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Introduction: Non-suicidal self-injury (NSSI) is a highly prevalent maladaptive behavior, often used to cope with intense negative affect. Rumination is an emotion regulation strategy that leads to fixation on and exacerbation of (typically) negative affective states. However, studies examining the relationship between rumination and NSSI have yielded mixed results, showing high degrees of heterogeneity., Methods: The present study conducted meta-analyses (k = 50) of the association between overall rumination and NSSI, and independent meta-analyses for each of four subtypes of rumination (general, depressive, brooding, reflection rumination). Potential moderators that may influence the magnitude of these relationships were also examined., Results: A small-to-moderate positive association between rumination and NSSI was found independent of rumination subtype. Moderating effects included NSSI outcome measure and study design for overall rumination and general rumination, respectively. Race was found to moderate the relationships between both brooding and depressive rumination and NSSI, though in inverse directions. An analysis of effect heterogeneity across studies suggested that undetected moderators may be present., Conclusion: Results of this study support the relationships between rumination subtypes and NSSI and identify factors that may impact these relationships. Continued research is needed to understand this association, particularly in more varied subtypes of rumination and cognitive-affective moderators., (© 2024 American Association of Suicidology.)

Importance: There is a lack of randomized clinical trial (RCT) data to guide many routine decisions in the care of children hospitalized for common conditions. A first step in addressing the shortage of RCTs for this population is to identify the most pressing RCT questions for children hospitalized with common conditions., Objective: To identify the most important and feasible RCT questions for children hospitalized with common conditions., Design, Setting, and Participants: For this consensus statement, a 3-stage modified Delphi process was used in a virtual conference series spanning January 1 to September 29, 2022. Forty-six individuals from 30 different institutions participated in the process. Stage 1 involved construction of RCT questions for the 10 most common pediatric conditions leading to hospitalization. Participants used condition-specific guidelines and reviews from a structured literature search to inform their development of RCT questions. During stage 2, RCT questions were refined and scored according to importance. Stage 3 incorporated public comment and feasibility with the prioritization of RCT questions., Main Outcomes and Measures: The main outcome was RCT questions framed in a PICO (population, intervention, control, and outcome) format and ranked according to importance and feasibility; score choices ranged from 1 to 9, with higher scores indicating greater importance and feasibility., Results: Forty-six individuals (38 who shared demographic data; 24 women [63%]) from 30 different institutions participated in our modified Delphi process. Participants included children's hospital (n = 14) and community hospital (n = 13) pediatricians, parents of hospitalized children (n = 4), other clinicians (n = 2), biostatisticians (n = 2), and other researchers (n = 11). The process yielded 62 unique RCT questions, most of which are pragmatic, comparing interventions in widespread use for which definitive effectiveness data are lacking. Overall scores for importance and feasibility of the RCT questions ranged from 1 to 9, with a median of 5 (IQR, 4-7). Six of the top 10 selected questions focused on determining optimal antibiotic regimens for 3 common infections (pneumonia, urinary tract infection, and cellulitis)., Conclusions and Relevance: This consensus statementhas identified the most important and feasible RCT questions for children hospitalized with common conditions. This list of RCT questions can guide investigators and funders in conducting impactful trials to improve care and outcomes for hospitalized children.

Evidence suggests an association between exposure to electronic cigarette (e-cigarette) marketing and e-cigarette use (vaping) among adolescents. However, there is limited evidence on exposure to e-cigarette marketing and susceptibility to future vaping, especially among Black and Latino adolescents. This study aimed to examine associations between exposure to e-cigarette marketing and susceptibility to future vaping among Black and Latino adolescents in the United States (US). Participants (N = 362; equal representation between Black and Latino adolescents) completed a baseline assessment (available in English and Spanish) including sociodemographic characteristics (e.g., racial/ethnic group, age, gender, sexual orientation, etc.), exposure to e-cigarette marketing, and susceptibility to future vaping. Exposure to e-cigarette marketing was recoded and organized into two categories (high exposure = 2 to 3; low exposure = 0 to 1). Cochran-Mantel-Haenszel tests were used to evaluate the association between exposure to e-cigarette marketing and susceptibility to future vaping, stratified by racial/ethnic group. Multiple logistic regressions assessed the association between exposure to e-cigarette marketing and susceptibility to future vaping, controlling for gender, sexual orientation, grade, and academic performance within each racial/ethnic group. Black adolescents reported significantly higher frequencies of exposure to e-cigarette marketing ( p = 0.005). A significant interaction was found between exposure to e-cigarette marketing and racial/ethnic group (X 2 (1) = 6.294, p = 0.012). Among Black adolescents, high exposure to e-cigarette marketing (vs. low exposure) was associated with a higher probability of susceptibility to future vaping (OR: 2.399, 95% CI 1.147-5.021, p = 0.020). For Latino adolescents, exposure to e-cigarette marketing was not associated with susceptibility to future vaping (OR: 0.503, 95% CI 0.245-1.03, p = 0.062). Future studies should evaluate how and where adolescents are exposed to e-cigarette marketing. Prevention efforts must include the implementation of effective counter-marketing campaigns and the reduction of exposure to e-cigarette marketing among Black and Latino adolescents.

Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic options for ACC. An extensive drug screen was conducted to identify compounds with potential activity against ACC cell lines. We further investigated the mechanism of action of the identified compound, TAK-243, its synergistic effects with current ACC therapeutics, and its efficacy in ACC models including patient-derived organoids and mouse xenografts. TAK-243, a clinical ubiquitin-activating enzyme (UAE) inhibitor, showed potent activity in ACC cell lines. TAK-243 inhibited protein ubiquitination in ACC cells, leading to the accumulation of free ubiquitin, activation of the unfolded protein response, and induction of apoptosis. TAK-243 was found to be effluxed out of cells by MDR1, a drug efflux pump, and did not require Schlafen 11 (SLFN11) expression for its activity. Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids. The tumor suppressive effects of TAK-243 and its synergistic effects with Venetoclax were further confirmed in a mouse xenograft model. These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage ACC. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors., Significance: ACC is a rare endocrine cancer with poor prognosis and limited therapeutic options. We report that TAK-243 is active alone and in combination with currently used therapies and with BCL2 and mTOR inhibitors in ACC preclinical models. Our results suggest implementation of TAK-243 in clinical trials for patients with advanced and metastatic ACC., (© 2024 The Authors; Published by the American Association for Cancer Research.)

PARP inhibitor (PARPi)-resistant BRCA-mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Here, we performed a quantitative high-throughput drug combination screen that identified the combination of an ATR inhibitor (ATRi) and an AKT inhibitor (AKTi) as an effective treatment strategy for both PARPi-sensitive and PARPi-resistant BRCAm HGSOC. The ATRi and AKTi combination induced DNA damage and R loop-mediated replication stress (RS). Mechanistically, the kinase domain of AKT1 directly interacted with DHX9 and facilitated recruitment of DHX9 to R loops. AKTi increased ATRi-induced R loop-mediated RS by mitigating recruitment of DHX9 to R loops. Moreover, DHX9 was upregulated in tumors from patients with PARPi-resistant BRCAm HGSOC, and high coexpression of DHX9 and AKT1 correlated with worse survival. Together, this study reveals an interaction between AKT1 and DHX9 that facilitates R loop resolution and identifies combining ATRi and AKTi as a rational treatment strategy for BRCAm HGSOC irrespective of PARPi resistance status., Significance: Inhibition of the AKT and ATR pathways cooperatively induces R loop-associated replication stress in high-grade serous ovarian cancer, providing rationale to support the clinical development of AKT and ATR inhibitor combinations. See related commentary by Ramanarayanan and Oberdoerffer, p. 793., (©2024 American Association for Cancer Research.)

Methotrexate (MTX) is a tight-binding dihydrofolate reductase (DHFR) inhibitor, used as both an antineoplastic and immunosuppressant therapeutic. MTX, like folate undergoes folylpolyglutamate synthetase-mediated γ-glutamylation, which affects cellular retention and target specificity. Mechanisms of MTX resistance in cancers include a decrease in MTX poly-γ-glutamylation and an upregulation of DHFR. Here, we report a series of potent MTX-based proteolysis targeting chimeras (PROTACs) to investigate DHFR degradation pharmacology and one-carbon biochemistry. These on-target, cell-active PROTACs show proteasome- and E3 ligase-dependent activity, and selective degradation of DHFR in multiple cancer cell lines. By comparison, treatment with MTX increases cellular DHFR protein expression. Importantly, these PROTACs produced distinct, less-lethal phenotypes compared to MTX. The chemical probe set described here should complement conventional DHFR inhibitors and serve as useful tools for studying one-carbon biochemistry and dissecting complex polypharmacology of MTX and related drugs. Such compounds may also serve as leads for potential autoimmune and antineoplastic therapeutics., Competing Interests: Declaration of interests S.R., G.R.B., L.L., and J.I. are listed as inventors for the patent application, WO2021262693A1 (“Methotrexate analogs and methods of use”)., (Published by Elsevier Ltd.)

The transition to motherhood in mammals is marked by changes in females' perception of and responsiveness to sensory stimuli from infants. Our understanding of maternally induced sensory plasticity relies most heavily on studies in uniparental, promiscuous house mice and rats, which may not be representative of rodent species with different life histories. We exposed biparental, monogamous California mouse (Peromyscus californicus) mothers and ovariectomized virgin females to one of four acoustic and olfactory stimulus combinations (Control: clean cotton and white noise; Call: clean cotton and pup vocalizations; Odor: pup-scented cotton and white noise; Call + Odor: pup-scented cotton and pup vocalizations) and quantified females' behavior and Fos expression in select brain regions. Behavior did not differ between mothers and ovariectomized virgins. Among mothers, however, those exposed to the Control condition took the longest to sniff the odor stimulus, and mothers exposed to the Odor condition were quicker to sniff the odor ball compared to those in the Call condition. Behavior did not differ among ovariectomized virgins exposed to the different conditions. Fos expression differed across conditions only in the anterior hypothalamic nucleus (AHN), which responds to aversive stimuli: among mothers, the Control condition elicited the highest AHN Fos and Call + Odor elicited the lowest. Among ovariectomized virgin females, Call elicited the lowest Fos in the AHN. Thus, reproductive status in California mice alters females' behavioral responses to stimuli from pups, especially odors, and results in the inhibition of defense circuitry in response to pup stimuli., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Cannabidiol (CBD) has therapeutic potential in companion animals. Shorter-term studies have determined that CBD is well tolerated in dogs with mild adverse effects and an increase in alkaline phosphatase (ALP) activity. There is need to assess CBD's long-term tolerability., Hypothesis: Determine the long-term tolerability of CBD administered PO to healthy dogs for 36 weeks at dosages of 5 and 10 mg/kg body weight (BW)/day. Our hypothesis was that CBD would be well tolerated by dogs., Methods: Eighteen healthy adult beagle dogs were randomly assigned to 3 groups of 6 each that received 0, 5, or 10 mg/kg BW/day CBD PO. Dogs were adapted to their housing for 3 weeks and received treatment for 36 weeks once daily with food. Adverse events (AEs) were recorded daily. Blood biochemistry profiles were monitored every 4 weeks. Data were analyzed as repeated measures over time using a mixed model, with significance at α = 0.05., Results: The 0 and 5 mg/kg treatment groups had similar fecal scores, and the 10 mg/kg treatment group had higher frequency of soft feces. No other significant AEs were noted. An increase (P < .0001) in ALP activity occurred in groups that received CBD. Remaining blood variables were within reference range., Conclusions and Clinical Importance: Chronic administration of CBD in healthy dogs at 5 mg/kg was better tolerated than 10 mg/kg, and both dosages caused an increase in ALP activity. Although our data does not indicate hepatic damage, it is recommended to monitor liver function in dogs receiving CBD chronically., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Studies indicate that doses of alglucosidase alfa (ALGLU) higher than label dose (20 mg/kg every other week) improve clinical outcomes in infantile-onset Pompe disease (IOPD). We investigated data from the Pompe Registry to determine the association between ALGLU dose and survival in IOPD., Results: We included 332 IOPD patients from the Registry as of January 2022 who had cardiomyopathy and were first treated at age < 1 year. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between ALGLU as a time-varying exposure and survival, adjusting for age at first treatment, sex, and cross-reactive immunologic material (CRIM)/immune tolerance induction (ITI) status. Dose was measured as average relative dose received over time (in multiples of label dose, range > 0 to 4 times label dose), current dose, and lagged dose. 81% patients received label dose at treatment initiation. Over time, 52% received a higher dose. Higher ALGLU dose over time was associated with improved survival: adjusted HR 0.40 (95% CI 0.22-0.73, p = 0.003) per 1-unit increase in average relative dose, with similar results for invasive ventilation-free survival (adjusted HR 0.48, 95% CI 0.28-0.84; p = 0.010). The association was consistent in patients first treated before or after 3 months of age and did not vary significantly by CRIM status. Results for current and lagged dose were similar to average dose., Conclusions: Higher ALGLU doses were associated with significantly improved overall and invasive ventilator-free survival in IOPD. Results were consistent across sensitivity analyses., (© 2023. The Author(s).)

Background: The association between statin use and risk of renal cell carcinoma (RCC) has been debated. We aimed to evaluate whether statin use is associated with RCC risk. Material and methods: We studied 100,195 women in the Nurses' Health Study (NHS) from 1994 to 2016; 91,427 women in the Nurses' Health Study II (NHS II) from 1999 to 2015; and 45,433 men in the Health Professionals Follow-up Study (HPFS) from 1990 to 2016. Statins and covariate data were collected at baseline and then biennially. Outcome was measured as incidence of total RCC and clinically relevant disease subgroups. Cox proportional hazards models estimated covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During follow-up, 661 participants developed RCC. There was no significant association between the use of statins and the risk of overall RCC, fatal RCC, or advanced or localized disease. Across cohorts, the adjusted HR for ever vs. never users was 0.97 (95% CI 0.81-1.16). Female ever users of statins were at increased risk of high-grade disease in the NHS only (HR 1.75, 95% CI 1.07-2.85). Among men only, ≥4 years of statin use was associated with an increased risk of clear cell RCC (HR 1.65, 95% CI 1.10-2.47). Conclusions: Statin use was not associated with the overall risk of RCC. However, it was associated with an increased risk of high-grade disease among women in the NHS cohort and an increased risk of clear cell RCC among men. The reasons for these inconsistent results by sex are unclear.

Understanding how resource characteristics influence variability in social and material inequality among foraging populations is a prominent area of research. However, obtaining cross-comparative data from which to evaluate theoretically informed resource characteristic factors has proved difficult, particularly for investigating interactions of characteristics. Therefore, we develop an agent-based model to evaluate how five key characteristics of primary resources (predictability, heterogeneity, abundance, economy of scale and monopolizability) structure pay-offs and explore how they interact to favour both egalitarianism and inequality. Using iterated simulations from 243 unique combinations of resource characteristics analysed with an ensemble machine-learning approach, we find the predictability and heterogeneity of key resources have the greatest influence on selection for egalitarian and nonegalitarian outcomes. These results help explain the prevalence of egalitarianism among foraging populations, as many groups probably relied on resources that were both relatively less predictable and more homogeneously distributed. The results also help explain rare forager inequality, as comparison with ethnographic and archaeological examples suggests the instances of inequality track strongly with reliance on resources that were predictable and heterogeneously distributed. Future work quantifying comparable measures of these two variables, in particular, may be able to identify additional instances of forager inequality. This article is part of the theme issue 'Evolutionary ecology of inequality'.

Objective: This study aimed to explore whether African American/Black and Hispanic/Latino adolescents are being asked about electronic cigarette (e-cigarette) use (vaping) and advised not to use them., Methods: In 2021, adolescents ( N = 362) with no vaping history, self-identified as African American/Black and/or Hispanic/Latino, and able to read and speak English and/or Spanish were recruited through partner schools and community-based organizations. Participants completed a survey reporting sociodemographic characteristics (e.g., race/ethnicity, gender, and language of preference) and they were asked about e-cigarette use and/or were advised not to use them by a health professional., Results: In total, 12% of African American/Black and 5% of Hispanic/Latino participants reported not seeing a health professional in the year prior to enrollment. Of the participants who reported visiting a health professional, 50.8% reported being asked and advised about vaping. Over one-quarter (28.4%) of participants were neither asked nor advised regarding vaping. Compared to English-speaking participants, Spanish-speaking participants were significantly less likely to be asked about e-cigarette use (45.2 vs. 63.9%, p = 0.009) and advised not to use them (40.3 vs. 66.9%, p < 0.001). Moreover, compared to African American/Black participants, Hispanic/Latino participants were significantly less likely to be advised not to use e-cigarettes (52.9 vs. 68.6%, p = 0.018). Furthermore, compared to male participants, female participants were significantly less likely to be advised not to use e-cigarettes (51.3 vs. 68.2%, p = 0.003)., Conclusion: Compared to English-speaking participants, Spanish-speaking participants were significantly less likely to self-report being asked about e-cigarette use and advised not to use them. Moreover, Hispanic/Latino and female adolescents were significantly less likely to self-report being advised not to use e-cigarettes compared to their Black/African American and male counterparts. Future research is needed to improve health professional attention toward asking about and advising against vaping among adolescents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Connolly, Croft, Ramírez-Palacios, Cai, Hill, Orfin, Rivera, Wilson, Li, McIntosh, Ossip, Cupertino and Cartujano-Barrera.)

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Despite decades of clinical trials, the overall survival rate for patients with relapsed and metastatic disease remains below 30%, underscoring the need for novel treatments. FGFR4, a receptor tyrosine kinase that is overexpressed in RMS and mutationally activated in 10% of cases, is a promising target for treatment. Here, we show that futibatinib, an irreversible pan-FGFR inhibitor, inhibits the growth of RMS cell lines in vitro by inhibiting phosphorylation of FGFR4 and its downstream targets. Moreover, we provide evidence that the combination of futibatinib with currently used chemotherapies such as irinotecan and vincristine has a synergistic effect against RMS in vitro. However, in RMS xenograft models, futibatinib monotherapy and combination treatment have limited efficacy in delaying tumor growth and prolonging survival. Moreover, limited efficacy is only observed in a PAX3-FOXO1 fusion-negative (FN) RMS cell line with mutationally activated FGFR4, whereas little or no efficacy is observed in PAX3-FOXO1 fusion-positive (FP) RMS cell lines with FGFR4 overexpression. Alternative treatment modalities such as combining futibatinib with other kinase inhibitors or targeting FGFR4 with CAR T cells or antibody-drug conjugate may be more effective than the approaches tested in this study.

Aggression and anger are associated with interpretation and attention biases. Such biases have become treatment targets for anger and aggressive behavior in cognitive bias modification (CBM) interventions. Several studies have evaluated the efficacy of CBM for the treatment of anger and aggressive behavior, with inconsistent results. The present study meta-analytically analyzed 29 randomized controlled trial studies (N = 2334) published in EBSCOhost and PubMed between March 2013 and March 2023 assessing the efficacy of CBM for anger and/or aggression. Included studies delivered CBMs that addressed either attention biases, interpretation biases, or both. Risk of publication bias and potential moderating effects of several participant-, treatment- and study-related factors were assessed. CBM significantly outperformed control conditions in the treatment of aggression (Hedge's G = -0.23, 95% CI [-0.35, -0.11], p < .001) and anger (Hedge's G = -0.18, 95% CI [-0.28, -0.07], p = .001) independent of treatment dose, participant demographic characteristics, and study quality, though overall effects were small. Follow-up analyses demonstrated that only CBMs targeting interpretation bias were efficacious for aggression outcomes, but not when baseline aggression was accounted for. Findings suggest that CBM demonstrates efficacy for the treatment aggressive behavior and to a lesser extent, anger., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

An intronic GGGGCC repeat expansion in C9orf72 is a common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeats are transcribed in both sense and antisense directions to generate distinct dipeptide repeat proteins, of which poly(GA), poly(GR), and poly(PR) have been implicated in contributing to neurodegeneration. Poly(PR) binding to RNA may contribute to toxicity, but analysis of poly(PR)-RNA binding on a transcriptome-wide scale has not yet been carried out. We therefore performed crosslinking and immunoprecipitation (CLIP) analysis in human cells to identify the RNA binding sites of poly(PR). We found that poly(PR) binds to nearly 600 RNAs, with the sequence GAAGA enriched at the binding sites. In vitro experiments showed that poly(GAAGA) RNA binds poly(PR) with higher affinity than control RNA and induces the phase separation of poly(PR) into condensates. These data indicate that poly(PR) preferentially binds to poly(GAAGA)-containing RNAs, which may have physiological consequences., (© 2023 Balendra et al.)

An animal's umwelt, comprising its perception of the sensory environment, which is inherently subjective, can change across the lifespan in accordance with major life events. In mammals, the onset of motherhood, in particular, is associated with a neural and sensory plasticity that alters a mother's detection and use of sensory information such as infant-related sensory stimuli. Although the literature surrounding mammalian mothers is well established, very few studies have addressed the effects of parenthood on sensory plasticity in mammalian fathers. In this review, we summarize the major findings on the effects of parenthood on behavioural and neural responses to sensory stimuli from pups in rodent mothers, with a focus on the olfactory, auditory, and somatosensory systems, as well as multisensory integration. We also review the available literature on sensory plasticity in rodent fathers. Finally, we discuss the importance of sensory plasticity for effective parental care, hormonal modulation of plasticity, and an exploration of temporal, ecological, and life-history considerations of sensory plasticity associated with parenthood. The changes in processing and/or perception of sensory stimuli associated with the onset of parental care may have both transient and long-lasting effects on parental behaviour and cognition in both mothers and fathers; as such, several promising areas of study, such as on the molecular/genetic, neurochemical, and experiential underpinnings of parenthood-related sensory plasticity, as well as determinants of interspecific variation, remain potential avenues for further exploration., (© 2023 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Objective: Non-suicidal self-injury (NSSI) is strongly associated with difficulties in emotion regulation, but its relationships with maladaptive cognitive processes are less clear., Method: The current study examined relationships between self-reported NSSI (presence, number of methods, frequency, recency, duration, functions) and negative cognitive processes (rumination, worry, self-criticism, perceived burdensomeness, thwarted belongingness) among 1,357 undergraduates. Cognition variables were submitted to exploratory factor analysis (EFA), and relationships were examined between the resulting factors and NSSI history (among the full sample) and NSSI severity and functions (among those with a history of NSSI)., Results: The EFA derived two higher order cognitive factors: repetitive negative thinking (RNT) and negative self-perception (NSP). Both RNT and NSP were significantly higher among participants with than those without a history of NSSI. Among those with NSSI, NSP, but not RNT, was positively related to lifetime NSSI frequency and number of methods, as well as recency (presence in the past 12 months) and total duration (in years) of NSSI engagement. Moreover, RNT and NSP were positively associated with aggregate intrapersonal (but not interpersonal) functions of NSSI. The two cognitive factors demonstrated differential relationships with the individual intrapersonal NSSI functions., Conclusions: Higher order categories of cognitive risk factors may have unique relationships with functions and severity of NSSI, with possible implications for more targeted approaches to risk assessment and intervention.HighlightsNegative thinking and self-perception were higher in people who engage in NSSI.Negative self-perception was associated with greater NSSI severity.Negative thinking and self-perception had different relations to NSSI functions.

Combination of anti-cancer drugs is broadly seen as way to overcome the often-limited efficacy of single agents. The design and testing of combinations are however very challenging. Here we present a uniquely large dataset screening over 5000 targeted agent combinations across 81 non-small cell lung cancer cell lines. Our analysis reveals a profound heterogeneity of response across the tumor models. Notably, combinations very rarely result in a strong gain in efficacy over the range of response observable with single agents. Importantly, gain of activity over single agents is more often seen when co-targeting functionally proximal genes, offering a strategy for designing more efficient combinations. Because combinatorial effect is strongly context specific, tumor specificity should be achievable. The resource provided, together with an additional validation screen sheds light on major challenges and opportunities in building efficacious combinations against cancer and provides an opportunity for training computational models for synergy prediction., (© 2023. The Author(s).)

Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene ( BRCA )-mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA -mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with BRCA -mutant HGSC. The treatment was well tolerated but yielded an objective response rate of 6% (1 of 17; one partial response) in patients with previous PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of Bloom syndrome RecQ helicase ( BLM ) and cyclin E1 ( CCNE1 ) overexpression or copy number gain/amplification were seen in patients who derived durable benefit from CHK1i. BRCA reversion mutation in previously PARPi-treated BRCA -mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork-related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with BRCA -mutant HGSC.

We report a comprehensive drug synergy study in acute myeloid leukemia (AML). In this work, we investigate a panel of cell lines spanning both MLL-rearranged and non-rearranged subtypes. The work comprises a resource for the community, with many synergistic drug combinations that could not have been predicted a priori, and open source code for automation and analyses. We base our definitions of drug synergy on the Chou-Talalay method, which is useful for visualizations of synergy experiments in isobolograms, and median-effects plots, among other representations. Our key findings include drug synergies affecting the chromatin state, specifically in the context of regulation of the modification state of histone H3 lysine-27. We report open source high throughput methodology such that multidimensional drug screening can be accomplished with equipment that is accessible to most laboratories. This study will enable preclinical investigation of new drug combinations in a lethal blood cancer, with data analysis and automation workflows freely available to the community., Competing Interests: Declaration of Conflicting Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Available evidence is mixed concerning associations between smoking status and COVID-19 clinical outcomes. Effects of nicotine replacement therapy (NRT) and vaccination status on COVID-19 outcomes in smokers are unknown., Methods: Electronic health record data from 104 590 COVID-19 patients hospitalized February 1, 2020 to September 30, 2021 in 21 U.S. health systems were analyzed to assess associations of smoking status, in-hospital NRT prescription, and vaccination status with in-hospital death and ICU admission., Results: Current (n = 7764) and never smokers (n = 57 454) did not differ on outcomes after adjustment for age, sex, race, ethnicity, insurance, body mass index, and comorbidities. Former (vs never) smokers (n = 33 101) had higher adjusted odds of death (aOR, 1.11; 95% CI, 1.06-1.17) and ICU admission (aOR, 1.07; 95% CI, 1.04-1.11). Among current smokers, NRT prescription was associated with reduced mortality (aOR, 0.64; 95% CI, 0.50-0.82). Vaccination effects were significantly moderated by smoking status; vaccination was more strongly associated with reduced mortality among current (aOR, 0.29; 95% CI, 0.16-0.66) and former smokers (aOR, 0.47; 95% CI, 0.39-0.57) than for never smokers (aOR, 0.67; 95% CI, 0.57, 0.79). Vaccination was associated with reduced ICU admission more strongly among former (aOR, 0.74; 95% CI, 0.66-0.83) than never smokers (aOR, 0.87; 95% CI, 0.79-0.97)., Conclusions: Former but not current smokers hospitalized with COVID-19 are at higher risk for severe outcomes. SARS-CoV-2 vaccination is associated with better hospital outcomes in COVID-19 patients, especially current and former smokers. NRT during COVID-19 hospitalization may reduce mortality for current smokers., Implications: Prior findings regarding associations between smoking and severe COVID-19 disease outcomes have been inconsistent. This large cohort study suggests potential beneficial effects of nicotine replacement therapy on COVID-19 outcomes in current smokers and outsized benefits of SARS-CoV-2 vaccination in current and former smokers. Such findings may influence clinical practice and prevention efforts and motivate additional research that explores mechanisms for these effects., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.)

Background: MiT-Renal Cell Carcinoma (RCC) is characterized by genomic translocations involving microphthalmia-associated transcription factor (MiT) family members TFE3, TFEB, or MITF. MiT-RCC represents a specific subtype of sporadic RCC that is predominantly seen in young patients and can present with heterogeneous histological features making diagnosis challenging. Moreover, the disease biology of this aggressive cancer is poorly understood and there is no accepted standard of care therapy for patients with advanced disease. Tumor-derived cell lines have been established from human TFE3-RCC providing useful models for preclinical studies., Methods: TFE3-RCC tumor derived cell lines and their tissues of origin were characterized by IHC and gene expression analyses. An unbiased high-throughput drug screen was performed to identify novel therapeutic agents for treatment of MiT-RCC. Potential therapeutic candidates were validated in in vitro and in vivo preclinical studies. Mechanistic assays were conducted to confirm the on-target effects of drugs., Results: The results of a high-throughput small molecule drug screen utilizing three TFE3-RCC tumor-derived cell lines identified five classes of agents with potential pharmacological efficacy, including inhibitors of phosphoinositide-3-kinase (PI3K) and mechanistic target of rapamycin (mTOR), and several additional agents, including the transcription inhibitor Mithramycin A. Upregulation of the cell surface marker GPNMB, a specific MiT transcriptional target, was confirmed in TFE3-RCC and evaluated as a therapeutic target using the GPNMB-targeted antibody-drug conjugate CDX-011. In vitro and in vivo preclinical studies demonstrated efficacy of the PI3K/mTOR inhibitor NVP-BGT226, Mithramycin A, and CDX-011 as potential therapeutic options for treating advanced MiT-RCC as single agents or in combination., Conclusions: The results of the high-throughput drug screen and validation studies in TFE3-RCC tumor-derived cell lines have provided in vitro and in vivo preclinical data supporting the efficacy of the PI3K/mTOR inhibitor NVP-BGT226, the transcription inhibitor Mithramycin A, and GPNMB-targeted antibody-drug conjugate CDX-011 as potential therapeutic options for treating advanced MiT-RCC. The findings presented here should provide the basis for designing future clinical trials for patients with MiT-driven RCC., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Small cell lung cancer (SCLC) is a recalcitrant malignancy with limited treatment options. Bromodomain and extraterminal domain inhibitors (BETis) have shown promising preclinical activity in SCLC, but the broad sensitivity spectrum limits their clinical prospects. Here, we performed unbiased high-throughput drug combination screens to identify therapeutics that could augment the antitumor activities of BETis in SCLC. We found that multiple drugs targeting the PI-3K-AKT-mTOR pathway synergize with BETis, among which mTOR inhibitors (mTORis) show the highest synergy. Using various molecular subtypes of the xenograft models derived from patients with SCLC, we confirmed that mTOR inhibition potentiates the antitumor activities of BETis in vivo without substantially increasing toxicity. Furthermore, BETis induce apoptosis in both in vitro and in vivo SCLC models, and this antitumor effect is further amplified by combining mTOR inhibition. Mechanistically, BETis induce apoptosis in SCLC by activating the intrinsic apoptotic pathway. However, BET inhibition leads to RSK3 upregulation, which promotes survival by activating the TSC2-mTOR-p70S6K1-BAD cascade. mTORis block this protective signaling and augment the apoptosis induced by BET inhibition. Our findings reveal a critical role of RSK3 induction in tumor survival upon BET inhibition and warrant further evaluation of the combination of mTORis and BETis in patients with SCLC.

SEQUIN is a web-based application (app) that allows fast and intuitive analysis of RNA sequencing data derived for model organisms, tissues, and single cells. Integrated app functions enable uploading datasets, quality control, gene set enrichment, data visualization, and differential gene expression analysis. We also developed the iPSC Profiler, a practical gene module scoring tool that helps measure and compare pluripotent and differentiated cell types. Benchmarking to other commercial and non-commercial products underscored several advantages of SEQUIN. Freely available to the public, SEQUIN empowers scientists using interdisciplinary methods to investigate and present transcriptome data firsthand with state-of-the-art statistical methods. Hence, SEQUIN helps democratize and increase the throughput of interrogating biological questions using next-generation sequencing data with single-cell resolution., Competing Interests: The authors declare no conflicts of interest.

Background: There has been an increase in allergy-related emergency department (ED) visits over the past several years. Underlying cardiovascular disease or respiratory disease and concurrent beta blocker or angiotensin-converting enzyme inhibitor use have been identified as potential risk factors for severe or refractory anaphylactic reactions. Conflicting evidence exists regarding the association between antihypertensive (AH) use and the incidence of refractory anaphylaxis., Objective: The purpose of this study was to determine the incidence of refractory anaphylaxis in patients presenting to the ED while prescribed select AH medications outpatient., Methods: This was a retrospective cohort study of all adult and pediatric patients presenting to the ED between February 16, 2021, and August 31, 2021, with a diagnosis of anaphylaxis. The primary objective was to compare the proportion of patients experiencing refractory anaphylaxis that were prescribed versus not prescribed AH medications in the outpatient setting., Results: A total of 101 patients were treated for anaphylaxis in the ED during the study timeframe with 13 patients in the AH group and 88 patients in the no AH group. There was no difference in the incidence of refractory anaphylaxis between groups (0% vs 9%; p=0.48). Significantly fewer patients in the AH group required any epinephrine doses compared to the no AH group (38% vs 88%; p<0.001)., Conclusions: Outpatient use of select AH medications was not associated with an increased incidence of refractory anaphylaxis in patients presenting to the ED., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Snider et al.)

HIV infection of astrocytes leads to restricted gene expression and replication but abundant expression of HIV early genes Tat, Nef and Rev. A great deal of neuroHIV research has so far been focused on Tat protein, its effects on astrocytes, and its roles in neuroHIV. In the current study, we aimed to determine effects of Nef expression on astrocytes and their function. Using transfection or infection of VSVG-pseudotyped HIV viruses, we showed that Nef expression down-modulated glial fibrillary acidic protein (GFAP) expression. We then showed that Nef expression also led to decreased GFAP mRNA expression. The transcriptional regulation was further confirmed using a GFAP promoter-driven reporter gene assay. We performed transcription factor profiling array to compare the expression of transcription factors between Nef-intact and Nef-deficient HIV-infected cells and identified eight transcription factors with expression changes of 1.5-fold or higher: three up-regulated by Nef (Stat1, Stat5, and TFIID), and five down-regulated by Nef (AR, GAS/ISRE, HIF, Sp1, and p53). We then demonstrated that removal of the Sp1 binding sites from the GFAP promoter resulted in a much lower level of the promoter activity and reversal of Nef effects on the GFAP promoter, confirming important roles of Sp1 in the GFAP promoter activity and for Nef-induced GFAP expression. Lastly, we showed that Nef expression led to increased glutamate uptake and decreased glutamate release by astrocytes and increased astrocyte proliferation. Taken together, these results indicate that Nef leads to down-modulation of GFAP expression and alteration of glutamate metabolism in astrocytes, and astrocyte proliferation and could be an important contributor to neuroHIV., Competing Interests: Conflict of interest The authors declare no competing interests., (copyright: © 2022 Wilson et al.)

Background: There is mixed evidence about the relations of current versus past cancer with severe COVID-19 outcomes and how they vary by patient and cancer characteristics., Methods: Electronic health record data of 104,590 adult hospitalized patients with COVID-19 were obtained from 21 United States health systems from February 2020 through September 2021. In-hospital mortality and ICU admission were predicted from current and past cancer diagnoses. Moderation by patient characteristics, vaccination status, cancer type, and year of the pandemic was examined., Results: 6.8% of the patients had current (n = 7,141) and 6.5% had past (n = 6,749) cancer diagnoses. Current cancer predicted both severe outcomes but past cancer did not; adjusted odds ratios (aOR) for mortality were 1.58 [95% confidence interval (CI), 1.46-1.70] and 1.04 (95% CI, 0.96-1.13), respectively. Mortality rates decreased over the pandemic but the incremental risk of current cancer persisted, with the increment being larger among younger vs. older patients. Prior COVID-19 vaccination reduced mortality generally and among those with current cancer (aOR, 0.69; 95% CI, 0.53-0.90)., Conclusions: Current cancer, especially among younger patients, posed a substantially increased risk for death and ICU admission among patients with COVID-19; prior COVID-19 vaccination mitigated the risk associated with current cancer. Past history of cancer was not associated with higher risks for severe COVID-19 outcomes for most cancer types., Impact: This study clarifies the characteristics that modify the risk associated with cancer on severe COVID-19 outcomes across the first 20 months of the COVID-19 pandemic. See related commentary by Egan et al., p. 3., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: The number of youth presenting to hospitals with suicidality and/or self-harm has increased substantially in recent years. We implemented a multihospital quality improvement (QI) collaborative from February 1, 2018 to January 31, 2019, aiming for an absolute increase in hospitals' mean rate of caregiver lethal means counseling (LMC) of 10 percentage points (from a baseline mean performance of 68% to 78%) by the end of the collaborative, and to evaluate the effectiveness of the collaborative on LMC, adjusting for secular trends., Methods: This 8 hospital collaborative used a structured process of alternating learning sessions and action periods to improve LMC across hospitals. Electronic medical record documentation of caregiver LMC was evaluated during 3 phases: precollaborative, active QI collaborative, and postcollaborative. We used statistical process control to evaluate changes in LMC monthly. Following collaborative completion, interrupted time series analyses were used to evaluate changes in the level and trend and slope of LMC, adjusting for covariates., Results: In the study, 4208 children and adolescents were included-1314 (31.2%) precollaborative, 1335 (31.7%) during the active QI collaborative, and 1559 (37.0%) postcollaborative. Statistical process control analyses demonstrated that LMC increased from a hospital-level mean of 68% precollaborative to 75% (February 2018) and then 86% (October 2018) during the collaborative. In interrupted time series analyses, there were no significant differences in LMC during and following the collaborative beyond those expected based on pre-collaborative trends., Conclusions: LMC increased during the collaborative, but the increase did not exceed expected trends. Interventions developed by participating hospitals may be beneficial to others aiming to improve LMC for caregivers of hospitalized youth with suicidality., (Copyright © 2022 by the American Academy of Pediatrics.)

Objective: Neighborhood conditions influence child health outcomes, but data examining association between local factors and hospital utilization are lacking. We determined if hospitals' mix of patients by neighborhood opportunity correlates with rehospitalization for common diagnoses at US children's hospitals., Methods: We analyzed all discharges in 2018 for children ≤18 years at 47 children's hospitals for 14 common diagnoses. The exposure was hospital-level mean neighborhood opportunity - measured by Child Opportunity Index (COI) - for each diagnosis. The outcome was same-cause rehospitalization within 365 days. We measured association via Pearson correlation coefficient. For diagnoses with significant associations, we also examined shorter rehospitalization time windows and compared unadjusted and COI-adjusted rehospitalization rates., Results: There were 256,871 discharges included. Hospital-level COI ranged from 17th to 70th percentile nationally. Hospitals serving lower COI neighborhoods had more frequent rehospitalization for asthma (ρ -0.34 [95% confidence interval -0.57, -0.06]) and diabetes (ρ -0.33 [-0.56, -0.04]), but fewer primary mental health rehospitalizations (ρ 0.47 [0.21, 0.67]). There was no association for 11 other diagnoses. Secondary timepoint analysis revealed increasing correlation over time, with differences by diagnosis. Adjustment for hospital-level COI resulted in 26%, 32%, and 45% of hospitals changing >1 decile in rehospitalization rank order for diabetes, asthma, and mental health diagnoses, respectively., Conclusions: Children's hospitals vary widely in their mix of neighborhoods served. Asthma, diabetes, and mental health rehospitalization rates correlate with COI, suggesting that neighborhood factors may influence outcome disparities for these conditions. Hospital outcomes may be affected by neighborhood opportunity, which has implications for benchmarking., (Copyright © 2022 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

We have coated a typical C18 column with the pH cationic charge controllable zwitterionic synthetic surfactant, cocamidopropyl betaine (CAPB), in order to generate a mixed mode reversed phase weak ion exchange column. As determined by the Thomas model, the column has an adsorbed surfactant capacity of 0.557 mmoles. The addition of 8.8 × 10 -4  M CAPB to the totally aqueous mobile phase ensured stability of the surfactant on the column and permitted separation of the four component sulfonamide mixture with micellar liquid chromatography (MLC) in under 11 min. Comparatively, with a dilute H 2 SO 4 mobile phase with no CAPB, the separation time for the sulfonamide mixture reached an excessive run time of an hour on the bare C18 chains. With CAPB in the mobile phase (no organic solvent present), a seven component sulfonamide mixture could be separated in less than 45 min. A five component short chain carboxylic acid mixture, separated in 20 min, was used to examine the ion exchange character of the column in pH environments of 2.3 and 4.6. Three phase MLC equilibrium analysis was also done in these pH environments with the sulfa drug and carboxylic acid mixtures to determine partition coefficients. Finally, a quite high molecular weight (70,000) anionic polystyrene sulfonate polymer was characterized by MLC with only CAPB and variable pH mobile phases; the optimal pH was determined to be 5.6. A totally aqueous mobile phase without CAPB was not suitable for profiling this polymer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Main Objective: There is limited information on how patient outcomes have changed during the COVID-19 pandemic. This study characterizes changes in mortality, intubation, and ICU admission rates during the first 20 months of the pandemic., Study Design and Methods: University of Wisconsin researchers collected and harmonized electronic health record data from 1.1 million COVID-19 patients across 21 United States health systems from February 2020 through September 2021. The analysis comprised data from 104,590 adult hospitalized COVID-19 patients. Inclusion criteria for the analysis were: (1) age 18 years or older; (2) COVID-19 ICD-10 diagnosis during hospitalization and/or a positive COVID-19 PCR test in a 14-day window (+/- 7 days of hospital admission); and (3) health system contact prior to COVID-19 hospitalization. Outcomes assessed were: (1) mortality (primary), (2) endotracheal intubation, and (3) ICU admission., Results and Significance: The 104,590 hospitalized participants had a mean age of 61.7 years and were 50.4% female, 24% Black, and 56.8% White. Overall risk-standardized mortality (adjusted for age, sex, race, ethnicity, body mass index, insurance status and medical comorbidities) declined from 16% of hospitalized COVID-19 patients (95% CI: 16% to 17%) early in the pandemic (February-April 2020) to 9% (CI: 9% to 10%) later (July-September 2021). Among subpopulations, males (vs. females), those on Medicare (vs. those on commercial insurance), the severely obese (vs. normal weight), and those aged 60 and older (vs. younger individuals) had especially high mortality rates both early and late in the pandemic. ICU admission and intubation rates also declined across these 20 months., Conclusions: Mortality, intubation, and ICU admission rates improved markedly over the first 20 months of the pandemic among adult hospitalized COVID-19 patients although gains varied by subpopulation. These data provide important information on the course of COVID-19 and identify hospitalized patient groups at heightened risk for negative outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT04506528 (https://clinicaltrials.gov/ct2/show/NCT04506528)., Competing Interests: The authors have declared that no competing interests exist.

The onset of mammalian maternal care is associated with plasticity in neural processing of infant-related sensory stimuli; however, little is known about sensory plasticity associated with fatherhood. We quantified behavioral and neural responses of virgin males and new fathers to olfactory and auditory stimuli from young, unfamiliar pups in the biparental California mouse (Peromyscus californicus). Each male was exposed for 10 min to one of four combinations of a chemosensory stimulus (pup-scented or unscented cotton [control]) and an auditory stimulus (pup vocalizations or white noise [control]). Behavior did not differ between fathers and virgins during exposure to sensory stimuli or during the following hour; however, males in both groups were more active both during and after exposure to pup-related stimuli compared to control stimuli. Fathers had lower expression of Fos in the main olfactory bulbs (MOB) but higher expression in the medial preoptic area (MPOA) and bed nucleus of the stria terminalis medial division, ventral part (STMV) compared to virgins. Lastly, males had higher Fos expression in MPOA when exposed to pup odor compared to control stimuli, and when exposed to pup odor and pup calls compared to pup calls only or control stimuli. These findings suggest that the onset of fatherhood alters activity of MOB, MPOA and STMV and that pup odors and vocalizations have additive or synergistic effects on males' behavior and MPOA activation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Borderline personality disorder (BPD) is associated with difficulties in emotion regulation (ER) abilities. Investigations of ER strategies in BPD have been less robust. This systematic review identified 55 studies comparing ER strategy use between individuals diagnosed with BPD versus psychiatric and non-psychiatric comparison groups. Individuals with BPD reported more frequent maladaptive and less frequent adaptive ER strategy use than non-psychiatric controls. Results were less consistent relative to psychiatric comparison groups, though individuals with BPD reported greater self-criticism and avoidance. Groups responded comparably to instructed use of adaptive (but not maladaptive) ER strategies. This body of research would benefit from further examination of the roles of psychiatric comorbidity and problematic behaviours in the relationship between BPD and ER strategies., (© 2022 John Wiley & Sons, Ltd.)

To disentangle the "obesity paradox" in renal cell carcinoma (RCC), we examined associations of body mass index (BMI) and weight change with RCC risk and survival in the Health Professionals Follow-up Study (HPFS) and Nurses' Health Study (NHS) 1 and 2. We estimated cohort-specific and summary covariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for RCC incidence, as well as RCC-specific survival among cases in the pooled HPFS and NHS data. Cumulative average BMI was associated with a higher risk of total RCC (summary HR 2.16, 95% CI 1.77-2.63 for BMI ≥30 vs 18-<25 kg/m 2 ; p trend <0.001) and fatal RCC (HR 2.03, 95% CI 1.37-3.01; p trend <0.001). Prediagnosis BMI was not associated with RCC death. However, first postdiagnosis BMI (HR 0.51, 95% CI 0.29-0.89; p trend 0.006) and prediagnosis to postdiagnosis weight change (HR 0.52, 95% CI 0.29-0.91; p trend 0.001) were significantly inversely associated with RCC death. These results support obesity as a risk factor for total and fatal RCC. They undermine the obesity paradox by suggesting that weight loss around diagnosis, and not low BMI itself, is associated with worse prognosis. PATIENT SUMMARY: We studied obesity in kidney cancer and found that obesity is associated with getting and dying from the disease. Body mass index at diagnosis is not an ideal factor for predicting prognosis, as patients who have lost weight are likely to have more aggressive cancer., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The purpose of this pilot study was to assess the immediate impact of vaping prevention graphic messages on the susceptibility to future vaping among Black and Latino adolescents (ages 12 to 17). Graphic messages (available in English and Spanish) were developed using participatory research procedures with Black and Latino adolescents. Recruitment was conducted by a team of diverse, bilingual (English and Spanish), trained recruiters. Participants ( n = 362) were randomized in a 1:1:1:1 schema to receive one of four graphic messages (health rewards, financial rewards, autonomy, and social norms). Overall, all graphic messages but one showed a slight decrease in the number of participants susceptible to future vaping, though none of these differences was statistically significant. The graphic message on health rewards decreased the number of participants susceptible to future vaping the most (55.7% vs. 50%, at pre- vs. post-viewing, p = 0.125), followed by the graphic messages on social norms and autonomy (55.1% vs. 52.8%, p = 0.687; 55.4% vs. 52.2%, p = 0.435; respectively). The graphic message on financial rewards increased the number of participants susceptible to future vaping slightly (52.7% vs. 53.8%, p = 1.00). Future research is needed to evaluate susceptibility to future vaping before and after exposure to different and/or repeated vaping prevention graphic messages.

Objectives: Rhabdomyolysis in children is a highly variable condition with presentations ranging from myalgias to more severe complications like acute renal failure. We sought to explore demographics and incidence of pediatric rhabdomyolysis hospitalizations and rates of associated renal failure, as our current understanding is limited., Methods: This was a retrospective analysis using the Healthcare Cost and Utilization Project Kids' Inpatient Database to identify children hospitalized with a primary diagnosis of rhabdomyolysis. Data were analyzed for demographic characteristics, as well as geographic and temporal trends. Multivariable logistic regression was used to identify characteristics associated with rhabdomyolysis-associated acute renal failure., Results: From 2006 to 2016, there were 8599 hospitalized children with a primary diagnosis of rhabdomyolysis. Overall, hospitalizations for pediatric rhabdomyolysis are increasing over time, with geographic peaks in the South and Northeast regions, and seasonal peaks in March and August. Though renal morbidity was diagnosed in 8.5% of children requiring hospitalization for rhabdomyolysis, very few of these patients required renal replacement therapy (0.41%), and death was rare (0.03%). Characteristics associated with renal failure included male sex, age greater than 15 years, and non-Hispanic Black race., Conclusions: Though renal failure occurs at a significant rate in children hospitalized with rhabdomyolysis, severe complications, including death, are rare. The number of children hospitalized with rhabdomyolysis varies by geographic region and month of the year. Future studies are needed to explore etiologies of rhabdomyolysis and laboratory values that predict higher risk of morbidity and mortality in children with rhabdomyolysis., (Copyright © 2022 by the American Academy of Pediatrics.)

Background: Hospitalized children have high rates of tobacco smoke exposure; parents who smoke may be receptive to interventions during their child's hospitalization., Objective: We tested the efficacy of a smoking cessation intervention for parents of hospitalized children., Methods: We conducted a randomized, single-blind clinical trial from 12/14-5/18 at the Children's Hospital Colorado. Hospitalized children who had a parent who smoked tobacco were eligible., Intervention: Intervention participants received motivational interviewing sessions, 2 weeks of nicotine replacement therapy; both groups received referral to the Quitline Consenting parents completed a questionnaire; urine was collected from the child for measurement of cotinine. Our primary outcome was: 1) increase in reporting "no one is allowed to smoke anywhere" in the home (smoke-free home rule). Additional outcomes included: 2) change in child's cotinine from baseline to 1 year, and 3) parental quitting at 1 year. Data were analyzed using Chi-square and t tests for bivariable data, and multivariable logistic and linear regression., Results: Of 1641 eligible families approached, 252 were randomized (15%); 149 families had follow-up data at 12 months (59%). In the adjusted analysis, there was no difference between the groups in smoke free home rules, or child cotinine level; in an intention-to-treat analysis, 15% in the intervention group versus 8% of controls reported quit (p=0.07)., Conclusions: A smoking cessation intervention can be delivered to parents of hospitalized children. While hospitalization provides an opportunity to help parents quit smoking, more efficient and effective engagement strategies are needed to optimize tobacco control success., (Copyright © 2021 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Dysregulated anger, and its common behavioral urge, aggression, pose substantial costs to public health and society. Though some studies have shown DBT to be efficacious in treating aggression and anger dyscontrol, the overall effects of DBT on these outcomes are unknown. To address this limitation, a systematic review with meta-analysis was conducted on 34 studies (N = 2536) published in PsycINFO and PubMed between January 1994 and February 2022 assessing the effect of DBT on anger and/or aggression. Included studies were empirical research articles published in a peer-reviewed journal and assessed the delivery of DBT on quantitative outcome measures of anger or aggression. Included studies delivered the standard outpatient DBT program or DBT adapted for the population and treatment setting, though all studies included the core components of DBT. Risk of publication bias was assessed. Results demonstrated that DBT significantly reduced anger (Hedge's G = -0.21, 95% CI [-0.32, -0.11]) independent of study design and participant variables, though longer treatment duration was associated with greater reductions in anger. There was also a non-significant trend for DBT in reducing aggression (Hedge's G = -0.10, 95% CI [-0.21, 0.00]). Findings from this study suggest that DBT demonstrates efficacy in reducing dysregulated anger transdiagnostically., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: How 5-alpha reductase inhibitor (5-ARI) use influences prostate cancer mortality is unclear. The objective of this study was to determine whether men taking 5-ARIs with regular health care access have increased prostate cancer mortality., Methods: We undertook two analyses in the Health Professionals Follow-up Study examining 5-ARI use, determined by biennial questionnaires, and prostate cancer. A cohort analysis followed 38,037 cancer-free men for prostate cancer incidence from 1996 through January 2017 and mortality through January 2019. A case-only analysis followed 4,383 men with localized/locally advanced prostate cancer for mortality over a similar period. HRs and 95% confidence intervals (CI) were calculated for prostate cancer incidence and mortality., Results: Men using 5-ARIs underwent more PSA testing, prostate exams and biopsies. Over 20 years of follow-up, 509 men developed lethal disease (metastases or prostate cancer death). Among men initially free from prostate cancer, 5-ARI use was not associated with developing lethal disease [HR, 1.02; 95% confidence interval (CI), 0.71-1.46], but was associated with reduced rates of overall and localized disease (HR, 0.71; 0.60-0.83). Among men diagnosed with prostate cancer, there was no association between 5-ARI use and cancer-specific (HR, 0.78; 95% CI, 0.48-1.27) or overall survival (HR, 0.88; 95% CI, 0.72-1.07)., Conclusions: Men using 5-ARIs were less likely to be diagnosed with low-risk prostate cancer, without increasing long-term risk of lethal prostate cancer or cancer-specific death after diagnosis., Impact: Our results provide evidence that 5-ARI use is safe with respect to prostate cancer mortality in the context of regular health care access. See related commentary by Hamilton, p. 1259., (©2022 American Association for Cancer Research.)

Objective: A GGGGCC repeat expansion in the C9orf72 gene is the most common cause of genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). As potential therapies targeting the repeat expansion are now entering clinical trials, sensitive biomarker assays of target engagement are urgently required. Our objective was to develop such an assay., Methods: We used the single molecule array (Simoa) platform to develop an immunoassay for measuring poly(GP) dipeptide repeat proteins (DPRs) generated by the C9orf72 repeat expansion in cerebrospinal fluid (CSF) of people with C9orf72 -associated FTD/ALS., Results and Conclusions: We show the assay to be highly sensitive and robust, passing extensive qualification criteria including low intraplate and interplate variability, a high precision and accuracy in measuring both calibrators and samples, dilutional parallelism, tolerance to sample and standard freeze-thaw and no haemoglobin interference. We used this assay to measure poly(GP) in CSF samples collected through the Genetic FTD Initiative (N=40 C9orf72 and 15 controls). We found it had 100% specificity and 100% sensitivity and a large window for detecting target engagement, as the C9orf72 CSF sample with the lowest poly(GP) signal had eightfold higher signal than controls and on average values from C9orf72 samples were 38-fold higher than controls, which all fell below the lower limit of quantification of the assay. These data indicate that a Simoa-based poly(GP) DPR assay is suitable for use in clinical trials to determine target engagement of therapeutics aimed at reducing C9orf72 repeat-containing transcripts., Competing Interests: Competing interests: SP, SM, YL, JG and RB were paid employees of Wave Life Sciences during completion of this work. JDR is on a Medical Advisory Board for Wave Life Sciences. JMS has received research funding from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly), has consulted for Roche Pharmaceuticals, Biogen, Merck and Eli Lilly, given educational lectures sponsored by GE Healthcare, Eli Lilly, and Biogen, and serves on a Data Safety Monitoring Committee for Axon Neuroscience SE. HZ has served at scientific advisory boards for Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies and CogRx, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). JBR has provided consultancy unrelated to the current work for Asceneuron, Astex, Biogen, UCB, SV Health, Curasen., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Secondhand smoke (SHS) exposure creates health risks for non-smokers and is especially detrimental to children. This study evaluated whether immediate feedback in response to poor indoor air quality in children's bedrooms can reduce the potential for SHS exposure, as measured by adherence to a World Health Organization (WHO) indoor air standard., Methods: Homes that contained children and an adult who regularly smoked inside (n=298) had an air particle monitor installed in the child's bedroom. These devices measured the concentration of particulate matter (PM2.5) for approximately three months and, for half of the participants, immediately provided aversive feedback in response to elevated PM2.5. Hierarchical linear models were fit to the data to assess whether the intervention increased the probability that: 1) a given day was below the WHO guideline for daily exposure, and 2) a household established and maintained a smoke-free home (SFH), operationalized as achieving 30 consecutive days below the WHO guideline. The intervention's impact was calculated as group-by-time effects., Results: The likelihood that a child's bedroom met the WHO indoor air quality standard on a given day increased such that the baseline versus post-baseline odds ratio (OR) of maintaining indoor PM2.5 levels below the WHO guideline was 2.38 times larger for participants who received the intervention. Similarly, the baseline versus post-baseline OR associated with achieving an SFH was 3.49 times larger for participants in the intervention group., Conclusions: The real-time intervention successfully drove clinically meaningful changes in smoking behavior that mitigated indoor PM2.5 levels in children's bedrooms and thereby reduced SHS exposure. These results demonstrate the effectiveness of targeting sensitive microenvironments by giving caregivers actionable information about children's SHS risks. Future extensions should examine additional microenvironments and focus on identifying the potential for SHS exposure before it occurs., Competing Interests: The authors have each completed and submitted an ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors declare that they have no competing interests, financial or otherwise, related to the current work. K. M. Wilson reports consulting fees from American Academy of Pediatrics’ Julius B. Richmond Center of Excellence, outside the submitted work., (© 2022 Berardi V. et al.)

SARS-CoV-2 is the causative viral pathogen driving the COVID-19 pandemic that prompted an immediate global response to the development of vaccines and antiviral therapeutics. For antiviral therapeutics, drug repurposing allows for rapid movement of the existing clinical candidates and therapies into human clinical trials to be tested as COVID-19 therapies. One effective antiviral treatment strategy used early in symptom onset is to prevent viral entry. SARS-CoV-2 enters ACE2-expressing cells when the receptor-binding domain of the spike protein on the surface of SARS-CoV-2 binds to ACE2 followed by cleavage at two cut sites by TMPRSS2. Therefore, a molecule capable of inhibiting the protease activity of TMPRSS2 could be a valuable antiviral therapy. Initially, we used a fluorogenic high-throughput screening assay for the biochemical screening of 6030 compounds in NCATS annotated libraries. Then, we developed an orthogonal biochemical assay that uses mass spectrometry detection of product formation to ensure that hits from the primary screen are not assay artifacts from the fluorescent detection of product formation. Finally, we assessed the hits from the biochemical screening in a cell-based SARS-CoV-2 pseudotyped particle entry assay. Of the six molecules advanced for further studies, two are approved drugs in Japan (camostat and nafamostat), two have entered clinical trials (PCI-27483 and otamixaban), while the other two molecules are peptidomimetic inhibitors of TMPRSS2 taken from the literature that have not advanced into clinical trials (compounds 92 and 114). This work demonstrates a suite of assays for the discovery and development of new inhibitors of TMPRSS2.

Objective: This study aimed to investigate the impacts of feature selection on driver cognitive distraction (CD) detection and validation in real-world nonautomated and Level 2 automated driving scenarios., Background: Real-time driver state monitoring is critical to promote road user safety., Method: Twenty-four participants were recruited to drive a Tesla Model S in manual and Autopilot modes on the highway while engaging in the N-back task. In each driving mode, CD was classified by the random forest algorithm built on three "hand-crafted" glance features (i.e., percent road center [PRC], the standard deviation of gaze pitch, and yaw angles), or through a large number of features that were transformed from the output of a driver monitoring system (DMS) and other sensing systems., Results: In manual driving, the small set of glance features was as effective as the large set of machine-generated features in terms of classification accuracy. Whereas in Level 2 automated driving, both glance and vehicle features were less sensitive to CD. The glance features also revealed that the misclassified driver state was the result of the dynamic fluctuations and individual differences of cognitive loads under CD., Conclusion: Glance metrics are critical for the detection and validation of CD in on-road driving., Applications: The paper suggests the practical value of human factors domain knowledge in feature selection and ground truth validation for the development of driver monitoring technologies.

Background: Racial disparities in prostate cancer incidence and mortality rates are considerable. We previously found in the Health Professionals Follow-up Study (HPFS) that African-American men had an 80% higher prostate cancer risk than White men. With 21 additional years of follow-up and four-fold increase in cases, we undertook a contemporary analysis of racial differences in prostate cancer incidence and mortality in HPFS., Methods: For 47,679 men, we estimated HRs and 95% confidence intervals (CI) for the association between race and risk of prostate cancer through 2016 using Cox proportional hazards regression. Multivariable models (mHR) were adjusted for lifestyle, diet, family history, and PSA screening collected on biennial questionnaires., Results: 6,909 prostate cancer cases were diagnosed in White, 89 in African-American, and 90 in Asian-American men. African-Americans had higher prostate cancer incidence (mHR = 1.31; 95% CI, 1.06-1.62) and mortality (mHR = 1.67; 95% CI, 1.00-2.78), and lower PSA screening prevalence than White men. The excess risk was greater in the pre-PSA screening era (HR = 1.68; 95% CI, 1.14-2.48) than the PSA screening era (HR = 1.20; 95% CI, 0.93-1.56). Asian-Americans had lower prostate cancer risk (mHR = 0.74; 95% CI, 0.60-0.92), but similar risk of fatal disease compared with white men., Conclusions: Racial differences in prostate cancer incidence and mortality in HPFS are not fully explained by differences in lifestyle, diet, family history, or PSA screening., Impact: Additional research is necessary to address the disproportionately higher rates of prostate cancer in African-American men., (©2022 American Association for Cancer Research.)

To investigate flexibility in vocal signaling by rodent pups, we examined whether olfactory stimuli influence characteristics of pup calls and how these calls may be affected by sex and litter size in California mice (Peromyscus californicus). Pups were isolated and recorded during a 3-min baseline period followed by a 5-min exposure to bedding containing scent from their home cage, scent from the home cage of an unfamiliar family, coyote urine, or no scent (control). Latency to call, call rate, and call characteristics (duration, frequency, and amplitude) were compared between the baseline and scent-exposure periods and among olfactory conditions. Compared with the control condition, pups from two-pup litters called more quietly when exposed to odor from a predator, whereas pups from three-pup litters called more loudly. Additionally, pups showed nonsignificant tendencies to reduce call rates in response to odors from their home cage and to increase call rates when exposed to predator urine. Last, males produced higher-frequency calls and more ultrasonic vocalizations than females. These results indicate that pup calling behavior in this species can be influenced by acute olfactory stimuli as well as litter size and sex. The flexibility of pup calling in response to these three variables potentially increases the communication value of pup calls and helps shape the parents' responses., (© 2022 Wiley Periodicals LLC.)

Sulpiride in vegetable shortening (VS) stimulates prolactin in horses for up to 10 days. Although effective, a pharmaceutical grade vehicle is needed for clinical application of sulpiride in horses. Sucrose acetate isobutyrate (SAIB), a hydrophobic polymer, may be an alternative to VS. Four in vivo experiments assessed the efficacy of SAIB for delivery of sulpiride, estradiol cypionate (ECP), and estradiol benzoate (EB). The first three studies utilized geldings to compare prolactin and luteinizing hormone (LH) concentrations between sulpiride delivered in VS and SAIB, and ECP or EB delivered in SAIB. Sulpiride stimulated (P < .01) prolactin similarly between vehicles. Geldings pretreated with EB had higher (P < .05) prolactin responses to sulpiride compared to ECP-treated geldings on days 5, 6 and 9. Both estradiol-sulpiride treatments stimulated LH with no differences between ECP and EB. Experiment 3 compared a simultaneous injection of EB-sulpiride to a non-simultaneous injection (one day apart) of EB-sulpiride. Prolactin was stimulated (P < .05) in both treatment groups, but the response lasted 2 days longer in geldings treated a day apart. Plasma LH increased (P < .01) in both groups equally for 10 days. Experiment 4 applied simultaneous and non-simultaneous EB-sulpiride treatments to seasonally anovulatory mares to induce ovarian activity. Prolactin and LH were stimulated similarly between treatments; however, non-simultaneously treated mares tended (P = .07) to have an ovarian response earlier. In conclusion, SAIB was a suitable vehicle for administration of estradiol and sulpiride and could be an alternative to VS for sustained-release drug delivery., (Copyright © 2022. Published by Elsevier Inc.)

Understanding the influence of climate change and population pressure on human conflict remains a critically important topic in the social sciences. Long-term records that evaluate these dynamics across multiple centuries and outside the range of modern climatic variation are especially capable of elucidating the relative effect of—and the interaction between—climate and demography. This is crucial given that climate change may structure population growth and carrying capacity, while both climate and population influence per capita resource availability. This study couples paleoclimatic and demographic data with osteological evaluations of lethal trauma from 149 directly accelerator mass spectrometry 14C-dated individuals from the Nasca highland region of Peru. Multiple local and supraregional precipitation proxies are combined with a summed probability distribution of 149 14C dates to estimate population dynamics during a 700-y study window. Counter to previous findings, our analysis reveals a precipitous increase in violent deaths associated with a period of productive and stable climate, but volatile population dynamics. We conclude that favorable local climate conditions fostered population growth that put pressure on the marginal and highly circumscribed resource base, resulting in violent resource competition that manifested in over 450 y of internecine warfare. These findings help support a general theory of intergroup violence, indicating that relative resource scarcity—whether driven by reduced resource abundance or increased competition—can lead to violence in subsistence societies when the outcome is lower per capita resource availability.

Introduction: Ion mobility-mass spectrometry (IM-MS) is an emerging technique in the -omics fields that has broad potential applicability to the clinical lab. As a rapid, gas-phase structure-based separation technique, IM-MS offers promise in isomer separations and can be easily combined with existing LC-MS methods (i.e., LC-IM-MS). Several experimental conditions, including analyte cation adducts and drift composition further provide a means to tune separations for global and/or targeted applications., Objectives: The primary objective of this study was to demonstrate the utility of IM-MS under a range of experimental conditions for detection of glucocorticoids, and specifically for the separation of several isomeric pairs., Methods: LC-IM-MS was used to characterize 16 glucocorticoids including three isomer pairs: cortisone/prednisolone, betamethasone/dexamethasone, and flunisolide/triamcinolone acetonide. Collision cross section (CCS) values were measured for all common adducts (e.g., protonated and sodiated) using both step-field and single-field methods. Alternative alkali, alkaline earth, and transition metals were introduced, such that their adducts could also be measured. Finally, four different drift gases (helium, nitrogen, argon, and carbon dioxide) were compared for their relative separation capability., Results: LC-IM-MS offered a robust, multidimensional separation technique that allowed for the 16 glucocorticoids to be analyzed and separated in three-dimensions (retention time, CCS, and m / z ). Despite the relatively modest resolution of isomer pairs under standard conditions (i.e., nitrogen drift gas, sodiated ions, etc.), improvements were observed for alkaline earth and transition metals (notable barium adducts) and in carbon dioxide drift gas., Conclusion: In summary, LC-IM-MS offers potential as a clinical method due to its ease of coupling with traditional LC-MS methods and its promise for tuning separations to better resolve targeted and/or global isomers in complex biological samples., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could affect the work described in this article., (© 2022 THE AUTHORS.)