Strong and weak cross-inheritance of substance use disorders in a nationally representative sample.

Substance use disorders (SUDs) are moderately to highly heritable and are in part cross-transmitted genetically, as observed in twin and family studies. We performed exome-focused genotyping to examine the cross-transmission of four SUDs: alcohol use disorder (AUD, n = 4487); nicotine use disorder (NUD, n = 4394); cannabis use disorder (CUD, n = 954); and nonmedical prescription opioid use disorder (NMPOUD, n = 346) within a large nationally representative sample (n = 36,309), the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III). All diagnoses were based on in-person structured psychiatric interview (AUDADIS-5). SUD cases were compared alone and together to 3959 "super controls" who had neither a SUD nor a psychiatric disorder using an exome-focused array assaying 363,496 SNPs, yielding a representative view of within-disorder and cross-disorder genetic influences on SUDs. The 29 top susceptibility genes for one or more SUDs overlapped highly with genes previously implicated by GWAS of SUD. Polygenic scores (PGS) were computed within the European ancestry (EA) component of the sample (n = 12,505) using summary statistics from each of four clinically distinct SUDs compared to the 3959 "super controls" but then used for two distinctly different purposes: to predict SUD severity (mild, moderate, or severe) and to predict each of the other 3 SUDs. Our findings based on PGS highlight shared and unshared genetic contributions to the pathogenesis of SUDs, confirming the strong cross-inheritance of AUD and NUD as well as the distinctiveness of inheritance of opioid use disorder.

Black in Immuno Week: Who We Are, What We Did, and Why It Matters.

Our organization, Black in Immuno (@BlackInImmuno), was formed in September 2020 to celebrate, support, and amplify Black voices in immunology when social media campaigns like #BlackInTheIvory illuminated the shared overt and covert issues of systemic racism faced by Black researchers in all facets of science, technology, engineering, art, and mathematics. Black in Immuno was cofounded by a group of Black immunology trainees working at multiple institutions globally: Joël Babdor, E. Evonne Jean, Elaine Kouame, Alexis S. Mobley, Justine C. Noel, and Madina Wane. We devised Black in Immuno Week, held November 22-28, 2020, as a global celebration of Black immunologists. The week was designed to advocate for increased diversity and accessibility in immunology, amplify Black excellence in immunology, and create a community of Black immunologists who can support each other to flourish despite barriers in academia and other job sectors. The week contained live panels and scientific talks, a casual networking mixer, online advocacy and amplification sessions, and a series of wellness events. Our live-streamed programs reached over 300 individuals, and thousands of people kept the conversations going globally using #BlackInImmuno and #BlackInImmunoWeek on social media from five continents. Below, we highlight the events and significant takeaways of the week.

Prevalence and Correlates of Past-Year Recovery From DSM-5 Alcohol Use Disorder: Results From National Epidemiologic Survey on Alcohol and Related Conditions-III.

BACKGROUND: Little is known about remission, recovery, and other outcomes of alcohol use disorder (AUD) as defined by the DSM-5. METHODS: Data from a large representative sample of the United States was used to examine correlates of past-year AUD status among individuals with prior-to-past-year AUD: persistent AUD, symptomatic high-risk drinking, asymptomatic high-risk drinking, symptomatic low-risk drinking, asymptomatic low-risk drinking (nonabstinent recovery, NAR), and abstainer (abstinent recovery, AR). Multiple logistic regression analyses were conducted to compare: (i) AR and NAR with persistent AUD, (ii) AR with NAR, and (iii) asymptomatic and symptomatic high-risk drinking with AR and NAR. RESULTS: Among individuals with AUD prior to past year (n = 7,785), 34.2% were classified with persistent AUD, 8.8 and 1.6% were symptomatic high-risk and symptomatic low-risk drinkers, respectively, 21.5% were asymptomatic high-risk drinkers, 17.9% were asymptomatic low-risk drinkers, and 16.0% were abstainers. One-quarter of individuals with AUD prior to past year achieved AR or NAR without the benefit of treatment, while a much greater percentage of individuals achieving AR (43.2%) reported receiving treatment relative to those with NAR (12.3%). The number of lifetime AUD symptoms was greater among those achieving AR (among the treated) and lower among those achieving NAR relative to persistent AUD. The number of AUD symptoms was also greater among those achieving AR than NAR and lower among asymptomatic and symptomatic risk drinkers relative to those achieving AR and NAR. Consumption was greater among those achieving AR relative to those achieving NAR and greater among asymptomatic and symptomatic risk drinkers relative to AR and NAR. Odds of achieving AR or NAR relative to persistent AUD were generally lower among non-Hispanic Blacks and those with higher education, greater among women and married individuals, and lower among illicit drug users and individuals with histories of a personality disorder or mood/anxiety disorder. CONCLUSIONS: There appears to be a substantial level of recovery from AUD. Information on specific factors associated with AUD outcomes can be useful in targeting appropriate treatment efforts.

Lifetime Drinking Trajectories and Nonfatal Acute Myocardial Infarction.

BACKGROUND: The relation of lifetime drinking trajectories to coronary heart disease is not well understood. METHODS: Cases hospitalized for a nonfatal acute myocardial infarction (AMI) and healthy population-based controls matched on age and sex completed a physical examination and an interview covering known AMI risk factors and a detailed lifetime drinking history. Distinct lifetime drinking trajectories based on ounces of ethanol consumed per decade between ages 10 and 59 years were derived and characterized according to lifetime drinking patterns associated with each. Sex-specific multiple logistic regression analyses were conducted to estimate AMI risk among participants who never drank regularly compared to lifetime drinking trajectories and risk associated with distinct trajectories among former and current drinkers. RESULTS: Two lifetime drinking trajectories were derived, early peak and stable. Early peak trajectories were characterized by earlier onset of regular drinking, less frequent drinking, more drinks per drinking day, fewer total drinks, more frequent drunkenness per drinking year, and reduced alcohol intake or abstention by middle age. Never drinking regularly, reported by significantly more women than men, was associated with significantly higher AMI risk than stable lifetime drinking trajectories among men and in the sex-combined analysis of former drinkers only. Compared to stable lifetime drinking trajectories, early peak trajectories were associated with significantly higher AMI risk among male former drinkers, among sex-combined former drinkers, and among female current drinkers. CONCLUSIONS: Epidemiological studies of alcohol and health in populations over age 35 may have underestimated the impact of heavy episodic drinking during adolescence and emerging adulthood on the cardiovascular system.

Re-examining the relationship between alcohol consumption and coronary heart disease with a new lens.

Moderate alcohol consumption has been related to lower risk of coronary heart disease (CHD) in the literature. To examine whether alcohol drinking during the past 12 months and heaviest drinking period were differentially associated with the risk of CHD, we designed a case-control study using a population-based health survey of U.S. adults conducted from 2012 to 2013. Respondents who reported to have doctor-ascertained CHD served as cases (n = 1671), and those free of CHD and other alcohol-related health conditions served as controls (n = 17,629) in logistic regressions. Sex-specific quartiles of average daily ethanol intake were ascertained and calculated for the past 12 months and during the period of heaviest lifetime drinking. We further split current drinkers into reducers and non-reducers (past 12 months relative to the heaviest drinking period) to examine CHD risk profiles in association with the 12-month drinking level. Current-drinker reducers (AOR, 95% CI = 1.57 [1.10-2.27] for men; AOR, 95% CI = 1.33 [1.02-1.72] for women) and former drinkers (AOR, 95% CI = 2.06 [1.43-2.97] for men; AOR, 95% CI = 1.51 [1.19-1.92] for women) more often had CHD than lifetime abstainers. Male heavy drinkers during the heaviest drinking period (AOR, 95% CI = 2.25 [1.52-3.32]) were more likely to manifest CHD than lifetime abstainers. In addition, individuals with diagnosed CHD were significantly more likely to have reduced drinking in the past. A change in alcohol consumption over the life course among former and current drinkers may distort the true alcohol-CHD relationship.

Assessment of age-related differences in smoking status and health-related quality of life (HRQoL): Findings from the 2016 Behavioral Risk Factor Surveillance System.

Despite significant declines in the use of cigarettes, a significant proportion of adults smoke. This study explores the association between smoking and health-related quality of life (HRQoL) by age. The 2016 Behavioral Risk Factor Surveillance System survey was administered to adults in 50 states and District of Columbia (n = 437,195). Physically unhealthy days (PUDs) and mentally unhealthy days (MUDs)) were regressed on age strata (18-24, 25-34, 35-44, 45-54, 55-64, ≥ 65 years) and smoking status (never, former, someday, and everyday) using negative binomial regression models with adjustment for sociodemographic covariates. For each age group, everyday smoking highly predicted PUDs and MUDs. Predicted PUDs increased with age; predicted MUDs decreased with age. Among adults aged 45-54 and 55-64 years, 3-day difference in PUDs was observed between never smokers and everyday smokers. Among young adults (18-24 years), a 4.3-day difference in MUDs was observed between everyday and never smokers. The discrepancies were nonlinear with age. The observed relationship between smoking and HRQoL provides novel information about the need to consider age when designing community-based interventions. Additional research can provide needed depth to understanding the relationship between smoking and HRQoL in specific age groups.

State socioeconomic indicators and self-reported hypertension among US adults, 2011 behavioral risk factor surveillance system.

INTRODUCTION: Hypertension is the leading cause of chronic disease and premature death in the United States. To date, most risk factors for hypertension have been identified at the individual (micro) level. The association of macro-level (area) socioeconomic factors and hypertension prevalence rates in the population has not been studied extensively. METHODS: We used the 2011 Behavioral Risk Factor Surveillance System to examine whether state socioeconomic status (SES) indicators predict the prevalence of self-reported hypertension. Quintiles of state median household income, unemployment rate among the population aged 16 to 64 years, and the proportion of the population under the national poverty line were used as the proxy for state SES. Hypertension status was determined by the question "Have you ever been told by a doctor, nurse, or other health professional that you have high blood pressure?" Logistic regression was used to assess the relationship between state SES and hypertension with adjustment for individual covariates (demographic and socioeconomic factors and lifestyle behaviors). RESULTS: States with a median household income of $43,225 or less (odds ratio [95% confidence interval] = 1.16 [1.08-1.25]) and states with 18.7% or more of residents living below the poverty line (odds ratio [95% confidence interval] = 1.14 [1.04-1.24]) had a higher prevalence of hypertension than states with the most residents in the most advantageous quintile of the indicators. CONCLUSION: The observed state SES-hypertension association indicates that area SES may contribute to the burden of hypertension in community-dwelling adults.

Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119.

Mutations in additional sex combs like 1 (ASXL1) confer poor prognosis both in myeloid malignancies and in premalignant clonal hematopoiesis (CH). However, the mechanisms by which these mutations contribute to disease initiation remain unresolved, and mutation-specific targeting has remained elusive. To address this, we developed a human disease model that recapitulates the disease trajectory from ASXL1-mutant CH to lethal myeloid malignancy. We demonstrate that mutations in ASXL1 lead to the expression of a functional, truncated protein and determine that truncated ASXL1 leads to global redistribution of the repressive chromatin mark H2AK119Ub, increased transposase-accessible chromatin, and activation of both myeloid and stem cell gene-expression programs. Finally, we demonstrate that H2AK119Ub levels are tied to truncated ASXL1 expression levels and leverage this observation to demonstrate that inhibition of the PRC1 complex might be an ASXL1-mutant-specific therapeutic vulnerability in both premalignant CH and myeloid malignancy. SIGNIFICANCE: Mutant ASXL1 is a common driver of CH and myeloid malignancy. Using primary human HSPCs, we determine that truncated ASXL1 leads to redistribution of H2AK119Ub and may affect therapeutic vulnerability to PRC1 inhibition.

Exploring patterns of alcohol use and alcohol use disorder among Asian Americans with a finer lens.

BACKGROUND: National survey data suggest Asian Americans (AA) are less likely to consume alcohol and develop AUD than Americans in other groups. However, it is common for AA to be born outside of the US and carry gene variants that alter alcohol metabolism, both of which can lead to lower levels of alcohol involvement. The current study examined differences in alcohol use and AUD between AA and other groups before and after controlling for birth location and gene variants. DESIGN: Past year alcohol measures were examined from adults 18+ (N=22,848) in the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions III before and after controlling for birth location (inside or outside of the US) and gene variants (ALDH2*2 and ADH1B*2/ADH1B*3). Gender gaps in alcohol measures also were assessed. RESULTS: Before adjustments, AA were less likely than White Americans to drink in the previous year (OR=0.50, 95% CI 0.41-0.62), binge (OR=0.68, 95% CI 0.52-0.88), engage in frequent heavy drinking (OR=0.55, 95% CI 0.42-0.73), and reach criteria for AUD (OR=0.71, 95% CI 0.53-0.94). After controlling for birth location and gene variants, AA remained less likely to drink in the past year (OR=0.54, 95% CI 0.41-0.70) but all other differences disappeared. Gender gaps were only observed for AA born outside of the US, highlighting the importance of experience rather than racial category per se. CONCLUSIONS: Findings indicate that heterogeneity among AA leads to spurious generalizations regarding alcohol use and AUD and challenge the model minority myth.

A single cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis.

Hematopoietic multipotent progenitors (MPPs) regulate blood cell production to appropriately meet the biological demands of the human body. Human MPPs remain ill-defined whereas mouse MPPs have been well characterized with distinct immunophenotypes and lineage potencies. Using multiomic single cell analyses and complementary functional assays, we identified new human MPPs and oligopotent progenitor populations within Lin-CD34+CD38dim/lo adult bone marrow with distinct biomolecular and functional properties. These populations were prospectively isolated based on expression of CD69, CLL1, and CD2 in addition to classical markers like CD90 and CD45RA. We show that within the canonical Lin-CD34+CD38dim/loCD90CD45RA-MPP population, there is a CD69+ MPP with long-term engraftment and multilineage differentiation potential, a CLL1+ myeloid-biased MPP, and a CLL1-CD69-erythroid-biased MPP. We also show that the canonical Lin-CD34+CD38dim/loCD90-CD45RA+ LMPP population can be separated into a CD2+ LMPP with lymphoid and myeloid potential, a CD2-LMPP with high lymphoid potential, and a CLL1+ GMP with minimal lymphoid potential. We used these new HSPC profiles to study human and mouse bone marrow cells and observe limited cell type specific homology between humans and mice and cell type specific changes associated with aging. By identifying and functionally characterizing new adult MPP sub-populations, we provide an updated reference and framework for future studies in human hematopoiesis.

IDH1-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation.

Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at the time of acute myeloid leukemia (AML) diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSC). We confirm that IDH1-driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in the complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wild-type HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent the development and relapse of leukemia. SIGNIFICANCE: A high burden of pHSCs is associated with worse overall survival in AML. Using single-cell sequencing, metabolic assessment, and gene-edited human models, we find human pHSCs with IDH1 mutations to be metabolically vulnerable and sensitive to eradication by complex I inhibition. See related commentary by Steensma.

Genome engineering with Cas9 and AAV repair templates generates frequent concatemeric insertions of viral vectors.

CRISPR-Cas9 paired with adeno-associated virus serotype 6 (AAV6) is among the most efficient tools for producing targeted gene knockins. Here, we report that this system can lead to frequent concatemeric insertions of the viral vector genome at the target site that are difficult to detect. Such errors can cause adverse and unreliable phenotypes that are antithetical to the goal of precision genome engineering. The concatemeric knockins occurred regardless of locus, vector concentration, cell line or cell type, including human pluripotent and hematopoietic stem cells. Although these highly abundant errors were found in more than half of the edited cells, they could not be readily detected by common analytical methods. We describe strategies to detect and thoroughly characterize the concatemeric viral vector insertions, and we highlight analytical pitfalls that mask their prevalence. We then describe strategies to prevent the concatemeric inserts by cutting the vector genome after transduction. This approach is compatible with established gene editing pipelines, enabling robust genetic knockins that are safer, more reliable and more reproducible.

Trends in cigarette smoking rates and quit attempts among adults with and without diagnosed diabetes, United States, 2001-2010.

INTRODUCTION: Quitting smoking is a critical step toward diabetes control. It is not known whether smoking rates in adults with diabetes are similar to rates among adults who do not have the disease or whether people with diabetes have increased motivation to quit. We examined prevalence trends of current smoking and quit attempts among US adults with and without diagnosed diabetes from 2001 through 2010. METHODS: We used data from the 2001 through 2010 Behavioral Risk Factor Surveillance System, a state-based telephone survey of noninstitutionalized US adults, and conducted linear trend analysis and log linear regression. RESULTS: The adjusted prevalence of cigarette smoking among adults with diagnosed diabetes was 9% less than adults without diagnosed diabetes (adjusted prevalence ratio [APR], 0.91; 99% confidence interval [CI], 0.89-0.93). Declines in smoking prevalence were greater among adults without diabetes than adults with diagnosed diabetes (P < .001). Among smokers, the adjusted prevalence of quit attempts among adults with diagnosed diabetes was 13% higher than among adults without diagnosed diabetes (APR, 1.13; 99% CI, 1.11-1.15). Among adult smokers with diagnosed diabetes, quit attempts were stable over time for those aged 18 to 44 years and those with a high school education or less. Quit attempts were also stable for older smokers, non-Hispanic African Americans, and Hispanic smokers, regardless of diagnosed diabetes status. CONCLUSION: A large proportion of smokers with diagnosed diabetes seemed to have quit smoking, but more research is needed to confirm success and how difficult it was to achieve.

RUNX1 loss renders hematopoietic and leukemic cells dependent on IL-3 and sensitive to JAK inhibition.

Disease-initiating mutations in the transcription factor RUNX1 occur as germline and somatic events that cause leukemias with particularly poor prognosis. However, the role of RUNX1 in leukemogenesis is not fully understood, and effective therapies for RUNX1-mutant leukemias remain elusive. Here, we used primary patient samples and a RUNX1-KO model in primary human hematopoietic cells to investigate how RUNX1 loss contributes to leukemic progression and to identify targetable vulnerabilities. Surprisingly, we found that RUNX1 loss decreased proliferative capacity and stem cell function. However, RUNX1-deficient cells selectively upregulated the IL-3 receptor. Exposure to IL-3, but not other JAK/STAT cytokines, rescued RUNX1-KO proliferative and competitive defects. Further, we demonstrated that RUNX1 loss repressed JAK/STAT signaling and rendered RUNX1-deficient cells sensitive to JAK inhibitors. Our study identifies a dependency of RUNX1-mutant leukemias on IL-3/JAK/STAT signaling, which may enable targeting of these aggressive blood cancers with existing agents.

IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by inhibition of oxidative phosphorylation.

Rare preleukemic hematopoietic stem cells (pHSCs) harboring only the initiating mutations can be detected at the time of AML diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene-editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSCs). We confirm that IDH1 driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC Class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wildtype HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent development and relapse of leukemia.

Reprogramming Cancer into Antigen-Presenting Cells as a Novel Immunotherapy.

Therapeutic cancer vaccination seeks to elicit activation of tumor-reactive T cells capable of recognizing tumor-associated antigens (TAA) and eradicating malignant cells. Here, we present a cancer vaccination approach utilizing myeloid-lineage reprogramming to directly convert cancer cells into tumor-reprogrammed antigen-presenting cells (TR-APC). Using syngeneic murine leukemia models, we demonstrate that TR-APCs acquire both myeloid phenotype and function, process and present endogenous TAAs, and potently stimulate TAA-specific CD4+ and CD8+ T cells. In vivo TR-APC induction elicits clonal expansion of cancer-specific T cells, establishes cancer-specific immune memory, and ultimately promotes leukemia eradication. We further show that both hematologic cancers and solid tumors, including sarcomas and carcinomas, are amenable to myeloid-lineage reprogramming into TR-APCs. Finally, we demonstrate the clinical applicability of this approach by generating TR-APCs from primary clinical specimens and stimulating autologous patient-derived T cells. Thus, TR-APCs represent a cancer vaccination therapeutic strategy with broad implications for clinical immuno-oncology. SIGNIFICANCE: Despite recent advances, the clinical benefit provided by cancer vaccination remains limited. We present a cancer vaccination approach leveraging myeloid-lineage reprogramming of cancer cells into APCs, which subsequently activate anticancer immunity through presentation of self-derived cancer antigens. Both hematologic and solid malignancies derive significant therapeutic benefit from reprogramming-based immunotherapy. This article is highlighted in the In This Issue feature, p. 1027.

Niche-directed therapy in acute myeloid leukemia: optimization of stem cell competition for niche occupancy.

Acute myeloid leukemia (AML) is an aggressive malignancy of stem cell origin that contributes to significant morbidity and mortality. The long-term prognosis remains dismal given the high likelihood for primary refractory or relapsed disease. An essential component of relapse is resurgence from the bone marrow. To date, the murine hematopoietic stem cell (HSC) niche has been clearly defined, but the human HSC niche is less well understood. The design of niche-based targeted therapies for AML must account for which cellular subsets compete for stem cell occupancy within respective bone marrow microenvironments. In this review, we highlight the principles of stem cell niche biology and discuss translational insights into the AML microenvironment as of 2021. Optimization of competition for niche occupancy is important for the elimination of measurable residual disease (MRD). Some of these novel therapeutics are in the pharmacologic pipeline for AML and may be especially useful in the setting of MRD.

The Cell Type-Specific 5hmC Landscape and Dynamics of Healthy Human Hematopoiesis and TET2-Mutant Preleukemia.

The conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is a key step in DNA demethylation that is mediated by ten-eleven translocation (TET) enzymes, which require ascorbate/vitamin C. Here, we report the 5hmC landscape of normal hematopoiesis and identify cell type-specific 5hmC profiles associated with active transcription and chromatin accessibility of key hematopoietic regulators. We utilized CRISPR/Cas9 to model TET2 loss-of-function mutations in primary human hematopoietic stem and progenitor cells (HSPC). Disrupted cells exhibited increased colonies in serial replating, defective erythroid/megakaryocytic differentiation, and in vivo competitive advantage and myeloid skewing coupled with reduction of 5hmC at erythroid-associated gene loci. Azacitidine and ascorbate restored 5hmC abundance and slowed or reverted the expansion of TET2-mutant clones in vivo. These results demonstrate the key role of 5hmC in normal hematopoiesis and TET2-mutant phenotypes and raise the possibility of utilizing these agents to further our understanding of preleukemia and clonal hematopoiesis. SIGNIFICANCE: We show that 5-hydroxymethylation profiles are cell type-specific and associated with transcriptional abundance and chromatin accessibility across human hematopoiesis. TET2 loss caused aberrant growth and differentiation phenotypes and disrupted 5hmC and transcriptional landscapes. Treatment of TET2 KO HSPCs with ascorbate or azacitidine reverted 5hmC profiles and restored aberrant phenotypes. This article is highlighted in the In This Issue feature, p. 265.

Visual impairment and health-related quality of life among elderly adults with age-related eye diseases.

PURPOSE: To examine the association between age-related eye disease (ARED), visual impairment, and health-related quality of life (HRQOL). METHODS: We used data from the 2006 and 2008 Behavioral Risk Factor Surveillance System to examine self-reported visual impairment and two HRQOL domains-physical impairment (including poor general health, physical unhealthy days, activity-limitation days, and disability) and mental distress (including mental unhealthy days, life dissatisfaction, major depression, lifetime depression, and anxiety) for people aged 65 years or older, by ARED status. RESULTS: People with any ARED were more likely than those without to report visual impairment as well as physical impairment and mental distress. The prevalence of visual impairment (P trend <0.001) and physical impairment (P trend <0.001) increased with increasing number of eye diseases after controlling for all covariates. There was no significant linear trend, however, in mental distress among people with one or more eye diseases. CONCLUSION: ARED was found to be associated with visual impairment and poorer HRQOL. Increasing numbers of AREDs were associated with increased levels of visual impairment and physical impairment, but were not associated with levels of mental distress.

Trends in selected chronic conditions and behavioral risk factors among women of reproductive age, behavioral risk factor surveillance system, 2001-2009.

INTRODUCTION: Some potentially modifiable risk factors and chronic conditions cause significant disease and death during pregnancy and promote the development of chronic disease. This study describes recent trends of modifiable risk factors and controllable chronic conditions among reproductive-aged women. METHODS: Data from the 2001 to 2009 Behavioral Risk Factor Surveillance System, a representative state-based telephone survey of health behavior in US adults, was analyzed for 327,917 women of reproductive age, 18 to 44 years. We calculated prevalence ratios over time to assess trends for 4 selected risk factors and 4 chronic conditions, accounting for age, race/ethnicity, education, health care coverage, and individual states. RESULTS: From 2001 to 2009, estimates of 2 risk factors improved: smoking declined from 25.9% to 18.8%, and physical inactivity declined from 25.0% to 23.0%. One risk factor, heavy drinking, did not change. From 2003 to 2009, the estimates for 1 risk factor and 4 chronic conditions worsened: obesity increased from 18.3% to 24.7%, diabetes increased from 2.1% to 2.9%, high cholesterol increased from 10.3% to 13.6%, asthma increased from 13.5% to 16.2%, and high blood pressure increased from 9.0% to 10.1%. All trends were significant after adjustment, except that for heavy drinking. CONCLUSION: Among women of reproductive age, prevalence of smoking and physical inactivity improved, but prevalence of obesity and all 4 chronic conditions worsened. Understanding reasons for the improvements in smoking and physical activity may support the development of targeted interventions to reverse the trends and help prevent chronic disease and adverse reproductive outcomes among women in this age group.