Search

The laboratory rat emerges as a useful tool for studying the interaction between the host and its microbiome. To advance principles relevant to the human microbiome, we systematically investigated and defined a multi-tissue full lifespan microbial biogeography for healthy Fischer 344 rats. Microbial community profiling data was extracted and integrated with host transcriptomic data from the Sequencing Quality Control (SEQC) consortium. Unsupervised machine learning, Spearman’s correlation, taxonomic diversity, and abundance analyses were performed to determine and characterize the rat microbial biogeography and the identification of four inter-tissue microbial heterogeneity patterns (P1-P4). The 11 body habitats harbor a greater diversity of microbes than previously suspected. Lactic acid bacteria (LAB) abundances progressively declined in lungs from breastfeed newborn to adolescence/adult and was below detectable levels in elderly rats. LAB’s presence and levels in lungs were further evaluated by PCR in the two validation datasets. The lung, testes, thymus, kidney, adrenal, and muscle niches were found to have age-dependent alterations in microbial abundance. P1 is dominated by lung samples. P2 contains the largest sample size and is enriched for environmental species. Liver and muscle samples were mostly classified into P3. Archaea species were exclusively enriched in P4. The 357 pattern-specific microbial signatures were positively correlated with host genes in cell migration and proliferation (P1), DNA damage repair and synaptic transmissions (P2), as well as DNA transcription and cell cycle in P3. Our study established a link between metabolic properties of LAB with lung microbiota maturation and development. Breastfeeding and environmental exposure influence microbiome composition and host health and longevity. The inferred rat microbial biogeography and pattern-specific microbial signatures would be useful for microbiome therapeutic approaches to human health and good quality of life.Graphical Abstract

Firearm injury is a significant public health concern among youth living in the United States. Youth with exposure to violence (ETV) are more susceptible to carrying and using a firearm. Few researchers, however, have examined psychological mechanisms undergirding the association between ETV and firearm aggression. Retaliatory attitudes have been discussed as a potential mediator linking ETV with firearm aggression. Moreover, organized activity participation may disrupt direct and indirect pathways connecting ETV to firearm aggression. We tested: (a) the mediating role of retaliatory attitudes in the ETV-firearm aggression link, and (b) the moderating role of organized activity participation among 570 youth with past year illicit drug use and seeking emerging department care in an urban emergency department (ages 14-24; 58.8% males). Using multigroup path analysis, ETV indirectly influenced firearm aggression through retaliatory attitudes for youth not involved organized activities. Organized activities also buffered the association between retaliatory attitudes (mediator) and firearm aggression (outcome). Organized activities may, therefore, prevent firearm aggression by reducing retaliatory attitudes among youth contending with ETV. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Introduction /Objectives: The objectives were to conduct a survey of cardiologists on their recent experiences with cats that have dilated cardiomyopathy (DCM), and to retrospectively review individual cases of feline DCM. Animals, Materials and Methods Part One: A survey was distributed to cardiologists with questions regarding caseload and clinical management of cats with DCM diagnosed over the past two years. Part Two: Cardiologists completing the survey were invited to submit data from cats recently diagnosed with DCM. Data on signalment, clinical signs, diet, echocardiographic measurements, and outcome were recorded. Results Part One: From 52 completed surveys, many cardiologists responded that measuring and supplementing taurine and recommending a diet change in cats with DCM are common practices. Few (15%) cardiologists reported an increase in number of feline DCM cases over the past two years, although some had cases that improved even if taurine deficiency was not present. Part Two: Twenty of 37 (54%) cats ate low pea/lentil (low PL) diets and 14/37 (38%) ate high pea/lentil (high PL) diets at the time of diagnosis; three had incomplete diet information. Two of 13 cats (15%) in which taurine was measured had levels below the reference range. After adjusting for other variables, cats eating high PL diets that changed diets post-diagnosis had a significantly longer survival time compared to cats eating high PL diets that did not change diets post-diagnosis (P=0.025). Conclusions Additional research is warranted to determine whether there could be a possible association between diet and DCM in cats.

Background Sex differences in addiction have been described in humans and animal models. A key factor that influences addiction in both males and females is adolescent experience. Adolescence is associated with higher vulnerability to substance use disorders, and male rodents subjected to adolescent social isolation (SI) stress form stronger preferences for drugs of abuse in adulthood. However, little is known about how females respond to SI, and few studies have investigated the transcriptional changes induced by SI in the brain’s reward circuitry. Methods We tested the hypothesis that SI alters the transcriptome in a persistent and sex-specific manner in prefrontal cortex, nucleus accumbens, and ventral tegmental area. Mice were isolated or group housed from postnatal day P22 to P42, then group housed until ∼P90. Transcriptome-wide changes were investigated by RNA sequencing after acute or chronic cocaine or saline administration. Results We found that SI disrupts sex-specific transcriptional responses to cocaine and reduces sex differences in gene expression across all three brain regions. Furthermore, SI induces gene expression profiles in males that more closely resemble group-housed females, suggesting that SI “feminizes” the male transcriptome. Coexpression analysis reveals that such disruption of sex differences in gene expression alters sex-specific gene networks and identifies potential sex-specific key drivers of these transcriptional changes. Conclusions Together, these data show that SI has region-specific effects on sex-specific transcriptional responses to cocaine and provide a better understanding of reward-associated transcription that differs in males and females.

Objective Mobile technologies allow for accessible and cost-effective health monitoring and intervention delivery. Despite these advantages, mobile health (mHealth) engagement is often insufficient. While monetary incentives may increase engagement, they can backfire, dampening intrinsic motivations and undermining intervention scalability. Theories from psychology and behavioral economics suggest useful nonmonetary strategies for promoting engagement; however, examinations of the applicability of these strategies to mHealth engagement are lacking. This proof-of-concept study evaluates the translation of theoretically-grounded engagement strategies into mHealth, by testing their potential utility in promoting daily self-reporting. Method A microrandomized trial (MRT) was conducted with adolescents and emerging adults with past-month substance use. Participants were randomized multiple times daily to receive theoretically-grounded strategies, namely reciprocity (the delivery of inspirational quote prior to self-reporting window) and nonmonetary reinforcers (e.g., the delivery of meme/gif following self-reporting completion) to improve proximal engagement in daily mHealth self-reporting. Results Daily self-reporting rates (62.3%; n = 68) were slightly lower than prior literature, albeit with much lower financial incentives. The utility of specific strategies was found to depend on contextual factors pertaining to the individual's receptivity and risk for disengagement. For example, the effect of reciprocity significantly varied depending on whether this strategy was employed (vs. not employed) during the weekend. The nonmonetary reinforcement strategy resulted in different outcomes when operationalized in various ways. Conclusions While the results support the translation of the reciprocity strategy into this mHealth setting, the translation of nonmonetary reinforcement requires further consideration prior to inclusion in a full scale MRT. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Unmaintained vacant land in urban areas is associated with a number of negative outcomes for residents of urban areas, including mental and physical health, safety, and quality of life. Community programs which promote land parcel maintenance in urban neighborhoods have been found to reverse some of the effects that unmaintained land has on nearby residents. We explored how land parcel maintenance is associated with mental health outcomes using data collected in Flint, MI in 2017–2018. Trained observers assessed the maintenance of approximately 7200 land parcels and surveyed 691 residents (57% Female, 53% Black, M age = 51). We aggregated resident and parcel rating data to 463 street segments and compared three structural equation models (SEM) to estimate the mediating effects of fear of crime on the association of parcel qualities on mental distress for residents. We found that fear of crime mediated the association between parcel maintenance values and mental distress indicating that poor maintenance predicted more fear of crime which was associated with mental distress. Our findings add to our understanding about the mechanism by which vacant lot improvements may operate to enhance psychological well-being of residents who live on streets with vacant and unkept lots.

The objective of this study was to assess parents’ firearm storage behaviors during the COVID-19 pandemic and characterize reasons why some parents made their firearms more accessible during this time. In June-July 2020, the study team conducted the FACTS National Survey—a cross-sectional, web-based, survey of 2,924 parents and their teens (ages14–18) regarding firearm-related practices. We weighted descriptive analyses to be nationally representative of parents of teens in the United States. We utilized qualitative thematic analysis to identify parents’ reasons for making firearms more accessible. Five percent of firearm-owning parents of teens reported making their firearms more accessible during the beginning of the COVID-19 pandemic. Reasons why parents increased the ease of firearm access included: (1) Increased civil unrest and riots; (2) Threat of home invasion and/or crime victimization; (3) Fear of panic and the unknown; and (4) Easier access and greater protection, threat unspecified. Some parents—largely motivated by fear—chose to store firearms in a more accessible manner during the beginning of the COVID-19 pandemic to protect their family against possible external threats. Understanding the fear that motivates parents’ decisions regarding storage practices might aid interventions focused on harm reduction and safer storage.

Firearms are the leading cause of death for high-school age teens. To inform prevention efforts, we characterize the prevalence of healthcare provider (HCP) counseling of caregivers of teens around firearm safety, safety conversation elements, and caregiver receptivity towards counseling. A cross-sectional web survey (6/24/2020-7/22/2020) was conducted among caregivers (n = 2924) of teens (age:14-18). Weights were applied to generate nationally representative estimates. Bivariate analyses and multivariate regressions were examined. Among respondents, 56.0% were women, 75.1% were non-Hispanic White, and mean (SD) age was 47.4. Firearm safety was the least discussed topic among caregivers reporting their teen received HCP preventative counseling (14.9%). For caregivers receiving counseling, the most common issues discussed were household firearms screening (75.7%); storing firearms locked (66.8%); and storing firearms unloaded (53.0%). Only 24.6% of caregivers indicated firearm safety was an important issue for teen HCPs to discuss and only 21.9% trusted teen HCPs to counsel about firearm safety. Female caregivers (aOR = 1.86;95%CI = 1.25-2.78), those trusting their teen's HCP to counsel on firearm safety (aOR = 9.63;95%CI = 6.37-14.56), and those who received teen HCP firearm safety counseling (aOR = 5.14;95%CI = 3.02-8.72) were more likely to favor firearm safety counseling. Caregivers of teens with prior firearm safety training (aOR = 0.50;95%CI = 0.31-0.80) were less likely to agree that firearm safety was an important preventative health topic. In conclusion, few caregivers receive preventive counseling on firearm safety from their teen's HCP, with trust a key barrier to effective intervention delivery. Future research, in addition to understanding barriers and establishing effective strategies to increase safety practices, should focus on increasing provider counseling competency.

SARS-CoV-2 has had an unprecedented impact on human health and highlights the need for genomic epidemiology studies to increase our understanding of the evolution and spread of pathogens and to inform policy decisions. Most efforts have focused on international or country-wide transmission, which are unable to highlight state-wide trends. We sequenced virus genomes from over 22,000 patients tested at Mayo Clinic Laboratories between 2020-2022 and leveraged detailed patient metadata to describe county-to-county spread in Minnesota. Our findings indicate that spread in the state was mostly dominated by viruses from Hennepin County, which contains the largest metropolis. For many counties, we found that state government restrictions eventually led to a decrease in the diversity of circulating viruses from other counties and that their complete removal in May of 2021 saw a drastic revert to levels at or greater than those observed during the months before. We also linked over 14,000 genomes with patient risk characteristics and infection-related phenotypes from the Mayo Clinic electronic health record. We found that the genetic relationship of Omicron viruses was structured by clinical outcomes when stratifying by patient risk factor and variant of concern. However, we were unable to identify nucleotide variants that drove this association.

Parents of children with autism spectrum disorder (ASD) may be at greater risk for developing antivaccine beliefs that lead to vaccine delays and/or refusals for their children. We investigated current parental vaccine hesitancy, parents’ beliefs about causes of children’s developmental delays, and children’s vaccination histories among parents of children with ASD or non-ASD developmental delays. Data were analyzed from 89/511 parents (17.4%) who completed the Parent Attitudes About Childhood Vaccines questionnaire and the Revised Illness Perception Questionnaire; 46.1% had childhood vaccination records available. Overall, 21/89 (23.6%, 95% confidence interval [CI]: 15.0-34.0) of parents were vaccine hesitant (ASD n = 19/21 [90.5%], non-ASD n = 2/21 [9.5%]). Parents of children with ASD were significantly more likely to agree with “toxins in vaccines” as a cause of their child’s developmental delays (28.4% vs 5.0%, P = .034). The odds of being vaccine hesitant were 11.9 times (95% CI 2.9-48.0) greater among parents who agreed versus disagreed that toxins in vaccines caused their children’s developmental delays. Rates of prior vaccine receipt did not differ between hesitant and nonhesitant groups.

Community rapid response may reduce opioid overdose harms, but is hindered by the lack of timely data. To address this need, we created and evaluated the Michigan system for opioid overdose surveillance (SOS). SOS integrates suspected fatal overdose data from Medical Examiners (MEs), and suspected non-fatal overdoses (proxied by naloxone administration) from the Michigan Emergency Medical Services (EMS) into a web-based dashboard that was developed with stakeholder feedback. Authorised stakeholders can view approximate incident locations and automated spatiotemporal data summaries, while the general public can view county-level summaries. Following Centers for Disease Control and Prevention (CDC) surveillance system evaluation guidelines, we assessed simplicity, flexibility, data quality, acceptability, sensitivity, positive value positive (PVP), representativeness, timeliness and stability of SOS. Data are usually integrated into SOS 1-day postincident, and the interface is updated weekly for debugging and new feature addition, suggesting high timeliness, stability and flexibility. Regarding representativeness, SOS data cover 100% of EMS-based naloxone adminstrations in Michigan, and receives suspected fatal overdoses from MEs covering 79.1% of Michigan’s population, but misses those receiving naloxone from non-EMS. PVP of the suspected fatal overdose indicator is nearly 80% across MEs. Because SOS uses pre-existing data, added burden on MEs/EMS is minimal, leading to high acceptability; there are over 300 authorised SOS stakeholders (~6 new registrations/week) as of this writing, suggesting high user acceptability. Using a collaborative, cross-sector approach we created a timely opioid overdose surveillance system that is flexible, acceptable, and is reasonably accurate and complete. Lessons learnt can aid other jurisdictions in creating analogous systems.

OBJECTIVE: Women with ovarian cancer who have a pathogenic germline variant in BRCA1 or BRCA2 (BRCA) have been shown to have better 5-year survival after diagnosis than women who are BRCA-wildtype (non-carriers). Modifiable lifestyle factors, including smoking, physical activity and body mass index (BMI) have previously been associated with ovarian cancer survival; however, it is unknown whether these associations differ by germline BRCA status. METHODS: We investigated measures of lifestyle prior to diagnosis in two cohorts of Australian women with invasive epithelial ovarian cancer, using Cox proportional hazards regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In the combined studies (n=1,923), there was little association between physical activity, BMI or alcohol intake and survival, and no difference by BRCA status. However, the association between current smoking status before diagnosis and poorer survival was stronger for BRCA variant carriers (HR 1.98; 95% CI 1.20-3.27) than non-carriers (HR 1.18; 95% CI 0.96-1.46; p-interaction 0.02). We saw a similar differential association with smoking when we pooled results from two additional cohorts from the USA and UK (n=2,120). Combining the results from all four studies gave a pooled-HR of 1.94 (95% CI 1.28-2.94) for current smoking among BRCA variant carriers compared to 1.08 (0.90-1.29) for non-carriers. CONCLUSIONS: Our results suggest that the adverse effect of smoking on survival may be stronger for women with a BRCA variant than those without. Thus, while smoking cessation may improve outcomes for all women with ovarian cancer, it might provide a greater benefit for BRCA variant carriers.

Background and objectives Total laryngectomy in thyroid cancer is controversial. Functional and oncologic outcomes are needed to inform surgical indications in this population. Methods A retrospective cohort study was performed at a tertiary referral center from 1997 to 2018 to identify patients with a diagnosis of thyroid carcinoma who underwent total laryngectomy. Complications, survival outcomes, and functional outcomes were analyzed. Results Thirty patients met the inclusion criteria. The mean age was 62 years (range, 30-88 years) and the male-to-female ratio was 1:2.75. The most common diagnosis was well-differentiated thyroid cancer (53.3%), followed by poorly differentiated (30%) and anaplastic (16.7%). Total laryngectomy was performed with a 10% rate of Clavien-Dindo Grade III-V complications. The median overall survival was 40 months (range, 1-237). Five-year overall survival was 39.5% and disease-specific survival was 51.1%. Locoregional control was achieved in 80.0% of patients. Twelve months postoperatively, 100% of surviving patients were taking oral intake and 86.4% had a self-reported functional voice. Conclusion Total laryngectomy for locally advanced thyroid cancer is safe and provides acceptable rates of locoregional control. While the risk of distant metastases remains high, advances in systemic therapy may justify aggressive local control strategies to improve the quality of life.

ObjectivesTo evaluate motivations for firearm possession among urban young adults and determine if differences emerge between parents and non-parents, and to identify if storage practices differed according to motivation for firearm possession and parenting status.MethodsWe used cross-sectional data among young adults seeking urban emergency department treatment at Hurley Medical Center between 2017 and 2018. Our analyses, completed in 2020, included 194 firearm-possessing young adults, 95 of whom were young parents.ResultsFirearm-possessing parents were more likely to have a firearm for protection, than for any other motivation, compared with firearm-possessing non-parents (OR: 2.38, 95% CI 1.06 to 5.46). A significant interaction between parenting status and motivation for possession indicated the association between protective motivations and locked storage was significantly different between parents and non-parents, whereby there was a decreased odds of locked storage among non-parents who were motivated to possess a firearm for protection compared with any other motivation, but this association did not exist for parents (interaction OR=10.57, pConclusionParental motivation for possessing a firearm most often lies in the desire to protect families. This motivation, however, does not necessitate unsafe storage.

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased mean pulmonary arterial pressure. Elevated plasma and lung concentrations of oxidized lipids, including 15-hydroxyeicosatetraenoic acid (15-HETE), have been demonstrated in patients with PAH and animal models. We previously demonstrated that feeding mice with 15-HETE is sufficient to induce pulmonary hypertension, but the mechanisms remain unknown. RNA sequencing data from the mouse lungs on 15-HETE diet revealed significant activation of pathways involved in both antigen processing and presentation and T cell–mediated cytotoxicity. Analysis of human microarray from patients with PAH also identified activation of identical pathways compared with controls. We show that in both 15-HETE–fed mice and patients with PAH, expression of the immunoproteasome subunit 5 is significantly increased, which was concomitant with an increase in the number of CD8/CD69 (cluster of differentiation 8 / cluster of differentiation 69) double-positive cells, as well as pulmonary arterial endothelial cell apoptosis in mice. Human pulmonary arterial endothelial cells cultured with 15-HETE were more prone to apoptosis when exposed to CD8 cells. Cultured intestinal epithelial cells secreted more oxidized lipids in response to 15-HETE, which is consistent with accumulation of circulating oxidized lipids in 15-HETE–fed mice. Administration of an apoA-I (apolipoprotein A-I) mimetic peptide, Tg6F (transgenic 6F), which is known to prevent accumulation of circulating oxidized lipids, not only inhibited pulmonary arterial endothelial cell apoptosis but also prevented and rescued 15-HETE–induced pulmonary hypertension in mice. In conclusion, our results suggest that (1) 15-HETE diet induces pulmonary hypertension by a mechanism that involves oxidized lipid-mediated T cell–dependent pulmonary arterial endothelial cell apoptosis and (2) Tg6F administration may be a novel therapy for treating PAH.

OBJECTIVE: Same day use of alcohol and cannabis is prevalent among emerging/young adults and increases the risk for negative consequences. Although motives for alcohol and cannabis use are well-documented, specific motives on co-use days are under-investigated. We examined differences in motives on single substance use (i.e., alcohol or cannabis) versus co-use days in a sample of primarily cannabis-using emerging/young adults. METHODS: Participants (N=97) aged 18–25 (M(age)=22.2) were recruited from an urban Emergency Department (55.7% female, 46.4% African American, 57.7% public assistance) for a prospective daily diary study about risk behaviors. Participants received prompts for 28 daily text message assessments (up to 2716 surveys possible) of substance use and motives (social, enhancement, coping, conformity). We divided use days into three groups: alcohol use only (n=126), cannabis use only (n=805), and co-use (n=237). Using fixed effects regression modeling, we fit models to estimate within-person effects of alcohol and cannabis motives on day type (alcohol/cannabis co-use versus single use). RESULTS: In adjusted models, greater cannabis-related enhancement and social motives were associated with increased likelihood of co-use days compared to cannabis-only days. In contrast, greater alcohol-related social motives were associated with co-use days versus alcohol-only days in unadjusted, but not in adjusted models. CONCLUSIONS: Findings suggest that cannabis use motives associated with increasing positive affect may be most compelling for those engaging in alcohol/cannabis use on a given day. Intervention programs for alcohol/cannabis use should address alcohol and cannabis use motives in relation to increasing positive affect and engaging in social situations.

Introduction Exposure to violence is a risk factor for firearm carriage. Youth exposed to violence also have difficulty envisioning positive future outcomes (e.g., educational outcomes), which can increase the likelihood of firearm carriage over time. Researchers, however, have not yet examined whether changes in exposure to violence over time can influence the developmental trajectories of firearm carriage. To address this gap, we (1) examined the longitudinal association between exposure to violence and firearm carriage (grades 9 to 12) and then (2) examined whether changes in future expectations mediated this longitudinal association. Method The longitudinal association between exposure to violence and firearm carriage through future expectations was examined among 850 adolescents from the Flint Adolescent Study. Participants were recruited from four high schools in a midwestern city in the United States. Parallel latent growth models and latent growth mediation models were estimated. Results A positive association was observed between the rate of change in exposure to violence and firearm carriage. Exposure to violence also indirectly increased the risk for firearm carriage over time by decreasing future expectation in the 9th grade. Conclusions Our results support the idea that helping youth develop positive attitude about educational success may help reduce firearm carriage. Increasing positive expectations about future may help prevent firearm carriage within the context of violence exposure.

Pediatric residents report lack of confidence in providing firearm safety anticipatory guidance. A self-paced online curriculum, including video demonstration of firearms, safe storage options, and counseling methods for families improved resident self-efficacy, confidence, and knowledge surrounding firearm injury prevention counseling.

Fears persist despite compelling evidence refuting associations between vaccines and autism spectrum disorder (ASD). We compared vaccine hesitancy (VH) and beliefs about illness causes among parents of children in four groups: ASD, non-ASD developmental disorders, rheumatologic conditions, and the general pediatric population. VH was 19.9% overall; parents of children with ASD reported highest VH rates (29.5%) and more frequently attributed ASD to toxins in vaccines (28.9% vs. 15.7%, p=0.004). The odds of VH were increased among parents who attributed their child's condition to diet or eating habits (aOR 4.2; 95% CI: 1.6, 11.2) and toxins found in vaccines (aOR 20, 95% CI: 7.1, 55.9). Parents who attributed the condition to chance or bad luck were less likely to be vaccine hesitant (aOR 0.1; 95% CI: 0.03, 0.5).

The focus of the current investigation is to examine the temporal relationship of gambling onset and alcohol, tobacco, and cannabis initiation in adolescents and young adults (M age = 20.3 years) by examining the prevalence and pattern of onset for each substance and gambling pairing and the associated risk between gambling and each substance use. Data were drawn from the multiwave Missouri Family Study (n = 1,349) of African American (AA; n = 450) and White families (n = 317) enriched for risk for alcohol use disorder and includes those who were assessed for gambling behaviors and problems: AA (360 males, 390 females) and White (287 males, 312 females). Findings indicated racial differences in the overall prevalence of gambling behaviors and substance use as well as patterns of initiation-particularly within gambling/alcohol and gambling/tobacco for males. Survival models revealed some similarities as well as differences across race and gender groups in associations of gambling with initiation of substances, as well as substances with initiation of gambling. Alcohol use (AA males only) and cannabis use (AA males and White females) elevated the hazards of initiating gambling. In contrast, gambling significantly elevated the hazards of initiation alcohol across 3 of 4 groups and of cannabis use in AA males only. The results highlight some overlapping as well as distinct risk factors for both gambling and substance use initiation in this cohort enriched for vulnerability to alcohol use disorder (AUD). These findings have implications for integrating gambling prevention into existing substance use prevention and intervention efforts-particularly but not exclusively for young AA males. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Social buffering occurs when the presence of a companion attenuates the physiological and/or behavioral effects of a stressful or fear-provoking event. It represents a way in which social interactions can immediately and potently modulate behavior. As such, social buffering is one mechanism by which strong social support increases resilience to mental illness. Although the behavioral and neuroendocrine impacts of social buffering are well studied in multiple species, including humans, the neuronal underpinnings of this behavioral phenomenon remain largely unexplored. Previous work has shown that the infralimbic prefrontal cortex (IL-PFC) is important for processing social information and, in separate studies, for modulating fear and anxiety. Thus, we hypothesized that socially active cells within the IL-PFC may integrate social information to modulate fear responsivity. To test this hypothesis, we employed social buffering paradigms in male and female mice. Similar to prior studies in rats, we found that the presence of a cagemate reduced freezing in fear- and anxiety-provoking contexts. In accordance with previous work, we demonstrated that interaction with a novel or familiar conspecific induces activity in the IL-PFC as evidenced by increased immediate early gene (IEG) expression. We then utilized an activity-dependent tagging murine line, the ArcCreER(T2) mice, to express channelrhodopsin (ChR2) in neurons active during the social encoding of a new cagemate. We found that optogenetic reactivation of these socially active neuronal ensembles phenocopied the effects of cagemate presence in male and female mice in learned and innate fear contexts without being inherently rewarding or altering locomotion. These data suggest that a social neural ensemble within the IL-PFC may contribute to social buffering of fear. These neurons may represent a novel therapeutic target for fear and anxiety disorders.

In mammalian cells, much of signal transduction is mediated by weak protein-protein interactions between globular peptide-binding domains (PBDs) and unstructured peptidic motifs in partner proteins. The number and diversity of these PBDs (over 1,800 are known), their low binding affinities and the sensitivity of binding properties to minor sequence variation represent a substantial challenge to experimental and computational analysis of PBD specificity and the networks PBDs create. Here, we introduce a bespoke machine-learning approach, hierarchical statistical mechanical modeling (HSM), capable of accurately predicting the affinities of PBD-peptide interactions across multiple protein families. By synthesizing biophysical priors within a modern machine-learning framework, HSM outperforms existing computational methods and high-throughput experimental assays. HSM models are interpretable in familiar biophysical terms at three spatial scales: the energetics of protein-peptide binding, the multidentate organization of protein-protein interactions and the global architecture of signaling networks.

The Irish Sea is an important area for Norway Lobster Nephrops norvegicus fisheries, which are the most valuable fishing resource in the UK. Norway lobster are known to ingest microplastic pollution present in the sediment and have displayed reduced body mass when exposed to microplastic pollution. Here, we identified microplastic pollution in the Irish Sea fishing grounds through analysis of 24 sediment samples from four sites of differing proximity to the Western Irish Sea Gyre in both 2016 and 2019. We used µFTIR spectroscopy to identify seven polymer types, and a total of 77 microplastics consisting of fibres and fragments. The mean microplastics per gram of sediment ranged from 0.13 to 0.49 and 0 to 1.17 MP/g in 2016 and 2019, respectively. There were no differences in the microplastic counts across years, and there was no correlation of microplastic counts with proximity to the Western Irish Sea Gyre. Considering the consistently high microplastic abundance found in the Irish Sea, and the propensity of N. norvegicus to ingest and be negatively impacted by them, we suggest microplastic pollution levels in the Irish Sea may have adverse impacts on N. norvegicus and negative implications for fishery sustainability in the future.

Funder: Funding details are provided in the Supplementary Material, Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, ���select and shrink for summary statistics��� (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28���1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08���1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30���1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

PURPOSE OF REVIEW: Suicide is the second leading cause of death among Black youth ages 10–19 years. Between 1991 and 2017, rates of suicide among Black youth have been increasing faster than rates among any other race/ethnic group. There are many factors that may explain this increase, with gambling being suggested as one such potential risk factor. This review examines the association between gambling and suicide behaviors, and how these associations may vary between Black and White youth and young adults. The current review examines these associations using data from the Missouri Family Study (MOFAM). RECENT FINDINGS: Recent findings have revealed distinct patterns of substance use initiation and gambling behaviors between Black youth and White youth. While strong links between gambling and suicide behaviors have also been reported, whether the associations were consistent across race/ethnicity groups was not investigated, nor in these cross-sectional analyses was it possible to determine whether the gambling behaviors preceded or followed suicidality. Thus, there is a need to investigate whether there are differences in the associations of gambling and suicide behaviors at the race/ethnicity level in tandem with data that examine the sequence of the behaviors. The current report focuses on racial/ethnic differences using data that allow for sequencing the occurrence of the behaviors via the age of first gambling experience, and of first suicidal symptom, to better distinguish the nature of the association. SUMMARY: The current findings revealed that gambling initiation predicted suicide ideation among Black youth, while no significant association was found among White youth. This is of major public health concern, given the rising rates of suicide among Black youth, and the increased availability of gambling. The report did not find a link between gambling and suicide attempts. Culturally tailored interventions should be considered among schools, families, and clinicians/providers, to highlight the risk of adolescent gambling, particularly among Black youth.

Same-day alcohol and cannabis use is relatively common in adolescents and young adults, constituting a higher-risk behavior relative to single-substance use. However, the association between quantity of alcohol and cannabis use on co-use days is understudied. We examined the association between the quantity of alcohol and same-day cannabis use with a multilevel regression analysis in a sample of youth (16-24 years old) with risky alcohol use. Participants reported one or more days of alcohol and cannabis over the past month (N = 468). Quantity of cannabis use was highest on heavy drinking days [M = 0.91 grams, SD = 0.68] followed by moderate drinking days (M = 0.78 grams, SD = 0.63), and lowest on days without alcohol use (M = 0.74 grams, SD = 0.64, p < 0.001). In multilevel modeling analyses, adjusted for clustering within individuals, greater quantity of drinking on a given day was associated with greater cannabis use (estimate = 0.03, p < 0.001). When using alcohol and cannabis on the same day, greater alcohol use was associated with greater cannabis use. Preventing days of heavy use of multiple substances, particularly among at-risk drinkers, may complement interventions addressing co-use generally to prevent substance-related consequences.

The classical two-arm randomized clinical trial (RCT) is designed to test the efficacy or effectiveness of an intervention, which may consist of one or more components. However, this approach does not enable the investigator to obtain information that is important in intervention development, such as which individual components of the intervention are efficacious, which are not and possibly should be removed, and whether any components interact. The Multiphase Optimization Strategy (MOST) is a new framework for development, optimization, and evaluation of interventions. MOST includes the RCT for purposes of evaluation, but inserts a phase of research before the RCT aimed at intervention optimization. The optimization phase requires one or more separate trials similar in scope to an RCT, but employing a different experimental design. The design of the optimization trial is selected strategically so as to maximize the amount of scientific information gained using the available resources. One consideration in selecting this experimental design is the type of intervention to be optimized. If a fixed intervention, i.e. one in which the same intervention content and intensity is provided to all participants, is to be optimized, a factorial experiment is often appropriate. If an adaptive intervention, i.e. one in which intervention content or intensity is varied in a principled manner, is to be optimized, a sequential multiple-assignment randomized trial (SMART) is often a good choice. The objective of this article is to describe MOST and the scientific rationale for its use; describe two current applications of MOST in emergency medicine research, one using a factorial experiment and the other using a SMART; and discuss funding strategies and potential future applications in studying the care of individuals with acute illness, injury, or behavioral disorders.

Background and objectivesYouth violence is an alarming public health problem, yet, violence screening and interventions are not systematically offered in primary care (PC). This paper describes data from a pilot effectiveness-implementation trial of an efficacious youth violence prevention programme (SafERteens).MethodsThe study was conducted in two PC clinics: a university-affiliated satellite clinic and a community health centre. In phase 1, we obtained stakeholder feedback to customise the SafERteens package and enrolled a comparison group of adolescents (age 14–18) seeking care in two clinics. In phase 2, clinical staff delivered the SafERteens-PC intervention with adolescents, which is a single, behavioural health therapy session delivered one-on-one from clinic providers to youth patients, followed by text message (TM) reminders. In phase 3, we assessed planned maintenance. All participants reported past-year violent behaviour at intake and completed a 3-month follow-up assessment.ResultsBased on stakeholder interviews (n=13), we created a web-based SafERteens-PC programme package, including a three-item past-year violence screen, 30 min motivational interviewing-based brief intervention delivery tool, training videos and 2 months of TM boosters. We enrolled a comparison group (n=49) first, then an intervention group (n=61). Intervention delivery characteristics varied by clinic, including completion of intervention (75.9%; 62.5%), modality (100% delivered via telehealth; 60% via telehealth/40% in-person) and enrolment in TMs (81.8%; 55.0%); 91.8% completed the follow-up. Using an intention-to-treat approach, the intervention group showed significantly greater reductions in severe peer aggression (pConclusionsIf these challenges could be addressed, routine provision of behavioural health services for violence prevention in PC could have high impact on health outcomes for adolescents.

Narratives can have a powerful impact on our health-related beliefs, attitudes, and behaviors. The human papillomavirus (HPV) vaccine can protect against human papillomavirus that leads to different types of cancers. However, HPV vaccination rates are low. This study explored the effectiveness of a narrative-based interactive game about the HPV vaccines as a method to communicate knowledge and perhaps create behavioral outcomes. We developed a serious storytelling game called Vaccination Vacation inspired by personal narratives of individuals who were impacted by the HPV. We tested the game using a randomized control study of 99 adult participants and compared the HPV knowledge and vaccine beliefs of the Gamer Group (who played the game, n = 44) and the Reader group (who read a vaccine information sheet, n = 55). We also evaluated the usability of the game. In addition to high usability, the interactive game slightly impacted the beliefs about the HPV vaccine over standard delivery of vaccine information, especially among those who never received the HPV vaccine. We also observed some gender-based differences in perception towards usability and the likelihood of frequently playing the game. A narrative-based game could bring positive changes to players’ HPV-related health beliefs. The combination of more comprehensive HPV vaccine information with the narratives may produce a larger impact. Narrative-based games can be effectively used in other vaccine education interventions and warrant future research.

Platinum(II) compounds are a critical class of chemotherapeutic agents. Recent studies have highlighted the ability of a subset of Pt(II) compounds, including oxaliplatin but not cisplatin, to induce cytotoxicity via nucleolar stress rather than a canonical DNA damage response. In this study, influential properties of Pt(II) compounds were investigated using redistribution of nucleophosmin (NPM1) as a marker of nucleolar stress. NPM1 assays were coupled to calculated and measured properties such as compound size and hydrophobicity. The oxalate leaving group of oxaliplatin is not required for NPM1 redistribution. Interestingly, although changes in diaminocyclohexane (DACH) ligand ring size and aromaticity can be tolerated, ring orientation appears important for stress induction. The specificity of ligand requirements provides insight into the striking ability of only certain Pt(II) compounds to activate nucleolar processes.

Firearm injuries are the second-leading cause of death for US children and adolescents (ages 1–18). This analysis quantified the federal dollars granted to research for the leading US causes of death for this age group in 2008–17. Several federal data sources were queried. On average, in the study period, $88 million per year was granted to research motor vehicle crashes, the leading cause of death in this age group. Cancer, the third-leading cause of mortality, received $335 million per year. In contrast, $12 million—only thirty-two grants, averaging $597 in research dollars per death—went to firearm injury prevention research among children and adolescents. According to a regression analysis, funding for pediatric firearm injury prevention was only 3.3 percent of what would be predicted by mortality burden, and that level of funding resulted in fewer scientific articles than predicted. A thirtyfold increase in firearm injury research funding focused on this age group, or at least $37 million per year, is needed for research funding to be commensurate with the mortality burden.

We conducted a scoping review to determine the current state of knowledge and areas for advancements in research on the association of firearm laws with child and adolescent firearm-related outcomes. We queried Scopus, EMBASE, Pubmed, and CJ Abstracts for English language original empirical research articles on policies affecting child and adolescent firearm-related outcomes published between January 1, 1985 and July 1, 2018. Data were abstracted, and methodologic quality assessed. Twenty articles met inclusion criteria. Among the policies studied were child access prevention laws (12 studies) and minimum age restrictions for firearm purchase and possession (4 studies). Outside of child access prevention laws, which are associated with reductions in child and adolescent unintentional and firearm suicide deaths, there is, at best, equivocal evidence of policy effects. This area is understudied, particularly in regard to nonfatal firearm injuries, for which the lack of a national surveillance system hampers research efforts. Further rigorous firearm policy evaluations are needed.

Risk and protective factors for firearm assault (FA) have been established, but little is known about factor preceding transitions in FA behavior. We modeled covariate effects on individuals’ transitions in FA behavior (Yes/No) using inhomogeneous, continuous-time, Markov Chains. 3287 assessments were made across five initial biannual follow-ups, and two additional biannual follow-ups (an average of 2.2 years later) from a follow-on study; 2687 pairs of transitions were observed (2414 No-FA → No-FA; 89 No-FA → FA; 121 FA → No-FA; 63 FA → FA). Non-firearm peer violence (HR = 2.31, 95% CI [1.28,4.21]), firearm victimization (HR = 2.57, 95% CI [1.31,5.04]), and marijuana ASSIST sum (HR = 1.27, 95% CI [1.05,1.54]) all preceded transitions into FA, but not transitions out of FA. Delinquent peer associations both hastened transitions into FA (HR = 1.19, 95% CI [1.00,1.40]) and slowed transitions out of FA (HR = 0.84, 95% CI:[0.72,1.00]), with analogous findings regarding attitudes favoring retaliation. Efforts to prevent FA initiation should focus on those currently reporting firearm violence victimization, and on factors indicating an escalating delinquency trajectory (e.g. non-firearm violence, substance use), while programs focusing on peer influences and social norms may be effective at preventing FA regardless of current FA status.

Five teams of FACTS researchers conducted a series of rigorous scoping reviews of the existing published scientific literature from the fields of medicine, public health, psychology, behavioral health, and criminology from January of 1985 through April of 2018 utilizing the Preferred Reporting Items for Scoping Reviews (Tricco et al., Ann Intern Med 169:467–473, 2018) framework to guide the search strategy, study selection, data abstraction, and analysis process. These scoping reviews characterize the existing scientific literature in five key areas related to Firearm Injury Prevention among children and adolescents (age 0–17): (1) Adolescent Firearm Carriage; (2) Risk and Protective Factors for Firearm Injury; (3) Primary Prevention Initiatives; (4) Long-term consequences and secondary prevention of negative outcomes after a firearm injury; and, (5) Effects of existing law and policy interventions on pediatric firearm outcomes. In this special issue of the Journal of Behavioral Medicine, we present these five scoping review articles.

Intentional and unintentional firearm injury is the second leading cause of death for youth, underscoring the need for effective primary prevention approaches that focus on increasing safe storage by caregivers and decreasing handling/carriage among youth. This article describes the state of the science for prevention of firearm injuries among children and adolescents. We applied PRISMA guidelines to present results from a scoping review using PubMed, Scopus, CINAHL, and CJ Abstracts for original research articles published between January 1, 1985 and March 1, 2018 in the U.S. focusing on primary screening or interventions for primary prevention of pediatric firearm injuries. In total, 46 articles met inclusion criteria: safe storage (23), screening (2), firearm handling/carriage/use (21). Across school, healthcare, and community settings, few evidenced-based programs exist, and data on firearm safety technologies are lacking. Programs have generally not employed rigorous designs, and/or assessed behavioral (e.g., carriage) or injury-related firearm outcomes. Evidenced-based prevention programs are needed to mitigate firearm morbidity and mortality among youth.

The number of available donor organs limits lung transplantation, the only lifesaving therapy for the increasing population of patients with end-stage lung disease. A prevalent etiology of injury that renders lungs unacceptable for transplantation is gastric aspiration, a deleterious insult to the pulmonary epithelium. Currently, severely damaged donor lungs cannot be salvaged with existing devices or methods. Here we report the regeneration of severely damaged lungs repaired to meet transplantation criteria by utilizing an interventional cross-circulation platform in a clinically relevant swine model of gastric aspiration injury. Enabled by cross-circulation with a living swine, prolonged extracorporeal support of damaged lungs results in significant improvements in lung function, cellular regeneration, and the development of diagnostic tools for non-invasive organ evaluation and repair. We therefore propose that the use of an interventional cross-circulation platform could enable recovery of otherwise unsalvageable lungs and thus expand the donor organ pool., Gastric aspiration severely injures donor lungs, frequently making them unacceptable for transplantation. Here the authors show that an interventional cross-circulation platform enables the regeneration of severely damaged lungs in a swine model of gastric aspiration injury.

Parents are key to children’s health because they can influence children’s eating behavior and body image and can make health-related decisions for children. Despite their influence, research on parents’ opinions about parenting practices related to weight and eating is limited. Experimental vignettes examined parents’ perceptions of parent-child interactions around body image, eating, and weight loss. We manipulated vignette-child weight (healthy-weight, overweight) and communication tone (positive, negative, neutral) to assess their influence on parents’ perceptions. Parents (N=233, 27.5% fathers, 72.5% mothers) were randomly assigned to read one of six vignettes. When the vignette-child had overweight, parents were more likely to recommend seeking help for body image and that the vignette-parent should choose the restaurant food order. Parents were less opposed to commenting on the vignette-child’s weight when tone was positive. Parents were more likely to recommend weight-loss efforts that could be implemented by the family rather than those requiring professional assistance. This study is among the first to examine parents’ opinions about parenting practices related to weight and eating using an experimental design. Findings might inform future research and continued work on prevention and treatment applications to help align parents’ existing opinions about weight and eating with evidence-based health-promoting strategies.

OBJECTIVE: To examine the efficacious components of a computer-delivered brief intervention (CBI) for reducing marijuana use among adults presenting to a low-income urban emergency department (ED), which a prior report found to decrease marijuana use at a 6-month follow-up. METHOD: Participants were 237 ED patients reporting recent drug use (46% male; 54% African-American; mean age, 30.7) who were randomized to receive a CBI consisting of an interactive program guided by a virtual health counselor. The primary outcome was past 30-day marijuana use at 6-month follow-up assessed using the Timeline Follow-Back (TLFB). Intervention components related to change in marijuana use at 6 month follow-up examined in the current study included participant responses to items within five CBI domains that were rooted in motivational interviewing: goals for change, strengths, evoking-change (concerns about use and benefits of change), challenges, and tools for change. RESULTS: The evoking-change domain was related to significant reductions in marijuana use at 6 months (B=−2.91, SE=1.10, p

BACKGROUND Despite demonstrated effectiveness of child restraint systems (CRSs), use remains suboptimal. In this randomized pilot trial, we sought to determine the feasibility, acceptability, and potential efficacy of "Tiny Cargo, Big Deal" an ED-based intervention to promote guideline-concordant size-appropriate CRS use. METHODS Parents of children

The serotonin 1A receptor (5-HT1A) system has been extensively implicated in modulating mood and behavior. Notably, 5-HT1A levels in humans display remarkable variation, and differences in receptor levels have been linked with a variety of psychiatric disorders. Further, reduction of receptor levels by 30-50% in mice suggests that changes in receptor levels that model existing human variation are sufficient to drive behavioral alterations. As a result, genetic mechanisms that modulate human 5-HT1A levels may be important for explaining individual differences in mood and behavior, representing a potential source of psychiatric disease risk. One common genetic variant implicated in differential 5-HT1A levels is the G/C single nucleotide polymorphism (SNP) rs6295, located upstream of the human 5-HT1A gene. This SNP differentially binds the transcription factor, NUDR/Deaf1, leading to cell-type specific effects on transcription in vitro. To investigate the direct effects of this SNP in the heterogeneous cellular context of the brain, we generated humanized transgenic mice using a design that maximized the local transcriptional landscape of the human HTR1A gene while also controlling for effects of genomic insertion location. We integrated a 180 kb human bacteria artificial chromosome (BAC) transgene containing G- and C-alleles of rs6295 flanked by FRT or loxP sites. Subsequent deletion of each allele by Cre- or Flp-recombinase resulted in rs6295G and C alleles in the same genomic location. These alleles were bred onto a 5-HT1A null mouse such that the human BAC was the sole source of 5-HT1A in these mice. We generated three separate lines, two of which had detectable human 5-HT1A levels in the brain, although none displayed expression in the raphe. Of these, one line exhibited rs6295-dependent differences in 5-HT1A levels and differences in behavior, even though the overall levels were considerably lower than native expression levels. The line-dependent effect of rs6295 on protein levels and behavior may depend upon differences in background genetic factors or different insertion sites across each line. This work confirms that relatively subtle differences in 5-HT1A levels can contribute to differences in behavior and highlights the challenges of modeling human noncoding genetic variation in mice.

Summary The Drosophila intestine is an excellent system for elucidating mechanisms regulating stem cell behavior. Here we show that the septate junction (SJ) protein Neuroglian (Nrg) is expressed in intestinal stem cells (ISCs) and enteroblasts (EBs) within the fly intestine. SJs are not present between ISCs and EBs, suggesting Nrg plays a different role in this tissue. We reveal that Nrg is required for ISC proliferation in young flies, and depletion of Nrg from ISCs and EBs suppresses increased ISC proliferation in aged flies. Conversely, overexpression of Nrg in ISC and EBs promotes ISC proliferation, leading to an increase in cells expressing ISC/EB markers; in addition, we observe an increase in epidermal growth factor receptor (Egfr) activation. Genetic epistasis experiments reveal that Nrg acts upstream of Egfr to regulate ISC proliferation. As Nrg function is highly conserved in mammalian systems, our work characterizing the role of Nrg in the intestine has implications for the treatment of intestinal disorders that arise due to altered ISC behavior., Graphical abstract, Highlights • Nrg is expressed in ISCs and EBs of the Drosophila midgut • Nrg is necessary and sufficient for ISC proliferation • Increased Nrg expression with age drives ISC proliferation and intestinal dysplasia • Nrg acts to potentiate EGFR signaling in order to regulate ISC proliferation, In this article, Jones and colleagues demonstrate that Neuroglian (Nrg) is expressed in intestinal stem cells (ISCs) and enteroblasts of the Drosophila midgut, where it regulates ISC proliferation via the EGFR. Furthermore, data suggest that increased Nrg expression during aging contributes to ISC proliferation and intestinal dysplasia. These findings suggest a role for Nrg-EGFR signaling in the intestine, which could be implicated in age-related disease.

Investigating metal-ion solvation—in particular, the fundamental binding interactions—enhances the understanding of many processes, including hydrogen production via catalysis at metal centers and metal corrosion. Infrared spectra of the hydrated zinc dimer (Zn2+(H2O)n, n = 1–20) were measured in the O–H stretching region, using infrared multiple photon dissociation (IRMPD) spectroscopy. These spectra were then compared with those calculated by using density functional theory. For all cluster sizes, calculated structures adopting asymmetric solvation to one Zn atom in the dimer were found to lie lower in energy than structures adopting symmetric solvation to both Zn atoms. Combining experiment and theory, the spectra show that water molecules preferentially bind to one Zn atom, adopting water binding motifs similar to the Zn+(H2O)n complexes studied previously. A lower coordination number of 2 was observed for Zn2+(H2O)3, evident from the highly red-shifted band in the hydrogen bonding region. Photodissociation leading to loss of a neutral Zn atom was observed only for n = 3, attributed to a particularly low calculated Zn binding energy for this cluster size.

Background: Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC. Methods: We interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways. Results: Two approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 (N = 137), Cluster 1 cases (N = 134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery (P < 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed TP53 mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and ARID1A/PIK3CA mutation (P < 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes (N = 369 genes) were differentially expressed across cluster in transcriptomic subset analysis (P < 10−4). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNγ responses (P < 10−6). Conclusions: DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways. Impact: This work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics.

Background Youth violence is a leading cause of adolescent mortality, underscoring the need to integrate evidence-based violence prevention programs into routine emergency department (ED) care. Objectives To examine the translation of the SafERteens program into clinical care. Methods Hospital staff provided input on implementation facilitators/barriers to inform toolkit development. Implementation was piloted in a four-arm effectiveness-implementation trial, with youth (ages 14–18 years) screening positive for past 3-month aggression randomized to either SafERteens (delivered remotely or in-person) or enhanced usual care (EUC; remote or in-person), with follow-up at post-test and 3 months. During maintenance, ED staff continued in-person SafERteens delivery and external facilitation was provided. Outcomes were measured using the RE-AIM implementation framework. Results SafERteens completion rates were 77.6% (52/67) for remote and 49.1% (27/55) for in-person delivery. In addition to high acceptability ratings (e.g., helpfulness), post-test data demonstrated increased self-efficacy to avoid fighting among patients receiving remote (incidence rate ratio [IRR] 1.22, 95% confidence interval [CI] 1.09–1.36) and in-person (IRR 1.23, 95% CI 1.12–1.36) SafERteens, as well as decreased pro-violence attitudes among patients receiving remote (IRR 0.83, 95% CI 0.75–0.91) and in-person (IRR 0.87, 95% CI 0.77–0.99) SafERteens when compared with their respective EUC groups. At 3 months, youth receiving remote SafERteens reported less non-partner aggression (IRR 0.52, 95% CI 0.31–0.87, Cohen's d −0.39) and violence consequences (IRR 0.47, 95% CI 0.22–1.00, Cohen's d −0.49) compared with remote EUC; no differences were noted for in-person SafERteens delivery. Barriers to implementation maintenance included limited staff availability and a lack of reimbursement codes. Conclusions Implementing behavioral interventions such as SafERteens into routine ED care is feasible using remote delivery. Policymakers should consider reimbursement for violence prevention services to sustain long-term implementation.

Introduction Opioid use disorder (OUD) and related comorbid conditions are highly prevalent among patients presenting to emergency department (ED) settings. Research has developed few comprehensive disease management strategies for at-risk patients presenting to the ED that both decrease illicit opioid use and improve initiation and retention in medication treatment for OUD (MOUD). Methods The research team conducted a pilot pragmatic clinical trial that randomized 40 patients presenting to a single ED to a collaborative care intervention (n = 20) versus usual care control (n = 20) conditions. Interviewers blinded to patient intervention and control group status followed-up with participants at 1, 3, and 6 months after presentation to the ED. The 3-month Emergency Department Longitudinal Integrated Care (ED-LINC) collaborative care intervention for patients at risk for OUD included: 1) a Brief Negotiated Interview at bedside, 2) overdose education and facilitation of MOUD, 3) longitudinal proactive care management, 4) utilization of the statewide health information exchange platform for 24/7 tracking of recurrent ED utilization, and 5) weekly caseload supervision that incorporated measurement-based care treatment assessment with stepped-up care for patients with recalcitrant symptoms. Results Overall, the ED-LINC intervention was feasibly delivered and acceptable to patients. The pilot study achieved >80% follow-up rates at 1, 3, and 6 months. In adjusted longitudinal mixed model regression analyses, no statistically significant differences existed in days of opioid use over the past 30 days for ED-LINC intervention patients when compared to patients receiving usual care (incidence-rate ratio (IRR) 1.50, 95% CI 0.54–4.16). The unadjusted mean number of days of illicit opioid use decreased at the 1-month and 3-month follow-up time points for both groups. ED-LINC intervention patients had increased rates of MOUD initiation compared to control patients (50% versus 30%); intervention versus control comparisons did not achieve statistical significance, although power to detect significant differences in the pilot was limited. Conclusions The ED-LINC intervention for patients with OUD can be feasibly implemented and warrants testing in larger scale, adequately powered randomized pragmatic clinical trial investigations. Clinicaltrials.gov NCT03699085

Suppression of established populations of invasive alien species can be a complex and expensive process, which is frequently unsuccessful. The Asian clam, Corbicula fluminea (Müller, 1774), is considered a high impact invader that can adversely alter freshwater ecosystems and decrease their socioeconomic value. To date, C. fluminea continues to spread and persist within freshwater environments worldwide, despite repeated management attempts to prevent dispersal and suppress established populations. As extensive C. fluminea beds can often become exposed during low-water conditions, the direct application of hot or cold thermal shock treatments has been proposed as suitable mechanism for their control. Further, mechanical substrate disturbance may enhance the efficacy of thermal shock treatments by facilitating exposures to multiple layers of buried clams. In the present study, we advanced these methods by assessing combined applications of both hot and cold thermal shock treatments for control of C. fluminea, using steam spray (≥100 °C; 350 kPa), low- or high-intensity open-flame burns (~1000 °C) and dry ice (−78 °C). In a direct comparison of raking combined with hot thermal shock applications, both steam and high-intensity open-flame treatments tended to be most effective, especially following multiple applications. In addition, when hot thermal treatments are followed by a final cold shock (i.e. dry ice), steam treatments tended to be most effective. Further, when dry ice was applied either alone or prior to an application of a hot shock treatment, substantial if not complete C. fluminea mortality was observed. Overall, this study demonstrated that combined applications of hot and cold thermal shock treatments, applied following the disruption of the substrate, can substantially increase C. fluminea mortality compared to separate hot or cold treatments.

To better understand the full-length transcriptome of the nucleus accumbens (NAc)—a key brain reward region—in chronic cocaine treatment, we perform the first single molecule, long-read sequencing analysis using the Iso-seq method to detect 42,114 unique transcripts from mouse NAc polyadenylated RNA. Using GENCODE annotation as a reference, we find that over half of the Iso-seq derived transcripts are annotated, while 46% of them harbor novel splicing events in known genes; around 1% of them correspond to other types of novel transcripts, such as fusion, antisense and intergenic. Approximately 34% of the novel transcripts are matched with a compiled transcriptome assembled from published short-read data from various tissues, with the remaining 69% being unique to NAc. These data provide a more complete picture of the NAc transcriptome than existing annotations and can serve as a comprehensive reference for future transcriptomic analyses of this important brain reward region.

International audience; Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03–6.30, P = 3.1 × 10−9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.

Background Child with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection typically have mild symptoms that do not require medical attention, leaving a gap in our understanding of the spectrum of SARS-CoV-2-related illnesses that the viruses causes in children. Methods We conducted a prospective cohort study of children and adolescents (aged Results Of 382 children, 293 (77%) were SARS-CoV-2-infected. SARS-CoV-2-infected children were more likely to be Hispanic (P < .0001), less likely to have asthma (P = .005), and more likely to have an infected sibling contact (P = .001) than uninfected children. Children aged 6-13 years were frequently asymptomatic (39%) and had respiratory symptoms less often than younger children (29% vs 48%; P = .01) or adolescents (29% vs 60%; P < .001). Compared with children aged 6-13 years, adolescents more frequently reported influenza-like (61% vs 39%; P < .001) , and gastrointestinal (27% vs 9%; P = .002), and sensory symptoms (42% vs 9%; P < .0001) and had more prolonged illnesses (median [interquartile range] duration: 7 [4-12] vs 4 [3-8] days; P = 0.01). Despite the age-related variability in symptoms, wWe found no difference in nasopharyngeal viral load by age or between symptomatic and asymptomatic children. Conclusions Hispanic ethnicity and an infected sibling close contact are associated with increased SARS-CoV-2 infection risk among children, while asthma is associated with decreased risk. Age-related differences in clinical manifestations of SARS-CoV-2 infection must be considered when evaluating children for coronavirus disease 2019 and in developing screening strategies for schools and childcare settings.