aristaless-like homeobox-3 is wound induced and promotes a low-Wnt environment required for planarian head regeneration.

The planarian Schmidtea mediterranea is a well-established model of adult regeneration, which is dependent on a large population of adult stem cells called neoblasts. Upon amputation, planarians undergo transcriptional wounding programs and coordinated stem cell proliferation to give rise to missing tissues. Interestingly, the Wnt signaling pathway is key to guiding what tissues are regenerated, yet less known are the transcriptional regulators that ensure proper activation and timing of signaling pathway components. Here, we have identified an aristaless-like homeobox transcription factor, alx-3, that is enriched in a population of putative neural-fated progenitor cells at homeostasis, and is also upregulated in stem cells and muscle cells at anterior-facing wounds upon amputation. Knockdown of alx-3 results in failure of head regeneration and patterning defects in amputated tail fragments. alx-3 is required for the expression of several early wound-induced genes, including the Wnt inhibitor notum, which is required to establish anterior polarity during regeneration. Together, these findings reveal a role for alx-3 as an early wound-response transcriptional regulator in both muscle cells and stem cells that is required for anterior regeneration by promoting a low-Wnt environment.

What Goes into Patient Selection for Lung Cancer Screening? Factors Associated with Clinician Judgments of Suitability for Screening.

Rationale: Achieving the net benefit of lung cancer screening (LCS) depends on optimizing patient selection. Objective: To identify factors associated with clinician assessments that a patient was unlikely to benefit from LCS ("LCS-inappropriate") because of comorbidities or limited life expectancy. Methods: Retrospective analysis of patients assessed for LCS at 30 Veterans Health Administration facilities from January 1, 2015 to February 1, 2021. We conducted hierarchical mixed-effects logistic regression analyses to determine factors associated with clinicians' designations of LCS inappropriateness (primary outcome), accounting for 3-year predicted probability (i.e., competing risk) of non-lung cancer death. Measurements and Main Results: Among 38,487 LCS-eligible patients, 1,671 (4.3%) were deemed LCS-inappropriate by clinicians, whereas 4,383 (11.4%) had an estimated 3-year competing risk of non-lung cancer death greater than 20%. Patients with higher competing risks of non-lung cancer death were more likely to be deemed LCS-inappropriate (odds ratio [OR], 2.66; 95% confidence interval [CI], 2.32-3.05). Older patients (ages 75-80; OR, 1.45; 95% CI, 1.18-1.78) and those with interstitial lung disease (OR, 1.98; 95% CI, 1.51-2.59) were more likely to be deemed LCS-inappropriate than would be explained by competing risk of non-lung cancer death, whereas patients currently smoking (OR, 0.65; 95% CI, 0.58-0.73) were less likely to be deemed LCS-inappropriate, suggesting that clinicians over- or underweighted these factors. The probability of being deemed LCS-inappropriate varied from 0.4% to 74%, depending on the clinician making the assessment (median OR, 3.07; 95% CI, 2.89-3.25). Conclusion: Concerningly, the likelihood that a patient is deemed LCS-inappropriate is more strongly associated with the clinician making the assessment than with patient characteristics. Patient selection may be optimized by providing decision support to help clinicians assess net LCS benefit.

Quantifying the effectiveness of betaherpesvirus-vectored transmissible vaccines.

Transmissible vaccines have the potential to revolutionize how zoonotic pathogens are controlled within wildlife reservoirs. A key challenge that must be overcome is identifying viral vectors that can rapidly spread immunity through a reservoir population. Because they are broadly distributed taxonomically, species specific, and stable to genetic manipulation, betaherpesviruses are leading candidates for use as transmissible vaccine vectors. Here we evaluate the likely effectiveness of betaherpesvirus-vectored transmissible vaccines by developing and parameterizing a mathematical model using data from captive and free-living mouse populations infected with murine cytomegalovirus (MCMV). Simulations of our parameterized model demonstrate rapid and effective control for a range of pathogens, with pathogen elimination frequently occurring within a year of vaccine introduction. Our results also suggest, however, that the effectiveness of transmissible vaccines may vary across reservoir populations and with respect to the specific vector strain used to construct the vaccine.

The Development and Performance of Alternative Criteria for Lung Cancer Screening.

BACKGROUND: The recommendation for lung cancer screening (LCS) developed by the U.S. Preventive Services Task Force (USPSTF) may exclude some high-benefit people. OBJECTIVE: To determine whether alternative criteria can identify these high-benefit people. DESIGN: Model-based projections. SETTING: United States. PARTICIPANTS: People from the 1997-2014 National Health Interview Survey (NHIS) to develop alternative criteria using fast-and-frugal tree algorithms and from the 2014-2018 NHIS and the 2022 Behavioral Risk Factor Surveillance System for comparisons of USPSTF criteria versus alternative criteria. MEASUREMENTS: Life-years gained from LCS were estimated using the life-years gained from screening computed tomography (LYFS-CT) model. "High-benefit" was defined as gaining an average of at least 16.2 days of life from 3 annual screenings, which reflects high lung cancer risk and substantial life gains if lung cancer is detected by screening. RESULTS: The final alternative criteria were 1) people who smoked any amount each year for at least 40 years, or 2) people aged 60 to 80 years with at least 40 pack-years of smoking. The USPSTF and alternative criteria selected similar numbers of people for LCS. Compared with the USPSTF criteria, the alternative criteria had higher sensitivity (91% vs. 78%; P < 0.001) and specificity (86% vs. 84%; P < 0.001) for identifying high-benefit people. For racial and ethnic minorities, the alternative criteria provided greater gains in sensitivity than the USPSTF criteria (Black: 83% vs. 56% [P < 0.001]; Hispanic: 95% vs. 73% [P = 0.086]; Asian: 94% vs. 68% [P = 0.171]) at similar specificity. The alternative criteria identify high-risk, high-benefit groups excluded by the USPSTF criteria (those with a smoking duration of ≥40 years but <20 pack-years and a quit history of >15 years), many of whom are members of racial and ethnic minorities. LIMITATION: The results were based on model projections. CONCLUSION: These results suggest that simple alternative LCS criteria can identify substantially more high-benefit people, especially in some racial and ethnic groups. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs Lung Precision Oncology Program.

Phosphatidylserine orchestrates Myomerger membrane insertions to drive myoblast fusion.

Muscle cell fusion is a multistep process where the final step of the reaction drives progression beyond early hemifusion events to complete fusion. This step requires activity of the muscle-specific fusogen Myomerger, a single-pass transmembrane protein containing 84 amino acids with an ectodomain that includes two α-helices. Previous studies have demonstrated that Myomerger acts by destabilizing membranes through generation of elastic stresses in the outer leaflet of the plasma membrane. An obvious question is how such destabilizing activity might be regulated to avoid membrane and cellular damage, and how the two juxtaposed helices cooperate in fusion. Using cellular fusion assays and in vitro liposome assays, we report that the two helices possess unique characteristics, both of which are needed for full activity of the protein. We demonstrate that externalized phosphatidylserine (PS), a lipid previously implicated in myoblast fusion, has a determinant role in the regulation of Myomerger activity. The membrane-proximal, amphipathic Helix-1 is normally disordered and its α-helical structure is induced by PS, making membrane interactions more efficacious. The distal, more hydrophobic Helix-2 is intrinsically ordered, possesses an ability to insert into membranes, and augments the membrane-stressing effects of Helix-1. These data reveal that Myomerger fusogenic activity is an exquisitely orchestrated event involving its two ectodomain helices, which are controlled by membrane lipid composition, providing an explanation as to how its membrane-stressing activity is spatially and temporally regulated during the final step of myoblast fusion.

The American Cancer Society National Lung Cancer Roundtable strategic plan: Current challenges and future directions for shared decision making for lung cancer screening.

Shared decision making (SDM) between health care professionals and patients is essential to help patients make well informed choices about lung cancer screening (LCS). Patients who participate in SDM have greater LCS knowledge, reduced decisional conflict, and improved adherence to annual screening compared with patients who do not participate in SDM. SDM tools are acceptable to patients and clinicians. The importance of SDM in LCS is emphasized in recommendations from professional organizations and highlighted as a priority in the 2022 President's Cancer Panel Report. The updated 2022 national coverage determination from the Centers for Medicare & Medicaid Services reaffirms the value of SDM in offering LCS to eligible beneficiaries. The Shared Decision-Making Task Group of the American Cancer Society National Lung Cancer Roundtable undertook a group consensus process to identify priorities for research and implementation related to SDM for LCS and then evaluated current knowledge in these areas. Priority areas included: (1) developing feasible, adaptable SDM training programs for health care professionals; (2) understanding the impact of alternative health system LCS models on SDM practice and outcomes; (3) developing and evaluating new patient decision aids for use with diverse populations and in varied settings; (4) offering conceptual clarity about what constitutes a high-quality decision and developing appropriate quality measures; and (5) studying the use of prediction-augmented screening to support SDM in practice. Gaps in current research in all areas were observed. The authors conclude with a research and implementation agenda to advance the quality and implementation of SDM for persons who might benefit from LCS.

Investigating the role of tumour-to-skin proximity in predicting nodal metastasis in breast cancer.

BACKGROUND: Understanding the factors influencing nodal status in breast cancer is vital for axillary staging, therapy, and patient survival. The nodal stage remains a crucial factor in prognostication indices. This study investigates the relationship between tumour-to-skin distance (in T1-T3 tumours where the skin is not clinically involved) and the risk of nodal metastasis. METHODS: We retrospectively reviewed data from 100 patients who underwent neoadjuvant chemotherapy (NACT). Besides patient demographics and tumour variables, a radiologist retrospectively reviewed pre-operative MRI to measure tumour-to-skin distance. R core packages were used for univariate (χ2 and T-Wilcoxon tests) and bivariate logistic regression statistical analysis. RESULTS: Of 95 analysable datasets, patients' median age was 51 years (IQR: 42-61), 97% were symptomatic (rest screen detected), and the median tumour size was 43 mm (IQR, 26-52). On multivariate analysis, increasing invasive tumour size (p = 0.02), ER positivity (p = 0.007) and shorter tumour-to-skin distance (p = 0.05) correlated with nodal metastasis.  HER2 was not included in multivariate analysis as there was no association with nodal status on univariate analysis. In node-positive tumours, as tumour size increased, the tumour-to-skin distance decreased (r = - 0.34, p = 0.026). In node-negative tumours, there was no correlation (r = + 0.18, p = 0.23). CONCLUSION: This study shows that non-locally advanced cancers closer to the skin (and consequent proximity to subdermal lymphatics) are associated with a greater risk of nodal metastasis. Pre-operative identification of those more likely to be node positive may suggest the need for a second-look USS since a higher nodal stage may lead to a change in therapeutic strategies, such as upfront systemic therapy, node marking, and axillary clearance without the need to return to theatre following sentinel node biopsy.

Tackling Guideline Non-concordance: Primary Care Barriers to Incorporating Life Expectancy into Lung Cancer Screening Decision-Making-A Qualitative Study.

BACKGROUND: Primary care providers (PCPs) are often the first point of contact for discussing lung cancer screening (LCS) with patients. While guidelines recommend against screening people with limited life expectancy (LLE) who are less likely to benefit, these patients are regularly referred for LCS. OBJECTIVE: We sought to understand barriers PCPs face to incorporating life expectancy into LCS decision-making for patients who otherwise meet eligibility criteria, and how a hypothetical point-of-care tool could support patient selection. DESIGN: Qualitative study based on semi-structured telephone interviews. PARTICIPANTS: Thirty-one PCPs who refer patients for LCS, from six Veterans Health Administration facilities. APPROACH: We thematically analyzed interviews to understand how PCPs incorporated life expectancy into LCS decision-making and PCPs' receptivity to a point-of-care tool to support patient selection. Final themes were organized according to the Cabana et al. framework Why Don't Physicians Follow Clinical Practice Guidelines, capturing the influence of clinician knowledge, attitudes, and behavior on LCS appropriateness determinations. KEY RESULTS: PCP referrals to LCS for patients with LLE were influenced by limited knowledge of the life expectancy threshold at which patients are less likely to benefit from LCS, discomfort estimating life expectancy, fear of missing cancer at the point of early detection, and prioritization of factors such as quality of life, patient values, clinician-patient relationship, and family support. PCPs were receptive to a decision support tool to inform and communicate LCS appropriateness decisions if easy to use and integrated into clinical workflows. CONCLUSIONS: Our study suggests knowledge gaps and attitudes may drive decisions to offer screening despite LLE, a behavior counter to guideline recommendations. Integrating a LCS decision support tool that incorporates life expectancy within the electronic medical record and existing clinical workflows may be one acceptable solution to improve guideline concordance and increase confidence in selecting high benefit patients for LCS.

"It Can't Hurt!": Why Many Patients With Limited Life Expectancy Decide to Accept Lung Cancer Screening.

PURPOSE: Lung cancer screening (LCS) has less benefit and greater potential for iatrogenic harm among people with multiple comorbidities and limited life expectancy. Yet, such individuals are more likely to undergo screening than healthier LCS-eligible people. We sought to understand how patients with marginal LCS benefit conceptualize their health and make decisions regarding LCS. METHODS: We interviewed 40 people with multimorbidity and limited life expectancy, as determined by high Care Assessment Need scores, which predict 1-year risk of hospitalization or death. Patients were recruited from 6 Veterans Health Administration facilities after discussing LCS with their clinician. We conducted a thematic analysis using constant comparison to explore factors that influence LCS decision making. RESULTS: Patients commonly held positive beliefs about screening and perceived LCS to be noninvasive. When posed with hypothetical scenarios of limited benefit, patients emphasized the nonlongevity benefits of LCS (eg, peace of mind, planning for the future) and generally did not consider their health status or life expectancy when making decisions regarding LCS. Most patients were unaware of possible additional evaluations or treatment of screen-detected findings, but when probed further, many expressed concerns about the potential need for multiple evaluations, referrals, or invasive procedures. CONCLUSIONS: Patients in this study with multimorbidity and limited life expectancy were unaware of their greater risk of potential harm when accepting LCS. Given patient trust in clinician recommendations, it is important that clinicians engage patients with marginal LCS benefit in shared decision making, ensuring that their values of desiring more information about their health are weighed against potential harms from further evaluations.

Correlates of Past Childhood Homelessness in a Nationally Representative Sample of US Adults.

ABSTRACT: Limited empirical data have been available on the adult sequelae of childhood homelessness. Using nationally representative data from the National Epidemiologic Survey of Alcohol and Related Conditions-III, we compared a hierarchy of adults who were never homeless, those who were only homeless as children, and those who were homeless both as children and adults, hypothesizing greater adversity as one moved up the three-level hierarchy on sociodemographic, behavioral, and lifetime mental health diagnostic characteristics. As a further evaluation of the status of adults who were homeless as both children and adults, we compared this highest risk group to those who had been homeless only as adults. Individuals who experienced childhood homelessness were 46.9 times more likely than others to also experience adult homelessness. Testing the hierarchical hypothesis, compared with those who were never homeless, individuals who experienced homelessness only as children reported numerous associated disadvantages, including childhood sexual abuse/neglect, parental adversities, adult incarceration, psychiatric disorders, and low academic achievement/employment. Those reporting both child and adult homelessness, in contrast to childhood homelessness alone, additionally met the criteria for multiple substance use disorders, confirming our hierarchical hypothesis. Those reporting both child and adult homelessness also showed more numerous social and psychiatric problems when compared with those experiencing homelessness for the first time as adults. This study demonstrates how homelessness in childhood is associated with extensive social and psychiatric adversities in both childhood and adulthood.

Pentiptycene-based ladder polymers with configurational free volume for enhanced gas separation performance and physical aging resistance.

Polymers of intrinsic microporosity (PIMs) have shown promise in pushing the limits of gas separation membranes, recently redefining upper bounds for a variety of gas pair separations. However, many of these membranes still suffer from reductions in permeability over time, removing the primary advantage of this class of polymer. In this work, a series of pentiptycene-based PIMs incorporated into copolymers with PIM-1 are examined to identify fundamental structure-property relationships between the configuration of the pentiptycene backbone and its accompanying linear or branched substituent group. The incorporation of pentiptycene provides a route to instill a more permanent, configuration-based free volume, resistant to physical aging via traditional collapse of conformation-based free volume. PPIM-ip-C and PPIM-np-S, copolymers with C- and S-shape backbones and branched isopropoxy and linear n-propoxy substituent groups, respectively, each exhibited initial separation performance enhancements relative to PIM-1. Additionally, aging-enhanced gas permeabilities were observed, a stark departure from the typical permeability losses pure PIM-1 experiences with aging. Mixed-gas separation data showed enhanced CO2/CH4 selectivity relative to the pure-gas permeation results, with only ∼20% decreases in selectivity when moving from a CO2 partial pressure of ∼2.4 to ∼7.1 atm (atmospheric pressure) when utilizing a mixed-gas CO2/CH4 feed stream. These results highlight the potential of pentiptycene's intrinsic, configurational free volume for simultaneously delivering size-sieving above the 2008 upper bound, along with exceptional resistance to physical aging that often plagues high free volume PIMs.

Global monitoring of the impact of the COVID-19 pandemic through online surveys sampled from the Facebook user base.

Simultaneously tracking the global impact of COVID-19 is challenging because of regional variation in resources and reporting. Leveraging self-reported survey outcomes via an existing international social media network has the potential to provide standardized data streams to support monitoring and decision-making worldwide, in real time, and with limited local resources. The University of Maryland Global COVID-19 Trends and Impact Survey (UMD-CTIS), in partnership with Facebook, has invited daily cross-sectional samples from the social media platform's active users to participate in the survey since its launch on April 23, 2020. We analyzed UMD-CTIS survey data through December 20, 2020, from 31,142,582 responses representing 114 countries/territories weighted for nonresponse and adjusted to basic demographics. We show consistent respondent demographics over time for many countries/territories. Machine Learning models trained on national and pooled global data verified known symptom indicators. COVID-like illness (CLI) signals were correlated with government benchmark data. Importantly, the best benchmarked UMD-CTIS signal uses a single survey item whereby respondents report on CLI in their local community. In regions with strained health infrastructure but active social media users, we show it is possible to define COVID-19 impact trajectories using a remote platform independent of local government resources. This syndromic surveillance public health tool is the largest global health survey to date and, with brief participant engagement, can provide meaningful, timely insights into the global COVID-19 pandemic at a local scale.

Poor data stewardship will hinder global genetic diversity surveillance.

Genomic data are being produced and archived at a prodigious rate, and current studies could become historical baselines for future global genetic diversity analyses and monitoring programs. However, when we evaluated the potential utility of genomic data from wild and domesticated eukaryote species in the world's largest genomic data repository, we found that most archived genomic datasets (86%) lacked the spatiotemporal metadata necessary for genetic biodiversity surveillance. Labor-intensive scouring of a subset of published papers yielded geospatial coordinates and collection years for only 33% (39% if place names were considered) of these genomic datasets. Streamlined data input processes, updated metadata deposition policies, and enhanced scientific community awareness are urgently needed to preserve these irreplaceable records of today's genetic biodiversity and to plug the growing metadata gap.

Using Artificial Intelligence to Identify Tumor Microenvironment Heterogeneity in Non-Small Cell Lung Cancers.

Lung cancer heterogeneity is a major barrier to effective treatments and encompasses not only the malignant epithelial cell phenotypes and genetics but also the diverse tumor-associated cell types. Current techniques used to investigate the tumor microenvironment can be time-consuming, expensive, complicated to interpret, and often involves destruction of the sample. Here we use standard hematoxylin and eosin-stained tumor sections and the HALO AI nuclear phenotyping software to characterize 6 distinct cell types (epithelial, mesenchymal, macrophage, neutrophil, lymphocyte, and plasma cells) in both murine lung cancer models and human lung cancer samples. CD3 immunohistochemistry and lymph node sections were used to validate lymphocyte calls, while F4/80 immunohistochemistry was used for macrophage validation. Consistent with numerous prior studies, we demonstrated that macrophages predominate the adenocarcinomas, whereas neutrophils predominate the squamous cell carcinomas in murine samples. In human samples, we showed a strong negative correlation between neutrophils and lymphocytes as well as between mesenchymal cells and lymphocytes and that higher percentages of mesenchymal cells correlate with poor prognosis. Taken together, we demonstrate the utility of this AI software to identify, quantify, and compare distributions of cell types on standard hematoxylin and eosin-stained slides. Given the simplicity and cost-effectiveness of this technique, it may be widely beneficial for researchers designing new therapies and clinicians working to select favorable treatments for their patients.

Effects of the omega-3 fatty acid DHA on histone and p53 acetylation in diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) often develops resistance and/or relapses in response to immunochemotherapy. Epigenetic modifiers are frequently mutated in DLBCL, i.e., the lysine (histone) acetyltransferases CREBBP and EP300. Mutations in CBP/p300 can prevent the proper acetylation and activation of (i) enhancer sequences of genes required for essential functions (e.g., germinal center exit and differentiation) and (ii) the tumor suppressor p53. Based on evidence that omega-3 fatty acids (ω-3 FAs) affect histone acetylation in various cancers, we investigated whether ω-3 FA docosahexaenoic acid (DHA) could modify levels of histone and p53 acetylation in three DLBCL cell lines (at different CREBBP/EP300 mutational status) versus normal B cells. Exposure to DHA at clinically attainable doses was shown to significantly alter the genome-wide levels of histone posttranslational modifications in a cell-line-dependent and dose-dependent manner. Although histone acetylation did not increase uniformly, as initially expected, levels of p53 acetylation increased consistently. Quantitative reverse transcription polymerase chain reaction results revealed significant changes in expression of multiple genes, including increased expression of CREBBP and of PRDM1 (required for differentiation into plasma cells or memory B cells). Taken together, our results provide (to our knowledge) the first characterization of the epigenetic effects of ω-3 FAs in DLBCL.

Engaging Operational Partners Is Critical for Successful Implementation of Research Products: a Coincidence Analysis of Access-Related Projects in the Veterans Affairs Healthcare System.

BACKGROUND/OBJECTIVE: The Veterans Health Administration (VHA) has prioritized timely access to care and has invested substantially in research aimed at optimizing veteran access. However, implementing research into practice remains challenging. Here, we assessed the implementation status of recent VHA access-related research projects and explored factors associated with successful implementation. DESIGN: We conducted a portfolio review of recent VHA-funded or supported projects (1/2015-7/2020) focused on healthcare access ("Access Portfolio"). We then identified projects with implementable research deliverables by excluding those that (1) were non-research/operational projects; (2) were only recently completed (i.e., completed on or after 1/1/2020, meaning that they were unlikely to have had time to be implemented); and (3) did not propose an implementable deliverable. An electronic survey assessed each project's implementation status and elicited barriers/facilitators to implementing deliverables. Results were analyzed using novel Coincidence Analysis (CNA) methods. PARTICIPANTS/KEY RESULTS: Among 286 Access Portfolio projects, 36 projects led by 32 investigators across 20 VHA facilities were included. Twenty-nine respondents completed the survey for 32 projects (response rate = 88.9%). Twenty-eight percent of projects reported fully implementing project deliverables, 34% reported partially implementing deliverables, and 37% reported not implementing any deliverables (i.e., resulting tool/intervention not implemented into practice). Of 14 possible barriers/facilitators assessed in the survey, two were identified through CNA as "difference-makers" to partial or full implementation of project deliverables: (1) engagement with national VHA operational leadership; (2) support and commitment from local site operational leadership. CONCLUSIONS: These findings empirically highlight the importance of operational leadership engagement for successful implementation of research deliverables. Efforts to strengthen communication and engagement between the research community and VHA local/national operational leaders should be expanded to ensure VHA's investment in research leads to meaningful improvements in veterans' care. The Veterans Health Administration (VHA) has prioritized timely access to care and has invested substantially in research aimed at optimizing veteran access. However, implementing research findings into clinical practice remains challenging, both within and outside VHA. Here, we assessed the implementation status of recent VHA access-related research projects and explored factors associated with successful implementation. Only two factors were identified as "difference-makers" to adoption of project findings into practice: (1) engagement with national VHA leadership or (2) support and commitment from local site leadership. These findings highlight the importance of leadership engagement for successful implementation of research findings. Efforts to strengthen communication and engagement between the research community and VHA local/national leaders should be expanded to ensure VHA's investment in research leads to meaningful improvements in veterans' care.

Racial and ethnic differences in suicidal behavior and mental health service use among US adults, 2009-2020.

BACKGROUND: While suicide rates have recently declined for White individuals, rates among Black and Hispanic individuals have increased. Yet, little is known about racial/ethnic differences in precursors to suicide, including suicidal ideation (SI) and suicide attempts (SA). METHODS: Data from 2009-2020 National Survey of Drug Use and Health (NSDUH) consisted of non-institutionalized US civilians aged ⩾18 (n = 426 008). We compared proportions of White, Black, and Hispanics among adults reporting no past-year suicidal thoughts/behavior, SI, and SA. Multivariable-adjusted analyses were used to evaluate the independence of observed racial/ethnic differences in past-year SI, SA, and mental health service use. RESULTS: In the entire sample, 20 791 (4.9%) reported past-year SI only and 3661 (0.9%) reported a SA. Compared to White individuals, Black and Hispanic individuals were significantly less likely to report past-year SI [OR 0.73 (95% CI 0.69-0.77); OR 0.75 (95% CI 0.71-0.79), respectively], but more likely to report a past-year SA [OR 1.45 (95% CI 1.28-1.64); OR 1.19 (95% CI 1.04-1.37), respectively] even after multivariable adjustment. Black and Hispanic individuals were significantly less likely to use mental health services, but the lack of significant interactions between race/ethnicity and SI/SA in association with service use suggests differences in service use do not account for differences in SI or SA. CONCLUSIONS: Black and Hispanic individuals are significantly less likely than White individuals to report SI but more likely to report SAs, suggesting differences in suicidal behavior across race/ethnicity that may be impacted by socio-culturally acceptable expressions of distress and structural racism in the healthcare system.

Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice.

BACKGROUND: The pathophysiology of autism spectrum disorder (ASD) involves genetic and environmental factors. Mounting evidence demonstrates a role for the gut microbiome in ASD, with signaling via short-chain fatty acids (SCFA) as one mechanism. Here, we utilize mice carrying deletion to exons 4-22 of Shank3 (Shank3KO) to model gene by microbiome interactions in ASD. We identify SCFA acetate as a mediator of gut-brain interactions and show acetate supplementation reverses social deficits concomitant with alterations to medial prefrontal cortex (mPFC) transcriptional regulation independent of microbiome status. METHODS: Shank3KO and wild-type (Wt) littermates were divided into control, Antibiotic (Abx), Acetate and Abx + Acetate groups upon weaning. After six weeks, animals underwent behavioral testing. Molecular analysis including 16S and metagenomic sequencing, metabolomic and transcriptional profiling were conducted. Additionally, targeted serum metabolomic data from Phelan McDermid Syndrome (PMS) patients (who are heterozygous for the Shank3 gene) were leveraged to assess levels of SCFA's relative to ASD clinical measures. RESULTS: Shank3KO mice were found to display social deficits, dysregulated gut microbiome and decreased cecal levels of acetate - effects exacerbated by Abx treatment. RNA-sequencing of mPFC showed unique gene expression signature induced by microbiome depletion in the Shank3KO mice. Oral treatment with acetate reverses social deficits and results in marked changes in gene expression enriched for synaptic signaling, pathways among others, even in Abx treated mice. Clinical data showed sex specific correlations between levels of acetate and hyperactivity scores. CONCLUSION: These results suggest a key role for the gut microbiome and the neuroactive metabolite acetate in regulating ASD-like behaviors.

Formal γ-C(sp3)-H Activation of Ketones via Microwave-Promoted and Iminyl-Radical-Mediated 1,5-Hydrogen Atom Transfer.

Microwave irradiation of O-phenyloximes triggers N-O homolysis and 1,5-hydrogen atom transfer (HAT), resulting in formal γ-C-H functionalization of ketones after trapping of the radical intermediate and in situ imine hydrolysis. The Lewis acid InCl3·H2O facilitated HAT, enabling functionalization of benzylic and nonbenzylic secondary carbon atoms. Functionalization of primary carbons was feasible but afforded low yields, requiring ClCH2CO2H instead of InCl3·H2O as an additive. C-O and C-C bond formation could both be accomplished by this method.

Synthesis and biological evaluation of benzofuran piperazine derivatives as potential anticancer agents.

This work describes about the synthesis and evaluation of substituted benzofuran piperazines as potential anticancer agents. The synthesized candidates have been evaluated for their cell proliferation inhibition properties in six murine and human cancer cell lines. In vitro evaluation of apoptosis and cell cycle analysis with the lead candidate 1.19 reveals that necrosis might be an important pathway for the candidate compounds to cause cell death. Further, in vivo evaluation of the lead compound shows that this candidate is well tolerated in healthy mice. Additionally, an in vivo anticancer efficacy study in mice using a MDA-MB-231 xenograft model with the lead compound provides good anti-cancer efficacy.