The effect of dose-interval on antibody response to mRNA COVID-19 vaccines: a prospective cohort study.

Background: Vaccination against COVID-19 is highly effective in preventing severe disease and hospitalization, but primary COVID mRNA vaccination schedules often differed from those recommended by the manufacturers due to supply chain issues. We investigated the impact of delaying the second dose on antibody responses to COVID mRNA-vaccines in a prospective cohort of health-care workers in Quebec. Methods: We recruited participants from the McGill University Health Centre who provided serum or participant-collected dried blood samples (DBS) at 28-days, 3 months, and 6 months post-second dose and at 28-days after a third dose. IgG antibodies to SARS-CoV2 spike (S), the receptor-binding domain (RBD), nucleocapsid (N) and neutralizing antibodies to the ancestral strain were assessed by enzyme-linked immunosorbent assay (ELISA). We examined associations between long (≤89 days) versus short (<89 days) between-dose intervals and antibody response through multivariable mixed-effects models adjusted for age, sex, prior covid infection status, time since vaccine dose, and assay batch. Findings: The cohort included 328 participants who received up to three vaccine doses (>80% Pfizer-BioNTech). Weighted averages of the serum (n=744) and DBS (n=216) cohort results from the multivariable models showed that IgG anti-S was 31% higher (95% CI: 12% to 53%) and IgG anti-RBD was 37% higher (95% CI: 14% to 65%) in the long vs. short interval participants, across all time points. Interpretation: Our study indicates that extending the covid primary series between-dose interval beyond 89 days (approximately 3 months) provides stronger antibody responses than intervals less than 89 days. Our demonstration of a more robust antibody response with a longer between dose interval is reassuring as logistical and supply challenges are navigated in low-resource settings.

Multiplex Functional Characterization of Protein Variant Libraries in Mammalian Cells with Single-Copy Genomic Integration and High-Throughput DNA Sequencing.

Sequencing-based, massively parallel genetic assays have enabled simultaneous characterization of the genotype-phenotype relationships for libraries encoding thousands of unique protein variants. Since plasmid transfection and lentiviral transduction have characteristics that limit multiplexing with pooled libraries, we developed a mammalian synthetic biology platform that harnesses the Bxb1 bacteriophage DNA recombinase to insert single promoterless plasmids encoding a transgene of interest into a pre-engineered "landing pad" site within the cell genome. The transgene is expressed behind a genomically integrated promoter, ensuring only one transgene is expressed per cell, preserving a strict genotype-phenotype link. Upon selecting cells based on a desired phenotype, the transgene can be sequenced to ascribe each variant a phenotypic score. We describe how to create and utilize landing pad cells for large-scale, library-based genetic experiments. Using the provided examples, the experimental template can be adapted to explore protein variants in diverse biological problems within mammalian cells.

Assessment of Advanced Diagnostic Bronchoscopy Outcomes for Peripheral Lung Lesions: A Delphi Consensus Definition of Diagnostic Yield and Recommendations for Patient-centered Study Designs. An Official American Thoracic Society/American College of Chest Physicians Research Statement.

Background: Advanced diagnostic bronchoscopy targeting the lung periphery has developed at an accelerated pace over the last two decades, whereas evidence to support introduction of innovative technologies has been variable and deficient. A major gap relates to variable reporting of diagnostic yield, in addition to limited comparative studies. Objectives: To develop a research framework to standardize the evaluation of advanced diagnostic bronchoscopy techniques for peripheral lung lesions. Specifically, we aimed for consensus on a robust definition of diagnostic yield, and we propose potential study designs at various stages of technology development. Methods: Panel members were selected for their diverse expertise. Workgroup meetings were conducted in virtual or hybrid format. The cochairs subsequently developed summary statements, with voting proceeding according to a modified Delphi process. The statement was cosponsored by the American Thoracic Society and the American College of Chest Physicians. Results: Consensus was reached on 15 statements on the definition of diagnostic outcomes and study designs. A strict definition of diagnostic yield should be used, and studies should be reported according to the STARD (Standards for Reporting Diagnostic Accuracy Studies) guidelines. Clinical or radiographic follow-up may be incorporated into the reference standard definition but should not be used to calculate diagnostic yield from the procedural encounter. Methodologically robust comparative studies, with incorporation of patient-reported outcomes, are needed to adequately assess and validate minimally invasive diagnostic technologies targeting the lung periphery. Conclusions: This American Thoracic Society/American College of Chest Physicians statement aims to provide a research framework that allows greater standardization of device validation efforts through clearly defined diagnostic outcomes and robust study designs. High-quality studies, both industry and publicly funded, can support subsequent health economic analyses and guide implementation decisions in various healthcare settings.

Ranking Decision-Making Criteria for Early Adoption of Innovative Surgical Technologies.

Importance: There is no decision-making framework in the early-adoption stage of novel surgical technologies, putting the quality of health care and resource allocation of the health care system at risk. Objective: To investigate relevant weighted criteria that decision-makers may use to make an informed decision for the early adoption of innovative surgical technologies. Design, Setting, and Participants: This multi-institutional decision analytical modeling study used a mixed-methods multicriteria decision analysis (MCDA) and had 2 phases. First, a panel of 12 experts validated decision criteria in the literature and identified additional criteria. Second, 33 Canadian experts prioritized the main criteria (domains) using the composition pairwise-comparison weight-elicitation method (analytical hierarchy process model) and ranked their subcriteria using the direct-ranking elicitation method (Likert scale). Data were analyzed, and response consistency was estimated using the consistency ratio. Analysis of variance was used to assess for significant differences between expert responses. The MCDA was conducted at McGill University between 2021 and 2023. Data were collected nationally by inviting experts in Canada. Main Outcome and Measure: Criteria domain weights and subcriteria rankings. Priority vectors, which are priority scores analyzed and prioritized from expert responses, were used to rank criteria domains and subcriteria for decision-making on adopting new innovative surgical technologies. Results: A total of 45 experts (33 male [73.3%] and 12 female [26.7%]) were invited with different levels of education (22 experts with MD or equivalent, 13 experts with master's degree, and 12 experts with PhD degree) and years of experience (4 experts with <10, 12 experts with 11-20, 18 experts with 21-30, and 11 experts with >30 years). Surgeon experts (23 individuals) were from all surgical disciplines, and nonsurgeon experts (22 individuals) were administrative officers in surgical device procurement, health technology assessment experts, and hospital directors. A total of 7 domains and 44 subcriteria were identified. The MCDA model found that clinical outcomes had the highest priority vector, at 0.429, followed by patients and public relevance (0.135). Hospital-specific criteria (priority vector, 0.099), technology-specific criteria (priority vector, 0.092), and physician-specific criteria (priority vector, 0.087) were the next most highly ranked. The lowest priority vectors were for economic criteria, at 0.083, and finally policies and procedures, at 0.075. There was consensus in the responses (consistency ratio = 0.006), and there were no statistically significant differences between expert responses. Conclusions and relevance: This study weighted priority criteria domains in importance and established ranked subcriteria for decision-making of early adoption of surgical technologies. Putting these criteria into a framework may help surgeons and decision-makers make informed decisions for the early adoption of new surgical technologies.

Mammalian Genomic Manipulation with Orthogonal Bxb1 DNA Recombinase Sites for the Functional Characterization of Protein Variants.

The Bxb1 bacteriophage serine DNA recombinase is an efficient tool for engineering recombinant DNA into the genomes of cultured cells. Generally, a single engineered "landing pad" site is introduced into the cell genome, permitting the integration of transgenic circuits or libraries of transgene variants. While sufficient for many studies, the extent of genetic manipulation possible with a single recombinase site is limiting and insufficient for more complex cell-based assays. Here, we harnessed two orthogonal Bxb1 recombinase sites to enable alternative avenues for using mammalian synthetic biology to characterize transgenic protein variants. By designing plasmids flanked by a second pair of auxiliary recombination sites, we demonstrate that we can avoid the genomic integration of undesirable bacterial DNA elements using the same starting cells engineered for whole-plasmid integration. We also created "double landing pad" cells simultaneously harboring two orthogonal Bxb1 recombinase sites at separate genomic loci, allowing complex cell-based genetic assays. Integration of a genetically encoded calcium indicator allowed for the real-time monitoring of intracellular calcium signaling dynamics, including kinetic perturbations that occur upon overexpression of the wild-type or variant version of the calcium signaling relay protein STIM1. A panel of missense mutants of the HIV-1 accessory protein Vif was paired with various paralogs within the human Apobec3 innate immune protein family to identify combinations capable or incapable of interacting within cells. These cells allow transgenic protein variant libraries to be readily paired with assay-specific protein partners or biosensors, enabling new functional readouts for large-scale genetic assays for protein function.

Effect of Remote Cardiac Monitoring System Design on Response Time to Critical Arrhythmias.

INTRODUCTION: In many hospitals across the country, electrocardiograms of multiple at-risk patients are monitored remotely by telemetry monitor watchers in a central location. However, there is limited evidence regarding best practices for designing these cardiac monitoring systems to ensure prompt detection and response to life-threatening events. To identify factors that may affect monitoring efficiency, we simulated critical arrhythmias in inpatient units with different monitoring systems and compared their efficiency in communicating the arrhythmias to a first responder. METHODS: This was a multicenter cross-sectional in situ simulation study. Simulation participants were monitor watchers and first responders (usually nurses) in 2 inpatient units in each of 3 hospitals. Manipulated variables included: (1) number of communication nodes between monitor watchers and first responders; (2) central monitoring station location-on or off the patient care unit; (3) monitor watchers' workload; (4) nurses' workload; and (5) participants' experience. RESULTS: We performed 62 arrhythmia simulations to measure response times of monitor watchers and 128 arrhythmia simulations to measure response times in patient care units. We found that systems in which an intermediary between monitor watchers and nurses communicated critical events had faster response times to simulated arrhythmias than systems in which monitor watchers communicated directly with nurses. Responses were also faster in units colocated with central monitoring stations than in those located remotely. As the perceived workload of nurses increased, response latency also increased. Experience did not affect response times. CONCLUSIONS: Although limited in our ability to isolate the effects of these factors from extraneous factors on central monitoring system efficiency, our study provides a roadmap for using in situ arrhythmia simulations to assess and improve monitoring performance.

A Framework for Aiding the Translation of Scientific Evidence into Policy: The Experience of a Hospital-Based Technology Assessment Unit.

OBJECTIVES: Very few practical frameworks exist to guide the formulation of recommendations at hospital-based health technology assessment (HTA) units. The objectives of our study were: (i) to identify decision criteria specific to the context of hospital-based health technologies and interventions, (ii) to estimate the extent to which the expert community agrees on the importance of the identified criteria, (iii) to incorporate the identified criteria into a decision-aid tool, and (iv) to illustrate the application of a prototype decision-aid tool. METHODS: Relevant decision criteria were identified using existing frameworks for HTA recommendations, our past experience, a literature search, and feedback from a survey of diverse stakeholders. RESULTS: Based on the survey results, twenty-three decision criteria were incorporated into the final framework. We defined an approach that eschewed a scoring system, but instead relied on a visual means for arriving at a final recommendation, by juxtaposing the importance rating for each criterion against the results of the health technology assessment. For a technology to be approved, a majority of criteria considered important should also have received favorable findings. CONCLUSIONS: We created a simple and practical decision-aid tool that incorporates all decision criteria relevant to a hospital-based HTA unit. With its ease of use and accessibility, our tool renders the subjective decision-making process more structured and transparent.

Neighborhood Environmental Health and Premature Death From Cardiovascular Disease.

INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of death in the United States and disproportionately affects racial/ethnic minority groups. Healthy neighborhood conditions are associated with increased uptake of health behaviors that reduce CVD risk, but minority neighborhoods often have poor food access and poor walkability. This study tested the community-driven hypothesis that poor access to food at the neighborhood level and poor neighborhood walkability are associated with racial disparities in premature deaths from CVD. METHODS: We examined the relationship between neighborhood-level food access and walkability on premature CVD mortality rates at the census tract level for the city of Atlanta using multivariable logistic regression models. We produced maps to illustrate premature CVD mortality, food access, and walkability by census tract for the city. RESULTS: We found significant racial differences in premature CVD mortality rates and geographic disparities in food access and walkability among census tracts in Atlanta. Improved food access and walkability were associated with reduced overall premature CVD mortality in unadjusted models, but this association did not persist in models adjusted for census tract population composition and poverty. Census tracts with high concentrations of minority populations had higher levels of poor food access, poor walkability, and premature CVD mortality. CONCLUSION: This study highlights disparities in premature CVD mortality and neighborhood food access and walkability at the census tract level in the city of Atlanta. Improving food access may have differential effects for subpopulations living in the same area. These results can be used to calibrate neighborhood-level interventions, and they highlight the need to examine race-specific health outcomes.

Risk of Miscarriage in Women Receiving Antidepressants in Early Pregnancy, Correcting for Induced Abortions.

BACKGROUND: Earlier studies on the association between antidepressant use and miscarriage have obtained conflicting results after accounting for the role of depression, and none have taken into account the high risk of induced abortions in women using antidepressants. METHODS: We identified 41,964 pregnant women delivering between 1998 and 2002 using Quebec's health administration databases. We compared women prescribed antidepressants in the first trimester and with a recorded diagnosis of depression before pregnancy to (1) women with neither antidepressant use nor a depression diagnosis before or during pregnancy; (2) women with a depression diagnosis before pregnancy, but no antidepressants prescribed in the first trimester; and (3) women prescribed hypothyroid medication in the first trimester, but not antidepressants. We used log binomial regression to assess the adjusted relative risk of miscarriage, corrected for induced abortion risk. RESULTS: The miscarriage risk uncorrected for induced abortions was 16%, 10%, and 9% for depressed women exposed to antidepressants; unexposed depressed women; and unexposed, nondepressed women, respectively. These decreased to 11%, 8%, and 7% after correction for induced abortions. In multivariable analysis, the corrected risk of miscarriage relative to unexposed, nondepressed women was 1.3 (1.1-1.5) for antidepressant-exposed women and 1.1 (1.0-1.2) for unexposed depressed women. The miscarriage relative risk for antidepressant users compared with unexposed depressed women was thus 1.2 (1.0-1.4). CONCLUSIONS: Antidepressant use in the first trimester is associated with an increased risk of miscarriage when compared with either nondepressed or depressed unexposed women, even after accounting for induced abortions.

Quantitative mass spectrometric immunoassay for the chemokine RANTES and its variants.

The chemokine RANTES plays a key role in inflammation, cell recruitment and T cell activation. RANTES is heterogenic and exists as multiple variants in vivo. Herein we describe the development and characterization of a fully quantitative mass spectrometric immunoassay (MSIA) for analysis of intact RANTES and its proteoforms in human serum and plasma samples. The assay exhibits linearity over a wide concentration range (1.56-200ng/mL), intra- and inter-assay precision with CVs <10%, and good linearity and recovery correlations. The assay was tested in different biological matrices, and it was benchmarked against an existing RANTES ELISA. The new RANTES MSIA was used to analyze RANTES and its proteoforms in a small clinical cohort, revealing the quantitative distribution and frequency of the native and truncated RANTES proteoforms. BIOLOGICAL SIGNIFICANCE: In the last two decades, RANTES has been studied extensively due to its association with numerous clinical conditions, including kidney-related, autoimmune, cardiovascular, viral and metabolic pathologies. Although a single gene product, RANTES is expressed in a range of cells and tissues presenting with different endogenously produced variants and PTMs. The structural variety and population diversity that has been identified for RANTES necessitate developing advanced methodologies that can provide insight into the protein heterogeneity and its function and regulation in disease. In this work we present a simple, efficient and high-throughput mass spectrometric immunoassay (MSIA) method for analysis of RANTES proteoforms. RANTES MSIA can detect and analyze RANTES proteoforms and provide an insight into the endogenous protein modifications.

Mass Spectrometric Immunoassay for the qualitative and quantitative analysis of the cytokine Macrophage Migration Inhibitory Factor (MIF).

BACKGROUND: The cytokine MIF (Macrophage Migration Inhibitory Factor) has diverse physiological roles and is present at elevated concentrations in numerous disease states. However, its molecular heterogeneity has not been previously investigated in biological samples. Mass Spectrometric Immunoassay (MSIA) may help elucidate MIF post-translational modifications existing in vivo and provide additional clarity regarding its relationship to diverse pathologies. RESULTS: In this work, we have developed and validated a fully quantitative MSIA assay for MIF, and used it in the discovery and quantification of different proteoforms of MIF in serum samples, including cysteinylated and glycated MIF. The MSIA assay had a linear range of 1.56-50 ng/mL, and exhibited good precision, linearity, and recovery characteristics. The new assay was applied to a small cohort of human serum samples, and benchmarked against an MIF ELISA assay. CONCLUSIONS: The quantitative MIF MSIA assay provides a sensitive, precise and high throughput method to delineate and quantify MIF proteoforms in biological samples.

Elevated plasma albumin and apolipoprotein A-I oxidation under suboptimal specimen storage conditions.

S-cysteinylated albumin and methionine-oxidized apolipoprotein A-I (apoA-I) have been posed as candidate markers of diseases associated with oxidative stress. Here, a dilute-and-shoot form of LC-electrospray ionization-MS requiring half a microliter of blood plasma was employed to simultaneously quantify the relative abundance of these oxidized proteoforms in samples stored at -80 °C, -20 °C, and room temperature and exposed to multiple freeze-thaw cycles and other adverse conditions in order to assess the possibility that protein oxidation may occur as a result of poor sample storage or handling. Samples from a healthy donor and a participant with poorly controlled type 2 diabetes started at the same low level of protein oxidation and behaved similarly; significant increases in albumin oxidation via S-cysteinylation were found to occur within hours at room temperature and days at -20 °C. Methionine oxidation of apoA-I took place on a longer time scale, setting in after albumin oxidation reached a plateau. Freeze-thaw cycles had a minimal effect on protein oxidation. In matched collections, protein oxidation in serum was the same as that in plasma. Albumin and apoA-I oxidation were not affected by sample headspace or the degree to which vials were sealed. ApoA-I, however, was unexpectedly found to oxidize faster in samples with lower surface-area-to-volume ratios. An initial survey of samples from patients with inflammatory conditions normally associated with elevated oxidative stress-including acute myocardial infarction and prostate cancer-demonstrated a lack of detectable apoA-I oxidation. Albumin S-cysteinylation in these samples was consistent with known but relatively brief exposures to temperatures above -30 °C (the freezing point of blood plasma). Given their properties and ease of analysis, these oxidized proteoforms, once fully validated, may represent the first markers of blood plasma specimen integrity based on direct measurement of oxidative molecular damage that can occur under suboptimal storage conditions.

Parallel workflow for high-throughput (>1,000 samples/day) quantitative analysis of human insulin-like growth factor 1 using mass spectrometric immunoassay.

Insulin-like growth factor 1 (IGF1) is an important biomarker for the management of growth hormone disorders. Recently there has been rising interest in deploying mass spectrometric (MS) methods of detection for measuring IGF1. However, widespread clinical adoption of any MS-based IGF1 assay will require increased throughput and speed to justify the costs of analyses, and robust industrial platforms that are reproducible across laboratories. Presented here is an MS-based quantitative IGF1 assay with performance rating of >1,000 samples/day, and a capability of quantifying IGF1 point mutations and posttranslational modifications. The throughput of the IGF1 mass spectrometric immunoassay (MSIA) benefited from a simplified sample preparation step, IGF1 immunocapture in a tip format, and high-throughput MALDI-TOF MS analysis. The Limit of Detection and Limit of Quantification of the resulting assay were 1.5 µg/L and 5 µg/L, respectively, with intra- and inter-assay precision CVs of less than 10%, and good linearity and recovery characteristics. The IGF1 MSIA was benchmarked against commercially available IGF1 ELISA via Bland-Altman method comparison test, resulting in a slight positive bias of 16%. The IGF1 MSIA was employed in an optimized parallel workflow utilizing two pipetting robots and MALDI-TOF-MS instruments synced into one-hour phases of sample preparation, extraction and MSIA pipette tip elution, MS data collection, and data processing. Using this workflow, high-throughput IGF1 quantification of 1,054 human samples was achieved in approximately 9 hours. This rate of assaying is a significant improvement over existing MS-based IGF1 assays, and is on par with that of the enzyme-based immunoassays. Furthermore, a mutation was detected in ∼1% of the samples (SNP: rs17884626, creating an A→T substitution at position 67 of the IGF1), demonstrating the capability of IGF1 MSIA to detect point mutations and posttranslational modifications.

Absence of CD4 or CD8 lymphocytes changes infiltration of inflammatory cells and profiles of cytokine expression in skin wounds, but does not impair healing.

The involvement of lymphocytes in skin wound healing has not been studied extensively. This study shows that CD4 and CD8 cells are present in significant numbers in skin wounds with peak levels at days 5-10 and 7-10, respectively. Both subsets expressed inflammatory and/or regulatory cytokines. To examine the function of CD4 and CD8 lymphocytes in tissue repair, wound healing was examined in mice deficient for either CD4 or CD8 cells. Wounds in CD4 deficient mice exhibited an initial delayed infiltration of CD8 cells followed by a relative increase in CD8 cells at day 10 and thereafter. Wounds in CD4 deficient mice also displayed up-regulated expression of IL1ß, IL-6, IL-17, IFN-γ, CXCL-1 and down-regulated expression of IL-4 as compared to wild-type mice. In contrast, wounds in CD8 deficient mice showed significantly decreased infiltration of CD4+ cells, neutrophils, and macrophages along with down-regulated expression of IL1ß, IL-6, TNF-α, CXCL-1, CCL-2 and up-regulated expression of IL-4 as compared to wild-type mice. Despite these significant changes in cytokine expression and inflammatory cell infiltrate, the rate of wound closure, wound breaking strength, collagen content and angiogenesis in either CD4 or CD8 deficiency showed no significant difference from that of wild-type mice. The results suggest that, despite being present and involved in wound inflammation, neither CD4+ nor CD8+ cells play critical roles in the healing process of skin wounds. Further studies are needed to investigate whether these cells might play critical roles in wounds that experience stress such as ischemia or infection.

Techniques for the analysis of cysteine sulfhydryls and oxidative protein folding.

SIGNIFICANCE: Modification of cysteine thiols dramatically affects protein function and stability. Hence, the abilities to quantify specific protein sulfhydryl groups within complex biological samples and map disulfide bond structures are crucial to gaining greater insights into how proteins operate in human health and disease. RECENT ADVANCES: Many different molecular probes are now commercially available to label and track cysteine residues at great sensitivity. Coupled with mass spectrometry, stable isotope-labeled sulfhydryl-specific reagents can provide previously unprecedented molecular insights into the dynamics of cysteine modification. Likewise, the combined application of modern mass spectrometers with improved sample preparation techniques and novel data mining algorithms is beginning to routinize the analysis of complex protein disulfide structures. CRITICAL ISSUES: Proper application of these modern tools and techniques, however, still requires fundamental understanding of sulfhydryl chemistry as well as the assumptions that accompany sample preparation and underlie effective data interpretation. FUTURE DIRECTIONS: The continued development of tools, technical approaches, and corresponding data processing algorithms will, undoubtedly, facilitate site-specific protein sulfhydryl quantification and disulfide structure analysis from within complex biological mixtures with ever-improving accuracy and sensitivity. Fully routinizing disulfide structure analysis will require an equal but balanced focus on sample preparation and corresponding mass spectral dataset reproducibility.

Smoking in preeclamptic women is associated with higher birthweight for gestational age and lower soluble fms-like tyrosine kinase-1 levels: a nested case control study.

BACKGROUND: Smoking paradoxically increases the risk of small-for-gestational-age (SGA) birth but protects against preeclampsia. Some studies have reported a "U-shaped" distribution of fetal growth in preeclamptic pregnancies, but reasons for this are unknown. We investigated whether cigarette smoking interacts with preeclampsia to affect fetal growth, and compared levels of soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating anti-angiogenic protein, in preeclamptic smokers and non-smokers. METHODS: From a multicenter cohort of 5337 pregnant women, we prospectively identified 113 women who developed preeclampsia (cases) and 443 controls. Smoking exposure was assessed by self-report and maternal hair nicotine levels. Fetal growth was assessed as z-score of birthweight for gestational age (BWGA). sFlt-1 was measured in plasma samples collected at the 24-26-week visit. RESULTS: In linear regression, smoking and preeclampsia were each associated with lower BWGA z-scores (ß = -0.29; p = 0.008, and ß = -0.67; p < 0.0001), but positive interaction was observed between smoking and preeclampsia (ß = +0.86; p = 0.0008) such that smoking decreased z-score by -0.29 in controls but increased it by +0.57 in preeclampsia cases. Results were robust to substituting log hair nicotine for self-reported smoking and after adjustment for confounding variables. Mean sFlt-1 levels were lower in cases with hair nicotine levels above vs. below the median (660.4 pg/ml vs. 903.5 pg/ml; p = 0.0054). CONCLUSIONS: Maternal smoking seems to protect against preeclampsia-associated fetal growth restriction and may account, at least partly, for the U-shaped pattern of fetal growth described in preeclamptic pregnancies. Smoking may exert this effect by reducing levels of the anti-angiogenic protein sFlt-1.

Childhood family psychosocial environment and coronary heart disease risk.

OBJECTIVE: Little is known about whether the childhood family psychosocial environment affects coronary heart disease (CHD). Study objectives were to evaluate associations of childhood family psychosocial environment (termed "risky families"; characterized by cold, unaffectionate interactions, conflict, aggression, neglect, and/or low nurturance) with calculated risk for CHD. METHODS: Study participants included 3554 participants of the Coronary Artery Risk Development in Young Adults Study, aged 33 to 45 years. Childhood family psychosocial environment was measured using a risky family questionnaire via self-report. Ten-year CHD risk was calculated using the validated Framingham risk algorithm. RESULTS: In a multivariable-adjusted regression analysis adjusted for age, race/ethnicity, and childhood socioeconomic position, a 1-unit (range, 0-21) increase in risky family score was associated with 1.0% (95% confidence interval = 0.4%-1.7%) and 1.0% (95% confidence interval = 0.2%-1.8%) higher CHD risk in women and men, respectively. Multiple mediation analyses suggested significant indirect effects of education, income, depressive symptomatology, and anger-out expression in women and education in men, indicating that these may be mediating mechanisms between childhood psychosocial environment and CHD risk. Of the modifiable Framingham algorithm components, smoking (in women and men) and high-density lipoprotein (in women) were the factors most strongly associated with risky family score. CONCLUSIONS: Childhood family psychosocial environment was positively associated with the calculated 10-year CHD risk. Mechanisms may include the potential negative impact of childhood family psychosocial environment on later-life socioeconomic position (e.g., education in men and women) and/or psychosocial functioning (e.g., depression and anger-out expression in women), which may in turn lead to higher CHD risk, particularly through smoking (in men and women) and low level of high-density lipoprotein cholesterol (in women).