Search

The digitization of healthcare for patient safety and efficiency introduced third party networks into closed hospital systems increasing the probability of cyberattacks and their consequences(1). In April 2021, a major vendor of a Radiation Oncology (RO) record and verify system (RVS) suffered a ransomware attack, affecting our department and many others across the United States. This article summarizes our response to the ransomware event including workflows, team member roles, responsibilities, communications and departmental recovery. The RVS created or housed accurate patient dose records for 6 locations. The immediate response to the ransomware attack was to shut down the system including the ability to treat patients. With the utilization of the hospital EMR and pre-existing interfaces with RVS, the department was able to safely continue patient radiotherapy treatments innovatively utilizing a direct Digital Imaging and Communications in Medicine (DICOM) transfer of patient data to the linear accelerators and implementing paper charting. No patients were treated in the first 24 hours of the attack. Within 48 hours of the ransomware event, 50% of patients were treated, and within 1 week, 95% of all patients were treated using direct DICOM transfer and paper charts. The RVS was completely unavailable for 2.5 weeks and full functionality was not restored for 4.5 weeks. A phased approach was adopted for re-introduction of patient treatments back into the RVS. Human capital costs included communication, outreach, workflow creation, quality assurance and extended clinical hours. Key lessons learned were to have a back-up of essential information, employ 'dry run' emergency training, having consistent parameter requirements across different vendor hardware and software, and having a plan for the recovery effort of restoring normal operations once software is operational. The provided report presents valuable information for the development of cyber-attack preparedness for RO departments., (Copyright © 2021 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Explaining the factors that influence past dietary variation is critically important for understanding changes in subsistence, health, and status in past societies; yet systematic studies comparing possible driving factors remain scarce. Here we compile the largest dataset of past diet derived from stable isotope δ 13 C‰ and δ 15 N‰ values in the Americas to quantitatively evaluate the impact of 7000 years of climatic and demographic change on dietary variation in the Central Andes. Specifically, we couple paleoclimatic data from a general circulation model with estimates of relative past population inferred from archaeologically derived radiocarbon dates to assess the influence of climate and population on spatiotemporal dietary variation using an ensemble machine learning model capable of accounting for interactions among predictors. Results reveal that climate and population strongly predict diet (80% of δ15N‰ and 66% of δ13C‰) and that Central Andean diets correlate much more strongly with local climatic conditions than regional population size, indicating that the past 7000 years of dietary change was influenced more by climatic than socio-demographic processes. Visually, the temporal pattern suggests decreasing dietary variation across elevation zones during the Late Horizon, raising the possibility that sociopolitical factors overrode the influence of local climatic conditions on diet during that time. The overall findings and approach establish a general framework for understanding the influence of local climate and demography on dietary change across human history., (© 2022. The Author(s).)

Intronic GGGGCC (G4C2) hexanucleotide repeat expansion within the human C9orf72 gene represents the most common cause of familial forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of repeat-containing C9orf72 RNA results in the production of neurotoxic dipeptide-repeat proteins (DPRs). Here, we developed a high-throughput drug screen for the identification of positive and negative modulators of DPR levels. We found that HSP90 inhibitor geldanamycin and aldosterone antagonist spironolactone reduced DPR levels by promoting protein degradation via the proteasome and autophagy pathways respectively. Surprisingly, cAMP-elevating compounds boosting protein kinase A (PKA) activity increased DPR levels. Inhibition of PKA activity, by both pharmacological and genetic approaches, reduced DPR levels in cells and rescued pathological phenotypes in a Drosophila model of C9ALS/FTD. Moreover, knockdown of PKA-catalytic subunits correlated with reduced translation efficiency of DPRs, while the PKA inhibitor H89 reduced endogenous DPR levels in C9ALS/FTD patient-derived iPSC motor neurons. Together, our results suggest new and druggable pathways modulating DPR levels in C9ALS/FTD., (© 2021 The Authors Published under the terms of the CC BY NC ND 4.0 license.)

Objectives: Evaluate the association between dexamethasone dosing and outcomes for children hospitalized with croup., Methods: This study was nested within a multisite prospective cohort study of children aged 6 months to 6 years admitted to 1 of 5 US children's hospitals between July 2014 and June /2016. Multivariable linear and logistic mixed-effects regression models were used to examine the association between the number of dexamethasone doses (1 vs >1) and outcomes (length of stay [LOS], cost, and 30-day same-cause reuse). All multivariable analyses included a site-specific random effect to account for clustering within hospital and were adjusted for age, sex, race and ethnicity, presenting severity, medical complexity, insurance, caregiver education, and hospital. In cost analyses, we controlled for LOS., Results: Among 234 children hospitalized with croup, patient characteristics did not differ by number of doses. The proportion receiving >1 dose varied by hospital (range 27.9%-57.1%). In adjusted analyses, >1 dose was not associated with same-cause reuse (odds ratio 0.87 [95% confidence interval (CI): 0.26 to 2.95]) but was associated with 45% longer LOS (relative risk = 1.45 [95% CI: 1.30 to 1.62]). When we controlled for LOS, >1 dose was not associated with differential cost ($-31.2 [95% CI $-424.4 to $362.0]). Eighty-two (35%) children received dexamethasone before presentation., Conclusions: We found significant interhospital variation in dexamethasone dosing and LOS. When we controlled for severity on presentation, >1 dexamethasone dose was associated with longer LOS but not reuse. Although incomplete adjustment for severity is one possible explanation, some providers may routinely keep children hospitalized to administer multiple dexamethasone doses., Competing Interests: FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Objective: To describe challenges in inpatient pediatric quality and safety during the coronavirus disease 2019 (COVID-19) pandemic., Methods: In a previous qualitative study, our team sought to broadly describe changes in pediatric inpatient care during the pandemic. For both that study and this ancillary analysis, we purposefully sampled participants from community and children's hospitals in the 6 US states with the highest COVID-19 hospitalization rates from March to May 2020. We recruited 2 to 3 participants from each hospital (administrators, front-line physicians, nurses, caregivers) for semistructured interviews. We used constant comparative methods to identify themes regarding quality and safety challenges during the pandemic., Results: We interviewed 30 participants from 12 hospitals. Participants described several impacts to clinical workflows, including decreased direct clinician-patient interactions and challenges to communication, partly addressed through innovative use of telehealth technology. Participants reported changes in the discharge and transfer process (eg, discharges, difficulties accessing specialized facilities). Participants also described impacts to hospital operations, including changes in quality monitoring and operations (eg, decreased staff, data collection), increased health risks for clinicians and staff (eg, COVID-19 exposure, testing delays), and staff and supply shortages. Participants voiced concerns that negative quality and safety impacts could include increased risk of preventable safety events and hospital readmissions, and decreased patient engagement, education, and satisfaction., Conclusions: We identified several impacts to clinical workflows and hospital operations during the pandemic that may have affected inpatient pediatric care quality and safety. Our findings highlight potentially important areas of focus for planning pandemic recovery, preparing for future pandemics, and conducting future research on inpatient pediatric quality and safety., Competing Interests: CONFLICT OF INTEREST: The authors have indicated they have no potential conflict of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Background: Experimental and epidemiologic evidence supports the role of circulating insulin-like growth factor-1 (IGF-1) levels with the risk of prostate cancer. Most circulating IGF-1 is bound to specific binding proteins, and only about 5% circulates in a free form. We explored the relation of free IGF-1 and other components of the IGF system with lethal prostate cancer., Methods: Using prospectively collected samples, we undertook a nested case-only analysis among 434 men with lethal prostate cancer and 524 men with indolent, nonlethal prostate cancer in the Physicians' Health Study and the Health Professionals Follow-up Study. Prediagnostic plasma samples were assayed for free IGF-1 and total IGF-1, acid labile subunit, pregnancy-associated plasma protein A (PAPP-A), and intact and total IGF binding protein 4. We estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the associations between IGF-1-related biomarkers and lethal prostate cancer using unconditional logistic regression models adjusted for age, height, and body mass index., Results: Men in the highest quartile of PAPP-A levels had 42% higher odds of lethal prostate cancer (pooled adjusted OR = 1.42, 95% CI = 1.04 to 1.92) compared with men in the lowest 3 quartiles. There were no statistically significant differences in the other plasma analytes. The positive association between PAPP-A and lethal prostate cancer was present among men with intact PTEN but not among those with tumor PTEN loss (2-sided P interaction = .001)., Conclusions: Our study provides suggestive evidence that among men who later develop prostate cancer, higher plasma PAPP-A levels measured prior to diagnosis are associated with increased risk of lethal compared with indolent disease., (© The Author(s) 2021. Published by Oxford University Press.)

Current high-throughput screening assay optimization is often a manual and time-consuming process, even when utilizing design-of-experiment approaches. A cross-platform, Cloud-based Bayesian optimization-based algorithm was developed as part of the National Center for Advancing Translational Sciences (NCATS) ASPIRE (A Specialized Platform for Innovative Research Exploration) Initiative to accelerate preclinical drug discovery. A cell-free assay for papain enzymatic activity was used as proof of concept for biological assay development and system operationalization. Compared with a brute-force approach that sequentially tested all 294 assay conditions to find the global optimum, the Bayesian optimization algorithm could find suitable conditions for optimal assay performance by testing 21 assay conditions on average, with up to 20 conditions being tested simultaneously, as confirmed by repeated simulation. The algorithm could achieve a sevenfold reduction in costs for lab supplies and high-throughput experimentation runtime, all while being controlled from a remote site through a secure connection. Based on this proof of concept, this technology is expected to be applied to more complex biological assays and automated chemistry reaction screening at NCATS, and should be transferable to other institutions.

The successional changes in the early intestinal microbiota occur concomitantly with the development, expansion, and education of the mucosal immune system. Although great attention of researchers has been focused on understanding the linkage between microbiota and immune functions, many essential details of the symbiotic relationship between the intestinal pioneer microbiota and the avian immune system remain to be discovered. This study was conducted to understand the impact of different early life intestinal colonizers on innate and adaptive immune processes in chicks and further identify immune-associated proteins expressed in the intestinal tissue. To accomplish it, we performed an in ovo application of two apathogenic Enterobacteriaceae isolates and lactic acid bacteria (L) to determine their influences on the intestinal proteome profile of broilers at the day of hatch (DOH) and at 10 days old. The results indicated that there were predicted biological functions of L-treated chicks associated with the activation and balanced function of the innate and adaptive immune systems. At the same time, the Enterobacteriaceae- exposed birds presented dysregulated immunological mechanisms or downregulated processes related to immune development. Those findings suggested that a proper immune function was dependent on specific gut microbiota exposure, in which the prenatal probiotic application may have favored the fitting programming of immune functions in chicks., 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 © 2021 Rodrigues, Wilson and Bielke.)

Objectives: The number of hospitalized coronavirus disease 2019 patients in March 2020 to April 2020 in our New York City hospital required increased physician staffing, including deployment of pediatricians to adult care. To improve the deployment process, we sought to understand the mindset, preparations for, and experience during deployment of pediatric faculty in our institution., Methods: Faculty members of the Department of Pediatrics completed pre- and postsurveys evaluating perspectives, fears, and preparations relevant to deployment. Demographic characteristics of the faculty members were collected. Survey questions included Likert scale, multiple choice, and free-text responses. Descriptive statistics, Fisher's exact test, and χ 2 test were used to compare groups. Free-text responses were categorized by topic. Survey responses were shared with leadership in real time and adjustments to the deployment process made., Results: The predeployment survey was sent to 202 pediatric faculty members, with a 29% ( n = 59) completion rate. Of the 36 deployed faculty, 29 (81%) completed all items of the postsurvey. The majority (74%, n = 42) expressed discomfort with care of adults and fear and/or nervousness about deployment (61%, n = 35). Most faculty (88%, n = 52) prepared for deployment and cited local guidelines and published literature as helpful preparation materials (55%, n = 16). Dissemination of details about schedules and role clarification before deployment were areas for improvement., Conclusions: Pediatric faculty facing deployment to adult care have concerns about the process of deployment as well as the work itself. Specific information distributed in advance, along with consistent and frequent communication, may help mitigate these fears., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

The use of Bruton tyrosine kinase (BTK) inhibitors to block B-cell receptor (BCR)-dependent NF-κB activation in lymphoid malignancies has been a major clinical advance, yet acquired therapeutic resistance is a recurring problem. We modeled the development of resistance to the BTK inhibitor ibrutinib in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma, which relies on chronic active BCR signaling for survival. The primary mode of resistance was epigenetic, driven in part by the transcription factor TCF4. The resultant phenotypic shift altered BCR signaling such that the GTPase RAC2 substituted for BTK in the activation of phospholipase Cγ2, thereby sustaining NF-κB activity. The interaction of RAC2 with phospholipase Cγ2 was also increased in chronic lymphocytic leukemia cells from patients with persistent or progressive disease on BTK inhibitor treatment. We identified clinically available drugs that can treat epigenetic ibrutinib resistance, suggesting combination therapeutic strategies., Significance: In diffuse large B-cell lymphoma, we show that primary resistance to BTK inhibitors is due to epigenetic rather than genetic changes that circumvent the BTK blockade. We also observed this resistance mechanism in chronic lymphocytic leukemia, suggesting that epigenetic alterations may contribute more to BTK inhibitor resistance than currently thought. See related commentary by Pasqualucci, p. 555 . This article is highlighted in the In This Issue feature, p. 549 ., (©2021 American Association for Cancer Research.)

Background: The COVID-19 pandemic has necessitated rapid changes in healthcare delivery in the United States, including changes in the care of hospitalized children. The objectives of this study were to identify major changes in healthcare delivery for hospitalized children during the COVID-19 pandemic, identify lessons learned from these changes, and compare and contrast the experiences of children's and community hospitals., Methods: We purposefully sampled participants from both community and children's hospitals serving pediatric patients in the six U.S. states with the highest COVID-19 hospitalization rates at the onset of the pandemic. We recruited 2-3 participants from each hospital (mix of administrators, front-line physicians, nurses, and parents/caregivers) for semi-structured interviews. We analyzed interview data using constant comparative methods to identify major themes., Results: We interviewed 30 participants from 12 hospitals. Participants described how leaders rapidly developed new hospital policies (e.g., directing use of personal protective equipment) and how this was facilitated by reviewing internal and external data frequently and engaging all relevant stakeholders. Hospital leaders optimized communication through regular, transparent, multi-modal, and bi-directional communication. Clinicians increased use of videoconference and telehealth to facilitate physical distancing, but these technologies may have disadvantaged non-English speakers. Due to declining volumes of hospitalized children and surges of adult patients, clinicians newly provided care for hospitalized adults. This was facilitated by developing care teams supported by adult hospitalists, multidisciplinary support via videoconference, and educational resources. Participants described how the pandemic negatively impacted clinicians' mental health, and they stressed the importance of mental health resources and wellness activities/spaces., Conclusions: We identified several major changes in inpatient pediatric care delivery during the COVID-19 pandemic, including the adoption of new hospital policies, video communication, staffing models, education strategies, and staff mental health supports. We outline important lessons learned, including strategies for successfully developing new policies, effectively communicating with staff, and supporting clinicians' expanding scope of practice. Potentially important focus areas in pandemic recovery include assessing and supporting clinicians' mental health and well-being, re-evaluating trainees' skills/competencies, and adapting educational strategies as needed. These findings can help guide hospital leaders in supporting pandemic recovery and addressing future crises., (© 2021. The Author(s).)

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56 dim CD57 + natural killer (NK) cells and exhausted CD8 + T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8 + T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C., (© 2021. The Author(s).)

Introduction: This multiyear, cross-sectional study explores the changes over time in how U.S. middle- and high-school students perceive the harm and addiction risk of E-cigarettes., Methods: This study analyzed 83,779 participants in the National Youth Tobacco Survey from 2015 to 2019. Associations of survey year with perceived harm and addiction risk of E-cigarettes were assessed using multivariable multinomial logistic regression models, adjusted for sociodemographic characteristics., Results: Smoking decreased over the 5 years (-1.85 percentage points, p=0.07); vaping increased (9.03 percentage points, p<0.01). Perceived harm of both combustible cigarettes and E-cigarettes increased with time. Male, older, and non-White students perceived less harm from smoking or vaping. Perceptions of the addictiveness of E-cigarettes increased over time: 26.31% of students considered E-cigarettes to be more addictive than combustible cigarettes in 2019, compared with 7.26% in 2016. Female and non-White students were more likely to think that E-cigarettes were at least as addictive as combustible cigarettes but also reported less knowledge about them., Conclusions: The perceptions of both harm and addictiveness of E-cigarettes have increased over time, independent of current use. Perceptions vary on the basis of age, sex, race/ethnicity, and current use. Efforts should be made to further educate adolescents about E-cigarettes and to regulate their sale and advertisement. Efforts to reduce the uptake of combustible cigarettes among adolescents have been successful and should be duplicated for E-cigarettes., (Copyright © 2021 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Using insurance as a single indicator of healthcare access in examining the association between race/ethnicity and healthcare encounter-based interventions for smoking may not be adequate. In this study, we assessed the role of healthcare access using multifactorial measures in accounting for racial/ethnic disparities in the receipt of provider-patient discussions, defined as either being asked about smoking or advised to quit smoking by providers. We identified adult current smokers from the 2015 National Health Interview Survey. We first conducted a latent class analysis (LCA) to identify the underlying patterns of healthcare access measured by 13 indicators of healthcare access and utilization. We then used a propensity score - based weighting approach to examine racial/ethnic disparities in receiving provider-patient discussions about smoking or quitting in stratified groups by the distinct healthcare access clusters. Out of the 4134 adult current smokers who visited a doctor or a healthcare provider during the past 12 months, 3265 (79.90%) participants were classified as having high healthcare access and 869 (20.10%) participants as having low healthcare access. Compared to non-Hispanic whites, Hispanics had significantly lower odds of being asked about smoking (OR 0.46, 95% CI (0.27-0.77)) and being advised to quit (OR 0.57, 95% CI (0.34-0.97)) in the low access group, but neither association was significant in the high access group. In addition to increasing health insurance coverage, reducing other healthcare access barriers for Hispanics will likely facilitate provider-patient discussion and promote tobacco cessation among Hispanic smokers., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The objectives were: 1) to explore the discordance between the Patient Global Health Assessment (PtGA) scores, the Physician Global Health Assessment (PhGA) scores, and Pain scores; and 2) to explore whether the PtGA during disease remission is associated with future disease flare in pJIA., Methods: Data from an NIH funded clinical trial (NCT00792233) evaluating flare were used (N = 137). PtGA, PhGA, and Pain scores were assessed. Flare was defined as any active arthritis. Spearman's correlation coefficients were calculated, and multivariable logistic regression was performed., Results: 122 patients had records of flare status, of which 63 developed flare, and 42 of these patients had a visit immediately prior to flare. For study subjects with a visit immediately prior to flare, the PtGA, pain scores, and PhGA all increased at time of flare. For every unit increase in PtGA and Pain scores, there was a 9% and 23% higher odds of developing flare, respectively (p = 0.76, p = 0.40). For every unit increase in the PhGA score, there was a substantially lower odds of developing flare (p = 0.05)., Conclusion: Our results demonstrate that the PtGA and Pain scores are strongly correlated with each other and increased at the visit prior to flare, while the PhGA scores are not. Further, the PtGA and Pain score have some predictive value for flare, while the PhGA does not. These findings highlight the value of patient input in medical care and decision-making, and support the development and use of more sophisticated PROs in the care of JIA patients.

Renewed debate over what benefits females might gain from producing extra-pair offspring emphasizes the possibility that apparent differences in quality between within-pair and extra-pair offspring are confounded by greater maternal investment in extra-pair offspring. Moreover, the attractiveness of a female's social mate can also influence contributions of both partners to a reproductive attempt. Here, we explore the complexities involved in parental investment decisions in response to extra-pair offspring and mate attractiveness with a focus on the female point of view. Adult zebra finches paired and reproduced in a colony setting. A male's early-life diet quality and his extra-pair reproductive success were used as metrics of his mating attractiveness. Females paired with males that achieved extra-pair success laid heavier eggs than other females and spent less time attending their nests than their mates or other females. Extra-pair nestlings were fed more protein-rich hen's egg than within-pair nestlings. Females producing extra-pair offspring had more surviving sons than females producing only within-pair offspring. Collectively, results show that females differentially allocate resources in response to offspring extra-pair status and their social mate's attractiveness. Females may also obtain fitness benefits through the production of extra-pair offspring., Competing Interests: KMW and NTB declare no conflicts of interests., (© 2021 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Background: The TMPRSS2:ERG gene fusion and PTEN loss are two of the most common somatic molecular alterations in prostate cancer. Here, we investigated the association of prediagnostic-circulating metabolomics and prostate cancer defined by ERG or PTEN status to improve understanding of these etiologically distinct molecular prostate cancer subtypes., Methods: The study was performed among 277 prostate cancer cases with ERG status, 211 with PTEN status, and 294 controls nested in the Health Professionals Follow-up Study (HPFS) and the Physicians' Health Study (PHS). We profiled 223 polar and non-polar metabolites using LC-MS in prediagnostic plasma specimens. We applied enrichment analysis and multinomial logistic regression models to identify biological metabolite classes and individual metabolites associated with prostate cancer defined by ERG or PTEN status., Results: Compared with noncancer controls, sphingomyelin ( P : 0.01), ceramide ( P : 0.04), and phosphatidylethanolamine ( P : 0.03) circulating levels were enriched among ERG-positive prostate cancer cases. Sphingomyelins ( P : 0.02), ceramides ( P : 0.005), and amino acids ( P : 0.02) were enriched among tumors exhibiting PTEN-loss; unsaturated diacylglycerols ( P : 0.003) were enriched among PTEN-intact cases; and unsaturated triacylglycerols were enriched among both PTEN-loss ( P : 0.001) and PTEN-intact ( P : 0.0001) cases. Although several individual metabolites identified in the above categories were nominally associated with ERG or PTEN-defined prostate cancer, none remained significant after accounting for multiple testing., Conclusions: The molecular process of prostate carcinogenesis may be distinct for men with different metabolomic profiles., Impact: These novel findings provide insights into the metabolic environment for the development of prostate cancer., (©2021 American Association for Cancer Research.)

Background: While public knowledge on the prevalence and adverse health effects of secondhand tobacco smoke exposure is well established, information on the prevalence of secondhand marijuana smoke (SHMS) exposure is limited., Methods: A convenience sample of parents of children attending 1 of 4 pediatric practices in the Mount Sinai Health System completed an anonymous questionnaire assessing demographics, housing characteristics, and the child's health status, as well as smoke incursions and household smoking behaviors., Results: About 450 parents completed the survey between 2018 and 2019; those with incomplete data were excluded, and 382 surveys were included in the analysis. Approximately 40% of the children were white; the median age was 15 months (interquartile range: 5-40 months). About 30.9% (n = 118) of participants reported marijuana incursions in their home while with their child, while 33.5% (n = 122) reported tobacco smoke incursions. SHMS exposure differed by race (P = .0043); and by housing types (P < .0001). Participants in New York City Housing Authority (NYCHA) developments were more likely to report smelling SHMS (adjusted odds ratio = 3.45, 95% confidence interval = 1.18, 10.10], P = .02). Those in Section 8 housing were also more likely to report smelling SHMS, but the association was not significant (adjusted odds ratio = 3.29, 95% confidence interval = 0.94, 11.55, P = .06). Approximately two thirds of the participants reported viewing marijuana smoke as being harmful to their child., Conclusions: About one third of the families enrolled in the study reported smelling SHMS while at home with their child. Reported marijuana smoke exposure was associated with living in NYCHA housing. Policies that limit all smoke in multiunit housing should be supported., (Copyright © 2021 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Objective: We aimed to examine the influence of increasing levels of discussion (both asked and advised, either asked or advised but not both, and neither asked nor advised) on quit behavior., Methods: We included 4133 adult current smokers from the 2015 National Health Interview Survey. The primary outcomes were quit intent and quit attempt, and the secondary outcomes were methods used for quitting. We used an instrumental variable analysis, as well as propensity score weighted and multivariable logistic regressions., Results: Compared to no discussion, having both or only one discussion, respectively, increased quit intent (OR = 1.65, 95% CI = 1.63-1.66 and OR = 1.02, 95% CI = 0.99-1.05), quit attempt (OR = 1.76, 95% CI = 1.75-1.77 and OR = 1.60, 95% CI = 1.57-1.63). Among those who attempted to quit (n = 1536), having both or only one discussion increased the use of pharmacologic (OR = 1.99, 95% CI = 1.97-2.02 and OR = 1.56, 95% CI = 1.49-1.63) or behavioral (OR = 2.01, 95% CI = 1.94-2.08 and OR = 2.91, 95% CI = 2.74-3.08) quit methods., Conclusions: Increasing levels of provider-patient discussion encourages quit behavior, and should be an integral part of reducing the health and economic burden of smoking. Strategies that promote the adherence and compliance of providers to communicate with patients may help increase the success of smoking cessation.

Small cell neuroendocrine cancers (SCNCs) are recalcitrant cancers arising from diverse primary sites that lack effective treatments. Using chemical genetic screens, we identified inhibition of ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, and topoisomerase I (TOP1), nuclear enzyme that suppresses genomic instability, as synergistically cytotoxic in small cell lung cancer (SCLC). In a proof-of-concept study, we combined M6620 (berzosertib), first-in-class ATR inhibitor, and TOP1 inhibitor topotecan in patients with relapsed SCNCs. Objective response rate among patients with SCLC was 36% (9/25), achieving the primary efficacy endpoint. Durable tumor regressions were observed in patients with platinum-resistant SCNCs, typically fatal within weeks of recurrence. SCNCs with high neuroendocrine differentiation, characterized by enhanced replication stress, were more likely to respond. These findings highlight replication stress as a potentially transformative vulnerability of SCNCs, paving the way for rational patient selection in these cancers, now treated as a single disease., Competing Interests: Declaration of interests H.D., A.Z., and F.T.Z. are employees of Merck KGaA, Darmstadt, Germany. B.E. is an employee of the EMD Serono Research & Development Institute Inc., Billerica, MA, USA; a business of Merck KGaA, Darmstadt, Germany. J.P. was an employee of the EMD Serono Research & Development Institute Inc., Billerica, MA, USA at the time of study. A.T., and Y.P. report research funding to the institution from the following entities: EMD Serono Research & Development Institute Inc., Billerica, MA, USA, AstraZeneca, Tarveda Therapeutics, and Prolynx Inc., (Published by Elsevier Inc.)

The objective of this research was to investigate potential changes to unfolding energy barriers for ubiquitin in the presence of the noncanonical amino acid β-methylamino-l-alanine (BMAA). Although BMAA has been implicated in neurodegenerative disease, its specific role remains unclear. We hypothesized that formation of a ubiquitin + BMAA noncovalent complex would alter the protein's unfolding dynamics in comparison with native ubiquitin alone or in noncovalent complexes with other amino acids. Ion mobility-mass spectrometry (IM-MS) revealed that at sufficiently high concentrations BMAA did in fact form a noncovalent complex with ubiquitin, and similar complexes were identified for a range of additional amino acids. Collision-induced unfolding (CIU) was used to interrogate the unfolding of native ubiquitin and these Ubq-amino acid complexes, showing a major transition from its compact native state (∼1200 Å 2 ) to an unfolded state (∼1400 Å 2 ) at activation energies in the range from 8.0 to 9.0 V (entrance grid delta). The Ubq-BMAA complex, on the other hand, was observed to have a significantly higher energy barrier to unfolding, requiring more than 10.5 V. This indicates that the complex remains more stable under native conditions and this may indicate that BMAA has attached to a critical binding location worthy of further study for its potential role in the onset of neurodegenerative disease.

Background: Biomarkers of exposure to marijuana smoke can be detected in the urine of children with exposure to secondhand marijuana smoke, but the prevalence is unclear., Methods: We studied children between the ages of 0 to 3 years who were coming in for well-child visits or hospitalized on the inpatient general pediatric unit between 2017 and 2018 at Kravis Children's Hospital at Mount Sinai. Parents completed an anonymous survey, and urine samples were analyzed for cotinine and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC), a metabolite of Δ9-tetrahydrocannabinol., Results: Fifty-three children had urine samples available for analysis. COOH-THC was detectable in 20.8% of the samples analyzed and urinary cotinine was detectable in 90.2%. High levels of tobacco exposure (defined as cotinine ≥2.0 ng/ml) were significantly associated with COOH-THC detection (p < 0.01). We found that 34.8% of children who lived in attached housing where smoking was allowed within the property had detectable COOH-THC compared to 13.0% of children who lived in housing where smoking was not allowed at all., Conclusions: This study adds to the growing evidence that children are being exposed to marijuana smoke, even in places where recreational marijuana use is illegal. It is critical that more research be done on the impact of marijuana smoke exposure on children's health and development., Impact: We found that 20.8% of the 53 children recruited from Mount Sinai Hospital had detectable marijuana metabolites in their urine. Children with household tobacco smoke exposure and children who lived in attached housing where smoking was allowed on the premises were more likely to have detectable marijuana smoke metabolites. This study adds to the growing evidence that children are being exposed to marijuana smoke, even in places where marijuana remains illegal by state law. As states consider marijuana legalization, it is critical that the potential adverse health effects from marijuana exposure in children be taken into account.

Relapsed pediatric rhabdomyosarcomas (RMS) and neuroblastomas (NBs) have a poor prognosis despite multimodality therapy. In addition, the current standard of care for these cancers includes vinca alkaloids that have severe toxicity profiles, further underscoring the need for novel therapies for these malignancies. Here, we show that the small-molecule rigosertib inhibits the growth of RMS and NB cell lines by arresting cells in mitosis, which leads to cell death. Our data indicate that rigosertib, like the vinca alkaloids, exerts its effects mainly by interfering with mitotic spindle assembly. Although rigosertib has the ability to inhibit oncogenic RAS signaling, we provide evidence that rigosertib does not induce cell death through inhibition of the RAS pathway in RAS-mutated RMS and NB cells. However, the combination of rigosertib and the MEK inhibitor trametinib, which has efficacy in RAS-mutated tumors, synergistically inhibits the growth of an RMS cell line, suggesting a new avenue for combination therapy. Importantly, rigosertib treatment delays tumor growth and prolongs survival in a xenograft model of RMS. In conclusion, rigosertib, through its impact on the mitotic spindle, represents a potential therapeutic for RMS., (©2020 American Association for Cancer Research.)

Background: We sought to evaluate whether elective caesarean section is associated with subsequent hospitalization for bronchiolitis., Methods: This is a retrospective cohort study that used the electronic medical record database of Clalit Health Services, the largest healthcare fund in Israel, serving over 4.5 million members and over half of the total population. The primary outcome was bronchiolitis admission in the first 2 years of life. We performed logistic regression analyses to identify independent associations. We repeated the analysis using boosted decision tree machine learning techniques to confirm our findings., Results: There were 124 553 infants enrolled between 2008 and 2010, and 5168 (4.1%) were hospitalized for bronchiolitis in the first 2 years of life. In logistic regression models stratified by seasons, elective caesarean section birth was associated with 15% increased odds (95% CI: 1.02-1.30) for infants born in the fall season, 28% increased odds (95% CI: 1.11, 1.47) for those born in the winter, 35% increased odds (95% CI: 1.12-1.62) for those born in the spring and 37% increased odds (95% CI: 1.18-1.60) for those born in the summer. In the boosted gradient decision tree analysis, the area under the curve for risk of bronchiolitis admission was 0.663 (95% CI: 0.652, 0.674) with timing of birth as the most important feature., Conclusion: Elective caesarean section, a potentially modifiable risk factor, is associated with increased odds of hospitalization for bronchiolitis in the first 2 years of life. These data should be considered when scheduling elective caesarean sections especially for infants born in spring and summer months., (© 2020 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Drug repurposing is a rapid approach to identify therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drugs and 49 investigational drugs. The anti-SARS-CoV-2 activities of 230 of these confirmed compounds, of which 38 are approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA-approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set is a useful resource for drug repurposing efforts, including design of new drug combinations for clinical trials for SARS-CoV-2., 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 © 2021 Chen, Shinn, Itkin, Eastman, Bostwick, Rasumussen, Huang, Shen, Hu, Wilson, Brooks, Guo, Zhao, Klump-Thomas, Simeonov, Michael, Lo, Hall and Zheng.)

Objective: Many children experience tobacco smoke exposure (TSE) and parents may take preventive measures to reduce TSE. The study goal is to assess if these strategies are associated with lower cotinine values, an objective biological measure of TSE., Methods: Families admitted to Children's Hospital Colorado from 2014 to 2018 who screened positive for TSE were invited to participate in a tobacco smoking cessation/reduction program. Caregivers were consented and asked about demographics, beliefs around smoking, and strategies to reduce TSE. Child urine samples were collected, tested for cotinine levels, and analyzed using geometric means. Bivariable comparisons and multivariable linear regression were completed using SAS v9.4 (SAS Institute, Cary, NC)., Results: Two hundred thirteen children (81.4%) are included in this analysis. The median ages of children and parents were 4 and 32 years respectively. Fifty-seven percent of children were male, 36% were Hispanic, and 55% were white. Fifty-six percent of parents had at least some college education and 69% had an annual income less than $50K. The median daily cigarettes smoked per day were 10. Eighty-eight percent reported using at least 1 type of protective measure to prevent TSE and 90% believed they protect other household members from TSE. None of the strategies had a significant relationship with lower cotinine levels on bivariable or multivariable analyses., Conclusions: Parental strategies to decrease TSE did not result in lower cotinine levels. Many measures are not evidence-based and do not protect children. Parent's clothing and homes may create a reservoir for nicotine. Education should focus on exposure elimination and cessation rather than protective measures., (Copyright © 2020 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine practices and beliefs of pediatric hospitalists regarding smoking cessation counseling for caregivers of hospitalized children., Methods: An electronic survey was distributed to 249 members of the Pediatric Research in Inpatient Settings Network over 6 weeks in 2017 (83 responses [33%]). Questions explored beliefs regarding the impact of tobacco smoke exposure (TSE) and practices in TSE screening, provision of counseling, resources, and pharmacotherapy. Nonparametric tests were used to compare groups on numeric variables, χ 2 tests were used to compare groups on nominal variables, and McNemar's test was used to compare dichotomous responses within subjects., Results: All respondents were familiar with the term "secondhand smoke," and >75% were familiar with "thirdhand smoke" (THS). Familiarity with THS was associated with more recent completion of training ( P = .04). Former smokers (7%) were less likely to agree that THS has a significant impact on a child's health ( P = .04). Hospitalists ask about TSE more often than they provide counseling, resources, or pharmacotherapy to caregivers who want to quit smoking. Hospitalists are more likely to ask about TSE and provide cessation counseling when patients have asthma as opposed to other diseases. Time was identified by 41% of respondents as a barrier for providing counseling and by 26% of respondents as a barrier for providing resources. Most respondents never prescribe pharmacotherapy (72%), nor do they follow-up with caregivers after hospitalization regarding cessation (87%)., Conclusions: Although most respondents ask about TSE, opportunities are missed for counseling and providing support to caregivers who want to quit smoking. Providers should be educated about THS, and systems should be streamlined to facilitate brief counseling sessions., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Wilson is deputy editor of Hospital Pediatrics; and Drs Dickinson, Thompson, and Gracely have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Objectives: Understanding patterns of parental tobacco use and their association with child exposure can help us target interventions more appropriately. We aimed to examine the association between parental smoking practices and cotinine levels of hospitalized children., Methods: This is a secondary analysis of data collected from parents of hospitalized children, recruited for a cessation intervention randomized controlled trial. Smoking parents were identified by using a medical record screening question. Parent-reported demographics and smoking habits were compared to child urine cotinine by using geometric means and log-transformed cotinine levels in multivariable linear regression analyses., Results: A total of 213 patients had complete baseline parent-interview and urine cotinine data. The median age was 4 (interquartile range: 1-9); 57% were boys; 56% were white, 12% were Black, and 23% were multiracial; 36% identified as Hispanic. Most families (54%) had 1 smoker in the home; 36% had 2, and 9% had ≥3. Many (77%) reported having a ban on smoking in the home, and 86% reported smoking only outside. The geometric mean cotinine level of the cohort was 0.98 ng/mL. Higher cotinine levels were associated with more smokers in the home (ratio of 2.99) and smoking inside the house (ratio of 4.11)., Conclusions: Having more smokers in the home and parents who smoke inside are associated with increased smoke exposure; however, even children whose families who smoke only outside the home have significant levels of cotinine, a marker for toxin exposure., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Background: Adherence to a healthy diet has been associated with reduced risk of chronic diseases. Identifying nutritional biomarkers of diet quality may be complementary to traditional questionnaire-based methods and may provide insights concerning disease mechanisms and prevention., Objective: To identify metabolites associated with diet quality assessed via the Alternate Healthy Eating Index (AHEI) and its components., Methods: This cross-sectional study used FFQ data and plasma metabolomic profiles, mostly lipid related, from the Nurses' Health Study (NHS, n = 1460) and Health Professionals Follow-up Study (HPFS, n = 1051). Linear regression models assessed associations of the AHEI and its components with individual metabolites. Canonical correspondence analyses (CCAs) investigated overlapping patterns between AHEI components and metabolites. Principal component analysis (PCA) and explanatory factor analysis were used to consolidate correlated metabolites into uncorrelated factors. We used stepwise multivariable regression to create a metabolomic score that is an indicator of diet quality., Results: The AHEI was associated with 83 metabolites in the NHS and 96 metabolites in the HPFS after false discovery rate adjustment. Sixty-three of these significant metabolites overlapped between the 2 cohorts. CCA identified "healthy" AHEI components (e.g., nuts, whole grains) and metabolites (n = 27 in the NHS and 33 in the HPFS) and "unhealthy" AHEI components (e.g., red meat, trans fat) and metabolites (n = 56 in the NHS and 63 in the HPFS). PCA-derived factors composed of highly saturated triglycerides, plasmalogens, and acylcarnitines were associated with unhealthy AHEI components while factors composed of highly unsaturated triglycerides were linked to healthy AHEI components. The stepwise regression analysis contributed to a metabolomics score as a predictor of diet quality., Conclusion: We identified metabolites associated with healthy and unhealthy eating behaviors. The observed associations were largely similar between men and women, suggesting that metabolomics can be a complementary approach to self-reported diet in studies of diet and chronic disease., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Despite decades of research, we still lack a clear explanation for the emergence and persistence of inequality. Here we propose and evaluate a marginal utility of inequality hypothesis that nominates circumscription and environmental heterogeneity as independent, necessary conditions for the emergence of intragroup material inequality. After coupling the Standard Cross-Cultural Sample (SCCS) with newly generated data from remote sensing, we test predictions derived from this hypothesis using a multivariate generalized additive model that accounts for spatial and historical dependence as well as subsistence mode. Our analyses show that the probability a society will be stratified increases significantly as a function of proxies of environmental heterogeneity and environmental circumscription. This supports the hypothesis that increasing environmental heterogeneity and circumscription drives the emergence and persistence of inequality among documented societies across the globe. We demonstrate how environmental heterogeneity and circumscription produce situations that limit individuals' options so that some may find it in their best interest to give up some autonomy for material gain, while others may find it in their best interest to give up some material resources for another individual's time or deference. These results support the marginal utility of inequality framework and enable future explorations of the ecological conditions that facilitate the emergence of intragroup inequality through time and across the globe.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in industrialized countries and has limited treatment options. Targeting ataxia-telangiectasia and Rad3-related/cell-cycle checkpoint kinase 1 (CHK1)-mediated S-phase and G 2 -M-phase cell-cycle checkpoints has been a promising therapeutic strategy in HGSOC. To improve the efficacy of CHK1 inhibitor (CHK1i), we conducted a high-throughput drug combination screening in HGSOC cells. PI3K/mTOR pathway inhibitors (PI3K/mTORi) showed supra-additive cytotoxicity with CHK1i. Combined treatment with CHK1i and PI3K/mTORi significantly attenuated cell viability and increased DNA damage, chromosomal breaks, and mitotic catastrophe compared with monotherapy. PI3K/mTORi decelerated fork speed by promoting new origin firing via increased CDC45, thus potentiating CHK1i-induced replication stress. PI3K/mTORi also augmented CHK1i-induced DNA damage by attenuating DNA homologous recombination repair activity and RAD51 foci formation. High expression of replication stress markers was associated with poor prognosis in patients with HGSOC. Our findings indicate that combined PI3K/mTORi and CHK1i induces greater cell death in HGSOC cells and in vivo models by causing lethal replication stress and DNA damage. This insight can be translated therapeutically by further developing combinations of PI3K and cell-cycle pathway inhibitors in HGSOC. SIGNIFICANCE: Dual inhibition of CHK1 and PI3K/mTOR pathways yields potent synthetic lethality by causing lethal replication stress and DNA damage in HGSOC, warranting further clinical development., (©2020 American Association for Cancer Research.)

The COVID-19 pandemic, caused by SARS-CoV-2, is a pressing public health emergency garnering a rapid response from scientists across the globe. Host cell invasion is initiated through direct binding of the viral spike protein to the host receptor angiotensin-converting enzyme 2 (ACE2). Disrupting the spike protein-ACE2 interaction is a potential therapeutic target for treating COVID-19. We have developed a proximity-based AlphaLISA assay to measure the binding of SARS-CoV-2 spike protein receptor binding domain (RBD) to ACE2. Utilizing this assay platform, a drug-repurposing screen against 3384 small-molecule drugs and preclinical compounds was carried out, yielding 25 high-quality primary hits, of which only corilagin was validated in cherry-picking. This established AlphaLISA RBD-ACE2 platform can facilitate evaluation of biologics or small molecules that can perturb this essential viral-host interaction to further the development of interventions to address the global health pandemic., Competing Interests: The authors declare no competing financial interest., (This article not subject to U.S. Copyright. Published 2020 by American Chemical Society.)

Initially, children were thought to be spared from disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a month into the epidemic, a novel multisystem inflammatory syndrome in children (MIS-C) emerged. Herein, we report on the immune profiles of nine MIS-C cases. All MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with intact neutralization capability. Cytokine profiling identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1), and mucosal immune dysregulation (IL-17A, CCL20, and CCL28). Immunophenotyping of peripheral blood revealed reductions of non-classical monocytes, and subsets of NK and T lymphocytes, suggesting extravasation to affected tissues. Finally, profiling the autoantigen reactivity of MIS-C plasma revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal, and immune-cell antigens. All patients were treated with anti-IL-6R antibody and/or IVIG, which led to rapid disease resolution., Competing Interests: Declaration of Interests DB reports ownership in Lab11 Therapeutics. S. Gnjatic reports consultancy and/or advisory roles for Merck, Neon Therapeutics and OncoMed and research funding from Bristol-Myers Squibb, Genentech, Immune Design, Agenus, Janssen R&D, Pfizer, Takeda, and Regeneron., (Published by Elsevier Inc.)

Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors are the Associate Editor (Dr Schroeder), Deputy Editor (Dr Wilson), and Editor-in-Chief (Dr Ralston) for Hospital Pediatrics.

Objective: Coffee may protect against multiple chronic diseases, particularly type 2 diabetes, but the mechanisms remain unclear., Research Design and Methods: Leveraging dietary and metabolomic data in two large cohorts of women (the Nurses' Health Study [NHS] and NHSII), we identified and validated plasma metabolites associated with coffee intake in 1,595 women. We then evaluated the prospective association of coffee-related metabolites with diabetes risk and the added predictivity of these metabolites for diabetes in two nested case-control studies ( n = 457 case and 1,371 control subjects)., Results: Of 461 metabolites, 34 were identified and validated to be associated with total coffee intake, including 13 positive associations (primarily trigonelline, polyphenol metabolites, and caffeine metabolites) and 21 inverse associations (primarily triacylglycerols [TAGs] and diacylglycerols [DAGs]). These associations were generally consistent for caffeinated and decaffeinated coffee, except for caffeine and its metabolites that were only associated with caffeinated coffee intake. The three cholesteryl esters positively associated with coffee intake showed inverse associations with diabetes risk, whereas the 12 metabolites negatively associated with coffee (5 DAGs and 7 TAGs) showed positive associations with diabetes. Adding the 15 diabetes-associated metabolites to a classical risk factor-based prediction model increased the C-statistic from 0.79 (95% CI 0.76, 0.83) to 0.83 (95% CI 0.80, 0.86) ( P < 0.001). Similar improvement was observed in the validation set., Conclusions: Coffee consumption is associated with widespread metabolic changes, among which lipid metabolites may be critical for the antidiabetes benefit of coffee. Coffee-related metabolites might help improve prediction of diabetes, but further validation studies are needed., (© 2020 by the American Diabetes Association.)

Objective: The purpose of this investigation was to elucidate the role of button-response complexity to targets in a response inhibition task., Background: Response inhibition is the ability to correctly inhibit an overt response to a target. The U.S. military is actively pursuing development of armed, combat robots as a force multiplier, which may present challenges to operators of combat robots in the form of response inhibition errors., Method: A total of 15 participants completed two 51-min versions of a modified sustained attention to response task (SART). Participants were outfitted with an electrocardiogram to index heart-rate variability and completed the NASA-Task Load Index (NASA-TLX) to index workload., Results: The results demonstrated that the complex SART reduced errors of commission (4%) and slowed response times (874 ms) to correct Go targets relative to the simple SART (14%, 739 ms). The NASA-TLX did not show differences between the modified SARTs; however, heart-rate variability did demonstrate that Soldiers had an increased autonomic stress response to the complex SART., Conclusion: Increasing the behavioral response requirement during a response inhibition task can decrease errors of commission; however, it comes at the cost of slower response times to target stimuli. Heart-rate variability may provide better insight into objective workload relative to subjective measures., Application: The use of complex behavioral responses may provide a viable option to reduce potential "friendly fire" or collateral damage by Soldiers remotely engaging a target-rich environment.

Background: The association between male pattern baldness and prostate cancer has been inconsistent. We prospectively investigated the association between baldness at age 45 and prostate cancer risk in the Health Professionals Follow-up Study (HPFS), focusing on clinical and molecular markers., Methods: Baldness was self-reported on the 1992 questionnaire using the modified Norwood-Hamilton scale prior to diagnosis. We estimated HRs between baldness and prostate cancer risk among 36,760 men, with follow-up through 2014. We also investigated whether baldness was associated with prostate cancer defined by tumor protein expression of androgen receptor and the presence of the TMPRSS2:ERG fusion., Results: During 22 years, 5,157 prostate cancer cases were identified. Fifty-six percent of the men had either frontal or vertex baldness. No significant associations were found between baldness and prostate cancer risk. Among men younger than 60 years, there was a statistically significant association between frontal and severe vertex baldness and overall prostate cancer (HR: 1.74; 95% confidence interval: 1.23-2.48). Baldness was not significantly associated with expression of molecular subtypes defined by AR and TMPRSS2:ERG IHC of prostate tumors., Conclusions: This study showed no association between baldness at age 45 and prostate cancer risk, overall or for clinical or molecular markers. The association between baldness and overall prostate cancer among younger men is intriguing, but caution is warranted when interpreting this finding., Impact: The null findings from this large cohort study, together with previous literature's inconclusive findings across baldness patterns, suggest that baldness is not a consistent biomarker for prostate cancer risk or progression., (©2020 American Association for Cancer Research.)

Quality control monitoring of cell lines utilized in biomedical research is of utmost importance and is critical for the reproducibility of data. Two key pitfalls in tissue culture are 1) cell line authenticity and 2) Mycoplasma contamination. As a collaborative research institute, the National Center for Advancing Translational Sciences (NCATS) receives cell lines from a range of commercial and academic sources, which are adapted for high-throughput screening. Here, we describe the implementation of routine NCATS-wide Mycoplasma testing and short tandem repeat (STR) testing for cell lines. Initial testing identified a >10% Mycoplasma contamination rate. While the implementation of systematic testing has not fully suppressed Mycoplasma contamination rates, clearly defined protocols that include the immediate destruction of contaminated cell lines wherever possible has enabled rapid intervention and removal of compromised cell lines. Data for >2000 cell line samples tested over 3 years, and case studies are provided. STR testing of 186 cell lines with established STR profiles revealed only five misidentified cell lines, all of which were received from external labs. The data collected over the 3 years since implementation of this systematic testing demonstrate the importance of continual vigilance for rapid identification of "problem" cell lines, for ensuring reproducible data in translational science research.

Tea and coffee have antioxidant and neuroprotective effects. Observational studies suggest that tea and coffee intake may reduce cancer risk, but data on glioma risk are inconclusive. We evaluated the association between tea, coffee and caffeine intake and glioma risk in the female Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII) and the male Health Professionals Follow-Up Study (HPFS). Cumulative intake was derived from validated quadrennial food frequency questionnaires. Glioma cases were confirmed by medical record review. Multivariable-adjusted hazard ratios of glioma by beverage intake category were estimated using Cox proportional hazards models. We documented 554 incident cases of glioma (256 in NHS, 87 in NHSII and 211 in HPFS). Compared to <1 cup/week, higher tea consumption was borderline inversely associated with glioma risk in pooled cohorts (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.49-1.10 for >2 cups/day, p-trend = 0.05), but not in women (HR = 0.74, 95% CI: 0.47-1.18 for >2 cups/day, p-trend = 0.11) or men (HR = 0.70, 95% CI: 0.30-1.60 for >2 cups/day, p-trend = 0.30) separately. Overall, we observed no significant associations between caffeinated, decaffeinated or total coffee intake and glioma risk. There were no material differences in the results with baseline values, 8-year lagged responses, or when limited to glioblastoma (n = 362). In three large prospective cohort studies, tea intake was borderline inversely associated with glioma risk. No significant associations were observed for coffee intake and glioma risk. These results merit further exploration in prospective studies., (© 2019 UICC.)

We assessed the relationship between acute and intermittent secondhand tobacco smoke (SHS) exposure with child and adolescent blood pressure (BP). We analyzed cross-sectional data from 3579 children and adolescents aged 8-17 years participating in the National Health and Nutrition Examination Survey (NHANES) collected between 2007 and 2012, with SHS exposure assessed via serum cotinine (a biomarker for acute exposures) and urine NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, a biomarker for intermittent exposures). BP percentiles and z-scores were calculated according to the 2017 guidelines established by the American Academy of Pediatrics. We used weighted linear regression accounting for the complex sampling weights from NHANES and adjusting for socio-demographic and clinical characteristics. Overall, 56% of the children were non-Hispanic white with a mean age of 12.6 years. There was approximately equal representation of boys and girls. Approximately 15.9% of participants lived in homes where smoking was present. In adjusted models, an interquartile range (IQR) increase in urinary NNAL was associated with 0.099 (95% CI: 0.033, 0.16) higher diastolic blood pressure (DBP) z-score, and with a 0.094 (95% CI: 0.011, 0.18) higher systolic blood pressure (SBP) z-score. The odds of being in the hypertensive range was 1.966 (95% CI: 1.31, 2.951) times greater among children with high NNAL exposures compared to those with undetectable NNAL. For serum cotinine, an IQR increase was associated with 0.097 (95% CI: 0.020, 0.17) higher DBP z-scores, but was not significantly associated with SBP z-scores. The associations of cotinine and NNAL with BP also differed by sex. Our findings provide the first characterization of the relationship between a major tobacco-specific metabolite, NNAL, and BP z-scores in a nationally representative population of US children., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Tyrosine kinase domain (TKD) mutations contribute to acquired resistance to FMS-like tyrosine kinase 3 (FLT3) inhibitors used to treat FLT3-mutant acute myeloid leukemia (AML). We report a cocrystal structure of FLT3 with a type I inhibitor, NCGC1481, that retained potent binding and activity against FLT3 TKD and gatekeeper mutations. Relative to the current generation of advanced FLT3 inhibitors, NCGC1481 exhibited superior antileukemic activity against the common, clinically relevant FLT3-mutant AML cells in vitro and in vivo.

Obesity is associated with a higher risk of advanced prostate cancer, but men with the same body mass index (BMI) may differ in their underlying metabolic health. Using metabolomics data from nested case-control studies in the Health Professionals Follow-Up Study, we calculated Pearson correlations between 165 circulating metabolites and three adiposity measures (BMI, waist circumference, and derived fat mass from a validated prediction equation) to identify adiposity-associated metabolites. We used Lasso to further select metabolites for prediction models of adiposity measures, which we used to calculate metabolic scores representing metabolic obesity. In an independent set of 212 advanced prostate cancer cases (T3b/T4/N1/M1 or lethal during follow-up) and 212 controls, we used logistic regression to evaluate the associations between adiposity measures and metabolic scores with risk of advanced disease. All adiposity measures were associated with higher blood levels of carnitines (Pearson r range, 0.16 to 0.18) and lower levels of glutamine ( r = -0.19) and glycine ( r, -0.29 to -0.20), in addition to alterations in various lipids. No adiposity measure or metabolic score was associated with risk of advanced prostate cancer (e.g., odds ratio for a 5 kg/m 2 increase in BMI 0.96 (95% CI: 0.73, 1.27) and BMI metabolic score 1.18 (95% CI: 0.57, 2.48)). BMI, waist circumference, and derived fat mass were associated with a broad range of metabolic alterations. Neither adiposity nor metabolic scores were associated with risk of advanced prostate cancer.

Pioneer colonization of the gastrointestinal tract (GIT) by bacteria is thought to have major influence on neonatal tissue development. Previous studies have shown in ovo inoculation of embryos with saline (S), species of Citrobacter (C, C2), or lactic acid bacteria (L) resulted in an altered microbiome on day of the hatch (DOH). The present study investigated GIT proteomic changes at DOH in relation to different inoculations. Embryos were inoculated in ovo with S or ∼10 2  cfu of C, C2, or L at 18 embryonic days. On DOH, the GIT was collected, and tissue proteins were extracted for analysis via tandem mass spectrometry. A total of 493 proteins were identified for differential comparison with S at P ≤ 0.10. Different levels were noted in 107, 39, and 78 proteins in C, C2, and L groups, respectively, which were uploaded to Ingenuity Pathway Analysis to determine canonical pathways and biological functions related to these changes. Three members of the cytokine family (interleukin [IL]-1β, IL6, and Oncostatin M) were predicted to be activated in C2, indicated with Z-score ≥ 1.50, which suggested an overall proinflammatory GIT condition. This was consistent with the activation of the acute-phase response signaling pathway seen exclusively in C2 (Z-score = 2.00, P < 0.01). However, activation (Z-score = 2.00) of IL-13, upregulation of peroxiredoxin-1 and superoxide dismutase 1, in addition to activation of nitric oxide signaling in the cardiovascular system of the L treatment may predict a state of increased antioxidant capacity and decreased inflammatory status. The nuclear factor erythroid 2-related factor 2 (NRF2)-mediated oxidative stress response (Z-score = 2.00, P < 0.01) was predicted to be upregulated in C which suggested that chicks were in an inflammatory state and associated oxidative stress, but the impact of these pathways differed from that of C2. These changes in the proteome suggest that pioneer colonizing microbiota may have a strong impact on pathways associated with GIT immune and cellular development., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: Statins are associated with lower risk of aggressive prostate cancer, but lethal prostate cancer is understudied and contributing mechanisms are unclear. We prospectively examined statins and lethal prostate cancer risk in the Health Professionals Follow-up Study (HPFS), tested associations with molecular subtypes, and integrated gene expression profiling to identify putative mechanisms., Experimental Design: Our study included 44,126 men cancer-free in 1990, followed for prostate cancer incidence through 2014, with statin use recorded on biennial questionnaires. We used multivariable Cox regression to examine associations between statins and prostate cancer risk overall, by measures of clinically significant disease, and by ERG and PTEN status. In an exploratory analysis, age-adjusted gene set enrichment analysis identified statin-associated pathways enriched in tumor and adjacent normal prostate tissue., Results: During 24 years of follow-up, 6,305 prostate cancers were diagnosed and 801 (13%) were lethal (metastatic at diagnosis or metastatic/fatal during follow-up). Relative to never/past use, current statin use was inversely associated with risk of lethal prostate cancer [HR, 0.76; 95% confidence interval (CI), 0.60-0.96] but not overall disease. We found a strong inverse association for risk of PTEN-null cancers (HR, 0.40; 95% CI, 0.19-0.87) but not PTEN-intact cancers (HR, 1.18; 95% CI, 0.95-1.48; P heterogeneity = 0.01). Associations did not differ by ERG. Inflammation and immune pathways were enriched in normal prostate tissue of statin ever ( n = 10) versus never users ( n = 103)., Conclusions: Molecular tumor classification identified PTEN and inflammation/immune activation as potential mechanisms linking statins with lower lethal prostate cancer risk. These findings support a potential causal association and could inform selection of relevant biomarkers for statin clinical trials., (©2019 American Association for Cancer Research.)