Faculty Bibliography

Th17 cells have been investigated in mice primarily for their contributions to autoimmune diseases. However, the pathways of differentiation of Th17 and related Th cells (type 17 cells) and the structure of the type 17 memory population in humans are not well understood; such understanding is critical for manipulating these cells in vivo. By exploiting differences in levels of surface CCR6, we found that human type 17 memory cells, including individual T cell clonotypes, form an elongated continuum of type 17 character along which cells can be driven by increasing RORγt. This continuum includes cells preserved within the memory pool with potentials that reflect the early preferential activation of multiple over single lineages. The phenotypes and epigenomes of CCR6+ cells are stable across cell divisions under noninflammatory conditions. Nonetheless, activation in polarizing and nonpolarizing conditions can yield additional functionalities, revealing, respectively, both environmentally induced and imprinted mechanisms that contribute differentially across the type 17 continuum to yield the unusual plasticity ascribed to type 17 cells.

Objective: To determine whether medical students significantly impact preceptor physicians"™ clinic volume and work after clinic (WAC), we compared the time to note completion and the number of patients seen per hour (PPH) for outpatient neurologists with and without students present in their clinic. Methods: Outpatient neurologists (n = 47) involved in the Johns Hopkins Neurology Clerkship from 2015 to 2017 were included. WAC for each patient encounter was calculated as the interval between the date and time of a scheduled patient appointment and the time of clinic note completion. The number of patient encounters per scheduled clinic hour (PPH) was also calculated for each preceptor. Measurements were compared for each preceptor, serving as their own control, to account for variability in efficiency between preceptors. Results: There was no statistically significant difference in WAC or PPH for individual preceptors with and without students (WAC p-value = 0.837; PPH p-value = 0.139). Preceptors did see significantly more patients per day with students than without (6.28 with students, 5.07 without students, p-value <0.001). Conclusions: In this study, assigning a student to an outpatient ambulatory clinic did not significantly increase work after clinic. In addition, students did not significantly alter the number of patients faculty saw per hour. Public Interest Summary: Both medical students and educators have highlighted the importance of greater student involvement in clinic in providing a valuable outpatient educational experience, but it is often difficult for academic programs to recruit physician preceptors willing to teach and actively involve students in outpatient clinics. This study shows that medical student presence in clinic does not delay physician preceptors"™ note completion and is not associated with less patients seen. To further optimize the outpatient educational and efficiency model, it is important for future investigations to evaluate training programs that enhance the efficacy of a student in clinic, particularly for students with less outpatient experience. This could encourage more preceptors to involve medical students in their clinic, potentially increasing student competence and interest in outpatient medicine.

BACKGROUND/UNASSIGNED:The mental health issues due to COVID-19, such as intolerance of uncertainty (IOU), anxiety, stress, and depression, have attracted extensive attention from researchers. The challenges for Pakistani university students could be worse than developed countries due to the lack of online courses/programs and online mental health support provided by academic institutions. Therefore, the current study aims to assess the intolerance of uncertainty, depression, anxiety, and stress of Pakistani university students after the second wave of COVID-19 and the relationship among these constructs. METHODS/UNASSIGNED:A convenience cross-sectional sampling method was used to collect data from university students in Pakistan between January 2021 and April 2022 via a structured online questionnaire. The Descriptive analysis focused on frequencies, percentages, mean, and standard deviation (SD) were calculated on IOU-12 and DASS-21. Covariance for the research model and confirmatory factor analyses fit indices for the IOU-12 and DASS-21 were analyzed by AMOS statistical packages. RESULTS/UNASSIGNED:As expected, anxiety, depression, and stress persist among Pakistani university students. On average, they report mild to moderate mental health problems regarding anxiety, depression, stress, and intolerance of uncertainty. Our results indicate a strong positive relationship among the three emotional distress components - anxiety, depression, and stress. However, our results suggest no significant relationship between IOU and the three subcomponents of emotional distress (anxiety, depression, and stress). LIMITATIONS/UNASSIGNED:First, the cross-sectional survey design means we cannot conclude on the causal relations. Second, the self-report questionnaire embeds subjectivity issues. Last, the generalizability of the sample to the whole student population in Pakistan is limited, considering the sampling method. CONCLUSION/UNASSIGNED:This study expanded the current knowledge in the psychological health domain (intolerance of uncertainty, anxiety, depression, and stress) due to the COVID-19 pandemic. In practice, higher education institutions should further mitigate university students' mental health issues. For researchers, our findings inspire future studies to delve into the relationship between IOU and mental health issues due to COVID-19 since our findings display contrary evidence for various reasons.

BACKGROUND:Conduct disorder (CD) is a common syndrome with far-reaching effects. Risk factors for the development of CD span social, psychological, and biological domains. Researchers note that predictive models of CD are limited if the focus is on a single risk factor or even a single domain. Machine learning methods are optimized for the extraction of trends across multidomain data but have yet to be implemented in predicting the development of CD. METHODS:Social (e.g., family, income), psychological (e.g., psychiatric, neuropsychological), and biological (e.g., resting-state graph metrics) risk factors were measured using data from the baseline visit of the Adolescent Brain Cognitive Development Study when youth were 9 to 10 years old (N = 2368). Applying a feed-forward neural network machine learning method, risk factors were used to predict CD diagnoses 2 years later. RESULTS:A model with factors that included social, psychological, and biological domains outperformed models representing factors within any single domain, predicting the presence of a CD diagnosis with 91.18% accuracy. Within each domain, certain factors stood out in terms of their relationship to CD (social: lower parental monitoring, more aggression in the household, lower income; psychological: greater attention-deficit/hyperactivity disorder and oppositional defiant disorder symptoms, worse crystallized cognition and card sorting performance; biological: disruptions in the topology of subcortical and frontoparietal networks). CONCLUSIONS:The development of an accurate, sensitive, and specific predictive model of CD has the potential to aid in prevention and intervention efforts. Key risk factors for CD appear best characterized as reflecting unpredictable, impulsive, deprived, and emotional external and internal contexts.

BT75, a boron-containing retinoid, is a novel retinoic acid receptor (RAR)α agonist synthesized by our group. Previous studies indicated that activation of retinoic acid (RA) signaling may attenuate progression of Alzheimer's disease (AD). Presently, we aimed to examine the anti-inflammatory effect of BT75 and explore the possible mechanism using cultured cells and an AD mouse model. Pretreatment with BT75 (1-25 µM) suppressed the release of nitric oxide (NO) and IL-1β in the culture medium of mouse microglial SIM-A9 cells activated by LPS. BMS195614, an RARα antagonist, partially blocked the inhibition of NO production by BT75. Moreover, BT75 attenuated phospho-Akt and phospho-NF-κB p65 expression augmented by LPS. In addition, BT75 elevated arginase 1, IL-10, and CD206, and inhibited inducible nitric oxide synthase (iNOS) and IL-6 formation in LPS-treated SIM-A9 cells, suggesting the promotion of M1-M2 microglial phenotypic polarization. C57BL/6 mice were injected intracerebroventricularly (icv) with streptozotocin (STZ) (3 mg/kg) to provide an AD-like mouse model. BT75 (5 mg/kg) or the vehicle was intraperitoneally (ip) injected to icv-STZ mice once a day for 3 weeks. Immunohistochemical analyses indicated that GFAP-positive cells and rod or amoeboid-like Iba1-positive cells, which increased in the hippocampal fimbria of icv-STZ mice, were reduced by BT75 treatment. Western blot results showed that BT75 decreased levels of neuronal nitric oxide synthase (nNOS), GFAP, and phosphorylated Tau, and increased levels of synaptophysin in the hippocampus of icv-STZ mice. BT75 may attenuate neuroinflammation by affecting the Akt/NF-κB pathway and microglial M1-M2 polarization in LPS-stimulated SIM-A9 cells. BT75 also reduced AD-like pathology including glial activation in the icv-STZ mice. Thus, BT75 may be a promising anti-inflammatory and neuroprotective agent worthy of further AD studies.

BACKGROUND/UNASSIGNED:More than 50 million people in the United States serve as uncompensated informal caregivers to chronically ill friends or family members. Providing care to a sick loved one can contribute to personal growth but can also cause significant strain. Caregiver distress refers to a constellation of physiological, psychological, interpersonal, and spiritual impairments that typically result when an individual's own health becomes affected while caring for another. Caregiver distress is highly prevalent, affecting an estimated 30-70% of individuals across various caregiver populations. Although evidence-based treatments for caregiver distress exist, they do not sufficiently address all its components. In recent years, clinical trials have demonstrated that psychedelic-assisted psychotherapy (PAP) may have applications for treating a range of medical and psychiatric conditions that have significant overlap in symptoms to those seen in caregiver distress. While no studies to date have examined PAP for caregiver distress, this article provides a rationale for investigating PAP as a potential novel treatment for this indication. METHODS/UNASSIGNED:A narrative review on the effects and clinical applications of PAP that significantly overlap with the dimensions of caregiver distress was conducted. Safety considerations, psychedelic selection, and therapeutic structure for studying PAP in the treatment of caregiver distress were also examined. RESULTS/UNASSIGNED:Psychologically, PAP has been shown to treat anxiety, depression, and reduce suicidal ideation. Physiologically, evidence suggests that psychedelics have anti-inflammatory properties, which may aid caregivers suffering from chronic inflammation. Interpersonally, PAP has been demonstrated to enhance feelings of empathy, connectedness, and strengthen social relationships, which can often become strained while caregiving. Spiritually, PAP has been shown to ameliorate existential distress and hopelessness in cancer patients, which may similarly benefit demoralized caregivers. CONCLUSION/UNASSIGNED:PAP has the potential to comprehensively treat all biopsychosocial-spiritual dimensions of caregiver distress.

Early treatment of behavioral problems can prevent their progression into intractable disorders. This study examined the impact of a multiple family group (MFG) intervention for children with behavior symptoms and their families. Fifty-four (n = 54) caregiver/child dyads with sub-clinical levels of oppositional defiant disorder (ODD) participated in a 16-week MFG. Child, caregiver, and family outcomes were assessed at baseline, post-treatment, and at 6 months follow-up. Significant decreases in impairment with parents, family members, and peers, and improvements in child self-esteem were found from baseline to follow-up. Caregiver stress increased; no significant changes in depression or perceived social support were found over time. The effectiveness of MFG as a preventive approach and areas of future research are discussed.

Individuals born with congenital heart disease (CHD) are at an increased risk of developing neurodevelopmental disorders. Despite this, studies are limited in their investigation of autism spectrum disorder in the context of CHD. This review provides an overview of the literature examining autism spectrum disorder in CHD and discusses strengths, limitations, and future directions. Recent efforts have been made to extrapolate the association between CHD and symptoms of autism. Findings suggest that the core features of autism spectrum disorder are also implicated in children with CHD, namely social-cognitive weaknesses, pragmatic language differences, and social problems. Compared to norm-referenced samples, separate studies have identified divergent and overlapping neuropsychological profiles among both patient groups, yet there are no studies directly comparing the two groups. There is emerging evidence of prevalence rates of autism diagnosis in CHD showing an increased odds of having autism spectrum disorder among children with CHD relative to the general population or matched controls. There also appears to be genetic links to this overlap, with several genes identified as being tied to both CHD and autism. Together, research points to potentially shared underlying mechanisms contributing to the pathophysiology of neurodevelopmental, neuropsychological, and clinical traits in CHD and autism spectrum disorder. Future investigation delineating profiles across these patient populations can fill a significant gap in the literature and aid in treatment approaches to improve clinical outcomes.

OBJECTIVE:Major depressive disorder (MDD) and bipolar disorder (BD) are considered whole-brain disorders with some common clinical and neurobiological features. It is important to investigate neural mechanisms to distinguish between the two disorders. However, few studies have explored the functional dysconnectivity between the two disorders from the whole brain level. METHODS:In this study, 117 patients with MDD, 65 patients with BD, and 116 healthy controls completed resting-state functional magnetic resonance imaging (R-fMRI) scans. Both edge-based network construction and large-scale network analyses were applied. RESULTS:Results found that both the BD and MDD groups showed decreased FC in the whole brain network. The shared aberrant network across patients involves the visual network (VN), sensorimotor network (SMN), dorsal attention network (DAN), and ventral attention network (VAN), which is related to the processing of external stimuli. The default mode network (DMN) and the limbic network (LN) abnormalities were only found in patients with MDD. Furthermore, results showed the highest decrease in edges of patients with MDD in between-network FC in SMN-VN, whereas in VAN-VN of patients with BD. CONCLUSIONS:Our findings indicated that both MDD and BD are extensive abnormal brain network diseases, mainly aberrant in those brain networks correlated to the processing of external stimuli, especially the attention network. Specific altered functional connectivity also was found in MDD and BD groups, respectively. These results may provide possible trait markers to distinguish the two disorders.