Intraosseous Treatment of Bone Marrow Lesions in the Knee: Surgical Technique.

Intraosseous injections of bone marrow aspirate concentrate have shown promise in the treatment of bone marrow lesions (BMLs) in the knee. With the wide-awake limited anesthesia no tourniquet (WALANT) technique, intraosseous injections can be performed with the patient under local anesthesia in the procedure room or operating room setting. This article describes 2 techniques to access the BML of interest. The "decompression route" involves drilling through the nearest cortex, and the "biologic route" involves drilling through healthy bone to promote bleeding and the introduction of healthy biologic tissue to the BML.

Identification of State Markers in Anorexia Nervosa: Replication and Extension of Inflammation-Associated Biomarkers Using Multiplex Profiling.

Background: Proteomics offers potential for detecting and monitoring anorexia nervosa (AN) and its variant, atypical AN (atyp-AN). However, research has been limited by small protein panels, a focus on adult AN, and lack of replication. Methods: In this study, we performed Olink multiplex profiling of 92 inflammation-related proteins in females with AN/atyp-AN (n = 64), all of whom were ≤90% of expected body weight, and age-matched healthy control individuals (n = 44). Results: Five proteins differed significantly between the primary AN/atyp-AN group and the healthy control group (lower levels: HGF, IL-18R1, TRANCE; higher levels: CCL23, LIF-R). The expression levels of 3 proteins (lower IL-18R1, TRANCE; higher LIF-R) were uniquely disrupted in participants with AN in our primary model. No unique expression levels emerged for atyp-AN. In the total sample, 12 proteins (ADA, CD5, CD6, CXCL1, FGF-21, HGF, IL-12B, IL18, IL-18R1, SIRT2, TNFSF14, TRANCE) were positively correlated with body mass index and 5 proteins (CCL11, FGF-19, IL8, LIF-R, OPG) were negatively correlated with body mass index in our primary models. Conclusions: Our results replicate the results of a previous study that demonstrated a dysregulated inflammatory status in AN and extend those results to atyp-AN. Of the 17 proteins correlated with body mass index, 11 were replicated from a previous study that used similar methods, highlighting the promise of inflammatory protein expression levels as biomarkers of AN disease monitoring. Our findings underscore the complexity of AN and atyp-AN by highlighting the inability of the identified proteins to differentiate between these 2 subtypes, thereby emphasizing the heterogeneous nature of these disorders.

We examined 73 inflammation proteins in adolescent girls with anorexia nervosa (AN) and atypical AN and compared them with age-matched healthy control girls. Significant differences were found, driven by 5 key proteins (lower: HGF, IL-18R1, TRANCE; higher: CCL23, LIF-R). Three proteins (TRANCE, LIF-R, IL-18R1) uniquely distinguished low-weight participants with AN from control participants. Our study reveals distinct inflammation patterns in AN and atypical AN and sheds light on potential state-specific factors that underlie these disorders.

Diagnosing and Treating Pediatric Autoimmune Neuropsychiatric Disorder Associated With Streptococcal Infections.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.Prim Care Companion CNS Disord 2024;26(3):23f03662. Author affiliations are listed at the end of this article.

Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors.

Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor gene NF1. Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild type NF1 allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover therapeutic vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs of NF1-proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially kill NF1-deficient cells, through which we identified 23 compounds capable of killing NF1-deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by method of action. Four clinically interesting drugs from these classes were tested in vivo using both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All drugs tested showed single agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor selumetinib. This HTS platform yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.

T Cell Repertoire Homogeneity and Blood-Gut Overlap in Patients With Inflammatory Bowel Disease.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) causes a marked increase in the number of T cells in the intestinal mucosa. Debate exists about whether these excess cells arise from local clonal proliferation or recruitment from the periphery. METHODS: CD8+ T cells were sorted from colon biopsy specimens and blood for T-cell receptor (TCR) ß-chain sequencing. Biopsy specimens from inflamed or uninflamed colon from ulcerative colitis or Crohn's disease cohorts were compared with colon biopsy specimens from people without IBD, as well as with autologous blood α4ß7+, α4ß7- effector/memory, terminal effector/memory CD45RA+ T cell, and mucosal-associated invariant T-cell CD8 subpopulations. RESULTS: CD8 TCR diversity in mucosa and blood did not correlate with inflammation. Repertoire overlap between any 2 distinct locations of a given person's colon was consistently high, although often lower between inflamed and uninflamed sites. CD8 TCR repertoires overlapped between the colon and each peripheral blood subpopulation studied, with the highest overlap seen for integrin α4ß7+ T cells. Inflamed tissue consistently overlapped more than uninflamed tissue with each blood subpopulation. CONCLUSIONS: CD8 T-cell clones are spread homogenously throughout the length of the colon. Although TCR repertoire overlap is greater within than between inflamed and uninflamed colon segments, a similar TCR diversity in both argues against local clonal expansion being the main source of excess cytotoxic T cells in inflamed mucosa. Rather, the increased TCR overlap observed between blood and inflamed mucosa supports the significance of T-cell trafficking in IBD pathogenesis, particularly concerning α4ß7+ T-cell populations.

Enhancing cerebral vasculature analysis with pathlength-corrected 2D angiographic parametric imaging: A feasibility study.

BACKGROUND: 2D angiographic parametric imaging (API) quantitatively extracts imaging biomarkers related to contrast flow and is conventionally applied to 2D digitally subtracted angiograms (DSA's). In the interventional suite, API is typically performed using 1-2 projection views and is limited by vessel overlap, foreshortening, and depth-integration of contrast motion. PURPOSE: This work explores the use of a pathlength-correction metric to overcome the limitations of 2D-API: the primary objective was to study the effect of converting 3D contrast flow to projected contrast flow using a simulated angiographic framework created with computational fluid dynamics (CFD) simulations, thereby removing acquisition variability. METHODS: The pathlength-correction framework was applied to in-silico angiograms, generating a reference (i.e., ground-truth) volumetric contrast distribution in four patient-specific intracranial aneurysm geometries. Biplane projections of contrast flow were created from the reference volumetric contrast distributions, assuming a cone-beam geometry. A Parker-weighted reconstruction was performed to obtain a binary representation of the vessel structure in 3D. Standard ray tracing techniques were then used to track the intersection of a ray from the focal spot with each voxel of the reconstructed vessel wall to a pixel in the detector plane. The lengths of each ray through the 3D vessel lumen were then projected along each ray-path to create a pathlength-correction map, where the pixel intensity in the detector plane corresponds to the vessel width along each source-detector ray. By dividing the projection sequences with this correction map, 2D pathlength-corrected in-silico angiograms were obtained. We then performed voxel-wise (3D) API on the ground-truth contrast distribution and compared it to pixel-wise (2D) API, both with and without pathlength correction for each biplane view. The percentage difference (PD) between the resultant API biomarkers in each dataset were calculated within the aneurysm region of interest (ROI). RESULTS: Intensity-based API parameters, such as the area under the curve (AUC) and peak height (PH), exhibited notable changes in magnitude and spatial distribution following pathlength correction: these now accurately represent conservation of mass of injected contrast media within each arterial geometry and accurately reflect regions of stagnation and recirculation in each aneurysm ROI. Improved agreement was observed between these biomarkers in the pathlength-corrected biplane maps: the maximum PD within the aneurysm ROI is 3.3% with pathlength correction and 47.7% without pathlength correction. As expected, improved agreement with ROI-averaged ground-truth 3D counterparts was observed for all aneurysm geometries, particularly large aneurysms: the maximum PD for both AUC and PH was 5.8%. Temporal parameters (mean transit time, MTT, time-to-peak, TTP, time-to-arrival, TTA) remained unaffected after pathlength correction. CONCLUSIONS: This study indicates that the values of intensity-based API parameters obtained with conventional 2D-API, without pathlength correction, are highly dependent on the projection orientation, and uncorrected API should be avoided for hemodynamic analysis. The proposed metric can standardize 2D API-derived biomarkers independent of projection orientation, potentially improving the diagnostic value of all acquired 2D-DSA's. Integration of a pathlength correction map into the imaging process can allow for improved interpretation of biomarkers in 2D space, which may lead to improved diagnostic accuracy during procedures involving the cerebral vasculature.

Perinatal folate levels do not influence tumor latency or multiplicity in a model of NF1 associated plexiform-like neurofibromas.

OBJECTIVE: In epidemiological and experimental research, high folic acid intake has been demonstrated to accelerate tumor development among populations with genetic and/or molecular susceptibility to cancer. Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder predisposing affected individuals to tumorigenesis, including benign plexiform neurofibromas; however, understanding of factors associated with tumor risk in NF1 patients is limited. Therefore, we investigated whether pregestational folic acid intake modified plexiform-like peripheral nerve sheath tumor risk in a transgenic NF1 murine model. RESULTS: We observed no significant differences in overall survival according to folate group. Relative to controls (180 days), median survival did not statistically differ in deficient (174 days, P = 0.56) or supplemented (177 days, P = 0.13) folate groups. Dietary folate intake was positively associated with RBC folate levels at weaning, (P = 0.023, 0.0096, and 0.0006 for deficient vs. control, control vs. supplemented, and deficient vs. supplemented groups, respectively). Dorsal root ganglia (DRG), brachial plexi, and sciatic nerves were assessed according to folate group. Mice in the folate deficient group had significantly more enlarged DRG relative to controls (P = 0.044), but no other groups statistically differed. No significant differences for brachial plexi or sciatic nerve enlargement were observed according to folate status.

Using the Sustainable Development Goals in undergraduate leadership programs.

Undergraduate leadership education prepares students for meaningful roles in various aspects of civic and professional life. In this article, the authors explore the contextual facets of undergraduate academic leadership programs and courses utilizing the Sustainable Development Goals (SDGs) as a framework for addressing local and global challenges through leadership education and development at two higher education institutions. Each example is described contextually followed by promising classroom practices embedded through the use of the SDG framework.

Postinfectious Inflammation, Autoimmunity, and Obsessive-Compulsive Disorder: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection, and Pediatric Acute-Onset Neuropsychiatric Disorder.

Postinfectious neuroinflammation has been implicated in multiple models of acute-onset obsessive-compulsive disorder including Sydenham chorea (SC), pediatric acute-onset neuropsychiatric syndrome (PANS), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). These conditions are associated with a range of autoantibodies which are thought to be triggered by infections, most notably group A streptococci (GAS). Based on animal models using huma sera, these autoantibodies are thought to cross-react with neural antigens in the basal ganglia and modulate neuronal activity and behavior. As is true for many childhood neuroinflammatory diseases and rheumatological diseases, SC, PANS, and PANDAS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. In this review article, we outline the accumulating evidence supporting the role neuroinflammation plays in these disorders. We describe work with animal models including patient-derived anti-neuronal autoantibodies, and we outline imaging studies that show alterations in the basal ganglia. In addition, we present research on metabolites, which are helpful in deciphering functional phenotypes, and on the implication of sleep in these disorders. Finally, we encourage future researchers to collaborate across medical specialties (e.g., pediatrics, psychiatry, rheumatology, immunology, and infectious disease) in order to further research on clinical syndromes presenting with neuropsychiatric manifestations.

Assessing medical student satisfaction with rural placement: The Australian Rural Clinical School Support Survey.

INTRODUCTION: Australia has a doctor shortage in rural settings, and rural placements for medical students have an important role in increasing the likelihood of students staying in rural settings throughout their careers. However, to date there is limited research regarding medical student perceptions of rural placement quality. OBJECTIVE: We aimed to determine factors that impact the overall medical student experience during rural placements. DESIGN: Cross-sectional survey. SETTING: Rural/remote clinical schools across Australia. PARTICIPANTS: Medical students on rural/remote clinical placements for at least 6 months. MAIN OUTCOME MEASURES: To assess factors impacting student experience on rural placements, we conducted a cross-sectional survey, known as the Australian Rural Clinical School Support Survey (ARCSSS) which was completed online by medical students across Australia. Demographic data were collected in addition to responses regarding academic teaching, extracurricular activities, and support services. Multiple choice and Likert scale questions were utilised. RESULTS: A total of 107 responses to our survey were analysed. The majority of participants were female (66.4%), and in their middle years of clinical education (55.1%). Overall, respondents showed high levels of satisfaction with clinical school supervisors, and clinical education. A high proportion of respondents indicated minimal accessibility of health and other support services. While a large proportion of participants indicated satisfaction with the rural placements, it was demonstrated that students were generally dissatisfied with school wellness activities and extracurricular activities. Financial insecurity was noted. CONCLUSION: The findings from our survey indicate there are numerous areas in which rural placements have been effective for medical students, and others in which improvement is needed. Furthermore, more research is required to better develop well-being initiatives that are effective in improving overall experience.

Use of high-speed angiography HSA-derived boundary conditions and Physics Informed Neural Networks (PINNs) for comprehensive estimation of neurovascular hemodynamics.

Purpose: Physics-informed neural networks (PINNs) and computational fluid dynamics (CFD) have both demonstrated an ability to derive accurate hemodynamics if boundary conditions (BCs) are known. Unfortunately, patient-specific BCs are often unknown, and assumptions based upon previous investigations are used instead. High speed angiography (HSA) may allow extraction of these BCs due to the high temporal fidelity of the modality. We propose to investigate whether PINNs using convection and Navier-Stokes equations with BCs derived from HSA data may allow for extraction of accurate hemodynamics in the vasculature. Materials and Methods: Imaging data generated from in vitro 1000 fps HSA, as well as simulated 1000 fps angiograms generated using CFD were utilized for this study. Calculations were performed on a 3D lattice comprised of 2D projections temporally stacked over the angiographic sequence. A PINN based on an objective function comprised of the Navier-Stokes equation, the convection equation, and angiography-based BCs was used for estimation of velocity, pressure and contrast flow at every point in the lattice. Results: Imaging-based PINNs show an ability to capture such hemodynamic phenomena as vortices in aneurysms and regions of rapid transience, such as outlet vessel blood flow within a carotid artery bifurcation phantom. These networks work best with small solution spaces and high temporal resolution of the input angiographic data, meaning HSA image sequences represent an ideal medium for such solution spaces. Conclusions: The study shows the feasibility of obtaining patient-specific velocity and pressure fields using an assumption-free data driven approach based purely on governing physical equations and imaging data.

Geometrically independent contrast dilution gradient (CDG) velocimetry using photon-counting 1000 fps High Speed Angiography (HSA) for 2D velocity distribution estimation.

Purpose: Previous studies have demonstrated the efficacy of contrast dilution gradient (CDG) analysis in determining large vessel velocity distributions from 1000 fps high-speed angiography (HSA). However, the method required vessel centerline extraction, which made it applicable only to non-tortuous geometries using a highly specific contrast injection technique. This study seeks to remove the need for a priori knowledge regarding the direction of flow and modify the vessel sampling method to make the algorithm more robust to non-linear geometries. Materials and Methods: 1000 fps HSA acquisitions were obtained in vitro with a benchtop flow loop using the XC-Actaeon (Varex Inc.) photon-counting detector, and in silico using a passive-scalar transport model within a computational fluid dynamics (CFD) simulation. CDG analyses were obtained using gridline sampling across the vessel, and subsequent 1D velocity measurement in both the x- and y-directions. The velocity magnitudes derived from the component CDG velocity vectors were aligned with CFD results via co-registration of the resulting velocity maps and compared using mean absolute percent error (MAPE) between pixels values in each method after temporal averaging of the 1-ms velocity distributions. Results: Regions well-saturated with contrast throughout the acquisition showed agreement when compared to CFD (MAPE of 18% for the carotid bifurcation inlet and MAPE of 27% for the internal carotid aneurysm), with respective completion times of 137 seconds and 5.8 seconds. Conclusions: CDG may be used to obtain velocity distributions in and surrounding vascular pathologies provided the contrast injection is sufficient to provide a gradient, and diffusion of contrast through the system is negligible.

Identification of State Markers in Anorexia Nervosa: Replication and Extension of Inflammation Associated Biomarkers Using Multiplex Profiling in Anorexia Nervosa and Atypical Anorexia Nervosa.

Proteomics provides an opportunity for detection and monitoring of anorexia nervosa (AN) and its related variant, atypical-AN (atyp-AN). However, research to date has been limited by the small number of proteins explored, exclusive focus on adults with AN, and lack of replication across studies. This study performed Olink Proseek Multiplex profiling of 92 proteins involved in inflammation among females with AN and atyp-AN (N = 64), all < 90% of expected body weight, and age-matched healthy controls (HC; N=44). After correction for multiple testing, nine proteins differed significantly in the AN/atyp-AN group relative to HC group ( lower levels: CXCL1, HGF, IL-18R1, TNFSF14, TRANCE; higher levels: CCL23, Flt3L, LIF-R, MMP-1). The expression levels of three proteins ( lower IL-18R1, TRANCE; higher LIF-R) were uniquely disrupted in females with AN. No unique expression levels emerged for atyp-AN. Across the whole sample, twenty-one proteins correlated positively with BMI (ADA, AXIN1, CD5, CD244, CD40, CD6, CXCL1, FGF-21, HGF, IL-10RB, IL-12B, IL18, IL-18R1, IL6, LAP TGF-beta-1, SIRT2, STAMBP, TNFRSF9, TNFSF14, TRAIL, TRANCE) and six (CCL11, CCL23, FGF-19, IL8, LIF-R, OPG) were negatively correlated with BMI. Overall, our results replicate the prior study demonstrating a dysregulated inflammatory status in AN, and extend these results to atyp-AN (AN/atyp-AN all < 90% of expected body weight). Of the 27 proteins correlated with BMI, 18 were replicated from a prior study using similar methods, highlighting the promise of inflammatory protein expression levels as biomarkers of disease monitoring. Additional studies of individuals across the entire weight spectrum are needed to understand the role of inflammation in atyp-AN.

Angiographic velocimetry analysis using contrast dilution gradient method with a 1000 frames per second photon-counting detector.

Purpose: Contrast dilution gradient (CDG) analysis is a quantitative method allowing blood velocity estimation using angiographic acquisitions. Currently, CDG is restricted to peripheral vasculature due to the suboptimal temporal resolution of current imaging systems. We investigate extension of CDG methods to the flow conditions of proximal vasculature using 1000 frames per second (fps) high-speed angiographic (HSA) imaging. Approach: We performed in-vitro HSA acquisitions using the XC-Actaeon detector and 3D-printed patient-specific phantoms. The CDG approach was used for blood velocity estimation expressed as the ratio of temporal and spatial contrast gradients. The gradients were extracted from 2D contrast intensity maps synthesized by plotting intensity profiles along the arterial centerline at each frame. In-vitro results obtained at various frame rates via temporal binning of 1000 fps data were retrospectively compared to computational fluid dynamics (CFD) velocimetry. Full-vessel velocity distributions were estimated at 1000 fps via parallel line expansion of the arterial centerline analysis. Results: Using HSA, the CDG method displayed agreement with CFD at or above 250 fps [mean-absolute error (MAE): 2.6±6.3 cm/s, p=0.05]. Relative velocity distributions correlated well with CFD at 1000 fps with universal underapproximation due to effects of pulsatile contrast injection (MAE: 4.3 cm/s). Conclusions: Using 1000 fps HSA, CDG-based extraction of velocities across large arteries is possible. The method is sensitive to noise; however, image processing techniques and a contrast injection, which adequately fills the vessel assist algorithm accuracy. The CDG method provides high resolution quantitative information for rapidly transient flow patterns observed in arterial circulation.

Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1). To address the critical need for novel therapeutics in MPNST, we aimed to establish an ex vivo 3D platform that accurately captured the genomic diversity of MPNST and could be utilized in a medium-throughput manner for drug screening studies to be validated in vivo using patient-derived xenografts (PDX). METHODS: Genomic analysis was performed on all PDX-tumor pairs. Selected PDX were harvested for assembly into 3D microtissues. Based on prior work in our labs, we evaluated drugs (trabectedin, olaparib, and mirdametinib) ex vivo and in vivo. For 3D microtissue studies, cell viability was the endpoint as assessed by Zeiss Axio Observer. For PDX drug studies, tumor volume was measured twice weekly. Bulk RNA sequencing was performed to identify pathways enriched in cells. RESULTS: We developed 13 NF1-associated MPNST-PDX and identified mutations or structural abnormalities in NF1 (100%), SUZ12 (85%), EED (15%), TP53 (15%), CDKN2A (85%), and chromosome 8 gain (77%). We successfully assembled PDX into 3D microtissues, categorized as robust (>90% viability at 48 h), good (>50%), or unusable (<50%). We evaluated drug response to "robust" or "good" microtissues, namely MN-2, JH-2-002, JH-2-079-c, and WU-225. Drug response ex vivo predicted drug response in vivo, and enhanced drug effects were observed in select models. CONCLUSIONS: These data support the successful establishment of a novel 3D platform for drug discovery and MPNST biology exploration in a system representative of the human condition.

Skin of color in dermatopathology: does color matter?

Skin of color (SoC) remains an understudied and under taught area of dermatology despite its rising importance. Race and ethnicity play a particularly important role in dermatology as skin pigmentation can affect the manifestation and presentation of many common dermatoses. With this review, we seek to review pertinent differences in SoC histology, as well as highlight the histopathology of conditions more common in SoC and address inherent bias that may affect accurate dermatopathology sign out.

Association of Primary Immunodeficiencies in Parents With Psychiatric Disorders and Suicidal Behavior in Their Offspring.

Importance: Maternal immune activation (MIA) leading to altered neurodevelopment in utero is a hypothesized risk factor for psychiatric outcomes in offspring. Primary antibody immunodeficiencies (PIDs) constitute a unique natural experiment to test the MIA hypothesis of mental disorders. Objective: To assess the association of maternal and paternal PIDs with psychiatric disorders and suicidal behavior in offspring. Design, Setting, and Participants: Cohort study of 4 294 169 offspring of parents with and without PIDs living in Sweden at any time between 1973 and 2013. Data were extracted from Swedish nationwide health and administrative registers and were analyzed from May 5 to September 30, 2022. All individuals with diagnoses of PIDs identified between 1973 and 2013 from the National Patient Register were included. Offspring were included if born before 2003. Parent-offspring pairs in which both parents had a history of PIDs were excluded. Exposures: Lifetime records of parental PIDs according to the International Classification of Diseases, Eighth Revision (ICD-8); International Classification of Diseases, Ninth Revision (ICD-9); and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes. Main Outcomes and Measures: Lifetime records of 10 psychiatric disorders and suicidal behavior identified using ICD-8, ICD-9, and ICD-10 diagnostic codes, including suicide attempts and death by suicide, among offspring. Covariates included sex, birth year, parental psychopathology, suicide attempts, and autoimmune diseases. Additional analyses excluded offspring with their own PIDs and autoimmune diseases. Poisson regression models were fitted separately for mothers and fathers to estimate incidence rate ratios (IRRs) and 95% CIs for the risk of psychiatric and suicidal behavior outcomes in the offspring of PID-exposed vs PID-unexposed mothers or fathers. Results: The cohort included 4 294 169 offspring (2 207 651 males [51.4%]) and 3 954 937 parents (1 987 972 females [50.3%]). A total of 7270 offspring (0.17%) had parents with PIDs, and 4 286 899 offspring had parents without PIDs. In fully adjusted models, offspring of mothers with PIDs had an increased risk of any psychiatric disorder, while no such risks were observed in offspring of fathers with PIDs (IRR, 1.17; 95% CI, 1.10-1.25 vs IRR, 1.03; 95% CI, 0.94-1.14; P < .001). Likewise, an increased risk of suicidal behavior was observed among offspring of mothers with PIDs but not offspring of fathers with PIDs (IRR, 1.20; 95% CI, 1.06-1.36 vs IRR, 1.10; 95% CI, 0.91-1.34; P = .01). For the offspring of mothers with PIDs, the risk of developing any psychiatric disorder was significantly higher for those with mothers with 6 of 10 individual disorders, with IRRs ranging from 1.15 (95% CI, 1.04-1.26) for anxiety and stress-related disorders and 1.15 (95% CI, 1.03-1.30) for substance use disorders to 1.71 (95% CI, 1.37-2.14) for bipolar disorders. Offspring of mothers with both PIDs and autoimmune diseases had the highest risk for any psychiatric disorder (IRR, 1.24; 95% CI, 1.11-1.38) and suicidal behavior (IRR, 1.44; 95% CI, 1.17-1.78). Conclusions and Relevance: Findings of this cohort study suggest that maternal, but not paternal, PIDs were associated with a statistically significant increased risk of psychiatric disorders and suicidal behavior in the offspring, particularly when PIDs co-occur with autoimmune diseases. These findings align with the MIA hypothesis of mental disorders, but the precise mechanisms remain to be elucidated.

A Survey of Demographics, Symptom Course, Family History, and Barriers to Treatment in Children with Pediatric Acute-Onset Neuropsychiatric Disorders and Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections.

Objective: Few large-scale studies of pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) have been conducted, and thus demographic data on these conditions are limited. The current study describes comorbid medical and psychiatric conditions in a self-referred cohort of children with PANS/PANDAS, along with treatment history, barriers to treatment, family medical and psychiatric history, and perceived caregiver burden in these conditions. Methods: A total of 441 primary caregivers of patients with infection-triggered PANS/PANDAS under the age of 18 were included in this online anonymous survey, reporting on a total of 490 children (due to some caregivers reporting multiple children in the family with PANS/PANDAS). Data were collected between July 2018 and May 2019. Primary caregivers completed questions pertaining to patient demographics, symptom presentation, disease course, family medical and psychiatric history, and severity of patients' obsessive-compulsive disorder (OCD) symptoms. Results: OCD was the most common psychiatric symptom reported in children at the onset of PANS/PANDAS (83.06%), along with a high percentage of medical and psychiatric comorbidities. Most psychiatric comorbidities began or worsened at the onset of PANS/PANDAS symptoms, while major depressive disorder was the most frequently reported psychiatric disorder to develop after PANS/PANDAS onset (10%). A high frequency of autoimmune and inflammatory conditions was reported in family members, with nearly 30% of mothers endorsing one or more autoimmune conditions (29.95%). Mean caregiver burden (Caregiver Burden Inventory; M = 44.0) fell above the "burnout" level, and standardized measures showed mildly elevated levels of depression, anxiety, and stress in caregivers (Depression, Anxiety, and Stress Scale-21; M = 11.85, 7.16, and 15.56, respectively). Conclusions: Primary caregivers of children with PANS/PANDAS reported a multitude of medical and psychiatric comorbidities in their children, along with a high frequency of autoimmune and psychiatric conditions in family members. Obsessive-compulsive symptoms were the most frequently reported psychiatric symptom. Caregivers of these patients experience elevated levels of burden, stress, anxiety, and depression. Further research is needed to better understand the varied disease course in PANS/PANDAS and to develop interventions to reduce caregiver burden in these disorders.

2D vessel contrast dilution gradient (CDG) analysis using 1000 fps high speed angiography (HSA) for velocity distribution estimation.

Purpose: Contrast dilution gradient (CDG) analysis is a technique used to extract velocimetric 2D information from digitally subtracted angiographic (DSA) acquisitions. This information may then be used by clinicians to quantitatively assess the effects of endovascular treatment on flow conditions surrounding pathologies of interest. The method assumes negligible diffusion conditions, making 1000 fps high speed angiography (HSA), in which diffusion between 1 ms frames may be neglected, a strong candidate for velocimetric analysis using CDG. Previous studies have demonstrated the success of CDG analysis in obtaining velocimetric one-dimensional data at the arterial centerline of simple vasculature. This study seeks to resolve velocity distributions across the entire vessel using 2D-CDG analysis with HSA acquisitions. Materials and Methods: HSA acquisitions for this study were obtained in vitro with a benchtop flow loop at 1000 fps using the XC-Actaeon (Direct Conversion Inc.) photon counting detector. 2D-CDG analyses were compared with computational fluid dynamics (CFD) via automatic co-registration of the results from each velocimetry method. This comparison was performed using mean absolute error between pixel values in each method (after temporal averaging). Results: CDG velocity magnitudes were slightly under approximated relative to CFD results (mean velocity: 27 cm/s, mean absolute error: 4.3 cm/s) as a result of incomplete contrast filling. Relative 2D spatial velocity distributions in CDG analysis agreed well with CFD distributions qualitatively. Conclusions: CDG may be used to obtain velocity distributions in and surrounding vascular pathologies provided diffusion is negligible relative to convection in the flow, given a continuous gradient of contrast.