Now showing items 1-20 of 1664

    • Utilizing Charged Membrane Technology for Endotoxin Removal with Potential Use in Endodontic Procedures

      Yeung, Wing-Yee; Ernst, Robert K.
      AIM: To examine the application of a positively-charged polyvinylidene fluoride (PVDF) membrane for removing liquids and endotoxins. METHODOLOGY: Absorbency and endotoxin removal of paper points from various manufacturers was compared with PVDF membrane. The paper points and the PVDF membrane were evaluated for endotoxin binding using Limulus Amebocyte Lysate (LAL) assay. New paper points and the PVDF membrane were evaluated for the presence of endotoxins. RESULTS: Absorbency and endotoxin removal with the 0.22µm PVDF membrane was significantly greater than any of the paper points tested. There was significantly more endotoxin found in new paper points compared to the PVDF membrane. CONCLUSION: Our study showed that the 0.22μm PVDF membrane was significantly more absorbent and removed more endotoxins than paper points. Commercially available paper points were found to be contaminated with endotoxins and mechanical agitation of the PVDF membrane did not release endotoxin.
    • Role of Vaccine-Induced IgG in Protection Against Bordetella Pertussis

      Masterson, Mary; Pasetti, Marcela F.
      Bordetella pertussis is a highly infectious respiratory pathogen that can induce severe bronchopneumonia and respiratory failure in infants (whooping cough). Vaccine formulations consisting of Diphtheria toxoid, Tetanus toxoid, and Acellular Pertussis (aP) components (DTaP and Tdap) protect against disease. It remains unclear how a parenteral vaccine, which primarily elicits systemic IgG, contributes to protection against a respiratory pathogen. The goal of this study was to investigate mechanisms by which vaccine-induced IgG reaches the respiratory mucosa and contributes to protection against B. pertussis infection. We hypothesized that pertussis-specific systemic IgG is transported from circulation into the airways via the neonatal Fc receptor (FcRn). To test this hypothesis, wild type mice and mice lacking FcRn (FcRn-/-) were immunized with DTaP or passively transferred DTaP-immune serum and challenged with B. pertussis. Post-challenge readouts included kinetics of Pertussis Toxin (PT) IgG in serum and bronchoalveolar lavage fluid (BALf), bacterial load quantification, and histopathology of lung tissues. WT vaccinated mice were able to clear the infection, whereas FcRn-/- vaccinated mice had residual bacterial counts and increased lung inflammation. Passive administration of DTaP-immune sera reduced lung colonization in both WT and FcRn-/- mice. However, FcRn-/- recipients exhibited moderate bronchopneumonia (absent in WT mice). The lower bacterial clearance and exacerbated tissue damage observed in actively and passively immunized FcRn-/- mice was not due to the absence of PT-IgG (or differences in IgG isotype) in BALf. Rather, WT and FcRn-/- mice had similar PT-IgG levels in serum and BALf, suggesting that FcRn-independent mechanisms mediate IgG transport across the lung. PT-IgG progressively increased in BALf of passively immunized FcRn-/- mice post-challenge (along with lung inflammation,) suggesting IgG also diffuses through damaged lung epithelium. We observed that neutrophils from FcRn-/- mice had lower B. pertussis opsonophagocytic capacity as compared to WT. This impairment in IgG-mediated antimicrobial function in the absence of FcRn could explain the increased inflammation in FcRn-/- mice. In conclusion, we have shown that pertussis-specific IgG translocation into the airways appears to be FcRn-independent, and that IgG-mediated B. pertussis neutrophil phagocytosis may contribute to bacterial clearance and tissue preservation post-infection through FcRn interactions.
    • Evaluation of a Poly(Lactic-Co-Glycolic) Acid-Coated β-Tricalcium Phosphate Bone Substitute for Alveolar Ridge Preservation: Multicenter Randomized Control Trial

      West, Brandon M.; Saito, Hanae
      Purpose: The aim of this study was to determine whether the efficacy of PLGA-β-TCP in Alveolar Ridge Preservation (ARP) with histological analysis of the extraction socket following four months healing was similar to FDBA + CP as the control. Materials and Methods: 45 adult patients in this multicenter randomized controlled clinical trial were randomly assigned into treatment group A [PLGA-β-TCP] or group B [FDBA + CP] for ARP of a single extraction socket. Results: 45 bone core samples were harvested. Vital bone was present in intimate contact with the surface of β-TCP graft particles. Histologic measurements revealed no statistically significant difference between the test and control groups in percent vital bone after four months healing. Conclusion: This investigation demonstrated the similar efficacy of PLGA- β-TCP to FDBA as a bone substitute in ARP.
    • Effects of Glycemic Control on Soft Tissue Wound Healing around Dental Implants for Patients with Type 2 Diabetes

      Hurwitz, Morgan Barker; Oates, Thomas W.
      This study evaluated the effects of glycemic status on soft tissue wound healing following dental implant placement. A total of 164 edentulous patients with HbA1c levels up to 11.5% received two mandibular transmucosal dental implants. Patients’ self-reported pain (VAS and # days with pain) and soft tissue healing (edema, erythema, exudate, oral pain, flap closure, infection, and hematoma) were evaluated one week after placement. HbA1c and diabetes status were not significantly associated with any soft tissue healing complications. Pain_VAS was significantly correlated with Edema, Infection, Days in Pain and Oral Pain. Flap Closure was correlated with Oral Pain. Infection was correlated with Oral Pain and Days_Pain. Stepwise regression also identified HbA1c as significantly contributing to the VAS pain score. The findings of this study clarify the low risk for post-surgical healing complications independent of poor glycemic control, extending the opportunities for dental implant therapy for patients with diabetes.
    • Patterns of Suicidal Risk and Its Relationship with Suicidal Ideation and Attempt: Practice and Policy Implications

      Nam, Boyoung; DeVylder, Jordan E.; Jacobson Frey, Jodi
      Despite efforts to prevent suicide, suicide mortality rate has been increasing since 2000. This dissertation examined distinct patterns of suicidal risk based on the interpersonal-psychological theory of suicide (IPTS; Joiner, 2005), and the most critical patterns of suicidal ideation and suicide attempt were explored using latent class analysis. A nationally representative sample of White, Black, Latinx, and Asian adults from the Collaborative Psychiatric Epidemiology Surveys (Alegria et al., 2016) was used. For White adults, five latent classes were identified, and respondents in the All Three with Alcohol/Drug Dependence, All Three without Alcohol/Drug Dependence, and Thwarted Belongingness + Perceived Burdensomeness classes were more likely to demonstrate suicidal ideation and suicide attempt than those in the Only Acquired Capability for Suicide class. For Black adults, six latent classes were identified, and respondents in the All Three with Alcohol/Drug Dependence and All Three without Alcohol/Drug Dependence classes were significantly more likely to attempt suicide than those in the Low Risk class. For Latinx respondents, four latent classes were identified, and respondents in the Thwarted Belongingness + Acquired Capability for Suicide class were significantly more likely to attempt suicide than respondents in the Low Risk class. For Asian respondents, three latent classes were identified, and respondents in Thwarted Belongingness + (Active) Acquired Capability for Suicide class had a significantly higher risk for suicidal ideation and suicide attempt than those in the Low Risk class. Findings of this dissertation supported the major tenets of the IPTS that individuals are at the greatest risk for suicide attempt when thwarted belongingness, perceived burdensomeness, and acquired capability for suicide coexist. In addition, this dissertation found some variations across the four racial/ethnic groups. Findings suggested that clinicians working with people with higher risk for suicide should explore multiple dimensions of suicidal risk, especially clients’ capability for suicide (e.g., past exposure to trauma and pain- and fear-reducing experiences). Suicide-prevention campaigns and trainings need to include exploration of past exposure to trauma, physical violence, and risk-taking behaviors as well as access to means in training sessions so that trainees can better detect people with higher risk of suicide attempt.
    • Deciphering relatedness and population demographics in diverse population structures by leveraging haplotype and rare variant sharing detected from whole genome sequencing

      Shetty, Amol Carl; O'Connor, Timothy D
      Genealogical analysis using genomic variants is essential for a variety of applications in human genetics such as estimating population structure, migration events and evolutionary history. The 1000 Genomes Project is an example of a study of human genomic diversity and continental population structure. Multiple studies illustrate the utility of genetic variation for the reconstruction of human migratory patterns within and between continental populations and the demographic events influencing evolutionary history. Current methods for assessment of population structure and genetic relatedness use individual genetic loci and do not take full advantage of the large number of markers provided by whole genome sequencing techniques. More recently, haplotype sharing or identity by descent (IBD) estimates have been used as a promising method to elucidate demographic admixture/migratory events. This dissertation focuses on the application of IBD sharing to decipher genetic relatedness and demographic events that influence population substructure. Knowledge of genome-wide patterns of IBD sharing among individuals helped distinguish between ancient and recent demographic events and detect fine-structure among the recently expanded and admixed New World populations from Peru. This addresses the gap in knowledge regarding the population fine-structure of indigenous and admixed communities from geographically distinct regions of Peru. IBD sharing, primarily utilized to study human demography, was applied to study fine-structure and demography of haploid malarial parasite populations in Southeast Asia which helped elucidate the migratory patterns of the parasite and guide the elimination strategies of the World Health Organization (WHO). Current IBD methods accurately detect long segments based on information from common variants. However, cohorts involving cryptic relatedness mostly share short IBD segments. In light of this limitation, rare variants arising from recent dramatic events of population expansion convey more information on short IBD segments than common variants. This knowledge of IBD sharing leveraged by rare variants influences the timescales at which familial relatedness and population structure can be assessed. In sum, this dissertation illustrates the utility of IBD segments of variable lengths and the accumulation of rare variants within these segments to detect fine-scale population structure at different evolutionary timescales and fills the gaps in knowledge in both human and non-human populations.
    • Elucidation of the Role of CD44 Receptor and its Intracellular Domain in the Progression of Prostate Cancer

      Senbanjo, Linda Temilade; Chellaiah, Meenakshi A
      Prostate cancer (PCa) is the second leading cause of cancer-related death in men in the United States partially due to metastatic spread to secondary sites in the bone, brain, lymph nodes and visceral organs. Here, we examine the mechanisms that can facilitate PCa progression/metastasis. CD44 is a multifunctional receptor that functions in tumorigenesis and cancer progression. Recent studies point to CD44 cleavage product; CD44 Intracellular Domain (ICD) as the fragment responsible for transcription of metastasis-related genes (MRGs). Using knockdown and overexpression strategy, we 1) determine the effect of androgen receptor (AR) and CD44 expression on stemness characteristics of PCa cells (PC3), 2) characterize CD44-ICD interaction with RUNX2 in PC3 cells and 3) determine the specificity of interaction of CD44-ICD sequences with RUNX2 and its contribution to PCa progression. We show SOX2 expression is high at mRNA and protein levels of bone metastatic PC3 cells that are AR-negative. Additionally, CD44 regulates the expression of SOX2 and knockdown of SOX2, or CD44 resulted in decrease of cell migration which was reversed with the re-expression of AR. To examine the contribution of CD44-ICD to the tumorigenic potential of PCa cells, we characterized CD44-ICD expression in PCa cells then determined its interaction with RUNX2, a transcription factor also known to promote tumorigenesis. We show the interaction of CD44-ICD/RUNX2 in the nucleus and overexpression of RUNX2 resulted in increased cell migration and tumorsphere formation via the upregulation of MRGs. Consistently, generation and overexpression of CD44-ICD-FL and CD44-ICD carboxyl-terminal deletion constructs resulted in increased interaction with RUNX2 in the nucleus with greater specificity for interacting with constructs: FL and D1 to D3. Likewise, these constructs show an increase in the expression of OPN and MMP-9 genes. However, CD44-ICD-FL, as well as D1 to D3 constructs, shows more specificity to the promoter of MMP-9 in CHIP assay analyses. This also corresponds with the expression levels of MMP-9 protein. These findings not only suggest the specificity of CD44-ICD function towards the expression of MMP-9 but also metastasis relevant events including migration and tumorigenesis. These also implicate CD44-ICD as a novel therapeutic target in cancer cells that express CD44.
    • Substance Use Disorders during Pregnancy: Comprehensive Care and Predictors of Delivery Outcomes

      Seger, Celeste Marie; Storr, Carla L.
      Introduction: Illicit substance use is increasing among pregnant women seeking treatment for substance use disorders. Resources are scarce for this vulnerable population in terms of addressing their complex needs. Comprehensive care programs offering perinatal care services and substance abuse treatment in a single location have been found to favorably treat pregnant clients and positively affect neonatal and maternal delivery outcomes. Purpose: To review comprehensive care program studies, evaluate research quality, and examine outcome criteria. Also, to examine the impact of pregnant women’s comprehensive care attendance and pre-treatment psychiatric severity on neonatal and maternal delivery outcomes. Methods: A systematic literature review was conducted on treatment programs offering a so called “one-stop” comprehensive care approach. A secondary analysis study was employed to examine the effects of treatment attendance on neonatal and maternal delivery outcomes for pregnant women with substance use disorders receiving comprehensive care. A subsequent secondary analysis study was completed to determine the relationship between pre-treatment psychiatric severity and delivery outcomes for pregnant clients with substance use disorders in a comprehensive program. Results: The literature review identified thirteen comprehensive care studies, most of which used an observational design. Overall study quality was assessed as moderate for reporting and strength of evidence. Outcome criteria measures often included neonatal parameters such as weight, estimated gestation age, neonatal abstinence syndrome, and hospital length of stay, and maternal delivery outcomes frequently included urine toxicology screens on delivery and hospital length of stay. The first data analysis indicated comprehensive care attendance was favorably related to most neonatal and maternal delivery outcomes. The second data analysis showed similar neonatal and maternal outcomes regardless of psychiatric severity grouping, suggesting comprehensive care as an effective treatment for those with high levels of psychiatric symptomology. Conclusion: Results across all three manuscripts illustrate comprehensive care models as a favorable treatment approach for pregnant women with substance use disorders.
    • Developing Therapies to Overcome Immunosuppressive Myeloid Cells in the Tumor Microenvironment

      Ceradoy, Justine Anne; Davila, Eduardo, Ph.D.
      Myeloid cells in the tumor microenvironment represent significant barriers to the development of successful cancer immunotherapies. A multi-kinase inhibitor, Regorafenib (Reg), and a DNA-PK inhibitor, NU7441 (NU) were shown in a previous study to reduce expression of immunoinhibitory proteins in adaptive immune cells while increasing stimulatory MHC-I on cancer cells. In this study, we explored whether these drugs could reverse the suppressive activity of myeloid-derived suppressor cells (MDSCs) and alternatively activated macrophages. To test this idea, we used splenocytes from tumor-bearing mice and a human monocytic cell line differentiated into suppressive macrophages and assessed Arginase activity, their ability to suppress effector T cells, and mRNA expression of immunosuppressive and activating markers. We showed that Reg/NU decrease arginase activity and increase immunoactivating markers. These data demonstrate that treatment of suppressive myeloid cells with Reg/NU confers a less suppressive phenotype and leads to the generation of a more activating phenotype.
    • The Role of Nociceptors in Orthodontic Tooth Movement, Pain, and Alveolar Bone Remodeling

      Elnabawi, Omar; Pae, Eung-Kwon
      Objective: To determine the effects of selectively ablating transient receptor potential vanilloid 1 (TRPV1)-expressing nociceptors on orthodontic tooth movement, pain, and alveolar bone remodeling. Methods: Resiniferatoxin (RTX) or vehicle was stereotaxically injected into left trigeminal ganglia in adult C57BL/6 mice. After 1 week, orthodontic spring was placed between left maxillary first molar and upper incisors. Pain level was evaluated by measuring mouse grimace scale (MGS) and bite force before and after 1, 3, and 7 days following the procedures. After 12 days, micro-CT was used to quantify tooth movement and analyzing alveolar bone changes. Results: Experimental tooth movement increased MGS scores and decreased bite force. RTX ablation of TRPV1+ nociceptors attenuated MGS scores and relieved the reduction in bite force. The extent of tooth movement was decreased in RTX-treated group, but interradicular alveolar bone volume was not affected. Conclusion: Selective ablation of TRPV1+ nociceptors significantly decreases tooth movement and pain.
    • A Comparative Study of Preventive Healthcare Behaviors Among African Immigrant Women (AIW) and African American Women (AAW): Barriers and Facilitators of Cervical Cancer Prevention

      Kuffour-Manu, Vera Akosua; Ogbolu, Yolanda; Johantgen, Mary E.
      Abstract Background: Early screening, detection, and treatment of cervical pre-cancerous cells could prevent up to 80% of cervical cancers and reduce cervical cancer mortality by 52% globally. In the United States cervical cancer incidence has decreased by as much as 50% over the past 40 years due to widespread utilization of preventive health services. Yet, health disparities in cervical cancer persist among African immigrant women (AIW) and African American women (AAW) in the US. There is limited research exploring the barriers and facilitators of preventive health services for AIW and AAW. Purpose: To explore perceived barriers and facilitators, and lived experiences of AIW and AAW related to cervical cancer prevention services. Methods: A qualitative study included 14 AIW and 14 AAW, residing in the Washington, DC-Baltimore Metropolitan area. Purposive sampling technique was used to recruit participants from churches,community center, grocery stores and a radio station. A semi-structured interview guide and a demographic questionnare were used for data collection. Data were analyzed using the Intepretative Phenomenological Analysis Method. Nvivo software was used to organize and code the data. Results: The mean age of participants was 41.1(11.9), with most of the women being college educated (93%), with health insurance (96%) that paid for cervical cancer prevention (89%). Many (79%) had not received HPV vaccine and 82% had a pap smear within 1-4years. AIW and AAW data were triangulated and revealed few differences between the groups. Six broad themes emerged grounded in the Health Belief Model. Barriers identified included limited knowledge and awareness of HPV infection, risk, and vaccines; myths related to abstinence, fear, and cleanliness of healthcare facilities; lack of trust and reliance on God for healing. Facilitators included the need to feel safe and healthy; prevent and treat disease; utilize informal and formal support systems; and receive recommendation from providers and public health education related to preventive services. Conclusion: Study findings can be used to mitigate barriers and enhance facilitators to develop culturally tailored interventions for AAW and AIW. The active engagement of health providers, the community and faith based partners can be leveraged to strengthen the development of prevention research.
    • The Role of LRP1 in Inflammation and Vasculopathies

      Au, Dianaly; Strickland, Dudley K.; Catania, Selen M.; 0000-0002-8797-833X
      The prevalence of overweight and obesity and a growing aging population has resulted in higher incidences of type 2 diabetes (T2D) and cardiovascular disease (CVD). Although risk factors for T2D and CVD have been known for decades, the molecular mechanisms involved in the pathophysiology of these multifaceted diseases and their interrelationship remain unclear. The LDL receptor-related protein 1 (LRP1) is a large endocytic and signaling receptor that is abundantly expressed in several tissues and possesses diverse biological functions, including chylomicron remnant clearance, involvement in insulin signaling and glucose homeostasis, modulation of the inflammatory response, atheroprotection, and maintenance of vascular integrity. We hypothesized that LRP1 may serve as a molecular link between metabolic processes and CVD development and employed tissue-specific LRP1 knockout mouse models to identify potential molecular mechanisms. Studies performed on macrophage-specific LRP1-deficient mice generated on an LDL receptor knockout background (LDLR-/-; macLRP1-/-) and challenged with a Western diet revealed that LRP1 expression in macrophages promotes hepatic inflammation and the development of glucose intolerance and insulin resistance by modulating Wnt signaling. Interestingly, studies performed on smooth muscle-specific LRP1-deficient (smLRP1-/-) mice identified a novel and critical role for LRP1 in modulating vascular smooth muscle cell (VSMC) contraction by regulating calcium signaling events. These results uncovered a potential mechanism by which LRP1 protects against aneurysm development. Studies performed on VSMCs isolated from an aneurysm patient, who also contains two heterozygous missense mutations within the LRP1 gene, showed dysregulation of the TGF-β and p53 signaling pathways. These results provide further biological evidence supporting the association of LRP1 with aortic aneurysms. The role of LRP1 in vascular remodeling was also investigated by inducing remodeling in smLRP1-/- mice using the carotid artery ligation model. Our results suggest that LRP1 protects against excessive vascular remodeling by modulating angiotensin II-mediated signaling. Taken together, this work reveals the complex roles of LRP1 in various tissues and provides evidence supporting LRP1 as a critical molecule that integrates metabolic processes with inflammation and vascular disease.
    • Immunosuppressive Drug Regimens that May Help Improve Survival and Reduce the Risks of Rejection, Infection, and Malignancy after a Lung Transplant

      Wijesinha, Marniker; Hirshon, Jon Mark; 0000-0002-6609-8456
      Background: Median survival among lung transplant recipients is below 6 years, and there is minimal knowledge regarding modifiable factors that may help improve long-term survival. Identifying induction and maintenance immunosuppressive regimens associated with optimal survival can potentially improve outcomes. Methods: We classified lung transplant recipients in the United States from 2003-2016 according to their induction and prophylactic cell cycle inhibitor maintenance therapies, within a tacrolimus-based regimen. We compared the different therapies via multivariable Cox Proportional Hazards models, generating adjusted hazard ratios for death, rejection, infection, and malignancy, the latter three of which utilized semi-competing risks methods. Since prophylactic sirolimus initiation is delayed by up to 1 year post-transplant, adjustments were made to avoid immortal time bias. Multiple imputation was utilized to handle missing data. Results: Sirolimus had the best survival among cell cycle inhibitor maintenance therapies: adjusted Hazard Ratio (HR)=0.71, p=0.003, compared to mycophenolate mofetil [MMF]; chronic rejection incidence was also reduced with sirolimus (HR=0.75, p=0.005). Azathioprine also had slightly better survival than MMF (HR=0.92, p=0.05), and reduced infection incidence (HR=0.62, p<0.0001). Among induction therapies, equine ATG had the best survival: HR=0.79, p=0.003, compared to no induction, as well as reduced rejection (HR=0.75, p=0.02) and infection (HR=0.57, p=0.008) incidence. The combination of induction and maintenance therapies associated with the most favorable survival was sirolimus + tacrolimus maintenance with no induction; HR=0.48, p=0.002 compared to MMF + tacrolimus with induction, and HR=0.41, p<0.0001 compared to MMF + tacrolimus with no induction. Conclusions: Sirolimus initiated in the first year within a tacrolimus-based regimen may significantly improve long-term survival compared to MMF in lung transplant recipients. Out of all combinations of maintenance and induction therapies studied, sirolimus + tacrolimus maintenance with no induction therapy was associated with the best survival. In patients whom sirolimus cannot be utilized for any reason, azathioprine may modestly improve survival compared to MMF. Additional long-term studies in lung transplantation are needed to confirm these findings.
    • Elucidating the Role of Fatty Acid Synthase in Oral Carcinogenesis and Potential Therapeutics

      Wisniewski, David John; Schneider, Abraham; 0000-0002-7514-7918
      The 5-year overall survival rate in oral squamous cell carcinoma (OSCC) has remained relatively unchanged over decades, due to late stage diagnosis and high recurrence rates. This work investigates two potential contributing risk factors associated with OSCC development: nicotine, present in traditional combustible tobacco cigarettes and electronic nicotine delivery systems, and high glucose as associated with Type II diabetes and hyperglycemia. A novel therapeutic, TVB-3166, for OSCC treatment was also studied through in vitro experiments, which may help improve clinical treatments for fully developed, often late-stage OSCC. Through cell viability and growth assays, scratch assays to mimic in vitro migration, and western blotting, we determined that both nicotine and high glucose caused oral dysplastic keratinocytes to exhibit an increase in malignant-like behavior. High expression levels of fatty acid synthase (FASN), a key de novo lipogenic enzyme, have been implicated in OSCC, and this work presents the first evidence that both nicotine and high glucose markedly increase oral dysplastic keratinocyte FASN expression, which drives epidermal growth factor receptor (EGFR) signaling, a key pro-oncogenic signaling pathway commonly associated with oral carcinogenesis. We also demonstrate that TVB-3166, a novel selective FASN inhibitor, induces apoptosis and reduces in vitro OSCC cell migration. Moreover, TVB-3166 inhibits basal EGFR activity and several other oncogenic signaling proteins. This further establishes a potential role for FASN and EGFR not only in the progression of oral epithelial dysplastic pre-malignant lesions, but in fully-developed OSCC tumors. Overall, this work suggests that both nicotine and high glucose play a role in OSCC progression, specifically as it relates to FASN-dependent EGFR activation. Further, the novel drug TVB-3166 should be investigated in future pre-clinical animal models as a potential adjunct to OSCC therapeutics. Through an improved understanding of risk factors for OSCC development, as well as determination of novel therapeutic strategies, this work aims to improve overall patient survival through prevention of OSCC development, as well as discovery of new adjunctive treatments for fully established tumors.
    • The association between services and recidivism for adjudicated youth with behavioral health problems

      Winters, Andrew Madison; Bright, Charlotte Lyn
      Research consistently shows that a considerable proportion of adjudicated youth have substantial behavioral health problems; however, few studies compare a range of services for adjudicated youth with behavioral health problems and the association with continued offending. Therefore, the purpose of this longitudinal study is to explore the role of services for youth with behavioral health problems, comparing types of services, and the association with continued offending. The sample consisted of adjudicated youth who were placed in an out-of-home setting (N=2277). As such, placement type was used to explore the role of services. Survival analysis was employed to assess the time at risk for recidivism. Multivariate results suggest boys compared with girls, and youth from urban areas are more likely to recidivate, while older youth and youth who were adjudicated for a felony offense were less likely to recidivate. Youth with a high index of mental health problems had a 16% lower hazard of recidivating, and youth with a moderate and high index of aggression had greater than twice the hazard of recidivating. Youth who were placed in community-based residential programs were 24% less likely to recidivate compared with a more secure setting. As the length of placement increased youth were less likely to recidivate, and youth who had multiple placements were more likely to recidivate. This study is among a few studies comparing a range of services for adjudicated youth with behavioral health problems and strengthens the literature on out-of-home placements. Results suggest community-based placements may act as a buffer for continued offending and aggression problems significantly increase the likelihood of further offending. Furthermore, outcomes from this study suggest a tailored service approach for youth with aggression problems prior to justice involvement is needed. This study provides empirical knowledge for practitioners and policy makers by highlighting service pathways for adjudicated youth with behavioral health problems. Further research is needed to explore key decision entry points in the justice system in which services are most effective at reducing ongoing court involvement. Moreover, future research is needed to address how symptoms and services may differ by gender, race and ethnicity, and age.
    • Histomorphometric Analysis of Mouse Growth Plate during Maturation and Senescence.

      Wilson, Kimberly; Enomoto-Iwamoto, Motomi
      The growth plate (GP) is cartilage tissue at both ends of long bones and plays an essential role for long bone formation and growth. GP changes in overall height, width, zone proportion, cell density and size during skeletal growth and becomes arrested upon skeletal maturation. There is limited information on GP microscopic changes. To establish GP histomorphometric parameters changes throughout skeletal maturation, the tibia of C57Bl/6J mice were evaluated from neonatal to young adult stages. GP histology in the proximal tibia was analyzed regarding total and zone height, width and area. The results showed unique GP changes in width, height and area during growth. The parameters also showed strong correlation with growth rate of the tibia. We studied GP proliferation activity and also found its correlation with tibia growth rate. The results of this study provide groundwork that will aid skeletal research on understanding of GP changes during bone growth.
    • Microglia Regulation of Sexually Dimorphic Amygdala Development

      VanRyzin, Jonathan; McCarthy, Margaret M., 1958-; 0000-0003-2990-6765
      Sex differences in the brain are established early in development and generate lasting changes in brain and behavior, a process known as sexual differentiation. Sexual differentiation of the amygdala produces a highly conserved sex difference in juvenile rough and tumble play behavior; however, the mechanisms underlying this sex difference are unknown. Here, we report that microglia, resident immune cells of the brain, actively shape the sexual differentiation of the amygdala. We found that microglia are more phagocytic in the amygdala of males from postnatal day 0 and 4, during which they also have a higher endocannabinoid (eCB) tone. Administering a masculinizing dose of testosterone to increase the eCB tone in females, or cannabinoid receptor agonists to female pups increased the number of phagocytic microglia and correspondingly decreased the number of newborn cells. Given these data, we hypothesized that microglia control the number of postnatally-born cells in the developing rat amygdala by phagocytosing newborn cells in an endocannabinoid-dependent manner. We found that these phagocytic microglia engulf newly proliferated cells, which are enriched for complement proteins. To directly implicate microglia phagocytosis, we used a function-blocking antibody against the complement receptor 3 (CR3) to prevent phagocytosis. Anti-CR3 antibody treatment increased the number of BrdU+ cells only in males, demonstrating that newborn cells can survive if phagocytosis is prevented. Moreover, administration of cannabinoid receptor antagonists to male pups occluded the effects of phagocytic blockade, suggesting that newborn cell phagocytosis was dependent on the developing ECB tone. Finally, to understand how these early life events manifest changes in the composition of the amygdala, we used a fate mapping approach to phenotype postnatally-born cells at the juvenile age. Our analysis found that the majority of newborn cells differentiated into astrocytes, which were overall higher in density in the posterodorsal region of the medial amygdala, an amygdalar nucleus essential to the integration of social stimuli. Together, these data indicate that sex differences in the local environment of the developing amygdala instruct microglia to actively phagocytose newborn cells as a means to sculpt later life architecture of the amygdala and produce sex differences in social play.
    • Firearm Injuries in Maryland, 2005-2014: Trends, Recidivism, and Costs

      THURMAN, PAUL; Johantgen, Mary E.; 0000-00022134-8415
      Background: Violent injuries related to firearms are common in the U.S., whether accidental or intentional. Restrictions on use of Federal dollars for research on injury prevention involving firearms has limited our knowledge of how firearm injury impacts the health care system. The objectives of this study are to characterize firearm injuries (FI) in Maryland, quantify recidivism, and to describe hospital treatment and their associated costs for Maryland. Methods: ED and inpatient hospital records utilizing E codes consistent with FI were linked across visits to create unique cases from 2005-2014. Recidivism was defined as any subsequent ED visit or hospitalization for FI. The relationship of social determinants of health derived from US Census data to the rate of FI hospitalization by zip code were examined with generalized linear models, as were FI associated hospital costs. Results: Those with a FI are primarily single young black males, with overall hospitalizations decreasing over the time period. While 9% died in their initial FI, recidivism occurred in 3% of the individuals. Personal Disadvantaged (IRR = 1.13) and Working Disadvantaged (IRR = 1.04) factors were associated with increased rates of FI within zip codes. Hospital costs were significantly predicted by being self-pay/charitable and injury severity, with estimated mean costs for one FI of $47,364. In 2013, FI hospitalizations totaled $14m, of which 25% (n=129) accounted for over $10m. Discussion and Implications: FI hospitalizations are decreasing and are increasingly linked to social determinants of health, which require multifaceted interventions with short term goals of interrupting ongoing violence and long-term goals of preventing future violence. The states are absorbing much of the health cost burden. Further research is needed, which should include developing a registry linking hospitalizations, deaths, and crime data that can be used to evaluate trends and effectiveness of interventions.
    • Effects of Alcohol Exposure during Developmental Phases on Brain Functional Connectivity

      Tang, Shiyu; Medina, Alexandre E.; Gullipalli, Rao P.
      Fetal alcohol spectrum disorders (FASD) is one of the most common causes of mental disability in the world. There is growing evidence that developmental alcohol exposure can cause reduced cognitive flexibility and alter multisensory processing, suggesting impairments in fronto-striatal and multisensory integrative cortical areas. The central hypothesis is that developmental alcohol exposure leads to impaired connectivity within these areas, and will result in reorganization of the large-scale brain network. We tested this hypothesis with two animal models that are known to exhibit abnormities in cognitive flexibility and sensory processing: (1) a rat FASD model with alcohol exposure from gestational day 6 to 20, similar to human gestation from the first to the late second trimester; (2) a ferret FASD model with alcohol exposure from postnatal day 10 to 30, similar to the third trimester of gestation in humans. These two models mimic alcohol exposure during early and late fetal stage humans. Our study revealed reduced resting-state functional connectivity within fronto-striatal circuit and a visual-tactile circuit in young adult animals with alcohol exposure during early fetal stage. Although alcohol exposure during late fetal stage did not alter the resting-state functional connectivity within fronto-striatal circuit, an increased functional connectivity within the visual-tactile circuit was detected in juvenile animals. Graph theoretical analysis was used to assess the alteration in brain network properties after alcohol exposure during early or late fetal stage. A reduction of large-scale brain network small-worldness was observed following alcohol exposure during early fetal stage. No significant group difference was observed following alcohol exposure during late fetal stage. In conclusion, the results supported the central hypothesis that developmental alcohol exposure alters resting-state functional connectivity within fronto-striatal circuit and visual-tactile circuit and may eventually alter the organization of large-scale brain networks. The timing of alcohol exposure plays an important role in the outcomes and should be taken into consideration in future research, the usage of diagnostic biomarkers and the application of intervention approaches.
    • Medical Costs of Alpha-1 Antitrypsin Deficiency-associated Chronic Obstructive Pulmonary Disease in the United States

      Sieluk, Jan; Mullins, C. Daniel; 0000-0002-1833-0273
      Objectives: The objective of this study was to isolate the healthcare resource utilization and economic burden attributable to the presence of a genetic factor among Chronic Obstructive Pulmonary Disease (COPD) patients with and without Alpha-1 Antitrypsin Deficiency (AATD), twelve months before and after their initial COPD diagnosis. Methods: Retrospective analysis of OptumLabs® Data Warehouse claims (OLDW; 2000 – 2017). The OLDW is a comprehensive, longitudinal real-world data asset with de-identified lives across claims and clinical information. AATD-associated COPD cases were matched with up to 10 unique non-AATD-associated COPD controls. Healthcare resource use and costs were assigned into the following categories: office (OV), outpatient (OP), and emergency room visits (ER), inpatients stays (IP), prescription drugs (RX), and other services (OTH). A generalized linear model was used to estimate total pre- and post-index (initial COPD diagnosis) costs from a third-party payer’s perspective (2018 USD) controlling for age, gender, race/ethnicity, census region, augmentation therapy use, oxygen use, insurance type, year of COPD diagnosis, and Charlson Comorbidity Score. Healthcare resource utilization was estimated using a negative binomial regression. Results: The study population consisted of 8,881 patients (953 cases matched with 7,928 controls). The AATD-associated COPD cohort had higher expenditures and use of OV and OTH services, as well as OV, OP, ER, RX, and OTH before and after the index date, respectively. Adjusted total cost ratios for AATD-associated COPD patients as compared to controls were 2.036 [95% CI: 1.601 – 2.590] and 1.976 [95% CI: 1.550 – 2.517] while the incremental cost difference totaled $6,861 [95% CI: $3,025 - $10,698] an $5,772 [95% CI: $1,940 - $9,604] per patient before and after the index date, respectively. Conclusions: Twelve months before and after their initial COPD diagnosis, patients with AATD incur higher healthcare utilization costs that are double the cost of similar patients without AATD. This study also suggests that increased costs of AATD-associated COPD are not solely attributable to augmentation therapy use. Future studies should further explore the relationship between augmentation therapy, healthcare resource use, and other AATD-associated COPD expenditures.