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Emergency nurses experience a myriad of negative consequences associated with workplace assault. The purpose of this study was to explore the experiences of emergency nurses using the Ecological Occupational Health Model of Workplace Assault.A descriptive qualitative design was used for this study. Data from 167 emergency nurse participants who described an episode of workplace assault were analyzed using a conventional content analysis method.Fourteen codes emerged from the qualitative data that related to 4 categories for the theme, Outcomes of Workplace Assault. The category "Consequences of Assault to Patients and Visitors" was supported by the following codes: use of limit setting; being evicted or removed from the emergency department; having charges pressed or being arrested; use of restraints; and retaliation against aggressor. "Effects on the Worker" was supported by the following codes: physical outcomes and response; psychological outcomes and response; physical support from peers; apologies; and debriefing/supportive care. "Effects on the Workplace" was supported by the following codes: calling for and response by police or security; and visitor response, support, or assistance. "Effects on Patient Care" was supported by the following codes: impact to treatment and work productivity.Workplace assault in the ED setting is associated with consequences of workplace assault to patients and visitors as well as negative effects to emergency nurses, the workplace, and patient care. Emergency nurses need to seek and also offer emotional support after workplace assault. Providing support could serve as a deterrent to retaliation while minimizing potential adverse impacts to nurses' psychological health and work productivity.

Although researchers have explored the link between depression and executive functioning (EF), the influence of early-life environmental and relational instability on this association has not been comprehensively assessed in adolescents. This cross-sectional study examined whether unpredictability of home environment in childhood moderated the relationship between depression and EF in adolescents. Participants were 138 adolescents aged 13 to 17 years (72% female; 47.8% White; 47.1% Hispanic). Diagnostic status (major depression versus healthy control) and depression severity were assessed using psycho-diagnostic interviews and self-reports from parents and adolescents. Participants also completed the Questionnaire of Unpredictability in Childhood (QUIC). EF was assessed using self-report (Behavior Rating Inventory of Executive Function, Second Edition; BRIEF2) and a battery of performance-based measures. Results showed that QUIC scores moderated the relationship between depression and BRIEF2 scores, such that high unpredictability was associated with poorer EF for adolescents exhibiting low depression severity. Participants with the highest levels of depression exhibited the poorest EF ratings, regardless of childhood unpredictability. Unpredictability was moderately associated with performance-based measures, but did not interact with depressive symptoms to predict complex performance-based EF. Recommendations include assessing for unpredictable childhood environment and acknowledging this risk factor for poor EF in youth with sub-threshold depression. Treatment implications are discussed with respect to family systems/parenting interventions, as mildly depressed adolescents growing up in unstable homes may be vulnerable to EF difficulties. Further, this study adds to the EF measurement literature by examining associations between self-report and performance-based EF instruments in a diverse sample of adolescents.

Workplace violence (WV) is a significant occupational hazard for home health care workers (HHCWs). HHCWs are frequently exposed to Type II (customer/client) WV incidents but minimal evidence exists about exposure to Type III (coworker) WV and exposure to Type IV (personal relationship) WV is unknown. Furthermore, exposure to WV incidents is often underreported by HHCWs. The Haddon Matrix guided this research study. A cross- sectional research design was used with HHCWs (n = 50) working in Southwest Ohio in April 2020. HHCWs completed the Workplace Violence Reporting Survey, a 76-item tool used to estimate the frequency and reporting of WV incidents. Data were analyzed using frequencies, percentages, means, and standard deviations. HHCWs were 86% female (n = 43). Patients (28.3%) followed by their families (17.4%) and intimate partners (10.9%) are the primary aggressors of verbal abuse. The incident was too minor (6.5%), no action would be taken (6.5%), and it’s part of the job (4.3%) are major reasons HHCWs underreported WV. Type II WV is most pervasive when the aggressor is the patient. HHCWs experience physical assault and sexual abuse in their work environment. HHCWs underreported verbal abuse and physical assault when the aggressor was an intimate partner.

Although Black American mothers and infants are at higher risk for morbidity and mortality than their White counterparts, the biological mechanisms underlying these phenomena remain largely unknown. To investigate the role that lifetime stressor exposure, perceived stressor severity, and systemic inflammatory markers might play, we studied how these factors were interrelated in 92 pregnant Black American women. We also compared inflammatory marker levels for women who did versus did not go on to give birth preterm. During the early third trimester, women completed the Stress and Adversity Inventory for Adults to assess the stressors they experienced over their lifetime. Women also provided blood samples for plasma interleukin (IL)-6, IL-8, IL-1β, and tumor necrosis factor (TNF)-α quantification. Preterm births were identified by medical record review. Controlling for relevant covariates, there were significant positive associations between average levels of both overall and acute perceived stressor severity and plasma IL-1β levels. Controlling for perceived stress at assessment and exposure to racial discrimination did not affect these results. Mediation models revealed that exposure to more chronic stressors was related to higher plasma IL-1β levels, as mediated by higher average levels of overall perceived stressor severity. Exposure to fewer acute stressors was related to higher plasma IL-1β levels, as mediated by higher average levels of acute perceived stressor severity. Finally, women who went on to give birth preterm had higher levels of plasma IL-6. These data thus highlight the potential importance of assessing and addressing lifetime stressor exposure among mothers before and during maternal-infant care.

ClinVar variant interpretations from May 2019 for variants identified in discovery cohorts

Germline loss-of-function mutations in BRCA1 interacting protein C-terminal helicase 1 (BRIP1) are associated with ovarian carcinoma and may also contribute to breast cancer risk, particularly among patients who develop disease at an early age. Normal BRIP1 activity is required for DNA interstrand cross-link (ICL) repair and is thus central to the maintenance of genome stability. Although pathogenic mutations have been identified in BRIP1, genetic testing more often reveals missense variants, for which the impact on molecular function and subsequent roles in cancer risk are uncertain. Next-generation sequencing of germline DNA in 2,160 early-onset breast cancer and 1,199 patients with ovarian cancer revealed nearly 2% of patients carry a very rare missense variant (minor allele frequency < 0.0001) in BRIP1. This is 3-fold higher than the frequency of all rare BRIP1 missense alleles reported in more than 60,000 individuals of the general population (P < 0.0001, χ2 test). Using CRISPR-Cas9 gene editing technology and rescue assays, we functionally characterized 20 of these missense variants, focusing on the altered protein's ability to repair ICL damage. A total of 75% of the characterized variants rendered the protein hypomorph or null. In a clinical cohort of >117,000 patients with breast and ovarian cancer who underwent panel testing, the combined OR associated with BRIP1 hypomorph or null missense carriers compared with the general population was 2.30 (95% confidence interval, 1.60–3.30; P < 0.0001). These findings suggest that novel missense variants within the helicase domain of BRIP1 may confer risk for both breast and ovarian cancer and highlight the importance of functional testing for additional variants.Significance:Functional characterization of rare variants of uncertain significance in BRIP1 revealed that 75% demonstrate loss-of-function activity, suggesting rare missense alleles in BRIP1 confer risk for both breast and ovarian cancer.

Supplementary methods; FS1: BRIP1 nonsense and frameshift mutations; FS2: BRIP1 expression in CRISPR cell lines; FS3: hydroxyurea and TMPyP4 challenge; FS4: HEK293TN CRISPR cell lines; FS5: HeLa stable clone rescues; FS6: Transient rescue screening assay; FS7: Degradation of missense mutant proteins; TS1: List of BRIP1 missense variants identified in cohorts

Parents whose infants are hospitalized in the neonatal intensive care unit (NICU) are at greater risk of difficulties in adjustment and coping, including a higher incidence of perinatal mood and anxiety disorders (PMADs). The presence of a PMAD is known to influence parent–infant bonding and developmental outcomes. Many organizations have advocated for parental screening for PMADs during pregnancy, as well as during NICU admission and post-discharge, to better identify families at risk and triage psychological care. Screening can be challenging for NICU providers due to constraints in time and resources. Screening protocols must include well-validated measures, trained staff to administer, and clear plans for addressing elevated risk. This highlights the need for the integration of mental health professionals into perinatal settings to help foster resilience in families during this vulnerable time.

African American women are more likely to experience preterm birth (

Background Among Black Americans, interpersonal racial discrimination is common. Stress, including following discrimination, contributes to pregnancy complications. In this secondary analysis, we provide data on associations among discrimination, stress, and their interaction across the life course and inflammation, perceived stress, and depressive symptoms during pregnancy. Methods During the early third trimester, Black American women (n = 93) completed the Experiences of Discrimination Scale, the Stress and Adversity Inventory, the Perceived Stress Scale, and the Center for Epidemiological Studies Depression Inventory. Plasma interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α), and IL-β levels were quantified. Associations were examined by linear regression, controlling for demographic, behavioral, and clinical covariates. Results Associations among racial discrimination and plasma IL-8, TNF-α, and IL-β levels depended upon average ratings of life course stress. When stress was low, discrimination in the mid tertile was associated with the highest levels of IL-8, TNF-α, and IL-β. Subscale analyses suggested that findings related to IL-8 were driven by chronic stress whereas findings related to TNF-α and IL-β were driven by acute stress. When examined together, greater discrimination but not greater life course stress was associated with higher prenatal perceived stress. In subscale analyses, the association between discrimination and prenatal perceived stress depended upon average ratings of life course acute stress. When acute stress was low, discrimination in the midtertile was associated with the highest levels of prenatal perceived stress. When acute stress was high, discrimination in the high tertile was associated with the highest levels of prenatal perceived stress. There were also direct associations among greater life course chronic stress, prenatal perceived stress, and prenatal depressive symptoms. Associations were attenuated when discrimination was included as a covariate. Conclusions The current analyses suggest that, among Black Americans, prenatal inflammation, perceived stress, and depressive symptoms may be shaped by racial discrimination and stress across the life course. In many cases, associations among discrimination and prenatal parameters depended upon how stressful exposures to life course stressors had been rated. The data suggest the potential for adaptive plasticity under some stress and highlight the deleterious nature of compounding stress.

Background: New graduate role transition for nurses and teachers is stressful. Poor adaptation may manifest as insomnia, which has implications for the new professionals, their employers, and the public served. This study examines factors that impact new graduate sleep, with the aim of identifying perceived helps and hindrances to sleep-during-transition. Methods: Targeted content analysis of transcripts from a larger longitudinal mixed methods study comparing new graduate sleep during their first year of practice. Study participants ( N = 21) answered questions in the final interview regarding the most positive and negative impact(s) on sleep during the transition year. Transcripts were analyzed and compared based on the new graduate sleep typology (i.e., Got Better, Got Worse, Stayed Varied) which emerged from the parent study. Findings: Most participants, regardless of sleep type, identified a person/group as most positively impacting sleep. They identified work thoughts, stress/anxiety, people, work hours/sleep schedules, and environmental factors as negatively impacting sleep. Work thoughts and stress/anxiety were mentioned together and most frequently by participants in all three sleep types. Conclusion/Applications to Practice: This study provided insight into new graduate nurse and teacher sleep during transition. Support persons and/or groups may be essential regardless of sleep type. Thought management/stress mitigation strategies and good sleep hygiene may also improve the sleep experiences of these new professionals. Occupational health nurses can support sleep-during-transition among new nurses and teachers by acting as sleep advocates. They may also identify a need for medical intervention and/or sleep specialists and should promote fatigue risk mitigating policies.

Purpose: The purpose of this study is to characterize mothers’ experiences within a mother/infant dyad postpartum primary care program (Dyad) following gestational diabetes mellitus (GDM) to inform improvements in the delivery of care. Methods: A qualitative pilot study of women (n = 10) enrolled in a mother/infant Dyad program was conducted in a primary care practice at a large, urban academic medical center. Respondents were asked a series of open-ended questions about their experience with GDM, the Dyad program, and health behaviors. Interviews were audio-recorded, transcribed verbatim, and analyzed using ground theory with NVivo 12 Plus software. Results: Three key themes emerged: (1) Dyad program experience, (2) implementation of health behavior changes, and (3) acknowledgment of future GDM and type 2 diabetes mellitus (T2DM) health risks. Respondents felt that the program conveniently served mother and infant health care needs in a single appointment. Respondents also valued support from primary care providers when implementing health behavior changes. The Dyad program provided an opportunity for respondents to understand their current and future risk for developing GDM and T2DM. Conclusions: Postpartum women enrolled in the Dyad program received highly personalized primary care services. The results of our study will help integrate patient-centered strategies into models for GDM care to maintain patient engagement in postpartum clinical services.

Premise With digitization and data sharing initiatives underway over the last 15 years, an important need has been prioritizing specimens to digitize. Because duplicate specimens are shared among herbaria in exchange and gift programs, we investigated the extent to which unique biogeographic data are held in small herbaria vs. these data being redundant with those held by larger institutions. We evaluated the unique specimen contributions that small herbaria make to biogeographic understanding at county, locality, and temporal scales. Methods We sampled herbarium specimens of 40 plant taxa from each of eight states of the United States of America in four broad status categories: extremely rare, very rare, common native, and introduced. We gathered geographic information from specimens held by large (≥100,000 specimens) and small (

Opportunistic infections (OIs) are the primary cause of HIV-related morbidity and mortality. To reduce the risk, the ART eligibility criteria were revised to start treatment before advanced disease...

Purpose To provide evidence-based recommendations on the use of inferior vena cava (IVC) filters in the treatment of patients with or at substantial risk of venous thromboembolic disease. Materials and Methods A multidisciplinary expert panel developed key questions to address in the guideline, and a systematic review of the literature was conducted. Evidence was graded based on a standard methodology, which was used to inform the development of recommendations. Results The systematic review identified a total of 34 studies that provided the evidence base for the guideline. The expert panel agreed on 18 recommendations. Conclusions Although the evidence on the use of IVC filters in patients with or at risk of venous thromboembolic disease varies in strength and quality, the panel provides recommendations for the use of IVC filters in a variety of clinical scenarios. Additional research is needed to optimize care for this patient population.

Offspring born preterm (i.e., before 37 weeks gestation) are more likely to die or experience longstanding illness compared to full term offspring. Maternal genetic variants (i.e., heritable, stable variations in the genetic code) and epigenetic modifications (i.e., chemical modifications to the genetic code that can affect which genes are turned on or off) in response to stress have been implicated in preterm birth. Fetal genetic variants have been linked to preterm birth; though, the role of offspring epigenetics in preterm birth remains understudied. This systematic review synthesizes the literature examining associations among stress during pregnancy and epigenetic modifications to offspring DNA, with 25 reports identified. Ten reports examined DNA methylation (i.e., addition/removal of methyl groups to/from DNA) across the epigenome. The remainder examined DNA methylation near genes of interest, primarily genes linked to hypothalamic-pituitary-adrenal axis function (NR3C1, FKBP51), growth/immune function (IGF2), and socioemotional regulation (SLC6A4, OXTR). The majority of reports noted associations among stress and offspring DNA methylation, primarily when perceived stress, anxiety, or depression served as the predictor. Findings suggest that differences in offspring epigenetic patterns may play a role in stress-associated preterm birth and serve as targets for novel interventions.

Conventional influenza vaccines fail to confer broad protection against diverse influenza A viruses with pandemic potential. Efforts to develop a universal influenza virus vaccine include refocusing immunity towards the highly conserved stalk domain of the influenza virus surface glycoprotein, hemagglutinin (HA). We constructed a non-replicating adenoviral (Ad) vector, encoding a secreted form of H1 HA, to evaluate HA stalk-focused immunity. The Ad5_H1 vaccine was tested in mice for its ability to elicit broad, cross-reactive protection against homologous, heterologous, and heterosubtypic lethal challenge in a single-shot immunization regimen. Ad5_H1 elicited hemagglutination inhibition (HI+) active antibodies (Abs), which conferred 100% sterilizing protection from homologous H1N1 challenge. Furthermore, Ad5_H1 rapidly induced H1-stalk-specific Abs with Fc-mediated effector function activity, in addition to stimulating both CD4+ and CD8+ stalk-specific T cell responses. This phenotype of immunity provided 100% protection from lethal challenge with a head-mismatched, reassortant influenza virus bearing a chimeric HA, cH6/1, in a stalk-mediated manner. Most importantly, 100% protection from mortality following lethal challenge with a heterosubtypic avian influenza virus, H5N1, was observed following a single immunization with Ad5_H1. In conclusion, Ad-based influenza vaccines can elicit significant breadth of protection in naive animals and could be considered for pandemic preparedness and stockpiling.

Anticoagulation is the cornerstone for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE). On occasion this is not possible because of bleeding complications or, rarely, breakthrough PE associated with this treatment method. The development of vena cava interruption in the 1970s was a critical advance in the treatment of these patients. Inferior vena cava (IVC) filter placement has been steadily increasing since their introduction. Nonetheless, the incidence of complications associated with placement of these devices is largely unknown. Most of the evidence regarding IVC filter complications relies on case reports, with very scarce data coming from larger randomized controlled trials. We aim to present a summary addressing long-term complications of IVC filters, as published in recent articles addressing problems such as IVC thrombosis, IVC filter migration, perforation, filter fracture, embolization, and tilting. We performed a PubMed search and Google Scholar search using different combination of “long term,” “complications,” “IVC filter,” and “vena cava filter.” We reviewed the publications available in English and reported the findings in this summary.

SHARPIN, together with RNF31/HOIP and RBCK1/HOIL1, form the linear ubiquitin chain assembly complex (LUBAC) E3 ligase that catalyzes M1-linked polyubiquitination. Mutations in RNF31/HOIP and RBCK/HOIL1 in humans and Sharpin in mice lead to autoinflammation and immunodeficiency, but the mechanism underlying the immune dysregulation remains unclear. We now show that the phenotype of the Sharpin(cpdm/cpdm) mice is dependent on CYLD, a deubiquitinase previously shown to mediate removal of K63-linked polyubiquitin chains. Dermatitis, disrupted splenic architecture, and loss of Peyer's patches in the Sharpin(cpdm/cpdm) mice were fully reversed in Sharpin(cpdm/cpdm) Cyld(−/−) mice. We observed enhanced association of RIPK1 with the death-signaling Complex II following TNF stimulation in Sharpin(cpdm/cpdm) cells, a finding dependent on CYLD since we observed reversal in Sharpin(cpdm/cpdm) Cyld(−/−) cells. Enhanced RIPK1 recruitment to Complex II in Sharpin(cpdm/cpdm) cells correlated with impaired phosphorylation of CYLD at serine 418, a modification reported to inhibit its enzymatic activity. The dermatitis in the Sharpin(cpdm/cpdm) mice was also ameliorated by the conditional deletion of Cyld using LysM-cre or Cx3cr1-cre indicating that CYLD-dependent death of myeloid cells is inflammatory. Our studies reveal that under physiological conditions, TNF- and RIPK1-dependent cell death is suppressed by the linear ubiquitin-dependent inhibition of CYLD. The Sharpin(cpdm/cpdm) phenotype illustrates the pathological consequences when CYLD inhibition fails.

Background Patients with IBD have increased risk for developing colorectal cancer (CRC), with poorer survival, compared to those without IBD. Despite surveillance colonoscopy, IBD post-colonoscopy CRC (PCCRC) rates are unacceptably high at 28-45%. We define surveillance colonoscopy quality, IBD-dysplasia and IBD-CRC prevalence, IBD-CRC characteristics, and IBD PCCRC rates at a tertiary IBD centre. Methods The GI Reporting Tool (Unisoft Medical Systems) was searched for IBD surveillance colonoscopy reports from April 2008–December 2018. Electronic medical records were reviewed. IBD phenotype and diagnosis date was confirmed on the Lothian IBD Registry. Follow-up was until September 2022. Results 1892 colonoscopies from 1262 patients were included. Median follow-up was 7.1 (4.4, 9.5) years. 885/1262 (70.1%) had UC, 344/1262 (27.3%) had Crohn’s, and 33/1262 (2.6%) had IBD-U. Median disease duration at colonoscopy was 16.8 (11, 24.6) years. 1825/1892 (96.5%) colonoscopies achieved caecal intubation, 1735/1840 (94.3%) adhered to biopsy guidelines and 704/1892 (37%) used chromoendoscopy. Histological inflammation was identified in 873/1823 (47.9%) cases; 57.2% in the right colon. Bowel preparation was poor in 194/1892 (10.3%) procedures and the most documented reason for not performing chromoendoscopy. Poor bowel preparation was associated with 23/60 (38.3%) poorly tolerated and 29/52 (55.8%) incomplete colonoscopies. Moviprep was superior to Picolax (p Dysplasia was identified in 145/1892 (7.7%) colonoscopies: 84/1892 (4.4%) sporadic, 22/1892 (1.2%) IBD-associated, and 39/1892 (2.1%) unspecified. IBD-CRC is rare, at 0.8 cases per 1000 patient years. Within the study period, 20/1262 (1.6%) patients had CRC diagnosed. 17/20 (85%) had UC and 3/20 (15%) had Crohn’s. 15/17 (88%) UC patients had E3 disease. 11/20 (55%) presented with lymph node or distant metastasis. 8/20 (40%) tumours had mucinous differentiation; only 1/15 (6.7%) was well differentiated. IBD-CRC patients had longer disease duration (28.3 (19.7, 37.8) years) compared to patients without CRC (22.25 (16.42, 29.85) years) at follow-up (p=0.028). The 3-year PCCRC rate was 15%. Conclusion IBD-CRC is rare however IBD PCCRC rates are unacceptably high. While this may reflect disease biology, a new approach to IBD surveillance is urgently needed. Interventions could include dedicated IBD surveillance lists, patient education around bowel preparation, and pre-screening for inflammation (e.g. faecal calprotectin). Cancer registry database linkage is now essential for us to identify IBD-CRC cases not identified by surveillance.

Health care providers (HCPs) who work primarily with Medicaid patients must be competent in identifying and addressing social determinants of health (SDH). A curricular gap exists between promoting an understanding of SDH and teaching HCPs how to recognize and increase empathy to manage them. The project aim was to develop two virtual reality simulations (VRSs) as innovative methods to teach HCPs to identify and manage SDH. A secondary aim was to decrease unconscious bias and increase empathy by experiencing SDH from their patients' perspective.Scripts for two VRSs were created by two HCP educators and clinicians. Scripts were evaluated by experts using an index of content validity (CVI). An advisory panel critiqued the scripts for appropriateness for VRSs, adequacy of evidence-based practice, and use of VRS equipment and software. The panel participated in a focus group and completed a final evaluation. The VRSs then were pilot tested with five HCPs who assessed content and utility and participated in interviews. This led to iterative improvements. Qualitative data were analyzed using a content analysis approach.The VRS scripts demonstrated adequate content-related validity evidence with CVI scores of 0.81 and 0.75. The expert panel found the VRS easy to use, useful as an educational tool, while promoting empathy for patients. Overall, participants were satisfied with using the VRS as an educational experience.Through VRS technology, this project addresses a curricular gap in HCP training on SDH. VRS can be a useful tool to increase HCPs' understanding of SDH and, potentially, their empathy for patients.

Listeria monocytogenescauses severe foodborne illness in pregnant women and immunocompromised individuals. After the intestinal phase of infection, the liver plays a central role in the clearance of this pathogen through its important functions in immunity. However, recent evidence suggests that during long-term infection of hepatocytes, a subpopulation ofListeriamay escape eradication by entering a persistence phase in intracellular vacuoles. Here, we examine whether this long-term infection alters hepatocyte defense pathways, which may be instrumental for bacterial persistence. We first optimized cell models of persistent infection in human hepatocyte cell lines HepG2 and Huh7 and primary mouse hepatocytes (PMH). In these cells,Listeriaefficiently entered the persistence phase after three days of infection, while inducing a potent interferon response, of type I in PMH and type III in HepG2, while Huh7 remained unresponsive. RNA-sequencing analysis identified a common signature of long-termListeriainfection characterized by the overexpression of a set of genes involved in antiviral immunity and the under-expression of many acute phase protein (APP) genes, particularly involved in the complement and coagulation systems. Infection also altered the expression of cholesterol metabolism-associated genes in HepG2 and Huh7 cells. The decrease in APP transcripts was correlated with lower protein abundance in the secretome of infected cells, as shown by proteomics, and also occurred in the presence of APP inducers (IL-6 or IL-1β). Collectively, these results reveal that long-term infection withListeriaprofoundly deregulates the innate immune functions of hepatocytes, which could generate an environment favorable to the establishment of persistent infection.

BACKGROUND: There is growing interest in the antidepressant potential of statins. We tested whether statin use is associated with cognitive markers previously found to indicate psychological vulnerability to depression within the context of the COVID-19 pandemic. METHODS: Between April 2020 and February 2021, we conducted an observational online study of 2043 adults in the United Kingdom. Participants completed cognitive tasks assessing processes related to depression vulnerability, including affective bias and reward processing. We also measured working memory, medication use, and current psychiatric symptoms. Using mixed analysis of covariance and regression models, we compared participants on statins alone (n = 81), antihypertensive medication alone (n = 126), both medications (n = 111), and on neither medication (n = 1725). RESULTS: Statin use was associated with reduced recognition of angry and fearful faces (F1 = 9.19, p = .002; F1 = 6.9, p = .009) and with increased misclassification of these expressions as positive. Increased recognition of angry faces at baseline predicted increased levels of depression and anxiety 10 months later (β = 3.61, p = .027; β = 2.37, p = .002). Statin use was also associated with reduced learning about stimuli associated with loss (F1,1418 = 9.90, p = .002). These indicators of reduced negative bias were not seen in participants taking antihypertensive medication alone, suggesting that they were related to statin use in particular rather than nonspecific demographic factors. In addition, we found no evidence of an association between statin use and impairment in working memory. CONCLUSIONS: Statin use was associated with cognitive markers indicative of reduced psychological vulnerability to depression, supporting their potential use as a prophylactic treatment for depression. ispartof: BIOLOGICAL PSYCHIATRY vol:92 issue:7 pages:543-551 ispartof: location:United States status: published

Germline loss-of-function mutations in BRCA1 interacting protein C-terminal helicase 1 (BRIP1) are associated with ovarian carcinoma and may also contribute to breast cancer risk, particularly among patients who develop disease at an early age. Normal BRIP1 activity is required for DNA interstrand cross-link (ICL) repair and is thus central to the maintenance of genome stability. Although pathogenic mutations have been identified in BRIP1, genetic testing more often reveals missense variants, for which the impact on molecular function and subsequent roles in cancer risk are uncertain. Next-generation sequencing of germline DNA in 2,160 early-onset breast cancer and 1,199 patients with ovarian cancer revealed nearly 2% of patients carry a very rare missense variant (minor allele frequency < 0.0001) in BRIP1. This is 3-fold higher than the frequency of all rare BRIP1 missense alleles reported in more than 60,000 individuals of the general population (P < 0.0001, χ2 test). Using CRISPR-Cas9 gene editing technology and rescue assays, we functionally characterized 20 of these missense variants, focusing on the altered protein's ability to repair ICL damage. A total of 75% of the characterized variants rendered the protein hypomorph or null. In a clinical cohort of >117,000 patients with breast and ovarian cancer who underwent panel testing, the combined OR associated with BRIP1 hypomorph or null missense carriers compared with the general population was 2.30 (95% confidence interval, 1.60–3.30; P < 0.0001). These findings suggest that novel missense variants within the helicase domain of BRIP1 may confer risk for both breast and ovarian cancer and highlight the importance of functional testing for additional variants. Significance: Functional characterization of rare variants of uncertain significance in BRIP1 revealed that 75% demonstrate loss-of-function activity, suggesting rare missense alleles in BRIP1 confer risk for both breast and ovarian cancer.

Somatic mutations of the isocitrate dehydrogenase 1 (IDH1) gene, mostly substituting Arg132 with histidine, are associated with better patient survival, but glioma recurrence and progression are nearly inevitable, resulting in disproportionate morbidity and mortality. Our previous studies demonstrated that in contrast to hemizygous IDH1R132H (loss of wild-type allele), heterozygous IDH1R132H is intrinsically glioma suppressive but its suppression of three-dimensional (3D) growth is negated by extracellular glutamate and reducing equivalent. This study sought to understand the importance of 3D culture in IDH1R132H biology and the underlying mechanism of the glutamate effect. RNA sequencing data of IDH1R132H-heterozygous and IDH1R132H-hemizygous glioma cells cultured under two-dimensional (2D) and 3D conditions were subjected to unsupervised hierarchal clustering and gene set enrichment analysis. IDH1R132H-heterozygous and IDH1R132H-hemizygous tumor growth were compared in subcutaneous and intracranial transplantations. Short-hairpin RNA against glutamate dehydrogenase 2 gene (GLUD2) expression was employed to determine the effects of glutamate and the mutant IDH1 inhibitor AGI-5198 on redox potential in IDH1R132H-heterozygous cells. In contrast to IDH1R132H-heterozygous cells, 3D-cultured but not 2D-cultured IDH1R132H-hemizygous cells were clustered with more malignant gliomas, possessed the glioblastoma mesenchymal signature, and exhibited aggressive tumor growth. Although both extracellular glutamate and AGI-5198 stimulated redox potential for 3D growth of IDH1R132H-heterozygous cells, GLUD2 expression was required for glutamate, but not AGI-5198, stimulation. 3D culture is more relevant to IDH1R132H glioma biology. The importance of redox homeostasis in IDH1R132H glioma suggests that metabolic pathway(s) can be explored for therapeutic targeting, whereas IDH1R132H inhibitors may have counterproductive consequences in patient treatment.

Natural killer (NK) cells mediate vital control of cancer and viral infection. They rely on MHC class I (MHC I)-specific self-receptors to identify and lyse diseased cells without harming self-MHC I-bearing host cells. NK cells bearing inhibitory self-receptors for host MHC I also undergo education, referred to as licensing, which causes them to become more responsive to stimulation via activation receptor signaling. Previous work has shown that licensed NK cells selectively expand during virus infections and they are associated with improved clinical response in human patients experiencing certain chronic virus infections, including HIV and hepatitis C virus. However, the importance of inhibitory self-receptors in NK-mediated virus immunity is debated as they also limit signals in NK cells emanating from virus-specific activation receptors. Using a mouse model of MHC I-dependent (H-2D k ) virus immunity, we discovered that NK cells depend on the Ly49G2 inhibitory self-receptor to mediate virus control, which coincided with host survival during murine cytomegalovirus infection. This antiviral effect further requires active signaling in NK cells via the Ly49R activation receptor that also binds H-2D k . In tandem, these functionally discordant Ly49 self-receptors increase NK cell proliferation and effector activity during infection, resulting in selective up-regulation of CD25 and KLRG1 in virus-specific Ly49R + Ly49G2 + NK cells. Our findings establish that paired self-receptors act as major determinants of NK cell-mediated virus sensing and immunity.

River channelization and artificial levees have decreased the hydrologic connectivity of river-floodplain systems around the world. In response, restoration through enhancing connectivity has been advocated to improve the functions of floodplains, but uncertain benefits and the possibility of phosphate release from re-flooded soils has limited implementation. In this study, we measured change in floodplain P, N, and sediment mass balances after restoration along channelized reaches in the lowland Pocomoke River, Maryland USA. Two floodplains (one headwater, one mainstem) restored through partial levee breaches were compared to two additional mainstem floodplains (one natural unchannelized, one unrestored channelized). Potential soluble reactive P (SRP) release from soil cores during experimental laboratory floods; soil P, Fe, and Al fractionation; and deposition and P and N content of sediment were measured before and after the restoration period, as well as in situ inputs and release of SRP and dissolved inorganic N from soils after restorations. Potential SRP release, during both the before and after restoration period, was greatest at the channelized mainstem and restored mainstem sites, lower at the restored headwater site, and small at the natural mainstem site. Both restored sites had smaller potential SRP release after restoration compared to before restoration. In situ SRP release slightly exceeded inputs to soils at connected sites during the post-restoration period, with less net release at the restored sites compared to the natural mainstem site. The magnitude of gross and net SRP release from soils in the field was smaller than, and uncorrelated with, potential SRP release estimated from laboratory experimental floods. Gross soil SRP release rates in the field were predictable using the ratio of soil oxalate-extractable P/Al. Sedimentation inputs of P and N increased at all sites during the post-restoration period, with rates at restored sites intermediate compared to the much higher rates at the natural mainstem site and somewhat lower rates at the channelized mainstem site. These sediment inputs of nutrients were much larger than rates of inorganic P and N release from soils, indicating net trapping of P and N after restoration. Restoring floodplain hydrologic connectivity showed moderate success at increasing the trapping of P, N, and sediment, with relatively little phosphate release, and therefore improving water quality.

Catastrophic bleeding is a feared complication of robotic abdominal procedures that involve dissection in close proximity to major vessels. In the event of uncontrollable hemorrhage, standard practice involves emergency undocking with conversion to laparotomy. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a rapid and life-saving technique gaining acceptance in the trauma setting for the management of catastrophic hemorrhage. The purpose of this study was to evaluate feasibility of REBOA for emergency hemostasis during robotic surgery. The surgical robot was docked to a REBOA mannequin to simulate an upper abdominal surgery. A femoral arterial line was placed in the mannequin. Supplies needed for REBOA insertion were opened and arranged on the surgical back table. The surgeon was seated at the console with an assistant scrubbed. A catastrophic vascular injury was announced. The time it took the surgeon to achieve aortic occlusion by the REBOA was recorded. Four surgeons participated and performed three timed trials each. Each surgeon, irrespective of experience with REBOA or years in surgical practice, was able to obtain aortic occlusion in less than 2 min. The mean time to aortic occlusion for all surgeons was 111 s. No manipulation of the robotic arms was required to perform the procedure. Aortic occlusion was achieved rapidly with REBOA. Ability to achieve prompt aortic control was not associated with surgical experience or prior familiarity with the REBOA device. Prophylactic femoral access and preparation of supplies facilitates prompt placement of the occlusion balloon. REBOA should be considered as a viable alternative to open laparotomy for temporary hemorrhage control during robotic surgery.

Background While benefits of greenness to health have been reported, findings specific to child respiratory health are inconsistent. Methods We utilized a prospective birth cohort followed from birth to age 7 years (n = 617). Residential surrounding greenness was quantified via Normalized Difference Vegetation Index (NDVI) within 200, 400, and 800 m distances from geocoded home addresses at birth, age 7 years, and across childhood. Respiratory health outcomes were assessed at age 7 years, including asthma and lung function [percent predicted forced expiratory volume in the first second (%FEV1), percent predicted forced vital capacity (%FVC), and percent predicted ratio of forced expiratory volume in the first second to forced vital capacity (%FEV1/FVC)]. We assessed associations using linear and logistic regression models adjusted for community deprivation, household income, and traffic-related air pollution. We tested for effect measure modification by atopic status. Results We noted evidence of positive confounding as inverse associations were attenuated upon adjustment in the multivariable models. We found evidence of effect measure modification of NDVI and asthma within 400 m at age 7 years by atopic status (p = 0.04), whereby children sensitized to common allergens were more likely to develop asthma as exposure to greenness increased (OR = 1.3, 95% CI: 0.9, 2.0) versus children not sensitized to common allergens (OR = 0.8, 95% CI: 0.5, 1.2). We found consistently positive associations between NDVI and %FEV1 and %FVC which similarly evidenced positive confounding upon adjustment. In the adjusted regression models, NDVI at 7 years of age was associated with %FEV1 (200 m: β = 2.1, 95% CI: 0.1, 3.3; 400 m: β = 1.6, 95% CI: 0.3, 2.9) and %FVC (200 m: β = 1.8, 95% CI: 0.7, 3.0; 400 m: β = 1.6, 95% CI: 0.3, 2.8; 800 m: β = 1.5, 95% CI: 0.1, 2.8). Adjusted results for %FEV1/FVC were non-significant except exposure at birth in the 400 m buffer (β = 0.81, 95% CI: 0.1, 1.5). We found no evidence of effect measure modification of NDVI by atopic status for objective measures of lung function. Conclusion Sensitivity to allergens may modify the effect of greenness on risk for asthma in children but greenness is likely beneficial for concurrent lung function regardless of allergic status.

Improved understanding of perinatal psychoneuroimmunology is needed, particularly to combat the high rates of maternal and infant mortality witnessed among Black Americans. We compared the success of recruitment by advertisement, in person, or by phone during the course of a prospective cohort study of perinatal psychoneuroimmunology among Black American women. Over 24 months, 363 women were assessed and 96 were enrolled. Women recruited by phone were less likely to complete full screening than women recruited by advertisement (OR = 0.32, p < 0.01) or in person (OR = 0.19, p < 0.01). Women recruited by advertisement were less likely to complete full screening than women recruited in person (OR = 0.60, p = 0.05). Odds of unsuccessful contact were 13.2 and 11.5 times greater among women recruited by phone versus by advertisement or in person, respectively (p values ≤ 0.01). Women recruited by advertisement and in person showed similar odds of unsuccessful contact (OR = 0.87, p = 0.76). Odds of screening decline were similar following recruitment in person or by phone when contact was successful (OR = 0.85, p = 0.76). Focusing on eligible women (n = 142), those recruited in person were significantly less likely to enroll than those recruited by advertisement (OR = 0.28, p < 0.01; Fig. 4). Considering all women (n = 363), odds of enrollment did not significantly differ among the recruitment groups (p values ≥ 0.09). Most (93.8%) enrolled women consented to biological specimen banking. Findings from this brief report provide a starting point for perinatal scientists to critically consider not only how to maximize research efforts but also how research team actions may perpetuate or assuage the research mistrust introduced by long-standing social inequities.

Ischemic myocardial disease is a major cause of death among humans worldwide; it results in scarring and pallor of the myocardium and triggers an inflammatory response that contributes to impaired left ventricular function. This response includes and is evidenced by the production of several inflammatory cytokines including TNFα, IL1β, IL4, IFNγ, IL10 and IL6. In the current study, myocardial infarcts were induced in 6 mo old male castrated sheep by ligation of the left circumflex obtuse marginal arteries (OM 1 and 2). MRI was used to measure parameters of left ventricular function that include EDV, ESV, EF, SVI, dp/dt max and dp/dt min at baseline and at 4 wk and 3 mo after infarct induction. We also measured serum concentrations of an array of cytokines. Postmortem histologic findings corroborate the existence of left ventricular myocardial injury and deterioration. Our data show a correlation between serum cytokine concentrations and the development of myocardial damage and left ventricular functional compromise.

2017-2018 Belmont Forum and BiodivERsA joint call for research proposals, under the BiodivScen ERA-Net COFUND programme, and with the funding organisations AEI, NWO, ECCyT and NSF Funding information, Allen-Perkins A, Magrach A, Dainese M, Garibaldi LA, Kleijn D, Rader R, Reilly JR, Winfree R, Lundin O, McGrady CM, Brittain C, Biddinger DJ, Artz DR, Elle E, Hoffman G, Ellis JD, Daniels J, Gibbs J, Campbell JW, Brokaw J, Wilson JK, Mason K, Ward KL, Gundersen KB, Bobiwash K, Gut L, Rowe LM, Boyle NK, Williams NM, Joshi NK, Rothwell N, Gillespie RL, Isaacs R, Fleischer SJ, Peterson SS, Rao S, Pitts-Singer TL, Fijen T, Boreux V, Rundlöf M, Viana BF, Klein AM, Smith HG, Bommarco R, Carvalheiro LG, Ricketts TH, Ghazoul J, Krishnan S, Benjamin FE, Loureiro J, Castro S, Raine NE, de Groot GA, Horgan FG, Hipólito J, Smagghe G, Meeus I, Eeraerts M, Potts SG, Kremen C, García D, Miñarro M, Crowder DW, Pisanty G, Mandelik Y, Vereecken NJ, Leclercq N, Weekers T, Lindstrom SAM, Stanley DA, Zaragoza-Trello C, Nicholson CC, Scheper J, Rad C, Marks EAN, Mota L, Danforth B, Park M, Bezerra ADM, Freitas BM, Mallinger RE, Oliveira da Silva F, Willcox B, Ramos DL, D da Silva E Silva F, Lázaro A, Alomar D, González-Estévez MA, Taki H, Cariveau DP, Garratt MPD, Nabaes Jodar DN, Stewart RIA, Ariza D, Pisman M, Lichtenberg EM, Schüepp C, Herzog F, Entling MH, Dupont YL, Michener CD, Daily GC, Ehrlich PR, Burns KLW, Vilà M, Robson A, Howlett B, Blechschmidt L, Jauker F, Schwarzbach F, Nesper M, Diekötter T, Wolters V, Castro H, Gaspar H, Nault BA, Badenhausser I, Petersen JD, Tscharntke T, Bretagnolle V, Willis Chan DS, Chacoff N, Andersson GKS, Jha S, Colville JF, Veldtman R, Coutinho J, Bianchi FJJA, Sutter L, Albrecht M, Jeanneret P, Zou Y, Averill AL, Saez A, Sciligo AR, Vergara CH, Bloom EH, Oeller E, Badano EI, Loeb GM, Grab H, Ekroos J, Gagic V, Cunningham SA, Åström J, Cavigliasso P, Trillo A, Classen A, Mauchline AL, Montero-Castaño A, Wilby A, Woodcock BA, Sidhu CS, Steffan-Dewenter I, Vogiatzakis IN, Herrera JM, Otieno M, Gikungu MW, Cusser SJ, Nauss T, Nilsson L, Knapp J, Ortega-Marcos JJ, González JA, Osborne JL, Blanche R, Shaw RF, Hevia V, Stout J, Arthur AD, Blochtein B, Szentgyorgyi H, Li J, Mayfield MM, Woyciechowski M, Nunes-Silva P, Halinski de Oliveira R, Henry S, Simmons BI, Dalsgaard B, Hansen K, Sritongchuay T, O'Reilly AD, Chamorro García FJ, Nates Parra G, Magalhães Pigozo C, Bartomeus I