Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis.

SIGNIFICANCE STATEMENT: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. BACKGROUND: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. METHODS: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234). RESULTS: We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. CONCLUSIONS: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.

Human stem cell-derived thymic epithelial cells enhance human T-cell development in a xenogeneic thymus.

BACKGROUND: Generation of thymic tissue from pluripotent stem cells would provide therapies for acquired and congenital thymic insufficiency states. OBJECTIVES: This study aimed to generate human thymic epithelial progenitors from human embryonic stem cells (hES-TEPs) and to assess their thymopoietic function in vivo. METHODS: This study differentiated hES-TEPs by mimicking developmental queues with FGF8, retinoic acid, SHH, Noggin, and BMP4. Their function was assessed in reaggregate cellular grafts under the kidney capsule and in hybrid thymi by incorporating them into swine thymus (SwTHY) grafts implanted under the kidney capsules of immunodeficient mice that received human hematopoietic stem and progenitor cells (hHSPCs) intravenously. RESULTS: Cultured hES-TEPs expressed FOXN1 and formed colonies expressing EPCAM and both cortical and medullary thymic epithelial cell markers. In thymectomized immunodeficient mice receiving hHSPCs, hES-TEPs mixed with human thymic mesenchymal cells supported human T-cell development. Hypothesizing that support from non-epithelial thymic cells might allow long-term function of hES-TEPs, the investigators injected them into SwTHY tissue, which supports human thymopoiesis in NOD severe combined immunodeficiency IL2Rγnull mice receiving hHSPCs. hES-TEPs integrated into SwTHY grafts, enhanced human thymopoiesis, and increased peripheral CD4+ naive T-cell reconstitution. CONCLUSIONS: This study has developed and demonstrated in vivo thymopoietic function of hES-TEPs generated with a novel differentiation protocol. The SwTHY hybrid thymus model demonstrates beneficial effects on human thymocyte development of hES-TEPs maturing in the context of a supportive thymic structure.

Diagnostic Utility of Exome Sequencing for Kidney Disease.

BACKGROUND: Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally. METHODS: We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings. RESULTS: In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management. CONCLUSIONS: Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases. (Funded by the National Institutes of Health and others.).

GeneLiFT: A novel test to facilitate rapid screening of genetic literacy in a diverse population undergoing genetic testing.

With the broader introduction of genomic medicine in research and clinical care, an increasing number of persons are offered genetic testing. Many factors, including genetic literacy, may impact the utilization of genetic results by patients and their families. We developed a rapid, self-administered measure of genetic literacy, called Genetic Literacy Fast Test (GeneLiFT). We next evaluated the association of GeneLiFT scores with the comprehension of limitations of genomic medicine in participants undergoing genetic testing in the NIH-sponsored eMERGE III study at Columbia University Irving Medical Center, New York. All participants underwent genetic screening for variants in 74 actionable genes associated with adult-onset disorders. A diverse cohort of 724 participants completed the survey (60% women, 45% less than 40 years old, and 53% self-reported White non-Hispanic ancestry). The GeneLiFT was validated using known group differences based on education, health literacy, and numeracy, and with questions assessing genetic knowledge. GeneLiFT identified multiple standard genetics terms, that is, jargon, not recognized by more than 50% of participants (including actionability and pathogenicity). Low genetic literacy, identified in 210 participants (29%), was significantly associated with poor understanding of the limitations of genetic testing (p-values < 10-9 ). This association was independent of education, health literacy, and numeracy levels, highlighting the importance of directly measuring genetic literacy. Low genetic literacy was also associated with low satisfaction with the informed consent process. GeneLiFT is a practical tool for rapid assessment of genetic literacy in large studies or clinical care. GeneLiFT will allow future research to efficiently assess the role of genetic literacy on the clinical impact of genetic testing.

Overall survival analysis in patients with metastatic breast cancer and liver or lung metastases treated with eribulin, gemcitabine, or capecitabine.

PURPOSE: The purpose of this study was to estimate the overall survival (OS) in real-world clinical practice in patients with metastatic breast cancer (MBC) and visceral metastases (liver or lung) treated in the third-line setting with eribulin, gemcitabine or capecitabine overall and in the major clinical categories of MBC (TNBC, HR+/HER2-, and HER2+). METHODS: A retrospective, observational study was conducted with de-identified patient electronic health records from the Cancer Treatment Centers of America (CTCA). Patients with a diagnosis of metastatic breast with lung or liver metastases, and treated with eribulin, gemcitabine, or capecitabine as third-line therapy were included in the analysis. Landmark survival was calculated as percentage of patients alive at 6, 12, 24, and 36 months. Overall survival was compared between treatment arms within TNBC and HR+/HER2- using log-rank analysis. Cox regression analyses was performed to estimate hazard ratios for comparison of treatments within TNBC and HR+/HER2- subtype. RESULTS: 443 patients with liver or lung metastases received third-line therapy with eribulin (n = 229), gemcitabine (n = 134), or capecitabine (n = 80). Eribulin patients had a higher percentage of patients alive at all landmark timepoints vs. gemcitabine, and a higher percentage of patients alive until 36 months vs. capecitabine. Median survival times showed that overall, and within the TNBC and HR+/HER2- subtype, patients receiving eribulin had a numerically higher median overall survival. CONCLUSIONS: This real-world evidence study is consistent with randomized clinical trial data and demonstrates consistency of eribulin effectiveness in MBC patients with lung or liver metastases overall and in TNBC and HR+/HER2- disease.

Correction: Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study.

The original version of this Article contained an error in the undergraduate degree awarded to the author Ian Halim, which was incorrectly given as BS. This has now been corrected to BA in both the PDF and HTML versions of the Article.

Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study.

PURPOSE: Recruitment of participants from diverse backgrounds is crucial to the generalizability of genetic research, but has proven challenging. We retrospectively evaluated recruitment methods used for a study on return of genetic results. METHODS: The costs of study design, development, and participant enrollment were calculated, and the characteristics of the participants enrolled through the seven recruitment methods were examined. RESULTS: A total of 1118 participants provided consent, a blood sample, and questionnaire data. The estimated cost across recruitment methods ranged from $579 to $1666 per participant and required a large recruitment team. Recruitment methods using flyers and staff networks were the most cost-efficient and resulted in the highest completion rate. Targeted sampling that emphasized the importance of Latino/a participation, utilization of translated materials, and in-person recruitments contributed to enrolling a demographically diverse sample. CONCLUSIONS: Although all methods were deployed in the same hospital or neighborhood and shared the same staff, each recruitment method was different in terms of cost and characteristics of the enrolled participants, suggesting the importance of carefully choosing the recruitment methods based on the desired composition of the final study sample. This analysis provides information about the effectiveness and cost of different methods to recruit adults for genetic research.

Observational study of clinical outcomes of eribulin mesylate in metastatic breast cancer after cyclin-dependent kinase 4/6 inhibitor therapy.

Aim: To examine the effectiveness of eribulin mesylate for metastatic breast cancer post cyclin-dependent kinase inhibitor (CDKi) 4/6 therapy. Materials & methods: US community oncologists reviewed charts of patients who had received eribulin from 3 February 2015 to 31 December 2017 after prior CDKi 4/6 therapy and detailed their clinical/treatment history, clinical outcomes (lesion measurements, progression, death) and toxicity. Results: Four patient cohorts were created according to eribulin line of therapy: second line, third line, per US label and fourth line with objective response rates/clinical benefit rates of 42.2%/58.7%, 26.1%/42.3%, 26.7%/54.1% and 17.9%/46.4%, respectively. Median progression-free survival/6-month progression-free survival (79.5% of all patients censored) by cohort was: 9.7 months/77.3%, 10.3 months/71.3%, not reached/70.4% and 4.0 months/0.0%, respectively. Overall occurrence of neutropenia = 23.5%, febrile neutropenia = 1.3%, peripheral neuropathy = 10.1% and diarrhea = 11.1%. Conclusion: Clinical outcome and adverse event rates were similar to those in clinical trials and other observational studies. Longer follow-up is required to confirm these findings.

Adverse Childhood Experiences and Early Initiation of Marijuana and Alcohol Use: The Potential Moderating Effects of Internal Assets.

INTRODUCTION: Early adolescence is a critical risk period for initiation of substance use. Internal assets (IAs), which are individual qualities guiding positive choices, and adverse childhood experiences (ACEs) are important protective and risk factors, respectively, against substance use. The purpose of this study is to investigate whether IAs modify associations between ACEs and early initiation of alcohol and marijuana use. METHOD: Data were from 9th and 11th graders who completed the 2013 Minnesota Student Survey (n = 79,339). Students reported on experiences of abuse, household dysfunction, and substance use. Multivariable logistic regressions examined associations between different types of ACEs and substance use. Interactions between IAs and ACEs were added to models to test effect modification. For significant interactions, main effects models were re-estimated at different percentiles of IAs. RESULT: IAs moderated associations of both abuse and household dysfunction with early initiation of marijuana (p <.003) and alcohol (p =.007) for females but not for males. For females with low IAs, odds of early initiation of marijuana were approximately twice as high as students without any ACEs. A similar pattern was detected for females' initiation of alcohol use. No effect modification was detected for IAs and experiencing only abuse or household dysfunction on initiation. CONCLUSION: Special attention should be paid to improving IAs among girls who have already experienced ACEs. Future research should examine protective factors that buffer the effects of ACEs for boys.

Infant birthweight in the US: the role of preconception stressful life events and substance use.

The purpose of this study was to determine the relationships among preconception stressful life events (PSLEs), women's alcohol and tobacco use before and during pregnancy, and infant birthweight. Data were from the Early Childhood Longitudinal Study-Birth Cohort (n = 9,350). Data were collected in 2001. Exposure to PSLEs was defined by indications of death of a parent, spouse, or previous live born child; divorce or marital separation; or fertility problems prior to conception. Survey data determined alcohol and tobacco usage during the 3 months prior to and in the final 3 months of pregnancy. We used staged multivariable logistic regression to estimate the effects of women's substance use and PSLEs on the risk of having a very low (<1,500 g, VLBW) or low (1,500-2,499 g, LBW) birthweight infant, adjusting for confounders. Women who experienced any PSLE were more likely to give birth to VLBW infants (adjusted odds ratio [AOR] = 1.35; 95 % confidence interval [CI] = 1.10-1.66) than women who did not experience any PSLE. Compared to women who never smoked, women who smoked prior to conception (AOR = 1.31; 95 % CI = 1.04-1.66) or during their last trimester (AOR = 1.98; 95 % CI = 1.56-2.52) were more likely to give birth to LBW infants. PSLEs and women's tobacco use before and during pregnancy are independent risk factors for having a lower birthweight baby. Interventions to improve birth outcomes may need to address women's health and health behaviors in the preconception period.

Can States Simultaneously Improve Health Outcomes and Reduce Health Outcome Disparities?

INTRODUCTION: Reducing racial health disparities is often stated as a population health goal, but specific targets for such improvement are seldom set. It is often assumed that improving overall health outcomes will be linked to disparity reduction, but this is not necessarily the case. METHODS: We compared the annual change from 1999 through 2013 in combined-race (black and white) mortality with the annual change in absolute and relative racial mortality disparities for US states. RESULTS: Median annual improvement in combined-race mortality was 1.08% per year. Annual overall mortality rate reductions ranged from 0.24% per year in Oklahoma to 1.83% per year in Maryland. For disparities, the median for the black-white absolute gap was 3.60% per year, and the median for the relative black-to-white ratio was 1.19% per year. There was no significant correlation between the combined-race measure and either the absolute (0.03) or relative disparity measure reductions (-0.17). CONCLUSION: For mortality in US states over a recent period, improvement in the population mean and disparity reduction do not usually occur together. The disparity reduction rates observed may provide realistic guidance for public and private policy makers in setting goals for reducing population health disparity and creating investment priorities. As a starting point for discussion, the observed national median annual percentage improvement of 1.1 per year combined, 3.6% per year absolute gap reduction, and 1.2% per year relative gap reduction would be modest and reasonable goals.

TNFR2 and IL-12 coactivation enables slanDCs to support NK-cell function via membrane-bound TNF-α.

Human blood NK cells exert strong cytotoxicity against transformed cells and produce different cytokines and chemokines with an important role in modulating immune responses. However, the nature of NK-cell function depends on NK-cell interaction with other immune cells. One type of immune cells that communicate with NK cells are 6-sulfo LacNAc DCs (slanDCs), which comprise a major subpopulation of proinflammatory human blood DCs. In this study, we investigated the molecular mechanisms by which slanDCs interact with NK cells. Our in vitro studies demonstrate that LPS-stimulated slanDCs enhance activation and function of NK cells essentially via membrane-bound TNF-α (mTNF-α). LPS stimulation upregulates expression of mTNF-α in slanDCs, and surface TNF receptor 2 (TNFR2) is upregulated on NK cells after coincubation with slanDCs. IL-12 secreted by slanDCs increases surface expression of TNFR2 in NK cells. TNFR2 signaling in NK cells leads to activation of NF-kB, a transcription factor for cytokines such as GM-CSF. GM-CSF provided by NK cells is responsible for enhancing IL-12 secretion in slanDCs. In conclusion, TNFR2 and IL-12 signaling, which support one another, enables slanDCs to enhance NK-cell function through mTNF-α, thereby regulating immune responses.

The TLR-2/TLR-6 agonist macrophage-activating lipopeptide-2 augments human NK cell cytotoxicity when PGE2 production by monocytes is inhibited by a COX-2 blocker.

Macrophage-activating lipopeptide-2 (MALP-2) is a potent inducer of proinflammatory cytokine secretion by macrophages, monocytes, and dendritic cells. MALP-2 was reported to be involved in natural killer (NK) cell activation and ensuing tumor rejection. However, the mechanism of MALP-2-mediated NK cell activation remained unclear. Therefore, we studied the effects of MALP-2 on cultured human NK cells. We found that MALP-2 had no direct effect on NK cells. Instead, MALP-2 acted on monocytes and triggered the release of different molecules such as interleukin (IL)-1ß, IL-6, IL-10, IL-12, IL-15, interferon gamma-induced protein (IP-10), and prostaglandin (PG)-E2. Our data show that monocyte-derived IP-10 could significantly induce NK cell cytotoxicity as long as the immunosuppression by PGE2 is specifically inhibited by cyclooxygenase (COX)-2 blockade. In summary, our results show that MALP-2-mediated stimulation of monocytes results in the production of several mediators which, depending on the prevailing conditions, affect the activity of NK cells in various ways. Hence, MALP-2 administration with concurrent blocking of COX-2 can be considered as a promising approach in MALP-2-based adjuvant tumor therapies.

Neighborhood disadvantage, preconception stressful life events, and infant birth weight.

OBJECTIVES: We sought to determine whether the effects of preconception stressful life events (PSLEs) on birth weight differed by neighborhood disadvantage. METHODS: We drew our data from the Early Childhood Longitudinal Study, Birth Cohort (2001-2002; n = 9300). We created a neighborhood disadvantage index (NDI) using county-level data from the 2000 US Census. We grouped the NDI into tertiles that represented advantaged, middle advantaged, and disadvantaged neighborhoods. Stratified multinomial logistic regressions estimated the effect of PSLEs on birth weight, controlling for confounders. RESULTS: We found a gradient in the relationship between women's exposure to PSLEs and having a very low birth weight (VLBW) infant by NDI tertile; the association was strongest in disadvantaged neighborhoods (adjusted odd ratio [AOR] = 1.62; 95% confidence interval [CI] = 1.04, 2.53), followed by middle (AOR = 1.39; 95% CI = 1.00, 1.93) and advantaged (AOR = 1.29; 95% CI = 0.91, 1.82) neighborhoods. We observed a similar gradient for women with chronic conditions and among minority mothers. CONCLUSIONS: Women who experienced PSLEs, who had chronic conditions, or were racial/ethnic minorities had the greatest risk of having VLBW infants if they lived in disadvantaged neighborhoods; this suggests exacerbation of risk within disadvantaged environments. Interventions to reduce rates of VLBW should focus on reducing the deleterious effects of stressors and on improving neighborhood conditions.

Predictors of alcohol and tobacco use prior to and during pregnancy in the US: the role of maternal stressors.

The purpose of the study was to understand the association between stressful life events prior to conception (PSLEs) and women's alcohol and tobacco use prior to and during pregnancy, and the continuation of such use through pregnancy. Data were from the Early Childhood Longitudinal Study-Birth Cohort (n = 9,350). Data were collected in 2001. Exposure to PSLEs was defined by indications of death of a parent, spouse, or previous live born child, divorce or marital separation, or fertility problems prior to conception. Survey data determined alcohol and tobacco usage during the 3 months prior to and in the final 3 months of pregnancy. Weighted regressions estimated the effect of PSLEs on alcohol and tobacco use at each time point and on the continuation of use, adjusting for confounders. Experiencing any PSLE increased the odds of tobacco use prior to (adjusted odds ratio [AOR] 1.52, 95 % confidence interval (CI) 1.23-1.87) and during pregnancy (AOR 1.57, 95 % CI 1.19-2.07). Women exposed to PSLEs smoked nearly five additional packs of cigarettes in the 3 months prior to pregnancy (97 cigarettes, p = 0.011) and consumed 0.31 additional alcoholic drinks during the last 3 months of pregnancy than unexposed women. PSLEs are associated with tobacco use before pregnancy and alcohol and tobacco use during pregnancy. Alcohol and tobacco screening and cessation services should be implemented prior to and during pregnancy, especially for women who have experienced PSLEs.

Determinants of cesarean delivery in the US: a lifecourse approach.

This study takes a lifecourse approach to understanding the factors contributing to delivery methods in the US by identifying preconception and pregnancy-related determinants of medically indicated and non-medically indicated cesarean section (C-section) deliveries. Data are from the Early Childhood Longitudinal Study-Birth Cohort, a nationally representative, population-based survey of women delivering a live baby in 2001 (n = 9,350). Three delivery methods were examined: (1) vaginal delivery (reference); (2) medically indicated C-section; and (3) non-medically indicated C-sections. Using multinomial logistic regression, we examined the role of sociodemographics, health, healthcare, stressful life events, pregnancy complications, and history of C-section on the odds of medically indicated and non-medically indicated C-sections, compared to vaginal delivery. 74.2 % of women had a vaginal delivery, 11.6 % had a non-medically indicated C-section, and 14.2 % had a medically indicated C-section. Multivariable analyses revealed that prior C-section was the strongest predictor of both medically indicated and non-medically indicated C-sections. However, we found salient differences between the risk factors for indicated and non-indicated C-sections. Surgical deliveries continue to occur at a high rate in the US despite evidence that they increase the risk for morbidity and mortality among women and their children. Reducing the number of non-medically indicated C-sections is warranted to lower the short- and long-term risks for deleterious health outcomes for women and their babies across the lifecourse. Healthcare providers should address the risk factors for medically indicated C-sections to optimize low-risk delivery methods and improve the survival, health, and well-being of children and their mothers.

Cost-Effectiveness of Injectable Extended-Release Naltrexone Compared With Methadone Maintenance and Buprenorphine Maintenance Treatment for Opioid Dependence.

BACKGROUND: The aim of this study was to estimate the cost-effectiveness of injectable extended-release naltrexone (XR-NTX) compared with methadone maintenance and buprenorphine maintenance treatment (MMT and BMT, respectively) for adult males enrolled in treatment for opioid dependence in the United States from the perspective of state-level addiction treatment payers. METHODS: A Markov model with daily time cycles was used to estimate the incremental cost per opioid-free day in a simulated cohort of adult males aged 18-65 over a 6-month period from the state health program perspective. RESULTS: XR-NTX is predicted to be more effective and more costly than methadone or buprenorphine in our target population, with an incremental cost per opioid-free day gained relative to the next-most effective treatment (MMT) of $72. The cost-effectiveness of XR-NTX relative to MMT was driven by its effectiveness in deterring opioid use while receiving treatment. CONCLUSIONS: XR-NTX is a cost-effective medication for treating opioid dependence if state addiction treatment payers are willing to pay at least $72 per opioid-free day.

Role of gamma-secretase in human umbilical-cord derived mesenchymal stem cell mediated suppression of NK cell cytotoxicity.

BACKGROUND: Mesenchymal stem cells (MSCs) are increasingly considered to be used as biological immunosuppressants in hematopoietic stem cell transplantation (HSCT). In the early reconstitution phase following HSCT, natural killer (NK) cells represent the major lymphocyte population in peripheral blood and display graft-vs-leukemia (GvL) effects. The functional interactions between NK cells and MSCs have the potential to influence the leukemia relapse rate after HSCT. Until date, MSC-NK cell interaction studies are largely focussed on bone marrow derived (BM)-MSCs. Umbilical cord derived (UC)-MSCs might be an alternative source of therapeutic MSCs. Thus, we studied the interaction of UC-MSCs with unstimulated allogeneic NK cells. RESULTS: UC-MSCs could potently suppress NK cell cytotoxicity in overnight cultures via soluble factors. The main soluble immunosuppressant was identified as prostaglandin (PG)-E2. Maximal PGE2 release involved IL-1ß priming of MSCs after close contact between the NK cells and UC-MSCs. Interestingly, blocking gamma-secretase activation alleviated the immunosuppression by controlling PGE2 production. IL-1 receptor activation and subsequent downstream signalling events were found to require gamma-secretase activity. CONCLUSION: Although the role of PGE2 in NK cell-MSC has been reported, the requirement of cell-cell contact for PGE2 induced immunosuppression remained unexplained. Our findings shed light on this puzzling observation and identify new players in the NK cell-MSC crosstalk.

Maternal stressful life events prior to conception and the impact on infant birth weight in the United States.

OBJECTIVES: We sought to determine if and to what extent a woman's exposure to stressful life events prior to conception (PSLEs) were associated with subsequent infant birth weight by using a nationally representative sample of US women. METHODS: We examined 9350 mothers and infants participating in the first wave of the Early Childhood Longitudinal Study, Birth Cohort in 2001. Weighted regressions estimated the effect of exposure on very low and low birth weight, adjusting for maternal sociodemographic and health factors and stress during pregnancy. RESULTS: Twenty percent of women experienced any PSLE. In adjusted analyses, exposed women were 38% more likely to have a very low birth weight infant than nonexposed women. Furthermore, the accumulation of PSLEs was associated with reduced infant birth weight. CONCLUSIONS: This was the first nationally representative study to our knowledge to investigate the impact of PSLEs on very low and low birth weight in the United States. Interventions aimed to improve birth outcomes will need to shift the clinical practice paradigm upstream to the preconception period to reduce women's exposure to stress over the life course and improve the long-term health of children.