Index and biological spectrum of human DNase I hypersensitive sites.

DNase I hypersensitive sites (DHSs) are generic markers of regulatory DNA1-5 and contain genetic variations associated with diseases and phenotypic traits6-8. We created high-resolution maps of DHSs from 733 human biosamples encompassing 438 cell and tissue types and states, and integrated these to delineate and numerically index approximately 3.6 million DHSs within the human genome sequence, providing a common coordinate system for regulatory DNA. Here we show that these maps highly resolve the cis-regulatory compartment of the human genome, which encodes unexpectedly diverse cell- and tissue-selective regulatory programs at very high density. These programs can be captured comprehensively by a simple vocabulary that enables the assignment to each DHS of a regulatory barcode that encapsulates its tissue manifestations, and global annotation of protein-coding and non-coding RNA genes in a manner orthogonal to gene expression. Finally, we show that sharply resolved DHSs markedly enhance the genetic association and heritability signals of diseases and traits. Rather than being confined to a small number of distal elements or promoters, we find that genetic signals converge on congruently regulated sets of DHSs that decorate entire gene bodies. Together, our results create a universal, extensible coordinate system and vocabulary for human regulatory DNA marked by DHSs, and provide a new global perspective on the architecture of human gene regulation.

Global reference mapping of human transcription factor footprints.

Combinatorial binding of transcription factors to regulatory DNA underpins gene regulation in all organisms. Genetic variation in regulatory regions has been connected with diseases and diverse phenotypic traits1, but it remains challenging to distinguish variants that affect regulatory function2. Genomic DNase I footprinting enables the quantitative, nucleotide-resolution delineation of sites of transcription factor occupancy within native chromatin3-6. However, only a small fraction of such sites have been precisely resolved on the human genome sequence6. Here, to enable comprehensive mapping of transcription factor footprints, we produced high-density DNase I cleavage maps from 243 human cell and tissue types and states and integrated these data to delineate about 4.5 million compact genomic elements that encode transcription factor occupancy at nucleotide resolution. We map the fine-scale structure within about 1.6 million DNase I-hypersensitive sites and show that the overwhelming majority are populated by well-spaced sites of single transcription factor-DNA interaction. Cell-context-dependent cis-regulation is chiefly executed by wholesale modulation of accessibility at regulatory DNA rather than by differential transcription factor occupancy within accessible elements. We also show that the enrichment of genetic variants associated with diseases or phenotypic traits in regulatory regions1,7 is almost entirely attributable to variants within footprints, and that functional variants that affect transcription factor occupancy are nearly evenly partitioned between loss- and gain-of-function alleles. Unexpectedly, we find increased density of human genetic variation within transcription factor footprints, revealing an unappreciated driver of cis-regulatory evolution. Our results provide a framework for both global and nucleotide-precision analyses of gene regulatory mechanisms and functional genetic variation.

Metabolomic and genetic architecture of gestational diabetes subtypes.

AIMS/HYPOTHESIS: Physiological gestational diabetes mellitus (GDM) subtypes that may confer different risks for adverse pregnancy outcomes have been defined. The aim of this study was to characterise the metabolome and genetic architecture of GDM subtypes to address the hypothesis that they differ between GDM subtypes. METHODS: This was a cross-sectional study of participants in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study who underwent an OGTT at approximately 28 weeks' gestation. GDM was defined retrospectively using International Association of Diabetes and Pregnancy Study Groups/WHO criteria, and classified as insulin-deficient GDM (insulin secretion <25th percentile with preserved insulin sensitivity) or insulin-resistant GDM (insulin sensitivity <25th percentile with preserved insulin secretion). Metabolomic analyses were performed on fasting and 1 h serum samples in 3463 individuals (576 with GDM). Genome-wide genotype data were obtained for 8067 individuals (1323 with GDM). RESULTS: Regression analyses demonstrated striking differences between the metabolomes for insulin-deficient or insulin-resistant GDM compared to those with normal glucose tolerance. After adjustment for covariates, 33 fasting metabolites, including 22 medium- and long-chain acylcarnitines, were uniquely associated with insulin-deficient GDM; 23 metabolites, including the branched-chain amino acids and their metabolites, were uniquely associated with insulin-resistant GDM; two metabolites (glycerol and 2-hydroxybutyrate) were associated with the same direction of association with both subtypes. Subtype differences were also observed 1 h after a glucose load. In genome-wide association studies, variants within MTNR1B (rs10830963, p=3.43×10-18, OR 1.55) and GCKR (rs1260326, p=5.17×10-13, OR 1.43) were associated with GDM. Variants in GCKR (rs1260326, p=1.36×10-13, OR 1.60) and MTNR1B (rs10830963, p=1.22×10-9, OR 1.49) demonstrated genome-wide significant association with insulin-resistant GDM; there were no significant associations with insulin-deficient GDM. The lead SNP in GCKR, rs1260326, was associated with the levels of eight of the 25 fasting metabolites that were associated with insulin-resistant GDM and ten of 41 1 h metabolites that were associated with insulin-resistant GDM. CONCLUSIONS/INTERPRETATION: This study demonstrates that physiological GDM subtypes differ in their metabolome and genetic architecture. These findings require replication in additional cohorts, but suggest that these differences may contribute to subtype-related adverse pregnancy outcomes.

Long-term outcomes of hospitalized patients with SARS-CoV-2/COVID-19 with and without neurological involvement: 3-year follow-up assessment.

BACKGROUND: Acute neurological manifestation is a common complication of acute Coronavirus Disease 2019 (COVID-19) disease. This retrospective cohort study investigated the 3-year outcomes of patients with and without significant neurological manifestations during initial COVID-19 hospitalization. METHODS AND FINDINGS: Patients hospitalized for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection between 03/01/2020 and 4/16/2020 in the Montefiore Health System in the Bronx, an epicenter of the early pandemic, were included. Follow-up data was captured up to 01/23/2023 (3 years post-COVID-19). This cohort consisted of 414 patients with COVID-19 with significant neurological manifestations and 1,199 propensity-matched patients (for age and COVID-19 severity score) with COVID-19 without neurological manifestations. Neurological involvement during the acute phase included acute stroke, new or recrudescent seizures, anatomic brain lesions, presence of altered mentation with evidence for impaired cognition or arousal, and neuro-COVID-19 complex (headache, anosmia, ageusia, chemesthesis, vertigo, presyncope, paresthesias, cranial nerve abnormalities, ataxia, dysautonomia, and skeletal muscle injury with normal orientation and arousal signs). There were no significant group differences in female sex composition (44.93% versus 48.21%, p = 0.249), ICU and IMV status, white, not Hispanic (6.52% versus 7.84%, p = 0.380), and Hispanic (33.57% versus 38.20%, p = 0.093), except black non-Hispanic (42.51% versus 36.03%, p = 0.019). Primary outcomes were mortality, stroke, heart attack, major adverse cardiovascular events (MACE), reinfection, and hospital readmission post-discharge. Secondary outcomes were neuroimaging findings (hemorrhage, active and prior stroke, mass effect, microhemorrhages, white matter changes, microvascular disease (MVD), and volume loss). More patients in the neurological cohort were discharged to acute rehabilitation (10.39% versus 3.34%, p < 0.001) or skilled nursing facilities (35.75% versus 25.35%, p < 0.001) and fewer to home (50.24% versus 66.64%, p < 0.001) than matched controls. Incidence of readmission for any reason (65.70% versus 60.72%, p = 0.036), stroke (6.28% versus 2.34%, p < 0.001), and MACE (20.53% versus 16.51%, p = 0.032) was higher in the neurological cohort post-discharge. Per Kaplan-Meier univariate survival curve analysis, such patients in the neurological cohort were more likely to die post-discharge compared to controls (hazard ratio: 2.346, (95% confidence interval (CI) [1.586, 3.470]; p < 0.001)). Across both cohorts, the major causes of death post-discharge were heart disease (13.79% neurological, 15.38% control), sepsis (8.63%, 17.58%), influenza and pneumonia (13.79%, 9.89%), COVID-19 (10.34%, 7.69%), and acute respiratory distress syndrome (ARDS) (10.34%, 6.59%). Factors associated with mortality after leaving the hospital involved the neurological cohort (odds ratio (OR): 1.802 (95% CI [1.237, 2.608]; p = 0.002)), discharge disposition (OR: 1.508 (95% CI [1.276, 1.775]; p < 0.001)), congestive heart failure (OR: 2.281 (95% CI [1.429, 3.593]; p < 0.001)), higher COVID-19 severity score (OR: 1.177 (95% CI [1.062, 1.304]; p = 0.002)), and older age (OR: 1.027 (95% CI [1.010, 1.044]; p = 0.002)). There were no group differences in radiological findings, except that the neurological cohort showed significantly more age-adjusted brain volume loss (p = 0.045) than controls. The study's patient cohort was limited to patients infected with COVID-19 during the first wave of the pandemic, when hospitals were overburdened, vaccines were not yet available, and treatments were limited. Patient profiles might differ when interrogating subsequent waves. CONCLUSIONS: Patients with COVID-19 with neurological manifestations had worse long-term outcomes compared to matched controls. These findings raise awareness and the need for closer monitoring and timely interventions for patients with COVID-19 with neurological manifestations, as their disease course involving initial neurological manifestations is associated with enhanced morbidity and mortality.

Weight stigma as a stressor: A preliminary multi-wave, longitudinal study testing the biobehavioral pathways of the Cyclic Obesity/Weight-Based Stigma (COBWEBS) model.

Higher weight individuals often face significant weight stigma. According to the Cyclic Obesity/Weight-Based Stigma (COBWEBS) model, weight stigma operates as a stressor that increases the stress hormone cortisol and promotes comfort eating, thus resulting in weight gain. Such weight gain is harmful as it exposes individuals to further stigmatization. Thus far, no study has yet tested the mechanistic pathways of the COBWEBS model and prospective longitudinal studies are severely lacking. To fill this gap, the current study tested the biobehavioral pathways of the COBWEBS model using a 4-wave yearlong longitudinal study comprising 348 higher weight individuals. Using a structural equation modeling framework, we tested three cross lagged panel models for the putative mediator, comfort eating. The models examined either synchronous and/or lagged effects across weight stigma, perceived stress, comfort eating, weight, and future weight stigma. The best fitting model revealed significant associations between baseline weight stigma, perceived stress, and comfort eating within the same month. However, comfort eating did not significantly predict weight four months later. Weight status and baseline weight stigma both predicted future weight stigma as expected. Additionally, a separate path model with hair cortisol found that weight stigma predicted perceived stress four months later, but stress did not predict aggregate cortisol levels from months 10 and 11. Hair cortisol also did not predict later weight. This preliminary work lays the foundation for identifying modifiable targets of weight stigma, thereby offering potential avenues to reduce weight stigma's harm on higher weight individuals.

The Role of Physician-Directed Duplex after Brachial Plexus Block in Arteriovenous Fistula Creation.

BACKGROUND: Best practice guidelines for dialysis access creation emphasize distal sites and autogenous tissue before more proximal sites and synthetic shunts. Pre-operative vein mapping is a useful modality to evaluate optimal access location; however, vein size is often underestimated secondary to patient hypovolemia, room temperature, and basal vascular tone. Supraclavicular brachial plexus blocks (BPB) are routinely performed to provide surgical anesthesia but also have known vasodilatory effects. Although many surgeons use both techniques, most do not repeat vein mapping after BPB to re-evaluate targets after block-mediated vasodilation. Therefore, we evaluated whether the role of physician-directed vein mapping after BPB resulted in more favorable access creations. METHODS: All patients who underwent primary ipsilateral access creation with physician-directed post-block duplex between 2017 and 2018 were evaluated. Vein mapping was reviewed for "theoretical access location" using the criterion of >2.5 mm vessels. Fistula preference was analogous to current indications with the following order of preference: wrist radiocephalic, forearm radiocephalic, brachiocephalic, brachiobasilic, and finally prosthetic graft. RESULTS: Forty-three patients met inclusion criteria. In total, physician-directed duplex after regional block resulted in the creation of higher preference accesses than predicted in 62.8% of patients. In 34.9% the access was at the predicted level and only 2.3% were at a lower preference. Furthermore, there were no differences in the maturation rates between accesses placed at higher preference locations than predicted compared to those at expected sites (74% vs. 79%, P = 0.38). The overall revision rate for higher preference access was 22.2% compared to 23.1% for equal/lower preference accesses. Of those accesses that failed, 83.3% of new accesses were created at the original theoretical location while 17.7% required placement of a lower preference access. CONCLUSIONS: Physician-directed ultrasound after BPB allows for identification of more preferential targets for access creation compared to pre-operative vein mapping. For access created at more preferential locations than pre-operatively predicted prior to BPB, there was no difference in maturation rates compared to those created at the theoretical vein mapping location.

Lung Cancer Screening Penetration in an Urban Underserved County.

PURPOSE: To compare residential geography, sex, socioeconomic status (SES), and race/ethnicity of patients screened at Montefiore's Lung Cancer Screening Program with those of patients diagnosed with lung cancer, assessing whether screening efforts are appropriately focused. METHODS: This retrospective cohort study involved patients within a multisite urban medical center undergoing lung cancer screening or diagnosed with lung cancer from January 1, 2015 to December 31, 2019. Inclusion criteria were residence within the Bronx, NY and age between 55 and 80 years. Institutional review board approval was obtained. Data were analyzed using the Wilcoxon two-sample t test and χ2. RESULTS: The cohorts comprised 1568 (50.3%) women and 1551 (49.7%) men (mean age 65.6 ± 6.16). The Southeast Bronx had the most diagnosed lung cancers (29.96%) and screenings (31.22%). Sex did not significantly differ (p = 0.053). Cancer and screening cohorts were from impoverished neighborhoods with mean SES of - 3.11 ± 2.78 and - 3.44 ± 2.80 (p < 0.01). The lower tier SES neighborhoods demonstrated more patients in the screening cohort than cancer cohort (p = 0.01). Both cohorts included a majority of Hispanic patients, although race/ethnicity differed significantly (p = 0.01). Lower SES neighborhoods showed no significant difference in race/ethnicity between cancer and screening cohorts (p = 0.262). CONCLUSION: Though statistically significant differences were found between cohorts, likely due to sample size, few clinically meaningful differences were found, implying our lung cancer screening program was effective in reaching the desired population. Demographics-based programs should be considered in global efforts to screen vulnerable populations.

Stress, mindfulness, and systemic lupus erythematosus: An overview and directions for future research.

Although the pathogenesis of autoimmunity is not fully understood, it is thought to involve genetic, hormonal, immunologic, and environmental factors. Stress has been evaluated as a potential trigger for autoimmunity and disease flares in patients with systemic lupus erythematosus (SLE). The physiologic changes that occur with stress involve numerous catecholamines, hormones, and cytokines that communicate intricately with the immune system. There is some evidence that these systems may be dysregulated in patients with autoimmune disease. Mindfulness-based techniques are practices aimed at mitigating stress response and have been shown to improve quality of life in general population. This review will discuss pathophysiology of chronic stress as it relates to SLE, evidence behind mindfulness-based practices in these patients, and directions for future research.

Percutaneous Treatments for Persistent Bronchopleural and Alveolar-Pleural Fistulae.

Percutaneous glue embolization was investigated as a treatment for bronchopleural fistulae (BPFs) and alveolar-pleural fistulae (APFs) associated with persistent air leak. Seven consecutive patients with persistent air leak were treated with percutaneous glue embolization of the BPF/APF from both iatrogenic and spontaneous causes. Treatment was performed using direct n-butyl cyanoacrylate (nBCA) glue injection for discrete, visible fistulae (n = 4), fibrin glue spray for suspected tiny multifocal leaks (n = 2), or both (n = 1). The number of treatments required per patient was 1 (n = 3), 2 (n = 3), or 3 (n = 1). Technical success was achieved in all cases. Follow-up showed resolution of all air leaks, with mean chest tube removal at 7.1 days after the embolization. The follow-up duration ranged from 2 to 47 months. No significant procedure-related morbidity, mortality, or recurrence was encountered. Percutaneous treatment for persistent BPFs and APFs showed good efficacy in this small case series and warrants further investigation.

Healthy versus unhealthy comfort eating for psychophysiological stress recovery in low-income Black and Latinx adults.

Low-income Black and Latinx individuals are disproportionately vulnerable to chronic stress and metabolic disease. Evidence suggests that these populations engage in elevated levels of comfort eating (i.e., eating comforting food to alleviate stress), which can harm diet quality. For this reason, many interventions discourage comfort eating. However, if comfort eating does indeed buffer stress, it may be a protective health behavior, particularly if healthy foods (e.g., strawberries) buffer stress as effectively as traditional unhealthy comfort foods (e.g., brownies). By choosing healthy foods, people may be able to simultaneously improve their nutrition and reduce their stress levels, both of which have the potential to reduce health disparities among chronically stressed populations. The present study tested the efficacy of healthy and unhealthy comfort eating for improving psychophysiological stress recovery. A sample of low-income Black and Latinx individuals (N = 129) were randomly assigned to consume a healthy food (e.g., grapes), unhealthy comfort food (e.g., chips), or no food after exposure to a laboratory stressor. Throughout, we measured participants' psychophysiological stress responses, including self-reported stress, rumination, autonomic nervous system activation (i.e., electrodermal activity (EDA), heart rate variability (HRV)) and neuroendocrine responses (i.e., salivary cortisol). We compared participants' stress recovery trajectories by condition and found no significant group differences (p = 0.12 for self-reported stress; p = 0.92 for EDA; p = 0.22 for HRV, p = 1.00 for cortisol). Participants in all conditions showed decreases in self-reported stress and in cortisol post-stressor (ps < 0.01), but rates of decline did not differ by condition (i.e., healthy or unhealthy comfort food, brief no-food waiting period). Although null, these results are important because they challenge the widely-held assumption that comfort foods help people decrease stress.

Weight stigma and health behaviors: evidence from the Eating in America Study.

BACKGROUND: Weight stigma is pervasive across the U.S. and is associated with poor health outcomes including all-cause mortality. One potential reason that weight stigma may be detrimental to health is that it begets poorer health behaviors. Therefore, the present study tested for associations between weight stigma and four health behaviors (i.e., eating behavior, alcohol use, sleep disturbance, and physical activity), while controlling for BMI and other potential confounds. SUBJECTS/METHODS: Participants (N = 2022) in the U.S. were recruited for the Eating in America Study using a Qualtrics panel between December 2019 and January 2020 and were census-matched according to national quotas for age, gender, income, race/ethnicity, and census region. Participants completed questionnaires about weight stigma, health behaviors, demographics, and anthropometric measurements. The current study employed a two-stage investigation: exploratory analyses were first performed on a random sample of the dataset (n = 438), then the remaining unexamined data were used to conduct confirmatory analyses that were preregistered on the Open Science Framework. RESULTS: Controlling for BMI, weight stigma was significantly associated with greater disordered eating (b = 0.34, 95% CI [0.31, 0.38], p < 0.001), comfort eating (b = 0.32, 95% CI [0.25, 0.39], p < 0.001), sleep disturbance (b = 0.27, 95% CI [0.20, 0.33], p < 0.001), and alcohol use (b = 0.30, 95% CI [0.11, 0.49], p = 0.002), but not lower physical activity (b = -0.04, 95% CI [-0.13, 0.05], p = 0.402) for individuals across the weight spectrum. BMI and perceived weight status significantly moderated the effects of weight stigma on disordered eating and alcohol use. No gender differences were found. These confirmatory analyses partially replicated the exploratory stage 1 findings. CONCLUSIONS: This study provides preliminary evidence that weight stigma is linked to several poor health behaviors, which may impact physical health.

Tyramine synthesis, vesicular packaging, and the SNARE complex function coordinately in astrocytes to regulate Drosophila alcohol sedation.

Identifying mechanisms underlying alcohol-related behaviors could provide important insights regarding the etiology of alcohol use disorder. To date, most genetic studies on alcohol-related behavior in model organisms have focused on neurons, leaving the causal roles of glial mechanisms less comprehensively investigated. Here, we report our studies on the role of Tyrosine decarboxylase 2 (Tdc2), which converts tyrosine to the catecholamine tyramine, in glial cells in Drosophila alcohol sedation. Using genetic approaches that drove transgene expression constitutively in all glia, constitutively in astrocytes and conditionally in glia during adulthood, we found that knockdown and overexpression of Tdc2, respectively, increased and decreased the sensitivity to alcohol sedation in flies. Manipulation of the genes tyramine ß-hydroxylase and tyrosine hydroxylase, which respectively synthesize octopamine and dopamine from tyramine and tyrosine, had no discernable effect on alcohol sedation, suggesting that Tdc2 affects alcohol sedation by regulating tyramine production. We also found that knockdown of the vesicular monoamine transporter (VMAT) and disruption of the SNARE complex in all glia or selectively in astrocytes increased sensitivity to alcohol sedation and that both VMAT and the SNARE complex functioned downstream of Tdc2. Our studies support a model in which the synthesis of tyramine and vesicle-mediated release of tyramine from adult astrocytes regulates alcohol sedation in Drosophila. Considering that tyramine is functionally orthologous to norepinephrine in mammals, our results raise the possibility that gliotransmitter synthesis release could be a conserved mechanism influencing behavioral responses to alcohol as well as alcohol use disorder.

Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.

BACKGROUND: As clinical exome sequencing (CES) becomes more common, understanding which patients are most likely to benefit and in what manner is critical for the general pediatrics community to appreciate. METHODS: Five hundred and twenty-three patients referred to the Pediatric Genetics clinic at Michigan Medicine were systematically phenotyped by the presence or absence of abnormalities for 13 body/organ systems by a Clinical Genetics team. All patients then underwent CES. RESULTS: Overall, 30% of patients who underwent CES had an identified pathogenic mutation. The most common phenotypes were developmental delay (83%), neuromuscular system abnormalities (81%), and multiple congenital anomalies (42%). In all, 67% of patients had a variant of uncertain significance (VUS) or gene of uncertain significance (GUS); 23% had no variants reported. There was a significant difference in the average number of body systems affected among these groups (pathogenic 5.89, VUS 6.0, GUS 6.12, and no variant 4.6; P < 0.00001). Representative cases highlight four ways in which CES is changing clinical pediatric practice. CONCLUSIONS: Patients with identified variants are enriched for multiple organ system involvement. Furthermore, our phenotyping provides broad insights into which patients are most likely to benefit from genetics referral and CES and how those results can help guide clinical practice more generally.

COVID-19 Outbreak - New York City, February 29-June 1, 2020.

New York City (NYC) was an epicenter of the coronavirus disease 2019 (COVID-19) outbreak in the United States during spring 2020 (1). During March-May 2020, approximately 203,000 laboratory-confirmed COVID-19 cases were reported to the NYC Department of Health and Mental Hygiene (DOHMH). To obtain more complete data, DOHMH used supplementary information sources and relied on direct data importation and matching of patient identifiers for data on hospitalization status, the occurrence of death, race/ethnicity, and presence of underlying medical conditions. The highest rates of cases, hospitalizations, and deaths were concentrated in communities of color, high-poverty areas, and among persons aged ≥75 years or with underlying conditions. The crude fatality rate was 9.2% overall and 32.1% among hospitalized patients. Using these data to prevent additional infections among NYC residents during subsequent waves of the pandemic, particularly among those at highest risk for hospitalization and death, is critical. Mitigating COVID-19 transmission among vulnerable groups at high risk for hospitalization and death is an urgent priority. Similar to NYC, other jurisdictions might find the use of supplementary information sources valuable in their efforts to prevent COVID-19 infections.

Conservation of trans-acting circuitry during mammalian regulatory evolution.

The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ∼8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is ∼95% similar with that derived from human TF footprints. However, only ∼20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity.

The Role of Welfare in Family Income Inequality: 1968-2016.

Income inequality among U.S. families with children has increased over recent decades, coinciding with a period of significant reforms in federal welfare policy. In the most recent reform eras, welfare benefits were significantly restructured and redistributed, which may have important implications for income inequality. Using data from the 1968-2016 March Supplement to the Current Population Survey (N = 1,192,244 families with children) merged with data from the historical Supplemental Poverty Measure, this study investigated how income inequality and, relatedly, the redistributive effects of welfare income and in-kind benefits changed, and whether such changes varied across states with different approaches to welfare policy. Results suggest that cash income from welfare became less effective at reducing income inequality after the 1996 welfare reform, because the share of income coming from cash welfare fell and was also less concentrated among the neediest families. At the same time, tax and in-kind benefits reduced inequality until the Great Recession. Consistent with the "race to the bottom" hypothesis, results suggest that the redistributive effects of welfare income dropped in all states regardless of their approach to welfare policy.

Epigenetic Silencing of TAP1 in Aldefluor+ Breast Cancer Stem Cells Contributes to Their Enhanced Immune Evasion.

Avoiding detection and destruction by immune cells is key for tumor initiation and progression. The important role of cancer stem cells (CSCs) in tumor initiation has been well established, yet their ability to evade immune detection and targeting is only partly understood. To investigate the ability of breast CSCs to evade immune detection, we identified a highly tumorigenic population in a spontaneous murine mammary tumor based on increased aldehyde dehydrogenase activity. We performed tumor growth studies in immunocompetent and immunocompromised mice. In immunocompetent mice, growth of the spontaneous mammary tumor was restricted; however, the Aldefluor+ population was expanded, suggesting inherent resistance mechanisms. Gene expression analysis of the sorted tumor cells revealed that the Aldefluor+ tumor cells has decreased expression of transporter associated with antigen processing (TAP) genes and co-stimulatory molecule CD80, which would decrease susceptibility to T cells. Similarly, the Aldefluor+ population of patient tumors and 4T1 murine mammary cells had decreased expression of TAP and co-stimulatory molecule genes. In contrast, breast CSCs identified by CD44+ CD24- do not have decreased expression of these genes, but do have increased expression of C-X-C chemokine receptor type 4. Decitabine treatment and bisulfite pyrosequencing suggests that DNA hypermethylation contributes to decreased TAP gene expression in Aldefluor+ CSCs. TAP1 knockdown resulted in increased tumor growth of 4T1 cells in immunocompetent mice. Together, this suggests immune evasion mechanisms in breast CSCs are marker specific and epigenetic silencing of TAP1 in Aldefluor+ breast CSCs contributes to their enhanced survival under immune pressure. Stem Cells 2018;36:641-654.

Convergent Evidence From Humans and Drosophila melanogaster Implicates the Transcription Factor MEF2B/Mef2 in Alcohol Sensitivity.

BACKGROUND: Self-Rating of the Effects of Alcohol (SRE) measures level of response to ethanol (EtOH) in humans. Interestingly, there is a positive relationship between the SRE and risk for abusing alcohol, suggesting mechanistic connections between SRE and alcohol abuse. METHODS: To identify candidate genes with a role in SRE and alcohol-related behavior more generally, we coupled human genetic analyses with studies in Drosophila melanogaster. We first performed a gene-based analysis of Genomewide association studies (GWAS) summary statistics for SRE in the Avon Longitudinal Study of Parents and Children sample. Based on prior findings in humans, orthology to fly genes, and the availability of genetic reagents, we selected a subset of these genes for studies on EtOH behavior in Drosophila. RESULTS: We found 37 genes with nominal associations in our SRE GWAS. We explored the role of 6 orthologous genes in Drosophila EtOH sedation and rapid tolerance. We found that the transcription factor Mef2 is required for normal EtOH sedation in flies. Pan-neuronal expression of 2 independent Mef2 RNAi transgenes significantly reduced Mef2 expression and made flies resistant to EtOH sedation. Additionally, flies with multiple independent mutant alleles of Mef2 were also resistant to EtOH sedation, confirming a role for Mef2 in this behavior. Altered expression of Mef2 did not change EtOH rapid tolerance or cause a net change in internal EtOH concentrations. CONCLUSIONS: Our studies indicate that MEF2B influences SRE in humans and that Mef2 impacts EtOH sedation in Drosophila.

Safety and Efficacy of Transjugular Liver Biopsy in Patients with Left Lobe-Only Liver Transplants.

PURPOSE: To evaluate efficacy and safety of transjugular liver biopsy (TJLB) via the left hepatic vein in patients with left lobe-only liver transplants (LLOTs). MATERIALS AND METHODS: Retrospective review revealed 43 TJLBs performed in 26 patients with LLOTs (mean age 51.3 y; range, 18-73 y) between January 2009 and June 2016 at a single institution. A comparison group of 44 randomly selected TJLBs performed in 37 orthotopic whole liver transplant (OWLT) recipients (mean age 57.6 y; range, 35-74 y) during the same time period was evaluated. Patient demographics, type and age of transplant, technical success, adequacy of samples, number of portal tracts obtained, pathologic diagnosis, and complication rate were reviewed. RESULTS: Technical success was achieved in 98% (42/43) of LLOT procedures. TJLB failed in 1 patient with LLOT, in whom no patent hepatic veins were identified. Technical success was achieved in 100% (44/44) in the OWLT group. Mean (SD) number of needle passes was 4.12 (1.25) in the LLOT group vs 3.95 (1.28) in the OWLT group (P = .54). Mean (SD) specimen length was 1.16 (0.75) cm in the LLOT group vs 1.19 (0.58) cm in the OWLT group (P = .78). Mean (SD) number of portal tracts obtained in the LLOT group was 10.7 (5.26) vs 12.3 (4.68) in the OWLT group (P = .17). No major complications were observed in either group. CONCLUSIONS: TJLB in adult patients with LLOTs appears safe and feasible, with favorable rates of technical success and adequacy of sampling.