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OBJECTIVES/GOALS: A negative circumferential resection margin (CRM) after surgical resection of rectal cancer decreases local recurrence and increases overall survival. While MRI is used to predict this risk, there is no predictive model that incorporates clinical factors to predict the risk of CRM positivity. METHODS/STUDY POPULATION: Utilizing the National Cancer Database from 2010-2014, we performed a retrospective study evaluating factors predictive for positive CRM after surgical resection of rectal cancer. The primary outcome was positive CRM (tumor≤1 mm from the surgical margin). Our population included patients with clinical stage I-III rectal cancer who underwent total mesorectal excision. For the primary outcome, multivariable logistic models were used to estimate the probability of a positive CRM. Model performance was evaluated by using the area under the receiver operating characteristic curve (AUC). Model calibration was assessed by examining the calibration plot. Bootstrapping method (300-iteration) was used to internally validate and estimate optimism-adjusted measures of discrimination and overall model fit. RESULTS/ANTICIPATED RESULTS: There were 28,790 patients included. 2,245 (7.8%) had positive CRM. Older age, race, larger tumor size, higher tumor grade, mucinous and signet tumor histology, APR, open operative approach, facility location, higher T stage, lymphovascular invasion, lack of neoadjuvant chemotherapy/radiation, and perineural invasion were all significantly associated with positive CRM (p DISCUSSION/SIGNIFICANCE: An objective model that predicts positive CRM and associated poor clinical outcomes is possible to be used in conjunction with MRI. Positive CRM is associated with specific patient demographics, tumor characteristics, and operative approach. These factors can be used to predict CRM positivity in the preoperative period and plan accordingly.

Abstract Background There are limited data on the prevalence of Lynch syndrome (LS) in women with primary ovarian cancer with mismatch repair deficiency (MMR‐D) by immunohistochemistry (IHC). Materials and Methods Three hundred and eight cases of primary ovarian, fallopian, and peritoneal cancer between January 2012 and December 2019 were evaluated for MMR‐D by IHC. The incidence of LS in this cohort was evaluated. Results MMR‐D by IHC was identified in 16 of 308 (5.2%) (95% CI: 3.2%–8.3%) primary ovarian‐related cancers. Most cases with MMR‐D were endometrioid (n = 11, 68.7%); (95% CI: 44.2%–86.1%). MSH2/MSH6 protein loss was detected in eight cases (50.0%); (95% CI: 28.0%–72.0%) and MLH1/PMS2 protein loss was detected in four cases (25.0%); (95% CI: 9.7%–50.0%). MSH6 protein loss was detected in two cases (12.5%); (95% CI: 2.2%–37.3%) and PMS2 protein loss was detected in two cases (12.5%); (95% CI: 2.2%–37.3%). All four cases with MLH1/PMS2 protein loss had MLH1 promotor hypermethylation. All 12 women with ovarian cancer suggestive of LS underwent germline testing and 8 (66.6%); (95% CI: 38.8%–86.5%) were confirmed to have LS. Conclusions Most ovarian cancers with somatic MMR‐D were confirmed to have LS in this cohort. Germline testing for LS in addition to BRCA1/2 for all women with an epithelial ovarian cancer would be efficient and would approach 100% sensitivity for identifying Lynch syndrome. Utilization of a multigene panel should also be considered, given the additional non‐Lynch germline mutation identified in this cohort.

Abstract Adjuvant ultrasound at 2 MHz with or without an ultrasound contrast agent improves the rate of thrombus resolution by recombinant tissue plasminogen activator (rt-PA) in laboratory and clinical studies. A sub-megahertz approach can further expand this therapy to a subset of patients with an insufficient temporal bone window, improving efficacy in unselected patient populations. The aim of this study was to determine if a clinical ultrasound contrast agent (UCA), Definity, and 220 kHz pulsed ultrasound accelerated rt-PA thrombolysis in a preclinical animal model of vascular occlusion. The effect of Definity and ultrasound on thrombus clearance was first investigated in vitro and subsequently tested in a xenographic porcine cerebral thromboembolism model in vivo. Two different microcatheter designs (end-hole, multi-side-hole) were used to infuse rt-PA and Definity at the proximal edge or directly into clots, respectively. Sonothrombolysis with Definity increased clot mass loss relative to saline or rt-PA alone in vitro, only when rt-PA was administered directly into clots via a multi-side-hole microcatheter. Combined treatment with rt-PA, Definity, and ultrasound in vivo increased the rate of reperfusion up to 45 min faster than clots treated with rt-PA or saline. In this porcine cerebral thromboembolism model employing retracted human clots, 220 kHz ultrasound, in conjunction with Definity increased the probability of early successful reperfusion with rt-PA.

Abstract Surveying cryptic, sparsely distributed taxa using autonomous recording units, although cost‐effective, provides imperfect knowledge about species presence. Summertime bat acoustic surveys in North America exemplify the challenges with characterizing sources of uncertainty: observation error, inability to census populations, and natural stochastic variation. Statistical uncertainty, if not considered thoroughly, hampers determining rare species presence accurately and/or estimating rangewide status and trends with suitable precision. Bat acoustic data are processed using an automated workflow in which proprietary or open‐source algorithms assign a species label to each recorded high‐frequency echolocation sequence. A false‐negative occurs, if a species is actually present but not recorded and/or all recordings from the species are of such poor quality that a correct species identity cannot be assigned to any observation. False positives for a focal species are a direct result of the presence and incorrect identification of a recording from another species. We compare four analytical approaches in terms of parameter estimation and their resulting (in)correct decisions regarding species presence or absence using realistic data‐generating scenarios for bat acoustic data within a simulation study. The current standard for deciding species presence or absence uses a multinomial likelihood‐ratio test p value (maximum likelihood estimate [MLE]‐metric) that accounts for known species misidentifications, but not imperfect detection and only returns a binary outcome (evidence of presence or not). We found that the MLE‐metric had estimated median correct decisions less than 60% for presence and greater than 85% for absence. Alternatively, a multispecies count detection model was equivalent to or better than the MLE‐metric for correct claims of rare species presence or absence using the posterior probability a species was present at a site and, importantly, provided unbiased estimates of relative activity and probability of occurrence, creating opportunities for reducing posterior uncertainty through the inclusion of meaningful covariates. Single‐species occupancy models with and without false‐positive detections removed were insufficient for determining local presence because of substantially biased occurrence and detection probabilities. We propose solutions to potential barriers for integrating local, short‐term and rangewide, long‐term acoustic surveys within a cohesive statistical framework that facilitates determining local species presence with uncertainty concurrent with estimating species–environment relationships.

Abstract Recurring glacial cycles through the Quaternary period drastically altered the size and distribution of natural populations of North American flora and fauna. The “southerly refugia model” has been the longstanding framework for testing the effects of glaciation on contemporary genetic patterns; however, insights from ancient DNA have contributed to the reconstruction of more complex histories for some species. The American badger, Taxidea taxus, provides an interesting species for exploring the genetic legacy of glacial history, having been hypothesized to have postglacially emerged from a single, southerly refugium to recolonize northern latitudes. However, previous studies have lacked genetic sampling from areas where distinct glacial refugia have been hypothesized, including the Pacific Northwest and American Far North (Yukon, Alaska). In order to further investigate the phylogeographic history of American badgers, we collected mitochondrial DNA sequence data from ancient subfossil material collected within the historical range (Alaska, Yukon) and combined them with new and previously published data from across the species' contemporary distribution (n = 1,207). We reconstructed a mostly unresolved phylogenetic tree and star‐like haplotype network indicative of emergence from a largely panmictic glacial refugium and recent population expansion, the latter further punctuated by significantly negative Tajima's D and Fu's Fs values. Although directionality of migration cannot be unequivocally inferred, the moderate to high levels of genetic variation exhibited by American badgers, alongside the low frequency of haplotypes with indels in the Midwest, suggest a potential recolonization into central North America after the hypothesized ice‐free corridor reopened ~13,000 years ago. Overall, the expanded reconstruction of phylogeographic history of American badgers offers a broader understanding of contemporary range‐wide patterns and identifies unique genetic units that can likely be used to inform conservation of at‐risk populations at the northern periphery.

Motivation and pleasure deficits are common in schizophrenia, strongly linked with poorer functioning, and may reflect underlying alterations in brain functions governing reward processing and goal pursuit. While there is extensive research examining cognitive and reward mechanisms related to these deficits in schizophrenia, less attention has been paid to psychological characteristics that contribute to resilience against, or risk for, motivation and pleasure impairment. For example, psychological tendencies involving positive future expectancies (e.g., optimism) and effective affect management (e.g., reappraisal, mindfulness) are associated with aspects of reward anticipation and evaluation that optimally guide goal-directed behavior. Conversely, maladaptive thinking patterns (e.g., defeatist performance beliefs, asocial beliefs) and tendencies that amplify negative cognitions (e.g., rumination), may divert cognitive resources away from goal pursuit or reduce willingness to exert effort. Additionally, aspects of sociality, including the propensity to experience social connection as positive reinforcement may be particularly relevant for pursuing social goals. In the current review, we discuss the roles of several psychological characteristics with respect to motivation and pleasure in schizophrenia. We argue that individual variation in these psychological dimensions is relevant to the study of motivation and reward processing in schizophrenia, including interactions between these psychological dimensions and more well-characterized cognitive and reward processing contributors to motivation. We close by emphasizing the value of considering a broad set of modulating factors when studying motivation and pleasure functions in schizophrenia.

Deep learning techniques have been applied to electroencephalogram (EEG) signals, with promising applications in the field of psychiatry. Schizophrenia is one of the most disabling neuropsychiatric disorders, often characterized by the presence of auditory hallucinations. Auditory processing impairments have been studied using EEG-derived event-related potentials and have been associated with clinical symptoms and cognitive dysfunction in schizophrenia. Due to consistent changes in the amplitude of ERP components, such as the auditory N100, some have been proposed as biomarkers of schizophrenia. In this paper, we examine altered patterns in electrical brain activity during auditory processing and their potential to discriminate schizophrenia and healthy subjects. Using deep convolutional neural networks, we propose an architecture to perform the classification based on multi-channels auditory-related EEG single-trials, recorded during a passive listening task. We analyzed the effect of the number of electrodes used, as well as the laterality and distribution of the electrical activity over the scalp. Results show that the proposed model is able to classify schizophrenia and healthy subjects with an average accuracy of 78% using only 5 midline channels (Fz, FCz, Cz, CPz, and Pz). The present study shows the potential of deep learning methods in the study of impaired auditory processing in schizophrenia with implications for diagnosis. The proposed design can provide a base model for future developments in schizophrenia research.

The hallmark of resting EEG spectra are distinct rhythms emerging from a broadband, aperiodic background. This aperiodic neural signature accounts for most of total EEG power, although its significance and relation to functional neuroanatomy remains obscure. We hypothesized that aperiodic EEG reflects a significant metabolic expenditure and therefore might be associated with the default mode network while at rest. During eyes-open, resting-state recordings of simultaneous EEG-fMRI, we find that aperiodic and periodic components of EEG power are only minimally associated with activity in the default mode network. However, a whole-brain analysis identifies increases in aperiodic power correlated with hemodynamic activity in an auditory-salience-cerebellar network, and decreases in aperiodic power are correlated with hemodynamic activity in prefrontal regions. Desynchronization in residual alpha and beta power is associated with visual and sensorimotor hemodynamic activity, respectively. These findings suggest that resting-state EEG signals acquired in an fMRI scanner reflect a balance of top-down and bottom-up stimulus processing, even in the absence of an explicit task.

The article announces that Dr. Judith M. Ford has received the 2010 Award for Distinguished Contributions to Psychophysiology from the Senior Awards Committee of the Society for Psychophysiological Research.

Type VI Secretion Systems (T6SSs) are widespread in bacteria and can dictate the development and organisation of polymicrobial ecosystems by mediating contact dependent killing. In Neisseria species, including Neisseria cinerea a commensal of the human respiratory tract, interbacterial contacts are mediated by Type four pili (Tfp) which promote formation of aggregates and govern the spatial dynamics of growing Neisseria microcolonies. Here, we show that N. cinerea expresses a plasmid-encoded T6SS that is active and can limit growth of related pathogens. We explored the impact of Tfp on N. cinerea T6SS-dependent killing within a colony and show that pilus expression by a prey strain enhances susceptibility to T6SS compared to a non-piliated prey, by preventing segregation from a T6SS-wielding attacker. Our findings have important implications for understanding how spatial constraints during contact-dependent antagonism can shape the evolution of microbial communities.

Abstract Background Germline mutations in the BRCA1 and BRCA2 genes predispose carriers to breast and ovarian cancer, and there remains a need to identify the specific genomic mechanisms by which cancer evolves in these patients. Here we present a systematic genomic analysis of breast tumors with BRCA1 and BRCA2 mutations. Methods We analyzed genomic data from breast tumors, with a focus on comparing tumors with BRCA1/BRCA2 gene mutations with common classes of sporadic breast tumors. Results We identify differences between BRCA-mutated and sporadic breast tumors in patterns of point mutation, DNA methylation and structural variation. We show that structural variation disproportionately affects tumor suppressor genes and identify specific driver gene candidates that are enriched for structural variation. Conclusions Compared to sporadic tumors, BRCA-mutated breast tumors show signals of reduced DNA methylation, more ancestral cell divisions, and elevated rates of structural variation that tend to disrupt highly expressed protein-coding genes and known tumor suppressors. Our analysis suggests that BRCA-mutated tumors are more aggressive than sporadic breast cancers because loss of the BRCA pathway causes multiple processes of mutagenesis and gene dysregulation.