Faculty Bibliography

PURPOSE: The prognosis for SHH-medulloblastoma (MB) patients with Li-Fraumeni syndrome (LFS) is poor. Due to lack of comprehensive data for these patients, it is challenging to establish effective therapeutic recommendations. We here describe the largest retrospective cohort of pediatric LFS SHH-MB patients to date and their clinical outcomes.
PATIENTS AND METHODS: N=31 patients with LFS SHH-MB were included in this retrospective multicenter study. TP53 variant type, clinical parameters including treatment modalities, event-free survival (EFS) and overall survival (OS), as well as recurrence patterns and incidence of secondary neoplasms, were evaluated.
RESULT(S): All LFS-MBs were classified as SHH subgroup, in 30/31 cases based on DNA methylation analysis. The majority of constitutional TP53 variants (72%) represented missense variants, and all except two truncating variants were located within the DNA-binding domain. 54% were large cell anaplastic, 69% gross totally resected and 81% had M0 status. The 2-(y)ear and 5-(y)ear EFS were 26% and 8,8%, respectively, and 2y- and 5y-OS 40% and 12%. Patients who received post-operative radiotherapy (RT) followed by chemotherapy (CT) showed significantly better outcomes (2y-EFS:43%) compared to patients who received CT before RT (30%) (p<0.05). The 2y-EFS and 2y-OS were similar when treated with protocols including high-dose chemotherapy (EFS:22%, OS:44%) compared to patients treated with maintenance-type chemotherapy (EFS:31%, OS:45%). Recurrence occurred in 73.3% of cases independent of resection or M-status, typically within the radiation field (75% of RT-treated patients). Secondary malignancies developed in 12.5% and were cause of death in all affected patients.
CONCLUSION(S): Patients with LFS-MBs have a dismal prognosis. This retrospective study suggests that upfront RT may increase EFS, while intensive therapeutic approaches including high-dose chemotherapy did not translate into increased survival of this patient group. To improve outcomes of LFS-MB patients, prospective collection of clinical data and development of treatment guidelines are required

Adverse childhood experiences (ACEs) are associated with poor mental health in adulthood. Comprehensive prevalence data encompassing all 10 ACE questionnaire items has not previously been described in a hospital-based outpatient psychiatric clinic. This study assessed the prevalence of 10 ACEs in such a clinic and correlated ACEs with indicators of case severity. For 252 patients newly evaluated in an urban clinic, a retrospective chart review was completed and data was collected on ACE questionnaire responses, psychiatric, substance-related, and medical diagnoses, psychiatric hospitalizations, suicide attempts, and suicide and violence risk. Patients in the clinic had an average of 3.4 ACEs, higher than national community sample averages of 1.6. The percentages of patients with at least one, two, and four ACEs were 82% (n = 207), 68% (n = 172), and 42% (n = 106) respectively (compared with 61%, 38%, and 15% nationally). ACEs had statistically significant correlations with an increased number of psychiatric diagnoses, substance use disorders, medical illnesses, suicide attempts, and suicide risk level. This study demonstrated that patients seeking psychiatric care from a hospital-based outpatient clinic are likely to be traumatized to a degree far exceeding what is typical in the general population. While a high prevalence of ACEs in a psychiatric population is an expected finding given the literature to date, this is the first study presenting data on the prevalence of ACEs in such a hospital-based community clinic. Additionally this study reinforces prior research correlating childhood adversity and case severity.

BACKGROUND:The association between adversity and psychopathology in adolescents and adults is characterized by equifinality. These associations, however, have not been assessed during early childhood when psychopathology first emerges. Defining adversity using both dimensional and cumulative risk approaches, we examined whether specific types of adversity are differentially associated with psychopathology in preschool-aged children. METHODS:Measures of threat, deprivation, and total adversities (i.e., cumulative risk) were calculated based on parent-reported information for 755 2- to 5-year old children recruited from pediatric primary care clinics. Logistic regression was used to estimate cross-sectional associations between type of adversity and anxiety, depression, ADHD, and behavioral disorder diagnoses. RESULTS:Threat and cumulative risk exhibited independent associations with psychopathology. Threat was strongly related to behavioral disorders. Cumulative risk was consistently related to all psychopathologies. CONCLUSIONS:Using mutually adjusted models, we identified differential associations between threat and psychopathology outcomes in preschool-aged children. This selectivity may reflect different pathways through which adversity increases the risk for psychopathology during this developmentally important period. As has been observed at other ages, a cumulative risk approach also effectively identified the cumulative impact of all forms of adversity on most forms of psychopathology during early childhood.

Non-invasive brain stimulation (NIBS), including transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS), is a potentially effective treatment strategy for a number of mental conditions. However, no quantitative evidence synthesis of randomized controlled trials (RCTs) of TMS or tDCS using the same criteria including several mental conditions is available. Based on 208 RCTs identified in a systematic review, we conducted a series of random effects meta-analyses to assess the efficacy of NIBS, compared to sham, for core symptoms and cognitive functioning within a broad range of mental conditions. Outcomes included changes in core symptom severity and cognitive functioning from pre- to post-treatment. We found significant positive effects for several outcomes without significant heterogeneity including TMS for symptoms of generalized anxiety disorder (SMD = -1.8 (95% CI: -2.6 to -1), and tDCS for symptoms of substance use disorder (-0.73, -1.00 to -0.46). There was also significant effects for TMS in obsessive-compulsive disorder (-0.66, -0.91 to -0.41) and unipolar depression symptoms (-0.60, -0.78 to -0.42) but with significant heterogeneity. However, subgroup analyses based on stimulation site and number of treatment sessions revealed evidence of positive effects, without significant heterogeneity, for specific TMS stimulation protocols. For neurocognitive outcomes, there was only significant evidence, without significant heterogeneity, for tDCS for improving attention (-0.3, -0.55 to -0.05) and working memory (-0.38, -0.74 to -0.03) in individuals with schizophrenia. We concluded that TMS and tDCS can benefit individuals with a variety of mental conditions, significantly improving clinical dimensions, including cognitive deficits in schizophrenia which are poorly responsive to pharmacotherapy.

Anxiety has been associated with reliance on reactive (stimulus-driven/reflexive) control strategies in response to conflict. However, this conclusion rests primarily on indirect evidence. Few studies utilize tasks that dissociate the use of reactive ('just in time') vs. proactive (anticipatory/preparatory) cognitive control strategies in response to conflict, and none examine children diagnosed with anxiety. The current study utilizes the AX-CPT, which dissociates these two types of cognitive control, to examine cognitive control in youth (ages 8-18) with and without an anxiety diagnosis (n = 56). Results illustrate that planful behavior, consistent with using a proactive strategy, varies by both age and anxiety symptoms. Young children (ages 8-12 years) with high anxiety exhibit significantly less planful behavior than similarly-aged children with low anxiety. These findings highlight the importance of considering how maturation influences relations between anxiety and performance on cognitive-control tasks and have implications for understanding the pathophysiology of anxiety in children.

Purpose : Automated segmentation of in-vivo lamina cribrosa (LC) has been challenging, owing to the complex 3D structure and decreased visibility in the lamina depth. Frangi's vesselness filter, which was originally developed for angiogram segmentation, have been successfully demonstrated in segmenting the ex-vivo LC from micro-CT and second harmonic generation microscopy images. In this project we are proposing a new approach of segmenting the in vivo LC from OCT scans, incorporating the Frangi's vesselness principle to facilitate in vivo LC image analysis in much greater detail compared to our previously described 3D analysis method. Methods : In-vivo spectral-domain OCT scans (Leica, Chicago, IL) were acquired from healthy non-human primates. Scans of varying degree of image quality were selected for the analysis and underwent automated brightness and local contrast enhancement. 3D Frangi's vesselness filter was applied using a fixed setting for scans of all qualities. Our previously described segmentation algorithm was then used to quantify the LC microstructure. The measurements generated from the Frangi analysis and from our own conventional method were compared with a standard reference (manually segmented LC by an expert). Paired t tests were performed to compare if the differences between standard reference and conventional method are greater than the differences between standard reference and Frangi analysis. The visibility of analyzable lamina and dice coefficient were also compared to the conventional method using the same test. Results : In vivo scans acquired from 5 rhesus macaques (3 males, 1 female, aged 4.3-10.7 yrs) were used for the analysis. No significant difference was detected for LC microstructure parameters between Frangi's approach and conventional method with respect to the standard reference, except for significantly higher pore count in Frangi's method (p=0.003; Table). Furthermore, visibility (Figure) was significantly higher for the Frangi method compared to the conventional approach (p<0.001) with no difference detected for the semantic segmentation, as reflected by the dice coefficient. Conclusions : The use of Frangi analysis substantially increase the analyzable lamina while providing similar quantification of the LC microstructure compared to our previous 3D analysis method. This improves the potential for automated and thorough volumetric analysis of in vivo OCT LC image

OBJECTIVE/UNASSIGNED:The study objective was to determine the relationship between lung resection and the development of postoperative hiatal hernia. METHODS/UNASSIGNED:Preoperative and postoperative computed tomography imaging from 373 patients from the International Early Lung Cancer Action Program and the Initiative for Early Lung Cancer Research on Treatment were compared at a median of 31.1 months of follow-up after resection of clinical early-stage non-small cell lung cancer. Incidence of new hiatal hernia or changes to preexisting hernias were recorded and evaluated by patient demographics, surgical approach, extent of resection, and resection site. RESULTS/UNASSIGNED: = .0003). CONCLUSIONS/UNASSIGNED:Both open and minimally invasive lung resection for clinical early-stage lung cancer are associated with new or enlarging postoperative hiatal hernia, especially after resections involving the left lower lobe.

OBJECTIVE:To model children's mental health policy making dynamics and simulate the impacts of knowledge broker interventions. DATA SOURCES/METHODS:Primary data from surveys (n = 221) and interviews (n = 64) conducted in 2019-2021 with mental health agency (MHA) officials in state agencies. STUDY DESIGN/METHODS:A prototype agent-based model (ABM) was developed using the PARTE (Properties, Actions, Rules, Time, Environment) framework and informed through primary data collection. In each simulation, a policy is randomly generated (salience weights: cost, contextual alignment, and strength of evidence) and discussed among agents. Agents are MHA officials and heterogenous in their properties (policy making power and network influence) and policy preferences (based on salience weights). Knowledge broker interventions add agents to the MHA social network who primarily focus on the policy's research evidence. DATA COLLECTION/EXTRACTION METHODS/METHODS:A sequential explanatory mixed method approach was used. Descriptive and regression analyses were used for the survey data and directed content analysis was used to code interview data. Triangulated results informed ABM development. In the ABM, policy makers with various degrees of decision influence interact in a scale-free network before and after knowledge broker interventions. Over time, each decides to support or oppose a policy proposal based on policy salience weights and their own properties and interactions. The main outcome is an agency-level decision based on policy maker support. Each intervention and baseline simulation runs 250 times across 50 timesteps. PRINCIPAL FINDINGS/RESULTS:Surveys and interviews revealed that barriers to research use could be addressed by knowledge brokers. Simulations indicated that policy decision outcomes varied by policy making context within agencies. CONCLUSIONS:This is the first application of ABM to evidence-informed mental health policy making focusing. Results suggest that the presence of knowledge brokers can: (1) influence consensus formation in MHAs, (2) accelerate policy decisions, and (3) increase the likelihood of evidence-informed policy adoption.

We developed a "gut-brain-axis questionnaire" (GBAQ) to obtain standardized person-specific "review of systems" data for microbiome-gut-brain-axis studies. Individual items were compared to PANSS symptom measures using dimensional, transdiagnostic and traditional categorical approaches.

This study investigated motor preparation and action-consequence prediction using the lateralized readiness potential (LRP). Motor impairments are common in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), which commonly co-occur. Alterations in predictive processes may impact motor planning. Whether motor planning deficits are characteristic of ASD broadly or magnified in the context of co-morbid ADHD is unclear. ASD children with (ASD + ADHD; n = 12) and without (ASD - ADHD; n = 9) comorbid ADHD and typical controls (n = 29) performed voluntary motor actions that either did or did not result in auditory consequences. ASD - ADHD children demonstrated LRP enhancement when their action produced an effect while ASD + ADHD children had attenuated responses regardless of action-effect pairings. Findings suggest influence of ADHD comorbidity on motor preparation and prediction in ASD.