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Background: Race dialogues, conversations about race and racism among individuals holding different racial identities, have been proposed as one component of addressing racism in medicine and improving the experience of racially minoritized patients. Drawing on work from several fields, we aimed to assess the scope of the literature on race dialogues and to describe potential benefits, best practices, and challenges of conducting such dialogues. Ultimately, our goal was to explore the potential role of race dialogues in medical education and clinical practice. Methods: Our scoping review included articles published prior to June 2, 2022, in the biomedicine, psychology, nursing and allied health, and education literatures. Ultimately, 54 articles were included in analysis, all of which pertained to conversations about race occurring between adults possessing different racial identities. We engaged in an interactive group process to identify key takeaways from each article and synthesize cross-cutting themes. Results: Emergent themes reflected the processes of preparing, leading, and following up race dialogues. Preparing required significant personal introspection, logistical organization, and intentional framing of the conversation. Leading safe and successful race dialogues necessitated trauma-informed practices, addressing microaggressions as they arose, welcoming participation and emotions, and centering the experience of individuals with minoritized identities. Longitudinal experiences and efforts to evaluate the quality of race dialogues were crucial to ensuring meaningful impact. Discussion: Supporting race dialogues within medicine has the potential to promote a more inclusive and justice-oriented workforce, strengthen relationships amongst colleagues, and improve care for patients with racially minoritized identities. Potential levers for supporting race dialogues include high-quality racial justice curricula at every level of medical education and valuation of racial consciousness in admissions and hiring processes. All efforts to support race dialogues must center and uplift those with racially minoritized identities. [ABSTRACT FROM AUTHOR]

Background: Despite higher breast cancer screening rates, black women still are more likely to have late-stage disease diagnosed. This disparity is influenced in part by structural and interpersonal racism. This prospective study sought to determine how interpersonal factors, including perceived discrimination, influence screening and stage of disease at diagnosis. Methods: A prospective cohort study analyzed adult women with stages I to IV breast cancer from the Miami Breast Cancer Disparities Study. Perceived discrimination and mistrust of providers were assessed using previously validated questionnaires. Multivariable logistic regression was used to evaluate the odds of screening mammography utilization and late-stage breast cancer at diagnosis. Results: The study enrolled 342 patients (54.4 % Hispanic, 15.8 % white, and 17.3 % black). Multivariate regression, after control for both individual- and neighborhood-level factors, showed that a higher level of perceived discrimination was associated with greater odds of late-stage disease (adjusted odds ratio [aOR], 1.06; range, 1.01–1.12); p = 0.022) and lower odds of screening mammography (aOR, 0.96; range, 0.92–0.99; p = 0.046). A higher level of perceived discrimination also was negatively correlated with multiple measures of provider trust. Discussion: This study identified that high perceived level of discrimination is associated with decreased odds of ever having a screening mammogram and increased odds of late-stage disease. Efforts are needed to reach women who experience perceived discrimination and to improve the patient–provider trust relationship because these may be modifiable risk factors for barriers to screening and late-stage disease presentation, which ultimately have an impact on breast cancer survival. [ABSTRACT FROM AUTHOR]

The VITAL-AF trial examined the effectiveness of screening for atrial fibrillation (AF) in older patients using a single-lead electrocardiogram (ECG) during primary care visits. The study found that screening did not significantly increase AF diagnoses over one year. Healthcare resource utilization was compared between the intervention and control groups, and participants with abnormal ECG readings had higher resource utilization while those with normal readings had lower utilization. Overall, cardiac testing, procedures, and visits were similar between the two groups. The study suggests that increased healthcare utilization for positive screens was balanced by less utilization among those with normal results. The findings may not be applicable to other settings or populations. The study was funded by Bristol Myers Squibb-Pfizer Alliance, but they had no involvement in the trial or data analysis. The authors disclosed potential conflicts of interest. [Extracted from the article]

Stereotactic ablative radiotherapy (SABR) is a standard-of-care for medically-inoperable-early-stage non-small cell lung cancer (NSCLC). One third of patients progress and chemotherapy is rarely used in this population. We questioned if addition of the immune-checkpoint-inhibitor (ICI) atezolizumab to standard-of-care SABR can improve outcomes. We initiated a multi-institutional single-arm phase I study (NCT02599454) enrolling twenty patients with the primary endpoint of maximum tolerated dose (MTD); secondary endpoints of safety and efficacy; and exploratory mechanistic correlatives. Treatment is well tolerated and full dose atezolizumab (1200 mg) is the MTD. Efficacy signals include early responses (after 2 cycles of ICI, before initiation of SABR) in 17% of patients. Biomarkers of functional adaptive immunity, including T cell activation in the tumor and response to ex-vivo stimulation by circulating T cells, are highly predictive of benefit. These results require validation and are being tested in a phase III randomized trial. Stereotactic ablative radiotherapy (SABR) is standard-of-care for patients with medically inoperable early-stage non-small cell lung cancer (NSCLC), however the risk of systemic recurrences remains high. Here the authors report the results of a phase I study testing the addition of atezolizumab (anti-PD-L1) to SABR in high risk, medically inoperable, early-stage, NSCLC. [ABSTRACT FROM AUTHOR]

Deep reinforcement learning has been successfully applied to the generation of goal-directed behavior in artificial agents. However, existing algorithms are often not designed to reproduce human-like behavior, which may be desired in many environments, such as human–robot collaborations, social robotics and autonomous vehicles. Here we introduce a model-free and easy-to-implement deep reinforcement learning approach to mimic the stochastic behavior of a human expert by learning distributions of task variables from examples. As tractable use-cases, we study static and dynamic obstacle avoidance tasks for an autonomous vehicle on a highway road in simulation (Unity). Our control algorithm receives a feedback signal from two sources: a deterministic (handcrafted) part encoding basic task goals and a stochastic (data-driven) part that incorporates human expert knowledge. Gaussian processes are used to model human state distributions and to assess the similarity between machine and human behavior. Using this generic approach, we demonstrate that the learning agent acquires human-like driving skills and can generalize to new roads and obstacle distributions unseen during training. [ABSTRACT FROM AUTHOR]

Routine tumor-node-metastasis (TNM) staging of colorectal cancer is imperfect in predicting survival due to tumor pathobiological heterogeneity and imprecise assessment of tumor spread. We leveraged Bayesian additive regression trees (BART), a statistical learning technique, to comprehensively analyze patient-specific tumor characteristics for the improvement of prognostic prediction. Of 75 clinicopathologic, immune, microbial, and genomic variables in 815 stage II–III patients within two U.S.-wide prospective cohort studies, the BART risk model identified seven stable survival predictors. Risk stratifications (low risk, intermediate risk, and high risk) based on model-predicted survival were statistically significant (hazard ratios 0.19–0.45, vs. higher risk; P < 0.0001) and could be externally validated using The Cancer Genome Atlas (TCGA) data (P = 0.0004). BART demonstrated model flexibility, interpretability, and comparable or superior performance to other machine-learning models. Integrated bioinformatic analyses using BART with tumor-specific factors can robustly stratify colorectal cancer patients into prognostic groups and be readily applied to clinical oncology practice. [ABSTRACT FROM AUTHOR]

The relationship between structural and functional connectivity in the human brain is a core question in network neuroscience, and a topic of paramount importance to our ability to meaningfully describe and predict functional outcomes. Graph theory has been used to produce measures based on the structural connectivity network that are related to functional connectivity. These measures are commonly based on either the shortest path routing model or the diffusion model, which carry distinct assumptions about how information is transferred through the network. Unlike shortest path routing, which assumes the most efficient path is always known, the diffusion model makes no such assumption, and lets information diffuse in parallel based on the number of connections to other regions. Past research has also developed hybrid measures that use concepts from both models, which have better predicted functional connectivity from structural connectivity than the shortest path length alone. We examined the extent to which each of these models can account for the structure–function relationship of interest using graph theory measures that are exclusively based on each model. This analysis was performed on multiple parcellations of the Human Connectome Project using multiple approaches, which all converged on the same finding. We found that the diffusion model accounts for much more variance in functional connectivity than the shortest path routing model, suggesting that the diffusion model is better suited to describing the structure–function relationship in the human brain at the macroscale. [ABSTRACT FROM AUTHOR]

We investigated the hypothesis that intra ejaculate sperm competition screens against the transmission of deleterious alleles, including new mutants, from male parent to offspring. Recent investigations have established that sperm haploid genotypes can have major effects on sperm traits such as cellular robustness, longevity, and fertilization success. However, there is no evidence that new mutations can meaningfully affect sperm phenotypes. We tested this directly by comparing sperm from mutagenized and non-mutagenized control males in Astyanax fish. We used N-ethyl-N-nitrosourea (ENU) to induce single base substitutions in spermatogonial stem cells. We looked at swimming velocity, an important factor contributing to fertilization success, and flagellar length. Variability in swimming velocity was significantly higher in sperm from mutagenized males than in control sperm, reflecting their increased allelic diversity. In contrast, flagellar length, which is fixed during diploid stages of spermatogenesis, was unaffected by ENU treatment. We briefly discuss the implications of intra-ejaculate screening for maintenance of anisogamy and for outcomes of assisted reproductive technology. [ABSTRACT FROM AUTHOR]

Huntington's Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials. Here, we present an alternative disease modifying therapy the orally available, brain penetrant small molecule branaplam. By promoting inclusion of a pseudoexon in the primary transcript, branaplam lowers mHTT protein levels in HD patient cells, in an HD mouse model and in blood samples from Spinal Muscular Atrophy (SMA) Type I patients dosed orally for SMA (NCT02268552). Our work paves the way for evaluating branaplam's utility as an HD therapy, leveraging small molecule splicing modulators to reduce expression of dominant disease genes by driving pseudoexon inclusion. Huntington's disease (HD) results from the abnormal expansion of CAG repeats in exon 1 of the HTT gene. Here, the authors show that orally available, brain penetrant molecule branaplam lowers HTT transcript by promoting inclusion of a poison exon or pseudoexon. [ABSTRACT FROM AUTHOR]

Background: Social determinants of health play a fundamental role in a patient's health status. In recent years, health systems across the nation have implemented numerous strategies aimed at identifying and addressing the health-related social needs of the patients they serve. Despite the influx of peer-reviewed research highlighting outcomes of specific health-related social needs interventions, the spectrum of practices utilized by primary care clinics has not been established. Objective: To determine the range of ways primary care clinics address health-related social needs after identification and initial contact with a frontline staff person is completed. Design: We conducted 12 semi-structured, in-person interviews with staff from purposively sampled clinics. If the interview included more than one staff person, all participants were interviewed together. Participants: Twenty-one administrative staff and frontline clinic personnel with experience in 24 separate primary care clinics in the Minneapolis-St. Paul, Minnesota metropolitan area. Approach: Interviews focused on the range of health-related social needs processes utilized by clinics, including staff titles, referral procedures, and barriers to addressing needs. Interview recordings were transcribed and coded using thematic analysis. Key Results: Thematic analysis identified variation in four key areas involving how clinics address patients' health-related social needs after identification and initial contact by frontline staff: clinic personnel involved in addressing needs, clinic referral processes, "resource" and "success" definitions, and barriers to accessing community-based supports. Conclusions: This study describes the large variation in primary care clinic practices to address health-related social needs after they are identified. The results suggest challenges to standardization and real-world application of previously published studies. Our findings also highlight the opportunity for improved relationships between health systems and community-based agencies. [ABSTRACT FROM AUTHOR]

Although functional connectivity and associated graph theory measures (e.g., centrality; how centrally important to the network a region is) are widely used in brain research, the full extent to which these functional measures are related to the underlying structural connectivity is not yet fully understood. Graph neural network deep learning methods have not yet been applied for this purpose, and offer an ideal model architecture for working with connectivity data given their ability to capture and maintain inherent network structure. Here, we applied this model to predict functional connectivity from structural connectivity in a sample of 998 participants from the Human Connectome Project. Our results showed that the graph neural network accounted for 89% of the variance in mean functional connectivity, 56% of the variance in individual-level functional connectivity, 99% of the variance in mean functional centrality, and 81% of the variance in individual-level functional centrality. These results represent an important finding that functional centrality can be robustly predicted from structural connectivity. Regions of particular importance to the model's performance as determined through lesioning are discussed, whereby regions with higher centrality have a higher impact on model performance. Future research on models of patient, demographic, or behavioural data can also benefit from this graph neural network method as it is ideally-suited for depicting connectivity and centrality in brain networks. These results have set a new benchmark for prediction of functional connectivity from structural connectivity, and models like this may ultimately lead to a way to predict functional connectivity in individuals who are unable to do fMRI tasks (e.g., non-responsive patients). [ABSTRACT FROM AUTHOR]

Purpose of Review: To provide the current state of the development and application of cardiovascular disease (CVD) prediction tools in people living with HIV (PLWH). Recent Findings: Several risk prediction models developed on the general population are available to predict CVD risk, the most notable being the US-based pooled cohort equations (PCE), the Framingham risk functions, and the Europe-based SCORE (Systematic COronary Risk Evaluation). In validation studies in cohorts of PLWH, these models generally underestimate CVD risk, especially in individuals who are younger, women, Black race, or predicted to be at low/intermediate risk. An HIV-specific CVD prediction model, the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) model, is available, but its performance is modest, especially in US-based cohorts. Enhancing CVD prediction with novel biomarkers of inflammation or coronary artery calcification is of interest but has not yet been evaluated in PLWH. Finally, studies on CVD risk prediction are lacking in diverse PLWH globally. Summary: While available risk models for CVD prediction in PLWH remain suboptimal, clinicians should remain vigilant of higher CVD risk in this population and should use any of these risk scores for risk stratification to guide preventive interventions. Focus on established traditional risk factors such as smoking remains critical in PLWH. Risk prediction functions tailored to PLWH in diverse settings will enhance clinicians' ability to deliver optimal preventive care. [ABSTRACT FROM AUTHOR]

Identifying the genetic factors that underlie complex traits is central to understanding the mechanistic underpinnings of evolution. Cave-dwelling Astyanax mexicanus populations are well adapted to subterranean life and many populations appear to have evolved troglomorphic traits independently, while the surface-dwelling populations can be used as a proxy for the ancestral form. Here we present a high-resolution, chromosome-level surface fish genome, enabling the first genome-wide comparison between surface fish and cavefish populations. Using this resource, we performed quantitative trait locus (QTL) mapping analyses and found new candidate genes for eye loss such as dusp26. We used CRISPR gene editing in A. mexicanus to confirm the essential role of a gene within an eye size QTL, rx3, in eye formation. We also generated the first genome-wide evaluation of deletion variability across cavefish populations to gain insight into this potential source of cave adaptation. The surface fish genome reference now provides a more complete resource for comparative, functional and genetic studies of drastic trait differences within a species. Mexican Tetra cavefish have long been of interest in understanding adaptation to severe environmental change. Here the authors present a chromosome-level genome for the proxy-ancestral surface fish, and use CRISPR gene-editing to show the role of the rx3 gene in eye size. [ABSTRACT FROM AUTHOR]

High intensity focused ultrasound (HIFU) rapidly and non-invasively destroys tumor tissue. Here, we sought to assess the immunomodulatory effects of MR-guided HIFU and its combination with the innate immune agonist CpG and checkpoint inhibitor anti-PD-1. Mice with multi-focal breast cancer underwent ablation with a parameter set designed to achieve mechanical disruption with minimal thermal dose or a protocol in which tumor temperature reached 65 °C. Mice received either HIFU alone or were primed with the toll-like receptor 9 agonist CpG and the checkpoint modulator anti-PD-1. Both mechanical HIFU and thermal ablation induced a potent inflammatory response with increased expression of Nlrp3, Jun, Mefv, Il6 and Il1β and alterations in macrophage polarization compared to control. Furthermore, HIFU upregulated multiple innate immune receptors and immune pathways, including Nod1, Nlrp3, Aim2, Ctsb, Tlr1/2/4/7/8/9, Oas2, and RhoA. The inflammatory response was largely sterile and consistent with wound-healing. Priming with CpG attenuated Il6 and Nlrp3 expression, further upregulated expression of Nod2, Oas2, RhoA, Pycard, Tlr1/2 and Il12, and enhanced T-cell number and activation while polarizing macrophages to an anti-tumor phenotype. The tumor-specific antigen, cytokines and cell debris liberated by HIFU enhance response to innate immune agonists. [ABSTRACT FROM AUTHOR]

Multiplex immunofluorescence (mIF) allows simultaneous antibody-based detection of multiple markers with a nuclear counterstain on a single tissue section. Recent studies have demonstrated that mIF is becoming an important tool for immune profiling the tumor microenvironment, further advancing our understanding of the interplay between cancer and the immune system, and identifying predictive biomarkers of response to immunotherapy. Expediting mIF discoveries is leading to improved diagnostic panels, whereas it is important that mIF protocols be standardized to facilitate their transition into clinical use. Manual processing of sections for mIF is time consuming and a potential source of variability across numerous samples. To increase reproducibility and throughput we demonstrate the use of an automated slide stainer for mIF incorporating tyramide signal amplification (TSA). We describe two panels aimed at characterizing the tumor immune microenvironment. Panel 1 included CD3, CD20, CD117, FOXP3, Ki67, pancytokeratins (CK), and DAPI, and Panel 2 included CD3, CD8, CD68, PD-1, PD-L1, CK, and DAPI. Primary antibodies were first tested by standard immunohistochemistry and single-plex IF, then multiplex panels were developed and images were obtained using a Vectra 3.0 multispectral imaging system. Various methods for image analysis (identifying cell types, determining cell densities, characterizing cell-cell associations) are outlined. These mIF protocols will be invaluable tools for immune profiling the tumor microenvironment. [ABSTRACT FROM AUTHOR]

In order to develop a practical model of breast cancer, with in vitro and syngeneic, immune-intact, in vivo growth capacity, we established a primary cell line derived from a mammary carcinoma in the transgenic FVB/N-Tg(MMTV-ErbB2*)NDL2-5Mul mouse, referred to as "NDLUCD". The cell line is adapted to standard cell culture and can be transplanted into syngeneic FVB/N mice. The line maintains a stable phenotype over multiple in vitro passages and rounds of in vivo transplantation. NDLUCD tumors in FVB/N mice exhibit high expression of ErbB2 and ErbB3 and signaling molecules downstream of ErbB2. The syngeneic transplant tumors elicit an immune reaction in the adjacent stroma, detected and characterized using histology, immunophenotyping, and gene expression. NDLUCD cells also express PD-L1 in vivo and in vitro, and in vivo transplants are reactive to anti-immune checkpoint therapy with responses conducive to immunotherapy studies. This new NDLUCD cell line model is a practical alternative to the more commonly used 4T1 cells, and our previously described FVB/N-Tg(MMTV-PyVT)634Mul derived Met-1fvb2 and FVB/NTg(MMTV-PyVTY315F/Y322F) derived DB-7fvb2 cell lines. The NDLUCD cells have, so far, remained genetically and phenotypically stable over many generations, with consistent and reproducible results in immune intact preclinical cohorts. [ABSTRACT FROM AUTHOR]

Parenting programs are an effective strategy to prevent multiple risky outcomes during adolescence. However, these programs usually enroll one caregiver and have low attendance. This study evaluated the preliminary results, cost, and satisfaction of adaptive recruitment and parenting interventions for immigrant Latino families. A mixed methods study was conducted integrating a pre-post design with embedded qualitative and process evaluations. Fifteen immigrant Latino families with an adolescent child aged 10-14 were recruited. Two-caregiver families received a home visit to increase enrollment of both caregivers. All families participated in an adaptive parenting program that included group sessions and a one-to-one component (online videos plus follow-up telephone calls) for those who did not attend the group sessions. The intervention addressed positive parenting practices using a strengths-based framework. Primary outcomes were the proportion of two-parent families recruited and intervention participation. Secondary outcomes were change in parenting self-efficacy, practices, fidelity, costs, and satisfaction. Participants completed questionnaires and interaction tasks before and after participating in the intervention. In addition, participants and program facilitators completed individual interviews to assess satisfaction with the program components. Overall, 23 parents participated in the intervention; 73% of two-parent families enrolled with both parents. Most participants completed 75% or more of the intervention. Fathers were more likely to use the one-to-one component of the intervention than mothers (p = .038). Participants were satisfied with program modifications. In sum, adaptive recruitment and parenting interventions achieved high father enrollment and high participation. These findings warrant further evaluation in randomized trials. [ABSTRACT FROM AUTHOR]

Lesbian, gay, bisexual, and transgender (LGBT) youth experience disproportionate rates of bullying compared to their heterosexual peers. Schools are well-positioned to address these disparities by creating supportive school climates for LGBT youth, but more research is needed to examine the variety of practices and professional development opportunities put in place to this end. The current study examines how school practices to create supportive LGBT student climate relate to student reports of bullying. Student-level data come from the 2013 Minnesota Student Survey, a state-wide survey of risk and protective factors. Ninth and eleventh grade students (N = 31,183) reported on frequency of physical and relational bullying victimization and perpetration and sexual orientation-based harassment. School administrators reported on six practices related to creating supportive LGBT school climate (N = 103 schools): having a point person for LGBT student issues, displaying sexual orientation-specific content, having a gay-straight alliance, discussing bullying based on sexual orientation, and providing professional development around LGBT inclusion and LGBT student issues. An index was created to indicate how many practices each school used (M = 2.45; SD = 1.76). Multilevel logistic regressions indicated that students attending schools with more supportive LGBT climates reported lower odds of relational bullying victimization, physical bullying perpetration, and sexual orientation-based harassment compared to students in schools with less supportive LGBT climates. Sexual orientation did not moderate these relations, indicating that LGBT-supportive practices may be protective for all students, regardless of their sexual orientation. Findings support school-wide efforts to create supportive climates for LGBQ youth as part of a larger bullying prevention strategy. [ABSTRACT FROM AUTHOR]

Adolescent substance use continues to be a significant public health problem. Parent training interventions are effective preventive strategies to reduce youth substance use. However, little is known about differences in effectiveness for youth across demographic characteristics. This review assessed the effectiveness of parent training programs at reducing adolescent substance use by participant gender, age, and race/ethnicity. Pubmed/MEDLINE, ERIC, CINAHL, and PsycINFO were searched from database origin to October 31, 2016. We included randomized controlled trials that evaluated parent training interventions; reported youth initiation or use of tobacco, alcohol, or other illicit substances; and included adolescents aged 10 to 19. Two independent reviewers extracted data. Disagreements were resolved by consensus or a third researcher. Data were synthesized using harvest plots stratified by participant demographics. A total of 1806 publications were identified and reviewed; 38 unique studies were included. Risk of bias of included studies was high. No studies targeted male teens or youth in late adolescence. Few studies targeted Asian-American, Black/African-American, or Hispanic/Latino adolescents. Overall, interventions including male and female youth and youth in early adolescence (age 10 to 14 or in 5th to 8th grade) were more beneficial than interventions including female-only or both young and older adolescents. Programs tailored to specific racial/ethnic groups, as well as programs designed for youth from multiple races/ethnic groups, were effective. Current evidence supports the benefits of offering parenting guidance to all families with adolescent children, regardless of the gender, age, or race/ethnicity of the adolescent. [ABSTRACT FROM AUTHOR]

Periodic food shortages are a major challenge faced by organisms in natural habitats. Cave-dwelling animals must withstand long periods of nutrient deprivation, as-in the absence of photosynthesis-caves depend on external energy sources such as seasonal floods. Here we show that cave-adapted populations of the Mexican tetra, Astyanax mexicanus, have dysregulated blood glucose homeostasis and are insulin-resistant compared to river-adapted populations. We found that multiple cave populations carry a mutation in the insulin receptor that leads to decreased insulin binding in vitro and contributes to hyperglycaemia. Hybrid fish from surface-cave crosses carrying this mutation weigh more than non-carriers, and zebrafish genetically engineered to carry the mutation have increased body weight and insulin resistance. Higher body weight may be advantageous in caves as a strategy to cope with an infrequent food supply. In humans, the identical mutation in the insulin receptor leads to a severe form of insulin resistance and reduced lifespan. However, cavefish have a similar lifespan to surface fish and do not accumulate the advanced glycation end-products in the blood that are typically associated with the progression of diabetes-associated pathologies. Our findings suggest that diminished insulin signalling is beneficial in a nutrient-limited environment and that cavefish may have acquired compensatory mechanisms that enable them to circumvent the typical negative effects associated with failure to regulate blood glucose levels. [ABSTRACT FROM AUTHOR]

The WNT signaling pathway is commonly altered during colorectal cancer development. The E3 ubiquitin ligase, RNF43, negatively regulates the WNT signal through increased ubiquitination and subsequent degradation of the Frizzled receptor. RNF43 has recently been reported to harbor frequent truncating frameshift mutations in sporadic microsatellite unstable (MSI) colorectal cancers. This study assesses the relative frequency of RNF43 mutations in hereditary colorectal cancers arising in the setting of Lynch syndrome. The entire coding region of RNF43 was Sanger sequenced in 24 colorectal cancers from 23 patients who either (i) carried a germline mutation in one of the DNA mismatch repair genes ( MLH1, MSH6, MSH2, PMS2), or (ii) showed immunohistochemical loss of expression of one or more of the DNA mismatch repair proteins, was BRAF wild type at V600E, were under 60 years of age at diagnosis, and demonstrated no promoter region methylation for MLH1 in tumor DNA. A validation cohort of 44 colorectal cancers from mismatch repair germline mutation carriers from the Australasian Colorectal Cancer Family Registry (ACCFR) were sequenced for the most common truncating mutation hotspots (X117 and X659). RNF43 mutations were found in 9 of 24 (37.5%) Lynch syndrome colorectal cancers. The majority of mutations were frameshift deletions in the G659 G7 repeat tract (29%); 2 cancers (2/24, 8%) from the one patient harbored frameshift mutations at codon R117 (C6 repeat tract) within exon 3. In the ACCFR validation cohort, RNF43 hotspot mutations were identified in 19/44 (43.2%) of samples, which was not significantly different to the initial series. The proportion of mutant RNF43 in Lynch syndrome related colorectal cancers is significantly lower than the previously reported mutation rate found in sporadic MSI colorectal cancers. These findings identify further genetic differences between sporadic and hereditary colorectal cancers. This may be because Lynch Syndrome cancers commonly arise in colorectal adenomas already bearing the APC mutation, whereas sporadic microsatellite unstable colorectal cancers arise from serrated polyps typically lacking APC mutation, decreasing the selection pressure on other WNT signaling related loci in Lynch syndrome. [ABSTRACT FROM AUTHOR]

Involvement in bullying and sexual harassment in adolescence is associated with a variety of internalizing, externalizing, and health-risk behaviors. Yet, the two behaviors are often studied independently. The current study examined how bullying and sexual harassment co-occur and whether social connections protected youth from risk patterns. The data for this study come from the 2013 Minnesota Student Survey ( N = 121,311; 50% female, 74% White, 26% received free or reduced-price lunch; M = 14.9, SD = 1.3). Students reported on bullying and sexual harassment victimization and perpetration. Using latent class analysis, youth were classified into five patterns: High- Risk of All Forms of Victimization and Perpetration (7%), Relational and Cyberbullying Victimization (17%), Sexual Harassment Victimization and Perpetration (8%), Physical Bullying Perpetration (6%), and Low- Risk (62%). Compared to the low-risk class, the four other classes had lower levels of social connections, particularly with teachers and parents. Older youth (9th and 11th grade students) were at greater risk for the sexual harassment pattern, while younger youth (8th grade students) were at greater risk for bullying patterns. The results indicate that efforts to reduce bullying should also address sexual harassment and social connections with adults. [ABSTRACT FROM AUTHOR]

Obesity is a rising issue especially in the United States that can lead to heart problems, type II diabetes, and respiratory problems. Since the 1970s, obesity rates in the United States have more than doubled in adults and children. Recent evidence suggests that exposure to certain chemicals, termed 'obesogens,' in utero may alter metabolic processes, predisposing individuals to weight gain. There is a need to develop a three-dimensional human tissue system that is able to model the effects of obesogens in vitro in order to better understand the impact of obesogens on early development. Human embryonic-derived stem cells in three-dimensional collagen embedded silk scaffolds were exposed to three different obesogens: Bisphenol A (BPA), Bisphenol S (BPS), and Tributyltin (TBT). The exposed tissues accumulated triglycerides and increased expression of adipogenic genes (Perilipin (PLIN1), peroxisome proliferator-activated receptor gamma (PPARy), fatty acid binding protein 4 (FABP4)) compared to equivalent control cultures with no obesogen exposure. These cultures were also compared to human adult stem cell cultures, which did not respond the same upon addition of obesogens. These results demonstrate the successful development of a representative tissue model of in utero obesogen exposures. This tissue system could be used to determine mechanisms of action of current obesogens and to screen other potential obesogens. [ABSTRACT FROM AUTHOR]

Migraine is a headache disorder characterized by sensitivity to light and sound. Recent research has revealed abnormal visual-spatial attention in migraineurs in between headache attacks. Here, we ask whether these attentional abnormalities can be attributed to specific regions of the known attentional network to help characterize the abnormalities in migraine. Specifically, the ventral frontoparietal network of attention is involved with assessing the behavioural relevance of unattended stimuli. Given the decreased suppression of unattended stimuli reported in migraineurs, we hypothesized that migraineurs would have abnormal processing in the ventral portion of the frontoparietal network of attention. To address this, we used functional magnetic resonance imaging to assess the attentional control networks during visual spatial-orienting tasks in migraineurs (N = 16) as compared to non-migraine controls (N = 16). We employed two visual orienting paradigms with target discrimination tasks: (1) voluntary orienting to central arrow cues, and (2) reflexive orienting to peripheral flash cues. While both groups showed activation in the key areas of attentional processing networks, migraineurs showed less activation than non-migraine controls in a key area of the ventral frontoparietal network of attention, the right temporal parietal junction (rTPJ), during both voluntary and reflexive visual spatial orienting. Given the role of rTPJ is to assess the visual environment for behaviorally relevant sensory stimuli outside the focus of attention and signal other attentional areas to reorient attention to behaviorally salient stimuli, our findings fit with previous research showing that migraineurs lack suppression of unattended events and have heightened orienting to sudden onset stimuli in peripheral locations. [ABSTRACT FROM AUTHOR]

Adipose tissue engineering is a diverse area of research where the developed tissues can be used to study normal adipose tissue functions, create disease models in vitro, and replace soft tissue defects in vivo. Increasing attention has been focused on the highly specialized metabolic pathways that regulate energy storage and release in adipose tissues which affect local and systemic outcomes. Non-invasive, dynamic measurement systems are useful to track these metabolic pathways in the same tissue model over time to evaluate long term cell growth, differentiation, and development within tissue engineering constructs. This approach reduces costs and time in comparison to more traditional destructive methods such as biochemical and immunochemistry assays and proteomics assessments. Towards this goal, this review will focus on important metabolic functions of adipose tissues and strategies to evaluate them with non-invasive in vitro methods. Current non-invasive methods, such as measuring key metabolic markers and endogenous contrast imaging will be explored. [ABSTRACT FROM AUTHOR]

Objective: To determine patient and provider characteristics associated with increased risk of nondetection of mental health problems by primary care physicians.Design: Cross-sectional patient and physician surveys conducted as part of the Medical Outcomes Study.Participants: We studied 19,309 patients and 349 internists and family physicians.Measurements and Main Results: We counted "detection" of a mental health problem whenever physicians reported, in a postvisit survey, that they thought the patient had a mental health problem or that they had counseled or referred the patient for mental health. Key independent variables included patient self-reported demographic characteristics, health-related quality of life (HRQOL), depression diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders, and physician demographics and proclivity to provide counseling for depression. Logistic regression analysis, adjusted for HRQOL, revealed physicians were less likely to detect mental health problems in African Americans (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.46 to 0.86), men (OR, 0.64; 95% CI, 0.54 to 0.75), and patients younger than 35 years (OR, 0.61; 95% CI, 0.44 to 0.84), and more likely to detect them in patients with diabetes (OR, 1.4; 95% CI, 1.0 to 1.8) or hypertension (OR, 1.3; 95% CI, 1.1 to 1.6). In a model that included DSM-III diagnoses, odds of detection remained reduced for African Americans as well as for Hispanics (OR, 0.29; 95% CI, 0.11 to 0.71), and patients with more-severe DSM-III diagnoses were more likely to be detected. Physician proclivity toward providing counseling for depression influenced the likelihood of detection.Conclusions: Patients' race, gender, and coexisting medical conditions affected physician awareness of mental health problems. Strategies to improve detection of mental health problems among African Americans, Hispanics, and men should be explored and evaluated. [ABSTRACT FROM AUTHOR]

Despite the prevalence and significant morbidity resulting from estrogen receptor positive (ER) breast adenocarcinomas, there are only a few models of this cancer subtype available for drug development and arguably none for studying etiology. Those models that do exist have questionable clinical relevance. Given our goal of developing luminal models, we focused on six cell lines derived by minimal mutagenesis from normal human breast cells, and asked if any could generate clinically relevant xenografts, which we then extensively characterized. Xenografts of one cell line, 184AA3, consistently formed ER adenocarcinomas that had a high proliferative rate and other features consistent with 'luminal B' intrinsic subtype. Squamous and spindle cell/mesenchymal differentiation was absent, in stark contrast to other cell lines that we examined or others have reported. We explored intratumoral heterogeneity produced by 184AA3 by immunophenotyping xenograft tumors and cultured cells, and characterized marker expression by immunofluorescence and flow cytometry. A CD44 subpopulation was discovered, yet their tumor forming ability was far less than CD44 cells. Single cell cloning revealed the phenotypic plasticity of 184AA3, consistent with the intratumoral heterogeneity observed in xenografts. Characterization of ER expression in cultures revealed ER protein and signaling is intact, yet when estrogen was depleted in culture, and in vivo, it did not impact cell or tumor growth, analogous to therapeutically resistant ER cancers. This model is appropriate for studies of the etiology of ovarian hormone independent adenocarcinomas, for identification of therapeutic targets, predictive testing, and drug development. [ABSTRACT FROM AUTHOR]

Image-based classification of histology sections, in terms of distinct components (e.g., tumor, stroma, normal), provides a series of indices for histology composition (e.g., the percentage of each distinct components in histology sections), and enables the study of nuclear properties within each component. Furthermore, the study of these indices, constructed from each whole slide image in a large cohort, has the potential to provide predictive models of clinical outcome. For example, correlations can be established between the constructed indices and the patients' survival information at cohort level, which is a fundamental step towards personalized medicine. However, performance of the existing techniques is hindered as a result of large technical variations (e.g., variations of color/textures in tissue images due to non-standard experimental protocols) and biological heterogeneities (e.g., cell type, cell state) that are always present in a large cohort. We propose a system that automatically learns a series of dictionary elements for representing the underlying spatial distribution using stacked predictive sparse decomposition. The learned representation is then fed into the spatial pyramid matching framework with a linear support vector machine classifier. The system has been evaluated for classification of distinct histological components for two cohorts of tumor types. Throughput has been increased by using of graphical processing unit (GPU), and evaluation indicates a superior performance results, compared with previous research. [ABSTRACT FROM AUTHOR]

Background: Lack of timely medication intensification and inadequate medication safety monitoring are two prevalent and potentially modifiable barriers to effective and safe chronic care. Innovative applications of health information technology tools may help support chronic disease management. Objective: To examine the clinical impact of a novel health IT tool designed to facilitate between-visit ordering and tracking of future laboratory testing. Design and Participants: Clinical trial randomized at the provider level (n = 44 primary care physicians); patient-level outcomes among 3,655 primary care patients prescribed 5,454 oral medicines for hyperlipidemia, diabetes, and/or hypertension management over a 12-month period. Main Measures: Time from prescription to corresponding follow-up laboratory testing; proportion of follow-up time that patients achieved corresponding risk factor control (A1c, LDL); adverse event laboratory monitoring 4 weeks after medicine prescription. Key Results: Patients whose physicians were allocated to the intervention (n = 1,143) had earlier LDL laboratory assessment compared to similar patients (n = 703) of control physicians [adjusted hazard ratio (aHR): 1.15 (1.01-1.32), p = 0.04]. Among patients with elevated LDL (486 intervention, 324 control), there was decreased time to LDL goal in the intervention group [aHR 1.26 (0.99-1.62)]. However, overall there were no significant differences between study arms in time spent at LDL or HbA1c goal. Follow-up safety monitoring (e.g., creatinine, potassium, or transaminases) was relatively infrequent (ranging from 7 % to 29 % at 4 weeks) and not statistically different between arms. Intervention physicians indicated that lack of reimbursement for non-visit-based care was a barrier to use of the tool. Conclusions: A health IT tool to support between-visit laboratory monitoring improved the LDL testing interval but not LDL or HbA1c control, and it did not alter safety monitoring. Adoption of innovative tools to support physicians in non-visit-based chronic disease management may be limited by current visit-based financial and productivity incentives. [ABSTRACT FROM AUTHOR]

Objective: To determine how frequently veterans use non-Department of Veterans Affairs (VA) sources of care in addition to primary care provided by the VA and to assess the association of this pattern of "dual use" to patient characteristics and satisfaction with VA care.Design: Cross-sectional telephone survey of randomly selected patients from four VA medical centers.Participants: Of 1,240 eligible veterans, 830 (67%) participated in the survey.Measurements and Main Results: Survey data were used to assess whether a veteran reported receiving primary care from both VA and non-VA sources of care, as well as the proportion of all primary care visits made to non-VA providers. Of 577 veterans who reported VA primary care visits, 159 (28%) also reported non-VA primary care visits. Among these dual users the mean proportion of non-VA primary care visits was 0.50. Multivariate analysis revealed that the odds of dual use were reduced for those without insurance (odds ratio [OR] 0.34; 95% confidence interval [CI] 0.18, 0.66) and with less education (OR 0.60; 95% CI 0.38, 0.92), while increased for those not satisfied with VA care (OR 2.40; 95% CI 1.40, 4.13). Among primary care dual users, the proportion of primary care visits made to non-VA providers was decreased for patients with heart disease ( p <.05) and patients with alcohol or drug dependence ( p <.05).Conclusions: Primary care dual use was common among these veterans. Those with more education, those with any type of insurance, and those not satisfied with VA care were more likely to be dual users. Non-VA care accounted for approximately half of dual users' total primary care visits. [ABSTRACT FROM AUTHOR]

Objective: To assess physicians' response to implementation of an emergency department (ED) pneumonia practice guideline and determine if the guideline changed physicians' knowledge and attitudes about pneumonia care.Design: Prospective intervention study with cross-sectional and longitudinal physician surveys.Setting: An urban, university teaching hospital ED.Participants: One hundred forty physicians who were responsible for the triage of at least one of 166 patients presenting to the ED with community-acquired pneumonia.Measurements: Physician characteristics, attitudes about pneumonia care and guidelines, and ratings of guideline helpfulness and effects on patient care were obtained by self administered questionnaire before, during, and after a yearlong intervention.Main Results: More than 73% of the physicians reported the guideline as helpful and more than 94% wanted it to be continued in the future. Most reported that the guideline would decrease costs and improve quality without any increase in adverse outcomes. Two thirds said they were more likely to treat patients with pneumonia as outpatients in the future because of the guideline. Among the 58 physicians with matching preintervention and postintervention survey data, the guideline decreased the beliefs that "all patients> 65 years old with pneumonia should be admitted," from 52% to 14% ( p <. 001), and that "patients with pneumonia have a> 15% mortality rate," from 11% to 5% ( p <.007). The intervention did not significantly change general attitudes about practice guidelines. House officers rated the guideline as more helpful than attending physicians ( p <. 02).Conclusions: This locally developed, actively implemented guideline was well regarded by physicians. Guidelines can change practice and also alter underlying knowledge and attitudes about disease management. They may be most useful to those with less experience. [ABSTRACT FROM AUTHOR]