Human papillomavirus and the landscape of secondary genetic alterations in oral cancers.

Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCCs) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCCs, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. In contrast, in HPV-negative OSCCs, T>C substitutions in the sequence context 5'-ATN-3' correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCCs. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1, and NFKBIA Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon (IFN) and nuclear factor kappa B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCCs, in contrast to their gains in HPV-negative OSCCs. High-ranking variant allele fractions implicated ZNF750, PIK3CA, and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

Isoforms of MUC16 activate oncogenic signaling through EGF receptors to enhance the progression of pancreatic cancer.

Aberrant expression of CA125/MUC16 is associated with pancreatic ductal adenocarcinoma (PDAC) progression and metastasis. However, knowledge of the contribution of MUC16 to pancreatic tumorigenesis is limited. Here, we show that MUC16 expression is associated with disease progression, basal-like and squamous tumor subtypes, increased tumor metastasis, and short-term survival of PDAC patients. MUC16 enhanced tumor malignancy through the activation of AKT and GSK3ß oncogenic signaling pathways. Activation of these oncogenic signaling pathways resulted in part from increased interactions between MUC16 and epidermal growth factor (EGF)-type receptors, which were enhanced for aberrant glycoforms of MUC16. Treatment of PDAC cells with monoclonal antibody (mAb) AR9.6 significantly reduced MUC16-induced oncogenic signaling. mAb AR9.6 binds to a unique conformational epitope on MUC16, which is influenced by O-glycosylation. Additionally, treatment of PDAC tumor-bearing mice with either mAb AR9.6 alone or in combination with gemcitabine significantly reduced tumor growth and metastasis. We conclude that the aberrant expression of MUC16 enhances PDAC progression to an aggressive phenotype by modulating oncogenic signaling through ErbB receptors. Anti-MUC16 mAb AR9.6 blocks oncogenic activities and tumor growth and could be a novel immunotherapeutic agent against MUC16-mediated PDAC tumor malignancy.

NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2021.

Identifying individuals with hereditary syndromes allows for timely cancer surveillance, opportunities for risk reduction, and syndrome-specific management. Establishing criteria for hereditary cancer risk assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provides recommendations for the assessment and management of patients at risk for or diagnosed with high-risk colorectal cancer syndromes. The NCCN Genetic/Familial High-Risk Assessment: Colorectal panel meets annually to evaluate and update their recommendations based on their clinical expertise and new scientific data. These NCCN Guidelines Insights focus on familial adenomatous polyposis (FAP)/attenuated familial adenomatous polyposis (AFAP) syndrome and considerations for management of duodenal neoplasia.

Including colon in intestinal transplantation: a focus on post-transplant renal function - a retrospective study.

Intestinal transplant recipients experience a high rate of renal complications secondary to dehydration due to increased ostomy output. It is hypothesized that inclusion of donor colon in the intestinal allograft may improve renal function in patients without functional native colon by improving fluid absorption. A single-center retrospective study of intestinal transplant recipients compared outcomes of patients receiving en bloc colon as part an intestinal allograft (ICTx), and those not receiving colon (CCNTx), as well as a control group of intestinal transplant recipients with functional native colon (ITx). Forty-seven patients (ICTx n = 17, CCNTx n = 15, ITx n = 15) were studied. One-year post-transplant renal function, as measured by change in glomerular filtration rate (GFR) and blood urea nitrogen (BUN) from baseline, was superior in ICTx (mean delta-GFR of -1.31 and delta-BUN of -1.46) compared to CCNTx (-6.54 and 17.54, P = 0.05 and P = 0.17, respectively) and similar to the ITx controls (0.55 and 2.09). Recipients of donor colon experienced a higher rate of ileostomy reversal when compared to CCNTx (62.5% vs. 20%, P = 0.0008), which was similar to the ITx controls (60%). These findings support the inclusion of en bloc donor colon in the intestinal allograft for recipients without functional native colon.

IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer.

OBJECTIVE: Limited efficacy of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) has prompted investigation into combination therapy. We hypothesised that interleukin 6 (IL-6) blockade would modulate immunological features of PDAC and enhance the efficacy of anti-programmed death-1-ligand 1 (PD-L1) checkpoint inhibitor therapy. DESIGN: Transcription profiles and IL-6 secretion from primary patient-derived pancreatic stellate cells (PSCs) were analyzed via Nanostring and immunohistochemistry, respectively. In vivo efficacy and mechanistic studies were conducted with antibodies (Abs) targeting IL-6, PD-L1, CD4 or CD8 in subcutaneous or orthotopic models using Panc02, MT5 or KPC-luc cell lines; and the aggressive, genetically engineered PDAC model (KrasLSL-G12D, Trp53LSL-R270H, Pdx1-cre, Brca2F/F (KPC-Brca2 mice)). Systemic and local changes in immunophenotype were measured by flow cytometry or immunohistochemical analysis. RESULTS: PSCs (n=12) demonstrated prominent IL-6 expression, which was localised to stroma of tumours. Combined IL-6 and PD-L1 blockade elicited efficacy in mice bearing subcutaneous MT5 (p<0.02) and Panc02 tumours (p=0.046), which was accompanied by increased intratumoural effector T lymphocytes (CD62L-CD44-). CD8-depleting but not CD4-depleting Abs abrogated the efficacy of combined IL-6 and PD-L1 blockade in mice bearing Panc02 tumours (p=0.0016). This treatment combination also elicited significant antitumour activity in mice bearing orthotopic KPC-luc tumours and limited tumour progression in KPC-Brca2 mice (p<0.001). Histological analysis revealed increased T-cell infiltration and reduced α-smooth muscle actin cells in tumours from multiple models. Finally, IL-6 and PD-L1 blockade increased overall survival in KPC-Brca2 mice compared with isotype controls (p=0.0012). CONCLUSIONS: These preclinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC.

Development and characterization of an inexpensive single-particle fluorescence spectrometer for bioaerosol monitoring.

Laser-induced fluorescence (LIF) techniques to analyze atmospheric aerosols are commonly applied for research and human exposure monitoring, but are very expensive or offer poor spectral resolution. Here, we discuss how a recently proposed instrument can acquire resolved fluorescence spectra from many individual particles in a single camera image using four excitation wavelengths matched with common biological fluorophores for particle discrimination at lower cost. We discuss emission intensity calibration and demonstrate spectral differentiation among four species of pollen. These data provide context for how the instrument could be developed for pollen and mold-spore detection or for use by citizen scientists.

Needle-based confocal laser endomicroscopy for the diagnosis of pancreatic cystic lesions: an international external interobserver and intraobserver study (with videos).

BACKGROUND AND AIMS: EUS-guided needle-based confocal laser endomicroscopy (nCLE) characteristics of common types of pancreatic cystic lesions (PCLs) have been identified; however, surgical histopathology was available in a minority of cases. We sought to assess the performance characteristics of EUS nCLE for differentiating mucinous from non-mucinous PCLs in a larger series of patients with a definitive diagnosis. METHODS: Six endosonographers (nCLE experience >30 cases each) blinded to all clinical data, reviewed nCLE images of PCLs from 29 patients with surgical (n = 23) or clinical (n = 6) correlation. After 2 weeks, the assessors reviewed the same images in a different sequence. A tutorial on available and novel nCLE image patterns was provided before each review. The performance characteristics of nCLE and the κ statistic for interobserver agreement (IOA, 95% confidence interval [CI]), and intraobserver reliability (IOR, mean ± standard deviation [SD]) for identification of nCLE image patterns were calculated. Landis and Koch interpretation of κ values was used. RESULTS: A total of 29 (16 mucinous PCLs, 13 non-mucinous PCLs) nCLE patient videos were reviewed. The overall sensitivity, specificity, and accuracy for the diagnosis of mucinous PCLs were 95%, 94%, and 95%, respectively. The IOA and IOR (mean ± SD) were κ = 0.81 (almost perfect); 95% CI, 0.71-0.90; and κ = 0.86 ± 0.11 (almost perfect), respectively. The overall specificity, sensitivity, and accuracy for the diagnosis of serous cystadenomas (SCAs) were 99%, 98%, and 98%, respectively. The IOA and IOR (mean ± SD) for recognizing the characteristic image pattern of SCA were κ = 0.83 (almost perfect); 95% CI, 0.73-0.92; and κ = 0.85 ± 0.11 (almost perfect), respectively. CONCLUSIONS: EUS-guided nCLE can provide virtual histology of PCLs with a high degree of accuracy and inter- and intraobserver agreement in differentiating mucinous versus non-mucinous PCLs. These preliminary results support larger multicenter studies to evaluate EUS nCLE. (Clinical trial registration number: NCT02516488.).

High-grade pancreatic intraepithelial lesions: prevalence and implications in pancreatic neoplasia.

BACKGROUND: High-grade pancreatic intraepithelial neoplasia (PanIN-3), a precursor of pancreatic ductal adenocarcinoma (PDAC), is not universally detected in resected pancreatic neoplasms. We sought to determine the prevalence and prognostic relevance of PanIN-3 lesions in primary surgical resections of PDACs and intraductal papillary mucinous neoplasms (IPMNs). METHODS: A retrospective review of a tertiary care center pathology database (1/2000-6/2014) was performed. Demographics, imaging, pathology, disease-recurrence, and survival data were reviewed. RESULTS: A total of 458 patients who underwent primary pancreatic resection were included. "PanIN-3" lesions were found in 74 (16.2%) patients who either had PDAC (n=67) or main duct (MD)-IPMN (n=7). Among IPMN-MDs, PanIN-3 lesions were exclusively found in those with pathological evidence of chronic pancreatitis. For PDACs, the median overall survival (OS) for pancreata with PanIN-3 lesions was significantly better than those without (OS 1.12 years, inter-quartile range [IQR] 0.72, 2.05 years vs OS 0.86 years, IQR 0.64, 1.60 years respectively; P=0.04). Multivariate Cox regression analysis demonstrated that the presence of PanIN-3 lesions was associated with a reduced risk of death (HR=0.43; 95% CI: 0.23-0.82; P=0.01). CONCLUSIONS: Following primary resection of pancreatic adenocarcinoma, the lower survival observed in patients without PanIN-3 lesions might suggest a state of complete or accelerated transformation. Further investigations are necessary to validate these findings that might impact disease prognosis and management.

Distinct pathways of humoral and cellular immunity induced with the mucosal administration of a nanoemulsion adjuvant.

Nasal administration of an oil-in-water nanoemulsion (NE) adjuvant W805EC produces potent systemic and mucosal, Th-1- and Th-17-balanced cellular responses. However, its molecular mechanism of action has not been fully characterized and is of particular interest because NE does not contain specific ligands for innate immune receptors. In these studies, we demonstrate that W805EC NE adjuvant activates innate immunity, induces specific gene transcription, and modulates NF-κB activity via TLR2 and TLR4 by a mechanism that appears to be distinct from typical TLR agonists. Nasal immunization with NE-based vaccine showed that the TLR2, TLR4, and MyD88 pathways and IL-12 and IL-12Rß1 expression are not required for an Ab response, but they are essential for the induction of balanced Th-1 polarization and Th-17 cellular immunity. NE adjuvant induces MHC class II, CD80, and CD86 costimulatory molecule expression and dendritic cell maturation. Further, upon immunization with NE, adjuvant mice deficient in the CD86 receptor had normal Ab responses but significantly reduced Th-1 cellular responses, whereas animals deficient in both CD80 and CD86 or lacking CD40 failed to produce either humoral or cellular immunity. Overall, our data show that intranasal administration of Ag with NE induces TLR2 and TLR4 activation along with a MyD88-independent Ab response and a MyD88-dependent Th-1 and Th-17 cell-mediated immune response. These findings suggest that the unique properties of NE adjuvant may offer novel opportunities for understanding previously unrecognized mechanisms of immune activation important for generating effective mucosal and systemic immune responses.

Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma.

BACKGROUND: While surgical resection of pancreatic adenocarcinoma provides the only chance of cure, long-term survival remains poor. Immunotherapy may improve outcomes, especially as adjuvant to local therapies. Gene-mediated cytotoxic immunotherapy (GMCI) generates a systemic anti-tumor response through local delivery of an adenoviral vector expressing the HSV-tk gene (aglatimagene besadenovec, AdV-tk) followed by anti-herpetic prodrug. GMCI has demonstrated synergy with standard of care (SOC) in other tumor types. This is the first application in pancreatic cancer. METHODS: Four dose levels (3 × 10(10) to 1 × 10(12) vector particles) were evaluated as adjuvant to surgery for resectable disease (Arm A) or to 5-FU chemoradiation for locally advanced disease (Arm B). Each patient received two cycles of AdV-tk + prodrug. RESULTS: Twenty-four patients completed therapy, 12 per arm, with no dose-limiting toxicities. All Arm A patients were explored, eight were resected, one was locally advanced and three had distant metastases. CD8(+) T cell infiltration increased an average of 22-fold (range sixfold to 75-fold) compared with baseline (p = 0.0021). PD-L1 expression increased in 5/7 samples analyzed. One node-positive resected patient is alive >66 months without recurrence. Arm B RECIST response rate was 25 % with a median OS of 12 months and 1-year survival of 50 %. Patient-reported quality of life showed no evidence of deterioration. CONCLUSIONS: AdV-tk can be safely combined with pancreatic cancer SOC without added toxicity. Response and survival compare favorably to expected outcomes and immune activity increased. These results support further evaluation of GMCI with more modern chemoradiation and surgery as well as PD-1/PD-L1 inhibitors in pancreatic cancer.

A Developmentally Informed Systematic Review and Meta-Analysis of the Strength of General Psychopathology in Childhood and Adolescence.

Considerable support exists for higher-order dimensional conceptualizations of psychopathology in adults. A growing body of work has focused on understanding the structure of general and specific psychopathology in children and adolescents. No prior meta-analysis has examined whether the strength of the general psychopathology factor (p factor)-measured by explained common variance (ECV)-changes from childhood to adolescence. The primary objective of this multilevel meta-analysis was to determine whether general psychopathology strength changes across development (i.e. across ages) in childhood and adolescence. Several databases were searched in November 2021; 65 studies, with 110 effect sizes (ECV), nested within shared data sources, were identified. Included empirical studies used a factor analytic modeling approach that estimated latent factors for child/adolescent internalizing, externalizing, and optionally thought-disordered psychopathology, and a general factor. Studies spanned ages 2-17 years. Across ages, general psychopathology explained over half (~ 56%) of the reliable variance in symptoms of psychopathology. Age-moderation analyses revealed that general factor strength remained stable across ages, suggesting that general psychopathology strength does not significantly change across childhood to adolescence. Even if the structure of psychopathology changes with development, the prominence of general psychopathology across development has important implications for future research and intervention.

Explaining Brain-Behavior Relations: Inhibitory Control as an Intermediate Phenotype Between the N2 ERP and the Externalizing Spectrum in Childhood.

Identifying neural and cognitive mechanisms in externalizing problems in childhood is important for earlier and more targeted intervention. Meta-analytic findings have shown that smaller N2 event-related potential (ERP) amplitudes, thought to reflect inhibitory control, are associated with externalizing problems in children. However, it is unclear how (i.e., through which cognitive processes) N2 amplitudes relate to externalizing problems. We examined whether inhibitory control may be a cognitive process that links N2 amplitudes and externalizing problems in early childhood. Children (N = 147, 74 girls) were assessed at four time points, spanning 3-7 years of age. Children's externalizing behavior was assessed via questionnaires completed by mothers, fathers, and teachers/secondary caregivers. Children's inhibitory control was assessed using eleven performance-based tasks and two questionnaires. Developmental scaling linked differing measures of inhibitory control and externalizing behavior across ages onto the same scale. Children's N2 amplitudes were extracted from electroencephalography data collected during a go/no-go task. Smaller N2 amplitudes were associated with externalizing problems and poorer inhibitory control. A concurrent analysis of indirect effects revealed that poorer inhibitory control partially explained the association between smaller N2 amplitudes and externalizing problems, even when controlling for the child's age, sex, and socioeconomic status. This is among the first studies to link N2 amplitudes, inhibitory control, and externalizing problems during early childhood. Findings suggest that smaller N2 amplitudes may be an early neural indicator of inhibitory control deficits and externalizing psychopathology. Moreover, inhibitory control may be an important target for early intervention in the development of externalizing psychopathology.

Relaxin-2 is a novel biomarker for differentiated thyroid carcinoma in humans.

Relaxin's role in differentiated thyroid cancer (DTC) has been suggested but its characterization in a large clinical sample remains limited. We performed immunohistochemistry for relaxin-2 (RLN2), CD68 (total macrophages), CD163 (M2 macrophages) on tissue microarrays from 181 subjects with non-distant metastatic DTC, and 185 subjects with benign thyroid tissue. Mean pixels/area for each marker was compared between tumor and adjacent tissue via paired-t test and between DTC and benign subjects via t-test assuming unequal variances. RNA qPCR was performed for expression of RLN2, RLN1, and RXFP1 in cell lines. Amongst 181 cases, the mean age was 46 years, 75 % were females. Tumoral tissue amongst the DTC cases demonstrated higher mean expression of RLN2 (53.04 vs. 9.79; p < 0.0001) compared to tumor-adjacent tissue. DTC tissue also demonstrated higher mean expression of CD68 (14.46 vs. 4.79; p < 0.0001), and CD163 (23.13 vs. -0.73; p < 0.0001) than benign thyroid. These markers did not differ between tumor-adjacent and benign thyroid tissue groups; and amongst cases, did not differ by demographic or clinicopathologic features. RLN1 and RXFP1 expression was detected in a minority of the cell lines, while RLN2 was expressed by 6/7 cell lines. In conclusion, widespread RLN2 expression in DTC tissue and most cell lines demonstrates that RLN2 acts in a paracrine manner, and that RLN1 and RXFP1 are probably not involved in thyroid cancer cell signaling. RLN2 is a biomarker for thyroid carcinogenesis, being associated with but not secreted by immunosuppressive macrophages. These findings will guide further investigations for therapeutic avenues against thyroid cancer.

Characterization of Immune Infiltrate Along the Leading Edge of Differentiated Thyroid Cancer.

Background: Although the impact of tumor-immune infiltrate has been reported on differentiated thyroid cancer (DTC) behavior, the expression of immune checkpoints [programmed cell death protein 1 (PD-1) and its ligand (PD-L1)] alone has not been able to predict response to immunotherapies. We aimed to identify tumor-infiltrating immune cells and checkpoints associated with DTC. Methods: We performed multiplex immunofluorescence on deparaffinized thyroid tissue collected at thyroidectomy from 17 adults with DTC to characterize the tumor immune microenvironment for leukocytes (CD45+), T cells (CD3+), T regulatory cells (Tregs) (CD3+FOXP3+), CD4+ T cells (CD3+CD4+), CD8+ T cells (CD3+CD8+), macrophages (CD68+), M2 macrophages (CD68+CD163+), M1 Macrophages (CD68+ inducible nitric oxide synthase [iNOS]+), and immune checkpoints PD-1 and PD-L1. We compared the mean percentage expression of immune markers between tumor and adjacent thyroid tissue from the same patient by paired t-test and performed spatial analysis along the tumor's leading edge. Results: Immune checkpoints PD-1 and PD-L1 showed a significant increase in expression intratumorally as compared to adjacent thyroid tissue (p < 0.05). A higher trend for M2 macrophages was observed intratumorally compared to adjacent tissue. Along the leading edge, PD-L1 expression correlated negatively with CD45 and positively with CD163 intratumorally. On exploratory analysis, there was a nonsignificant trend for higher FOXP3 but less CD8 and iNOS expression in tumor from DTC with (n = 3) versus without distant metastases (n = 14). There was a nonsignificant trend for higher CD58 and iNOS expression in DTC with (n = 7) than without thyroiditis (n = 10). Conclusions: Higher tumoral PD-1 and PD-L1 expression indicate their role in DTC occurrence. A trend for more Tregs and M2 macrophages but less M1 macrophages intratumorally in patients with distant metastatic DTC, suggests their potential role as prognostic biomarkers. Future studies with larger sample sizes are needed to compare various clinicopathologic severities to harness tumor microenvironment for cancer prognostication and therapy.

Structural Basis for Multivalent MUC16 Recognition and Robust Anti-Pancreatic Cancer Activity of Humanized Antibody AR9.6.

Mucin-16 (MUC16) is a target for antibody-mediated immunotherapy in pancreatic ductal adenocarcinoma (PDAC) among other malignancies. The MUC16-specific monoclonal antibody AR9.6 has shown promise for PDAC immunotherapy and imaging. Here, we report the structural and biological characterization of the humanized AR9.6 antibody (huAR9.6). The structure of huAR9.6 was determined in complex with a MUC16 SEA (Sea urchin sperm, Enterokinase, Agrin) domain. Binding of huAR9.6 to recombinant, shed, and cell-surface MUC16 was characterized, and anti-PDAC activity was evaluated in vitro and in vivo. HuAR9.6 bound a discontinuous, SEA domain epitope with an overall affinity of 88 nmol/L. Binding affinity depended on the specific SEA domain(s) present, and glycosylation modestly enhanced affinity driven by favorable entropy and enthalpy and via distinct transition state thermodynamic pathways. Treatment with huAR9.6 reduced the in vitro growth, migration, invasion, and clonogenicity of MUC16-positive PDAC cells and patient-derived organoids (PDO). HuAR9.6 blocked MUC16-mediated ErbB and AKT activation in PDAC cells, PDOs, and patient-derived xenografts and induced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. More importantly, huAR9.6 treatment caused substantial PDAC regression in subcutaneous and orthotopic tumor models. The mechanism of action of huAR9.6 may depend on dense avid binding to homologous SEA domains on MUC16. The results of this study validate the translational therapeutic potential of huAR9.6 against MUC16-positive PDACs.

The P3 ERP in Relation to General Versus Specific Psychopathology in Early Childhood.

There is considerable covariation between externalizing and internalizing problems across the lifespan. Partitioning general and specific psychopathology is crucial to identify (a) processes that confer specific risk for externalizing versus internalizing problems and (b) transdiagnostic processes that confer risk for the covariation between externalizing and internalizing problems. The oddball P3 event-related potential (ERP) component, thought to reflect attentional orienting, has been widely examined in relation to psychopathology. However, prior studies have not examined the P3-or other aspects of neural functioning-in relation to general versus specific psychopathology in children. The present study examined whether children's (N = 124, ages 3-7 years) P3 amplitudes were associated with general versus specific psychopathology. Children's electroencephalography data were recorded during an oddball task. Parents rated their children's externalizing and internalizing problems. Using bifactor models to partition variance in parents' ratings of children's psychopathology symptoms, we examined children's P3 amplitudes in relation to three latent factors: (1) the general factor of psychopathology-the covariation of externalizing and internalizing psychopathology, (2) unique externalizing problems-the variance in externalizing problems after controlling for the general factor, and (3) unique internalizing problems. Results indicated that smaller P3 amplitudes were associated with unique externalizing problems at ages 3-5, and with general psychopathology at ages 6-7. Findings suggest that smaller P3 amplitudes may be associated with externalizing problems from a very young age. Moreover, there may be a developmental shift in the functional significance of the P3 in relation to general and specific psychopathology in childhood.

Pulmonary Hypertensive Changes Secondary to COVID-19 Pneumonia in a Chronically SARS-CoV-2-Infected Bilateral Lung Explant.

COVID-19, the syndrome caused by the novel coronavirus SARS-CoV-2, has spread throughout the world, causing the death of at least three million people. For the over 81 million who have recovered, however, the long-term effects are only beginning to manifest. We performed a bilateral lung transplant on a 31-year-old male patient for chronic hypoxic respiratory failure, severe pulmonary hypertension and radiographically identified pulmonary fibrosis five months after an acute COVID-19 infection. The explant demonstrated moderate pulmonary vascular remodeling with intimal thickening and medial hypertrophy throughout, consistent with pulmonary hypertension. The parenchyma demonstrated an organizing lung injury in the proliferative phase, with severe fibrosis, histiocytic proliferation, type II pneumocyte hyperplasia, and alveolar loss consistent with known COVID-19 pneumonia complications.This report highlights a novel histologic finding in severe, chronic COVID-19. Although the findings in acute COVID-19 pneumonia have been well-examined at autopsy, the chronic course of this complex disease is not yet understood. The case presented herein suggests that COVID-induced pulmonary hypertension may become more common as more patients survive severe SARS-CoV-2-related pneumonia. Pulmonologists and pulmonary pathologists should be aware of this possible association and look for the clinical, radiographic, and histologic criteria in the appropriate clinical setting.