there is variation in outcomes, with many studies showing few robust seizures long-term, especially convulsive seizures. We present an implementation of the IHKA model with frequent chronic convulsive seizures that are robust in frequency, duration and both sexes can be used.
Method(s): Our methods varied slightly from prior studies. We employed continuous wideband video-EEG from 2 cortical and 2 hippocampal sites to characterize chronic epilepsy outcomes in both sexes and 2 timepoints (2-4 and 10-12wks post-IHKA).
Result(s): Analysis of convulsive seizures at 2-4 and 10-12wks post-IHKA showed a robust frequency (2-4/day on average) and duration (typically 20-30 sec) at each time. Comparison of the 2 timepoints showed that seizure burden became more severe in approximately 50% of the animals. We show that almost all convulsive seizures could be characterized as either low-voltage fast or hypersynchronous onset seizures, which has not been reported in a mouse model of epilepsy and is important because these seizure types are found in humans. In addition, we report that high-frequency oscillations (HFOs, >250Hz) occur, resembling findings from IHKA in rats and TLE patients. Pathology in the hippocampus at the site of IHKA injection was similar to mesial temporal lobe sclerosis and reduced contralaterally.
Conclusion(s): In summary, our methods produce a model of TLE in mice with robust convulsive seizures, show variable progression, that HFOs are robust also, and that the model has seizures with onset patterns and pathology like human TLE. We believe our results will advance the ability to use the IHKA model of TLE in mice. The results also have important implications for our understanding of HFOs, progression and other topics of broad interest to the epilepsy research community including preclinical drug screening

The SARS-COV-2 (COVID-19) pandemic and associated social distancing guidelines have accelerated the telehealth transition in mental health. For those providing Behavioral Parent Training (BPT), this transition has called for moving sessions that are traditionally clinic-based, active, and directive to engaging, supporting, and treating families of children with behavior disorders remotely in their homes. Whereas many difficulties accompany this transition, the lessons learned during the current public health crisis have the potential to transform BPT service delivery on a large scale in ways that address many of its long-standing limitations. We describe both challenges and opportunities and consider the possibilities inherent in a large scale BPT service delivery model capable of increasing the reach and impact of evidence-based treatment for all families.

We assessed the effect of depression, hopelessness, and self-concept on HIV prevention attitudes and knowledge about infection, transmission and sexual risk behavior among adolescents living with HIV in Uganda. Utilizing longitudinal data from 635 adolescents living with HIV, multiple ordinary least square regression was used to evaluate associations between the three indicators of mental health functioning at baseline and HIV knowledge and prevention attitudes at 12-months follow-up. We found that depression (β = - 0.17; 95% CI - 0.31, - 0.04) and hopelessness (β = - 0.16; 95% CI - 0.28, - 0.04) scores at baseline were associated with a 0.17 and 0.16 average reduction in HIV prevention attitudes and HIV knowledge scores, respectively at 12-months follow-up. However, self-concept was not significantly associated with HIV knowledge or prevention attitudes. Adolescents living with HIV with greater levels of hopelessness are at increased risk of having limited HIV knowledge while those with greater symptoms of depression had less favorable HIV prevention attitudes.

The dentate gyrus not only gates the flow of information into the hippocampus, it also integrates and processes this information. Mossy cells (MCs) are a major type of excitatory neuron strategically located in the hilus of the dentate gyrus where they can contribute to this processing through networks of synapses with inhibitory neurons and dentate granule cells. Some prior work has suggested that MCs can form excitatory synapses with other MCs, but the role of these synapses in the network activity of the dentate gyrus has received little attention. Here, we investigated synaptic inputs to MCs in mouse hippocampal slices using a genetically encoded hybrid voltage sensor (hVOS) targeted to MCs by Cre-lox technology. This enabled optical recording of voltage changes from multiple MCs simultaneously. Stimulating granule cells and CA3 pyramidal cells activated well-established inputs to MCs and elicited synaptic responses as expected. However, the weak blockade of MC responses to granule cell layer stimulation by DCG-IV raised the possibility of another source of excitation. To evaluate synapses between MCs as this source, single MCs were stimulated focally. Stimulation of one MC above its action potential threshold evoked depolarizing responses in neighboring MCs that depended on glutamate receptors. Short latency responses of MCs to other MCs did not depend on release from granule cell axons. However, granule cells did contribute to the longer latency responses of MCs to stimulation of other MCs. Thus, MCs transmit their activity to other MCs both through direct synaptic coupling and through polysynaptic coupling with dentate granule cells. MC-MC synapses can redistribute information entering the dentate gyrus and thus shape and modulate the electrical activity underlying hippocampal functions such as navigation and memory, as well as excessive excitation during seizures.