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The epidermal barrier defends the body against dehydration and harmful substances. The commensal microbiota is essential for proper differentiation and repair of the epidermal barrier, an effect mediated by the aryl hydrocarbon receptor (AHR). However, the microbial mechanisms of AHR activation in skin are less understood. Tryptophan metabolites are AHR ligands that can be products of microbial metabolism. To identify microbially regulated tryptophan metabolites in vivo, we established a gnotobiotic model colonized with fifty human skin commensals and performed targeted mass spectrometry on murine skin. Indole-related metabolites were enriched in colonized skin compared to germ-free skin. In reconstructed human epidermis and in murine models of atopic-like barrier damage, these metabolites improved barrier repair and function individually and as a cocktail. These results provide a framework for the identification of microbial metabolites that mediate specific host functions, which can guide the development of microbe-based therapies for skin disorders., Competing Interests: Declaration of interests E.A.G. is a member of the L’Oreal Scientific Advisory Board and a paid consultant for Unilever., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Chronic wounds are a common and costly complication of diabetes, where multifactorial defects contribute to dysregulated skin repair, inflammation, tissue damage, and infection. We previously showed that aspects of the diabetic foot ulcer microbiota were correlated with poor healing outcomes, but many microbial species recovered remain uninvestigated with respect to wound healing. Here, we focused on Alcaligenes faecalis , a Gram-negative bacterium that is frequently recovered from chronic wounds but rarely causes infection. Treatment of diabetic wounds with A. faecalis accelerated healing during early stages. We investigated the underlying mechanisms and found that A. faecalis treatment promotes reepithelialization of diabetic keratinocytes, a process that is necessary for healing but deficient in chronic wounds. Overexpression of matrix metalloproteinases in diabetes contributes to failed epithelialization, and we found that A. faecalis treatment balances this overexpression to allow proper healing. This work uncovers a mechanism of bacterial-driven wound repair and provides a foundation for the development of microbiota-based wound interventions.

The host-microbiota relationship has evolved to shape mammalian physiology, including immunity, metabolism, and development. Germ-free models are widely used to study microbial effects on host processes such as immunity. Here, we find that both germ-free and T cell-deficient mice exhibit a robust sebum secretion defect persisting across multiple generations despite microbial colonization and T cell repletion. These phenotypes are inherited by progeny conceived during in vitro fertilization using germ-free sperm and eggs, demonstrating that non-genetic information in the gametes is required for microbial-dependent phenotypic transmission. Accordingly, gene expression in early embryos derived from gametes from germ-free or T cell-deficient mice is strikingly and similarly altered. Our findings demonstrate that microbial- and immune-dependent regulation of non-genetic information in the gametes can transmit inherited phenotypes transgenerationally in mice. This mechanism could rapidly generate phenotypic diversity to enhance host adaptation to environmental perturbations., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The more science advances, the more questions are asked. This compounding growth can make it difficult to keep up with current research directions. Furthermore, this difficulty is exacerbated for junior researchers who enter fields with already large bases of potentially fruitful research avenues. In this paper, we propose a novel task and a recommender system for research directions, RecSOI, that draws from statements of ignorance (SOIs) found in the research literature. By building researchers' profiles based on textual elements, RecSOI generates personalized recommendations of potential research directions tailored to their interests. In addition, RecSOI provides context for the recommended SOIs, so that users can quickly evaluate how relevant the research direction is for them. In this paper, we provide an overview of RecSOI's functioning, implementation, and evaluation, demonstrating its effectiveness in guiding researchers through the vast landscape of potential research directions., (© 2024. The Author(s).)

Strain-level variation in Staphylococcus aureus is a factor that contributes to disease burden and clinical outcomes in skin disorders and chronic wounds. However, the microbial mechanisms that drive these variable host responses are poorly understood. To identify mechanisms underlying strain-specific outcomes, we perform high-throughput phenotyping screens on S. aureus isolates cultured from diabetic foot ulcers. Isolates from non-healing wounds produce more staphyloxanthin, a cell membrane pigment. In murine diabetic wounds, staphyloxanthin-producing isolates delay wound closure significantly compared with staphyloxanthin-deficient isolates. Staphyloxanthin promotes resistance to oxidative stress and enhances bacterial survival in neutrophils. Comparative genomic and transcriptomic analysis of genetically similar clinical isolates with disparate staphyloxanthin phenotypes reveals a mutation in the sigma B operon, resulting in marked differences in stress response gene expression. Our work illustrates a framework to identify traits that underlie strain-level variation in disease burden and suggests more precise targets for therapeutic intervention in S. aureus-positive wounds., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Scientific discovery progresses by exploring new and uncharted territory. More specifically, it advances by a process of transforming unknown unknowns first into known unknowns, and then into knowns. Over the last few decades, researchers have developed many knowledge bases to capture and connect the knowns, which has enabled topic exploration and contextualization of experimental results. But recognizing the unknowns is also critical for finding the most pertinent questions and their answers. Prior work on known unknowns has sought to understand them, annotate them, and automate their identification. However, no knowledge-bases yet exist to capture these unknowns, and little work has focused on how scientists might use them to trace a given topic or experimental result in search of open questions and new avenues for exploration. We show here that a knowledge base of unknowns can be connected to ontologically grounded biomedical knowledge to accelerate research in the field of prenatal nutrition., Results: We present the first ignorance-base, a knowledge-base created by combining classifiers to recognize ignorance statements (statements of missing or incomplete knowledge that imply a goal for knowledge) and biomedical concepts over the prenatal nutrition literature. This knowledge-base places biomedical concepts mentioned in the literature in context with the ignorance statements authors have made about them. Using our system, researchers interested in the topic of vitamin D and prenatal health were able to uncover three new avenues for exploration (immune system, respiratory system, and brain development) by searching for concepts enriched in ignorance statements. These were buried among the many standard enriched concepts. Additionally, we used the ignorance-base to enrich concepts connected to a gene list associated with vitamin D and spontaneous preterm birth and found an emerging topic of study (brain development) in an implied field (neuroscience). The researchers could look to the field of neuroscience for potential answers to the ignorance statements., Conclusion: Our goal is to help students, researchers, funders, and publishers better understand the state of our collective scientific ignorance (known unknowns) in order to help accelerate research through the continued illumination of and focus on the known unknowns and their respective goals for scientific knowledge., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chronic wounds are a common and costly complication of diabetes, where multifactorial defects contribute to dysregulated skin repair, inflammation, tissue damage, and infection. We previously showed that aspects of the diabetic foot ulcer microbiota were correlated with poor healing outcomes, but many microbial species recovered remain uninvestigated with respect to wound healing. Here we focused on Alcaligenes faecalis , a Gram-negative bacterium that is frequently recovered from chronic wounds but rarely causes infection. Treatment of diabetic wounds with A. faecalis accelerated healing during early stages. We investigated the underlying mechanisms and found that A. faecalis treatment promotes re-epithelialization of diabetic keratinocytes, a process which is necessary for healing but deficient in chronic wounds. Overexpression of matrix metalloproteinases in diabetes contributes to failed epithelialization, and we found that A. faecalis treatment balances this overexpression to allow proper healing. This work uncovers a mechanism of bacterial-driven wound repair and provides a foundation for the development of microbiota-based wound interventions.

Breach of the skin barrier and subsequent wound healing occur in the context of microbial communities of bacteria, fungi, and viruses. These polymicrobial communities are dynamic and important components of the wound environment and are associated with differential healing outcomes. Here, we highlight both culture-dependent and -independent methods that have furthered our understanding of the wound microbiome. We discuss common themes that have developed from such studies about the microbial inhabitants of diverse wound types. We additionally explore the wide range of microbial mechanisms that influence healing, from invading pathogens to beneficial commensals. These insights can be leveraged to better predict healing outcomes and derive novel microbial-based therapies for chronic wounds., (Copyright © 2023 Cold Spring Harbor Laboratory Press; all rights reserved.)

The host-microbiota relationship has evolved to shape mammalian processes, including immunity, metabolism, and development 1-3 . Host phenotypes change in direct response to microbial exposures by the individual. Here we show that the microbiota induces phenotypic change not only in the individual but also in their succeeding generations of progeny. We found that germ-free mice exhibit a robust sebum secretion defect and transcriptional changes in various organs, persisting across multiple generations despite microbial colonization and breeding with conventional mice. Host-microbe interactions could be involved in this process, since T cell-deficient mice, which display defective sebum secretion 4 , also transgenerationally transmit their phenotype to progeny. These phenotypes are inherited by progeny conceived during in vitro fertilization using germ-free sperm and eggs, demonstrating that epigenetic information in the gametes is required for phenotypic transmission. Accordingly, small non-coding RNAs that can regulate embryonic gene expression 5 were strikingly and similarly altered in gametes of germ-free and T cell-deficient mice. Thus, we have uncovered a novel mechanism whereby the microbiota and immune system induce phenotypic changes in successive generations of offspring. This epigenetic form of inheritance could be advantageous for host adaptation to environmental perturbation, where phenotypic diversity can be introduced more rapidly than by genetic mutation.

The contribution and regulation of various CD4+ T cell lineages that occur with remitting vs progressive courses in sarcoidosis are poorly understood. We developed a multiparameter flow cytometry panel to sort these CD4+ T cell lineages followed by measurement of their functional potential using RNA-sequencing analysis at six-month intervals across multiple study sites. To obtain good quality RNA for sequencing, we relied on chemokine receptor expression to identify and sort lineages. To minimize gene expression changes induced by perturbations of T cells and avoid protein denaturation caused by freeze/thaw cycles, we optimized our protocols using freshly isolated samples at each study site. To accomplish this study, we had to overcome significant standardization challenges across multiple sites. Here, we detail standardization considerations for cell processing, flow staining, data acquisition, sorting parameters, and RNA quality control analysis that were performed as part of the NIH-sponsored, multi-center study, BRonchoscopy at Initial sarcoidosis diagnosis Targeting longitudinal Endpoints (BRITE). After several rounds of iterative optimization, we identified the following aspects as critical for successful standardization: 1) alignment of PMT voltages across sites using CS&T/rainbow bead technology; 2) a single template created in the cytometer program that was used by all sites to gate cell populations during data acquisition and cell sorting; 3) use of standardized lyophilized flow cytometry staining cocktails to reduce technical error during processing; 4) development and implementation of a standardized Manual of Procedures. After standardization of cell sorting, we were able to determine the minimum number of sorted cells necessary for next generation sequencing through analysis of RNA quality and quantity from sorted T cell populations. Overall, we found that implementing a multi-parameter cell sorting with RNA-seq analysis clinical study across multiple study sites requires iteratively tested standardized procedures to ensure comparable and high-quality results., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Magallon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In 2017, the European Commission installed 24 European Reference Networks (ERNs) for different categories of rare and complex conditions to facilitate cross-border health care via virtual case consultations in a secure Clinical Patient Management System (CPMS). The ERN for rare endocrine conditions (Endo-ERN) previously reviewed the CPMS, in which they detailed the difficulties physicians encountered with the system and proposed solutions to these that should enable the system to be used to a greater extent. This paper will further the endeavor of the first by performing a critical evaluation of the CPMS, assessing how these suggested improvements have been implemented, and if these have affected the usage of the system. The evaluation involves an assessment of CPMS usage statistics since its conception that takes into consideration the technical updates and the external factors that may have affected these, including data from a review survey following a training workshop for our new healthcare providers (HCPs) added in January 2022. It appears that the improvements made to the system since the first review, in particular the implementation of the Operational Helpdesk, have had a positive effect in increasing CPMS membership; however, the regular usage of the system continues to fluctuate. Several suggestions are made on how to further facilitate the use of CPMS by our members both individually and network-wide, by integrating CPMS activities with other network initiatives and further integrating these into national health care systems as well as looking for ways to measure patient satisfaction from the CPMS discussions outcomes.

Introduction: Sarcoidosis is a multiorgan granulomatous disorder thought to be triggered and influenced by gene-environment interactions. Sarcoidosis affects 45-300/100 000 individuals in the USA and has an increasing mortality rate. The greatest gap in knowledge about sarcoidosis pathobiology is a lack of understanding about the underlying immunological mechanisms driving progressive pulmonary disease. The objective of this study is to define the lung-specific and blood-specific longitudinal changes in the adaptive immune response and their relationship to progressive and non-progressive pulmonary outcomes in patients with recently diagnosed sarcoidosis., Methods and Analysis: The BRonchoscopy at Initial sarcoidosis diagnosis Targeting longitudinal Endpoints study is a US-based, NIH-sponsored longitudinal blood and bronchoscopy study. Enrolment will occur over four centres with a target sample size of 80 eligible participants within 18 months of tissue diagnosis. Participants will undergo six study visits over 18 months. In addition to serial measurement of lung function, symptom surveys and chest X-rays, participants will undergo collection of blood and two bronchoscopies with bronchoalveolar lavage separated by 6 months. Freshly processed samples will be stained and flow-sorted for isolation of CD4 +T helper (Th1, Th17.0 and Th17.1) and T regulatory cell immune populations, followed by next-generation RNA sequencing. We will construct bioinformatic tools using this gene expression to define sarcoidosis endotypes that associate with progressive and non-progressive pulmonary disease outcomes and validate the tools using an independent cohort., Ethics and Dissemination: The study protocol has been approved by the Institutional Review Boards at National Jewish Hospital (IRB# HS-3118), University of Iowa (IRB# 201801750), Johns Hopkins University (IRB# 00149513) and University of California, San Francisco (IRB# 17-23432). All participants will be required to provide written informed consent. Findings will be disseminated via journal publications, scientific conferences, patient advocacy group online content and social media platforms., Competing Interests: Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Motivation: Science progresses by posing good questions, yet work in biomedical text mining has not focused on them much. We propose a novel idea for biomedical natural language processing: identifying and characterizing the questions stated in the biomedical literature. Formally, the task is to identify and characterize statements of ignorance , statements where scientific knowledge is missing or incomplete. The creation of such technology could have many significant impacts, from the training of PhD students to ranking publications and prioritizing funding based on particular questions of interest. The work presented here is intended as the first step towards these goals., Results: We present a novel ignorance taxonomy driven by the role statements of ignorance play in research, identifying specific goals for future scientific knowledge. Using this taxonomy and reliable annotation guidelines (inter-annotator agreement above 80%), we created a gold standard ignorance corpus of 60 full-text documents from the prenatal nutrition literature with over 10 000 annotations and used it to train classifiers that achieved over 0.80 F1 scores., Availability and Implementation: Corpus and source code freely available for download at https://github.com/UCDenver-ccp/Ignorance-Question-Work. The source code is implemented in Python., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The three-month, multi-domain Memory Boot Camp program incorporates z-score neurofeedback (NFB), heart rate variability (HRV) biofeedback, and one-on-one coaching to teach memory skills and encourage behavior change in diet, sleep, physical fitness, and stress reduction., Objective: This prospective trial evaluates the Memory Boot Camp program for adults ages 55 to 85 with symptoms of Mild Cognitive Impairment (MCI) and subjective memory complaints., Methods: Participants were evaluated via the Montreal Cognitive Assessment (MoCA), NeuroTrax Global Cognitive Score, measures of anxiety, depression, sleep, quality of life, quantitative electroencephalography (QEEG), and HRV parameters at four timepoints: baseline, pre-program, post-program, and follow-up. The trial included a three-month waiting period between baseline and pre-program, such that each participant acted as their own control, and follow-up took place six months after completion of the program., Results: Participants' MoCA scores and self-reported measures of anxiety, depression, sleep quality, and quality of life improved after treatment, and these changes were maintained at follow-up. Physiological changes in HRV parameters after treatment were not significant, however, breathing rate and QEEG parameters were improved at post-program and maintained at follow-up. Finally, participants' improvement in MoCA score over the treatment period was correlated with their improvement in two brain oscillation parameters targeted by the z-score NFB protocol: relative power of delta and relative power of theta., Conclusions: Trial results suggest that the Memory Boot Camp program is a promising treatment strategy for older adults with symptoms of MCI and subjective memory complaints.

ADHD is a common condition that causes suffering for those affected and economic loss for society at large. The current standard treatment for ADHD includes stimulant medications, which are not effective for all patients, may include side effects, and can be non-medically misused. Z-score neurofeedback (NFB) and heart rate variability (HRV) biofeedback are alternative treatment strategies that have been associated with Attention-Deficit/Hyperactivity Disorder (ADHD) symptom improvement. We utilized a retrospective pre-post study design to quantify the change in clients' ADHD symptoms after combined NFB + HRV treatment (which included simultaneous z-score training at four sites). We also assessed whether relevant physiological measures changed in accordance with the protocol, which would be consistent with effective NFB + HRV training. Adults (n = 39) and children (n = 100) with Borderline or Clinical ADHD classifications by the Achenbach System of Empirically Based Assessment (ASEBA) received 30 sessions of NFB + HRV training. Measures were compared before and after treatment for the ASEBA, the Integrated Visual and Auditory Continuous Performance Test (IVA), ADHD medication use, HRV and breathing parameters, and quantitative electroencephalogram (QEEG) parameters. Average ASEBA Attention-Deficit/Hyperactive Problems score improved after treatment for adults and children (p < 0.0001), with Cohen effect sizes (d z ) of -1.21 and -1.17, respectively. 87.2% of adults and 80.0% of children experienced improvements of a magnitude greater than or equal to the Minimal Clinically Important Difference. After treatment, 70.8% of adults and 52.8% of children who began in the ASEBA Clinical range, and 80.0% of adults and 63.8% of children who began in the ASEBA Borderline range, were classified in the Normal range. IVA scores also improved after treatment. Changes in HRV and breathing pattern after treatment were consistent with the protocol. QEEG parameters after treatment were closer to the age-based normative mean, which is consistent with effective z-score NFB training.

The nature and presentation of eating pathology in ethnically diverse men are not well defined. This study examined associations among ethnicity, body image, and eating pathology in nonclinical college men (N = 343). Analysis of variance analyses indicated that markers of eating, weight, and shape concerns differed by ethnicity: Asian and Hispanic/Latino men reported more pathological levels than European and African American men. Hierarchical multiple regression analyses indicated that ethnicity moderated the relationship between drive for muscularity and body checking, which was strongest for Asian men. Results increase awareness of how ethnicity interacts with body image and eating pathology, which underscores the need for individualized, culturally sensitive treatment for ethnically diverse men.

Background: Sleep disorders in multiple sclerosis (MS) are associated with reduced health-related quality of life (HRQOL) and depression. However, research investigating and comparing how the two most common sleep disorders-insomnia and obstructive sleep apnea (OSA)-affect depression and HRQOL in MS is limited. The goal of this study is to examine the impact of diagnosed sleep disorders on patient-reported 1) HRQOL and 2) depressive symptoms in patients with MS., Methods: We performed a retrospective medical record review of 531 adult patients with MS: 287 (54%) with a comorbid sleep disorder (insomnia or OSA) and 244 (46%) without a diagnosed sleep disorder., Results: Neither 1) average ratings of depression or HRQOL nor 2) the proportion of moderate depression or moderately impaired HRQOL differed between individuals with MS and insomnia and those with MS and OSA. Neither sleep disorder predicted increased depression or poorer HRQOL. However, individuals with MS and a comorbid sleep disorder (insomnia or OSA) had poorer HRQOL compared with those without a diagnosed sleep disorder (MS only)., Conclusions: Presence of a diagnosed sleep disorder may negatively affect HRQOL in MS. Providers should continue to screen for sleep disorders given their negative impact on patients with MS and the availability of effective treatments for insomnia and OSA.

Background: Most skin cancers occur on the head and neck, areas of the body that are significant to an individual's body image (BI) perception. Poor BI is a robust risk factor for depression and decreased quality of life. Thus, patients with nonmelanoma head and neck skin cancer (NMHNSC) may be more vulnerable to BI disturbance and the negative sequelae of poor BI., Objective: Describe the nature of BI concerns in patients diagnosed with NMHNSC and assess how BI changes with treatment., Methods and Materials: Patients undergoing Mohs micrographic surgery (MMS) for NMHNSC completed assessments of BI and well-being before (N = 239) and 6 months after (N = 80) treatment with MMS. Demographic and tumor data were gathered through retrospective chart review., Results: Body image improved significantly 6 months after MMS, and the magnitude of this change was large (η = 0.18). Repair length (length of final scar irrespective of repair type) >4 cm predicted poorer BI at 6-month follow-up., Conclusion: Patients' BI improves after treatment with MMS for NMHNSC.

Objective: Body checking (BC) and body image avoidance (BIA) have been proposed as etiological and maintaining mechanisms for eating disorder (ED) pathology. To date, no comprehensive review summarizes the relationships of BC and BIA with ED pathology, body image dissatisfaction, or mood/affect., Method: Meta-analyses examined the relationships of BC and BIA with ED pathology, body image dissatisfaction, and mood/affect. Gender, publication status, and presence or absence of ED diagnoses were examined as potential moderators., Results: Results showed strong relationships between BC and ED pathology (ρ = 0.588) and BC and body image dissatisfaction (ρ = 0.631) and a moderate relationship between BC and mood/affect (ρ = 0.385). Similarly, results showed strong relationships between BIA and ED pathology (ρ = 0.553) and BIA and body image dissatisfaction (ρ = 0.543) and a moderate relationship between BIA and mood/affect (ρ = 0.392). Overall, limited evidence supported publication bias; however, publication bias may exist in the relationship between BIA and body image dissatisfaction in the literature. Subgroup moderator analyses suggested that gender moderates the strength of the relationships between BC and ED pathology, body image dissatisfaction, and mood/affect and between BIA and body image dissatisfaction., Discussion: Results are consistent with cognitive-behavioral models of ED pathology that suggest BC and BIA are behavioral expressions of overvaluation of weight and shape. Notably, more published research has investigated BC than BIA. Future studies, incorporating methods such as meta-analytic structural equation modeling, should examine these variables to further test cognitive-behavioral models of ED development and maintenance., (© 2018 Wiley Periodicals, Inc.)

Objective: Eating disorders (EDs) and social anxiety disorder (SAD) are highly co-occurring. This comorbidity is extremely relevant, given that individuals with comorbid ED-SAD are less likely to seek and/or benefit from ED treatment., Method: We used network analysis to conceptualize ED-SAD comorbidity in a sample of 2,215 participants with a primary diagnosis of ED, SAD, or no known diagnosis. We used novel network analyses methods to select symptoms for our models, identify potential illness pathways (i.e., bridge symptoms) between disorders and underlying vulnerabilities (e.g., perfectionism, social appearance anxiety), and to compare across sample types (e.g., clinical vs. nonclinical). We also tested several novel network analyses methods aimed at the following methodological concerns: (a) topological concerns (i.e., which items should be included in NA models), (b) how to use empirical indices to quantify bridge symptoms and (c) what differences in networks across samples mean., Results: We found that difficulty with drinking beverages and eating in public were bridge symptoms between ED and SAD. We also found that feeling nervous about one's appearance was a bridge symptom., Conclusions: We identified public eating and drinking as bridge symptoms between EDs and SAD. Future research is needed to test if interventions focused on public eating and drinking might decrease symptoms of both EDs and SAD. Researchers can use this study (code provided) as an exemplar for how to use network analysis, as well as to use network analysis to conceptualize ED comorbidity and compare network structure and density across samples., (© 2018 Wiley Periodicals, Inc.)

There is little research to date on the academic implications of teaching twins in the same or different classroom. Consequently, it is not clear whether twin classroom separation is associated with positive or negative educational outcomes. As a result, parents and teachers have insufficient evidence to make a well-informed decision when twins start school. This study addresses two research questions: Are there average positive or negative effects of classroom separation? Are twins taught in different classes more different from each other than twins taught in the same class? Twin pairs from two large representative samples from Quebec (Canada) and the United Kingdom were evaluated across a large age range (7 to 16 years) on academic achievement, several cognitive abilities and motivational measures. Our results show almost no sizable positive or negative average effect of classroom separation on twins' achievement, cognitive ability and motivation. Twin pairs at age 12 (Quebec, Canada) and at age 16 (United Kingdom) were slightly more similar on achievement if placed in the same classroom, with slightly greater similarity among monozygotic twins than dizygotic twins. However, the few effects found were weak, and it remains unclear whether they result from classroom separation or other factors. These results suggest that in terms of educational outcomes, policymakers should not impose rigid guidelines to separate twin pairs during their education. The choice of whether to educate twin pairs together or separately should be up to parents, twins and teachers, in response to twins' individual needs. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Our knowledge of the biological mechanisms underlying complex human disease is largely incomplete. While Semantic Web technologies, such as the Web Ontology Language (OWL), provide powerful techniques for representing existing knowledge, well-established OWL reasoners are unable to account for missing or uncertain knowledge. The application of inductive inference methods, like machine learning and network inference are vital for extending our current knowledge. Therefore, robust methods which facilitate inductive inference on rich OWL-encoded knowledge are needed. Here, we propose OWL-NETS (NEtwork Transformation for Statistical learning), a novel computational method that reversibly abstracts OWL-encoded biomedical knowledge into a network representation tailored for network inference. Using several examples built with the Open Biomedical Ontologies, we show that OWL-NETS can leverage existing ontology-based knowledge representations and network inference methods to generate novel, biologically-relevant hypotheses. Further, the lossless transformation of OWL-NETS allows for seamless integration of inferred edges back into the original knowledge base, extending its coverage and completeness.

Background: Skin cancer commonly occurs on areas that are salient to body image perception (i.e., head and neck). Patients with head and neck skin cancer (HNSC) may experience negative body image perceptions related to their disease, which is concerning, given the numerous negative sequelae of poor body image. However, there are no existing disease-specific measures of body image concerns in HNSC., Objective: To develop and examine the psychometric properties of a brief self-report, disease-specific measure of body image concerns in patients with HNSC-the Body Image Questionnaire (BIQ)., Materials and Methods: Patients with HNSC completed the BIQ before (n = 239) and 6 months after (n = 80) treatment with Mohs micrographic surgery. Analyses examined the internal consistency, convergent validity, and factor structure of the BIQ., Results: Internal consistency reliability was acceptable, and the measure demonstrated convergent validity with well-being. Four dimensions underlie the BIQ: appearance satisfaction, appearance avoidance, head/neck/skin-specific dissatisfaction, and perceived change., Conclusion: The BIQ is a valid and internally reliable disease-specific instrument that measures body image concerns in patients with HNSC.

In August 2015, more than 110 U.S. oncologists published an article detailing the deleterious effects of rising cancer drugs prices and calling for numerous reforms to our prescription drug system. These prices are the result of decades of political maneuvering; they reflect the way our country has chosen to pay for healthcare, to foster and reward innovation, and to promote a national free market system. While these choices have resulted in immense profits for pharmaceutical companies—and subsidized the development of prescription drugs globally—they have also left many cancer patients unable to afford their medications. And, without providing significant improvements in life expectancy, the rising prices of cancer drugs seem like an unreasonable burden on U.S. healthcare spending. A multitude of reforms have been proposed. At the federal level, many of the reforms seek to amend existing regulatory regimes, such as allowing Medicare to negotiate drug prices, reforming the patent system, and allowing patients to import drugs from other countries. The pharmaceutical and biotechnology industries have pushed back against almost all of them. Some of these proposals are more ambitious than others; some more likely to succeed. With costs rising every day, policy makers, legislators, and industry professionals need to focus their attention on those reforms that are attainable and will result in sustainable, reduced prescription drug prices. This paper discusses various U.S. regulatory frameworks that impact prescription drug prices and evaluates proposed reforms to these frameworks in terms of which ones are most likely to succeed.

Objective: We examined whether media exposure and media-induced stress contributed to eating disorder behaviors immediately and over the course of a day in women with anorexia nervosa (AN)., Method: Women with AN (N = 118) completed a 2-week ecological momentary assessment protocol during which they reported on exposure to food, shape, or weight-related media, associated stress, and eating behaviors., Results: Food, weight, or shape-related media exposure alone did not predict more frequent daily eating disorder behaviors. However, stress associated with media exposure was prospectively associated with a greater likelihood of binge eating and vomiting at the next assessment point. In addition, media-induced stress increased the probability of restrictive eating and fluid intake, vomiting, and laxative abuse across the day., Discussion: Media-induced stress may contribute to increased eating disorder behaviors in women with AN, as women who saw a media image and reported this experience as stressful were more likely to engage in momentary binge eating or vomiting. Reducing stress associated with viewing media images could be a potential target for therapeutic intervention with disordered eating. © 2015 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:617-621)., (© 2015 Wiley Periodicals, Inc.)

Objective: The overarching purpose of this study was to explore the relationships among acculturative stress, self-esteem, and eating pathology in Asian American and Latina female college students., Method: Participants (N = 638, mean age = 19.88) completed self-report measures of the variables of interest online., Results: Bivariate correlations indicated that for women of both ethnic groups, acculturative stress was negatively correlated with self-esteem and positively correlated with eating pathology. Multigroup structural equation modeling indicated that for Asian American and Latina women, self-esteem partially mediated the relationship between acculturative stress and eating pathology. However, self-esteem did not serve as a significant moderator of this relationship for either ethnic group., Conclusion: Overall, data suggest that acculturative stress is associated with increased eating pathology and self-esteem may mediate this relationship. These relationships suggest that assessment of eating pathology and self-esteem may be indicated for women presenting clinically with acculturative stress concerns., (© 2015 Wiley Periodicals, Inc.)

While the Body Checking Questionnaire (BCQ; Reas et al., 2002) is the most commonly-used measure of body checking behaviors, findings on the factor structure in nonclinical samples are mixed. This study investigated the factor structure and psychometric properties of the BCQ among nonclinical college women. In Study 1 (n=326), an exploratory factor analysis indicated factors corresponding to (a) behavioral and (b) visual checking. In Study 2 (n=1013), a confirmatory factor analysis revealed adequate fit for these factors, better than the original or total score solutions. Scales based upon the two factors demonstrated good internal consistency, convergent validity with measures of eating pathology, and sensitivity for detecting at-risk eating pathology. Results suggest an alternate two-factor solution that differs from the original three-factor solution., (Copyright © 2015. Published by Elsevier Ltd.)

Although there are several recent reviews of the pre-operative factors that influence treatment outcome for bariatric surgery, commensurate efforts to identify and review the predictive validity of post-operative variables are lacking. This review describes the post-operative psychosocial predictors of weight loss in bariatric surgery. Results suggest empirical support for post-operative binge eating, uncontrolled eating/grazing, and presence of a depressive disorder as negative predictors of weight loss outcomes; whereas, adherence to dietary and physical activity guidelines emerged as positive predictors of weight loss. With the exception of depression, psychological comorbidities were not consistently associated with weight loss outcomes. Results highlight the need for post-operative assessment of disordered eating and depressive disorder, further research on the predictive value of post-operative psychosocial factors, and development of targeted interventions.

Despite research documenting a relationship between social anxiety and perfectionism, very little research has examined the relationship between social anxiety and clinical perfectionism, defined as the combination of high personal standards and high maladaptive perfectionistic evaluative concern. In the current studies we examined whether clinical perfectionism predicted social anxiety in a large sample of undergraduates (N=602), in a clinical sample of participants diagnosed with social anxiety disorder (SAD; N=180), and by using a variance decomposition model of self- and informant-report of perfectionism (N=134). Using self-report, we found that an interaction of personal standards and evaluative concern predicted both social interaction anxiety and fear of scrutiny, but not in the theorized direction. Specifically, we found that self-report of low standards and high evaluative concern was associated with the highest levels of social anxiety, suggesting that when individuals with SAD hold low expectations for themselves combined with high concerns about evaluation, social anxiety symptoms may increase. Alternatively, when an informants' perspective was considered, and more consistent with the original theory, we found that the interaction of informant-only report of personal standards and shared-report (between both primary participant and informant) of concern over mistakes was associated with self-reported social anxiety, such that high concern over mistakes and high personal standards predicted the highest levels of social anxiety. Theoretical, clinical, and measurement implications for clinical perfectionism are discussed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Social anxiety and eating pathology frequently co-occur. However, there is limited research examining the relationship between anxiety and body checking, aside from one study in which social physique anxiety partially mediated the relationship between body checking cognitions and body checking behavior (Haase, Mountford, & Waller, 2007). In an independent sample of 567 college women, we tested the fit of Haase and colleagues' foundational model but did not find evidence of mediation. Thus we tested the fit of an expanded path model that included eating pathology and clinical impairment. In the best-fitting path model (CFI=.991; RMSEA=.083) eating pathology and social physique anxiety positively predicted body checking, and body checking positively predicted clinical impairment. Therefore, women who endorse social physique anxiety may be more likely to engage in body checking behaviors and experience impaired psychosocial functioning., (Published by Elsevier Ltd.)

Acute right iliac fossa pain is a common surgical presentation. The presentation is often non-specific and encompasses a wide differential, which creates a diagnostic challenge. Ultrasound is commonly the initial cross-sectional imaging modality and can be used as a tool to triage patients appropriately; assessing for appendicitis and other salient findings, which may indicate an alternative condition. Additionally, the dynamic nature of this imaging modality enables patient interaction. Following a systematic assessment of the abdomen and pelvis, a more focused interrogation of the right iliac fossa is performed. In this pictorial review, we illustrate the sonographic features of appendicitis and other conditions that can mimic appendicitis in its presentation. This highlights that through a systematic approach, it is possible to distinguish between these different pathologies, enabling clinicians to optimally manage the patient.

Although body checking and avoidance behaviors are common in women with eating disorders, minimal research has examined the nature or correlates of these behaviors in ethnically diverse female college students without eating disorders. Self-identified European American (n=268), Asian American (n=163), Latina (n=146), and African American (n=73) women completed self-report measures of body checking and avoidance, thin-ideal internalization, eating pathology, and clinical impairment. Results indicated that European and Asian American women reported significantly more body checking and avoidance than African American and Latina women. Generally, correlates of body checking and avoidance were consistent across ethnic groups: Regression analyses indicated that type of ethnicity predicted body checking and avoidance; and ethnicity, body checking, and body avoidance predicted eating pathology and clinical impairment. These associations suggest that body checking and avoidance are not benign behaviors in diverse nonclinical women., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Social anxiety and eating disorders are highly comorbid. Social appearance anxiety (i.e., fear of negative evaluation of one's appearance), general fear of negative evaluation, and perfectionism have each been proposed as risk factors for both social anxiety disorder and the eating disorders. However, no research to date has examined all three factors simultaneously. Using structural equation modeling in two diverse samples (N=236; N=136) we tested a model in which each of these risk factors were uniquely associated with social anxiety and eating disorder symptoms. We found support for social appearance anxiety as a shared risk factor between social anxiety and eating disorder symptoms, whereas fear of negative evaluation was a risk factor only for social anxiety symptoms. Despite significant zero-order relationships, two facets of perfectionism (high standards and maladaptive perfectionism) did not emerge as a risk factor for either disorder when all constructs were considered. These results were maintained when gender, body mass index, trait negative affect, and depression were included in the model. It is possible that treating negative appearance evaluation fears may reduce both eating disorder and social anxiety symptoms., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Women in substance abuse treatment increasingly report weight-related concerns as motivation for drug use. However, limited research has explored the nature of these concerns or examined whether women in substance abuse treatment with weight-related concerns related to drug use differ from those who do not on variables relevant to eating pathology. Using a sample of 297 women in substance abuse treatment, this study examined two intertwined issues: (1) the prevalence and nature of weight-related concerns related to drug use and (2) whether women who endorse weight-related concerns related to drug use differ from those without weight-related concerns on body dissatisfaction, eating pathology, perceived pressure and internalization of thin-ideal media, and appearance-related drug-use expectancies. Descriptive analyses indicated that the majority of participants were concerned about gaining weight during treatment and/or that weight gain could trigger drug relapse. Analyses of variance revealed that women who reported weight-based concerns (both with regards to weight gain during treatment and relapse potential) endorsed higher levels of body dissatisfaction, dieting, bulimic symptoms, and thin-ideal internalization than women who did not endorse weight-related concerns. Results suggest that substance abuse treatment programs should be aware of and address weight-related concerns around drug use for women., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Obesity and other eating-related problems are widespread and are associated with harmful physical, psychological, and social problems. The dramatic increases in rates of pediatric obesity has created a mounting need for psychologists and other mental health care providers to play a significant role in the assessment and treatment of youth with eating- and weight-related problems. Therefore, it is imperative for providers to be aware of the causes and consequences of eating- and weight-related problems and to be familiar with evidence-based assessment and intervention approaches. Currently, the most well-established intervention approaches are family-based behavioral treatments, and weight loss maintenance treatments with a socio-ecological focus are promising. This paper provides a comprehensive review of these topics and highlights the important roles that mental health care providers can have. Medical settings are often the patient's first point of contact within the healthcare system, making mental health care providers in such settings uniquely suited to assess for a broad range of eating- and weight-related problems and associated comorbidities, to deliver relevant evidence-based interventions, and to make appropriate referrals. Moving forward, providers and researchers must work together to address key questions related to the nature of eating- and weight-related problems in youth and to achieve breakthroughs in the prevention and treatment of such problems in this vulnerable population.

Background: Reliable information extraction applications have been a long sought goal of the biomedical text mining community, a goal that if reached would provide valuable tools to benchside biologists in their increasingly difficult task of assimilating the knowledge contained in the biomedical literature. We present an integrated approach to concept recognition in biomedical text. Concept recognition provides key information that has been largely missing from previous biomedical information extraction efforts, namely direct links to well defined knowledge resources that explicitly cement the concept's semantics. The BioCreative II tasks discussed in this special issue have provided a unique opportunity to demonstrate the effectiveness of concept recognition in the field of biomedical language processing., Results: Through the modular construction of a protein interaction relation extraction system, we present several use cases of concept recognition in biomedical text, and relate these use cases to potential uses by the benchside biologist., Conclusion: Current information extraction technologies are approaching performance standards at which concept recognition can begin to deliver high quality data to the benchside biologist. Our system is available as part of the BioCreative Meta-Server project and on the internet http://bionlp.sourceforge.net.

Members of the Puf family of RNA-binding proteins from Drosophila, Caenorhabditis elegans, and Dictyostelium are known to function as translational repressors. To identify mammalian proteins that might regulate posttranscriptional gene expression, we have characterized a novel murine Puf protein, PUM2. Pum2 transcripts were expressed in all murine tissues examined, suggesting the gene influences processes common to many cell types. Like all Puf family members, PUM2 contains a C-terminal RNA-binding domain related to the Drosophila Pumilio homology domain (PUM-HD). Two features found in the amino-terminus of PUM2, regions rich in serine and glutamine/alanine-rich regions, were also identified in most Puf family members. RNA sequences capable of binding with high affinity (6.5 nM) to a 48-kDa recombinant protein containing the PUM2 PUM-HD were isolated by using an iterative amplification-selection protocol (SELEX). The consensus sequence [UGUANAUARNNNNBBBBSCCS] of the PUM2 binding element (PBE) is related to, but distinct from, the 3' end of the Drosophila Nanos response element. The characterization of PUM2 and potential RNA-binding site will assist efforts to assess the extent and mechanism by which mammalian genes are regulated at a posttranscriptional level.

The steroidogenic acute regulatory protein (StAR) is required for the movement of cholesterol from the outer to the inner mitochondrial membrane, the site of cholesterol side chain cleavage. Here we describe a novel form of regulation of StAR gene expression in steroidogenic cells. Treatment of Y-1 BS1 adrenocortical cells with either low density lipoprotein (LDL) or high density lipoprotein (HDL) increases expression of endogenous StAR mRNA and protein in a dose-dependent manner. Induction of StAR mRNA by lipoprotein requires basal cAMP-dependent protein kinase, since the inhibitor, R(p)-8-Br-cAMP, inhibited induction of StAR protein by LDL. Likewise, basal StAR expression or LDL induction of StAR protein was not detectable in Y-1 kin-8 cells which are deficient in cAMP-dependent protein kinase. Aminoglutethimide and ketoconazole were used to determine if side chain cleavage of lipoprotein-derived cholesterol is required for induction of StAR mRNA. Treatment with either drug alone induced StAR mRNA expression 1.5-3-fold, while induction of StAR in cells treated with either drug plus LDL, was equal to, or greater than, induction seen with either agent alone, suggesting that lipoprotein does not regulate StAR via generation of an oxysterol intermediate. Both LDL and HDL increased expression of a mouse -966 StAR promoter-reporter construct 1.5-2.5-fold, indicating that regulation occurs at the level of transcription. In contrast, neither lipoprotein was able to induce transcription from a -966 StAR promoter in which the steroidogenic factor-1 site at -135 was abolished, indicating that regulation of StAR transcription by lipoproteins requires steroidogenic factor-1. The regulation of StAR gene expression by lipoproteins may represent a positive feedback circuit which links cholesterol availability with steroidogenic output.

The gene FUS (also known as TLS (for translocated in liposarcoma) and hnRNP P2) is translocated with the gene encoding the transcription factor ERG-1 in human myeloid leukaemias. Although the functions of wild-type FUS are unknown, the protein contains an RNA-recognition motif and is a component of nuclear riboprotein complexes. FUS resembles a transcription factor in that it binds DNA, contributes a transcriptional activation domain to the FUS-ERG oncoprotein and interacts with several transcription factors in vitro. To better understand FUS function in vivo, we examined the consequences of disrupting Fus in mice. Our results indicate that Fus is essential for viability of neonatal animals, influences lymphocyte development in a non-cell-intrinsic manner, has an intrinsic role in the proliferative responses of B cells to specific mitogenic stimuli and is required for the maintenance of genomic stability. The involvement of a nuclear riboprotein in these processes in vivo indicates that Fus is important in genome maintenance.

We have previously shown that protein kinase C (PKC) suppresses steroidogenesis in Y-1 adrenocortical cells. To ask directly if the PKCalpha isoform mediates this suppression, we have developed Y-1 cell lines in which PKCalpha is expressed from a tetracycline-regulated promoter. Induction of PKCalpha expression in these cell lines results in decreased P450 cholesterol side-chain cleavage enzyme (P450-SCC) activity as judged by the conversion of hydroxycholesterol to pregnenolone. Transcription of a P450-SCC promoter-luciferase construct is also reduced when PKCalpha expression is increased. However, expression of PKCalpha has no effect on 8-bromo-cAMP induction of steroidogenesis, indicating that these pathways function independently to regulate steroidogenesis. To determine the relationship between endogenous PKC activity and steroidogenesis, we examined 12 Y-1 subclones that were isolated by limited dilution cloning. In each of these subclones, steroid production correlates inversely with total PKC activity and with the expression of PKCalpha but not PKCepsilon or PKCzeta. These studies define for the first time the role of a specific PKC isoform (PKCalpha) in regulating steroidogenesis and P450-SCC activity in adrenocortical cells.

The association between peripheral astigmatic asymmetry and angle alpha was tested in the present study. Measurements were made in 34 eyes. Peripheral astigmatism was measured over the horizontal meridian using a Zeiss (Jena) Hartinger coincidence optometer and a Canon R-1 autorefractometer. Curves were fitted to the measured data of each eye and the minima determined by differentiation. Angle alpha was estimated by alignment of Purkinje images I (anterior cornea) and IV (posterior crystalline lens). Peripheral astigmatism was found to be symmetrical about a point on the nasal retina. This point departed from the visual axis by 8.8 +/- 7.0 degrees (Hartinger) and 9.4 +/- 9.8 degrees (Canon). Both values were found to be significantly higher than angle alpha 5.0 +/- 1.2 degrees. The results indicate that either peripheral astigmatic asymmetry is due to additional factors such as lack of symmetry in the peripheral curvature of individual optical surfaces, or that there is further misalignment of optical surfaces away from an optical axis.