Adverse Exposures Research Articles

Using Time-out for Child Conduct Problems in the Context of Trauma and Adversity

Exposure to adverse childhood experiences substantially increases the risk of chronic health problems. Originally designed to treat child conduct problems, parent management training programs have been shown to be effective in preventing children from being exposed to further adversity and supporting children's recovery from adversity; however, there are increasing concerns that a core component of these programs, the discipline strategy time-out, may be harmful for children with a history of exposure to adversity. To investigate the comparative benefits and potential harms to children exposed to adversity that are associated with parenting programs that include time-out. This nonrandomized waiting list-controlled clinical study was conducted at a specialist clinic for the treatment of conduct problems in Sydney, Australia. The self-referred sample included children with conduct problems and their caregivers. Eligibility was confirmed through clinician-administered interviews. Data were collected between February 14, 2018, and February 1, 2021. Caregivers participated in a 10-session, social learning-based parent management training program. Caregivers were provided with parenting strategies aimed at encouraging desired behaviors through effective reinforcement and managing misbehavior through consistent limit setting, including the use of time-outs. The primary outcome was the parent-reported Strengths and Difficulties Questionnaire score, and secondary outcomes included subscale scores from the clinician-administered Diagnostic Interview Schedule for Children, Adolescents, and Parents. Multi-informant measures of child adversity were collected using the parent-reported Adverse Life Experiences Scale and the clinician-rated Maltreatment Index. A total of 205 children were included in analysis (156 in the full intervention and 49 in the control condition; 158 boys [77.1%]; mean [SD] age, 5.6 [1.8] years [range, 2-9 years]). Compared with children with low adversity exposure, children with high adversity exposure showed greater reductions in the Strengths and Difficulties Questionnaire score from baseline (mean difference, 3.46 [95% CI, 1.51-5.41]; P < .001) to after treatment (mean difference, 1.49 [95% CI, -0.46 to 3.44]; P = .13) and in the internalizing symptom subscale score (baseline mean difference, 1.00 [95% CI, -2,00 to 0.00]; P = .50; posttreatment mean difference, 0.06 [95% CI, -0.82 to 0.94]; P = .90). No significant differences in the externalizing symptom subscale score were found. In this nonrandomized clinical study, children with high exposure to adversity experienced equivalent, if not greater, benefits associated with parenting programs that include time-out compared with children with low exposure to adversity. Results suggest that time-out was an effective component of parenting programs for children exposed to adversity. anzctr.org.au Identifier: ACTRN12617001472369.

Study protocol to explore the social effects of environmental exposure and lifestyle behaviours on pregnancy outcome: an overview of cohort of pregnant women study

IntroductionA growing number of international studies have highlighted the adverse consequences of lived experience in the first thousand days of pregnancy and early life on the probability of stillbirth, child...

Lack of Associations between Environmental Exposures and Environmental Enteric Dysfunction among 18-Month-Old Children in Rural Malawi.

Environmental enteric dysfunction (EED) is common and contributes to linear growth faltering (stunting) and mortality among children in low-resource settings. A few studies on the environmental causes of EED have been conducted but the exact exposures that cause or predispose children to EED are context-specific and not clear. This study aimed to assess associations between selected environmental exposures and EED markers among 620 18-month-old children. This was a secondary analysis of data from Malawian children who participated in a randomized controlled trial (iLiNS-DYAD, registered at clinicaltrials.gov as NCT01239693) from birth to 18 months of age. Data on environmental exposures, including drinking water source, sanitation, exposure to animals, housing materials, season, residential area, and food insecurity were collected at enrolment. Biomarkers of EED included concentrations of calprotectin, regenerating 1B protein (REG1B), and alpha-1-antitrypsin from stool samples to assess intestinal inflammation, repair, and permeability, respectively. We performed bivariate and multivariable analyses to assess associations between environmental exposures and EED biomarkers. Adjusting for possible confounders, we did not find associations between the selected environmental exposures and the three biomarkers. These results do not provide support for our hypothesis that the studied adverse environmental exposures are associated with increased concentrations of children’s EED markers in rural Malawi.

Does the distribution of adverse workplace psychosocial exposures differ by gender, race/ethnicity, or nativity?

Does the distribution of adverse workplace psychosocial exposures differ by gender, race/ethnicity, or nativity?

Prenatal Lipopolysaccharides Exposure Induces Transgenerational Inheritance of Hypertension.

Adverse environmental exposure during the prenatal period can lead to diseases in the offspring, including hypertension. Whether or not the hypertensive phenotype can be transgenerationally transmitted is not known. Pregnant Sprague Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) on gestation days 6, 8, 10, and 12 to generate the prenatal LPS exposure model. Blood pressure was monitored by both telemetry and tail-cuff method. RNA sequencing was performed to analyze transcriptome alteration in the kidney of the third generation. Tempol and spironolactone were used to test the potential preventative and therapeutic effect of targeting reactive oxygen species and mineralocorticoid receptor signaling, respectively. Molecular biological experiments were performed to illustrate the mechanism of epigenetic and transcription regulation. Prenatal LPS exposure can impair the ability to excrete a salt load and induce hypertension from the first to the third generations, with the fourth and fifth generations, inducing salt-sensitive hypertension. Compared with control pups, the transcriptome in the kidney of the hypertensive third-generation prenatal LPS-exposed offspring have upregulation of the Ras-related C3 botulinum toxin substrate 1 (Rac1) gene and activation of mineralocorticoid receptor signaling. Furthermore, we found that LPS exposure during pregnancy triggered oxidative stress that upregulated KDM3B (histone lysine demethylase 3B) in the oocytes of first-generation female rats, leading to an inheritable low level of H3K9me2 (histone H3 lysine 9 dimethylation), resulting in the transgenerational upregulation of Rac1. Based on these findings, we treated the LPS-exposed pregnant rats with the reactive oxygen species scavenger, tempol, which successfully prevented hypertension in the first-generation offspring and the transgenerational inheritance of hypertension. These findings show that adverse prenatal exposure induces transgenerational hypertension through an epigenetic-regulated mechanism and identify potentially preventive and therapeutic strategies for hypertension.

Early Life Determinants of Vascular Structure in Fetuses, Infants, Children, and Adolescents: A Systematic Review and Meta-Analysis

To investigate the association between early life exposures during the first 1000days (conception to age 24months) and aortic intima-media thickness (aIMT), an early indicator of cardiovascular disease (CVD) risk, in youths. The MEDLINE, Embase, Scopus, CINAHL, and Allied and Complementary Medicine databases were searched from inception to July 2021. Eligibility criteria included observational controlled studies in youths aged <20years with risk factors/exposures during the first 1000days and aIMT measurements (unadjusted mean±SD). Outcome data were pooled using a random-effects meta-analysis. Meta-regression was used to investigate confounders. A total of 8657 articles were identified, of which 34 were included in our meta-analysis. The age of participants ranged from 22.9weeks gestation in utero to 10.9years. In the meta-analysis (n=1220 cases, n=1997 controls), the following factors were associated with greater aIMT: small for gestational age (SGA) status (14 studies, mean difference, 0.082mm; 95% CI, 0.051-0.112; P<.001; I2=97%), intrauterine growth restriction (6 studies; mean difference, 0.198mm, 95% CI, 0.088-0.309; P<.001; I2=97%), preeclampsia (2 studies; mean difference, 0.038mm; 95% CI, 0.024-0.051; P<.001; I2=38%), and large for gestational age (LGA) status (3 studies; mean difference, 0.089mm; 95% CI, 0.043-0.0136; P<.001; I2=93%). In meta-regression, older age (P<.001), higher prevalence of maternal smoking (P=.04), and SGA (P<.001) were associated with greater difference in aIMT in preterm participants compared with controls. Limitations included the high heterogeneity present in most meta-analyses and the scope of our meta-regression. Adverse early life exposures are associated with greater aIMT in youths, consistent with an increased risk for CVD later in life. Further research is needed to determine whether intervention and preventive strategies deliver clinical benefits to improve future cardiovascular health.

The Subjective Impact and Timing of Adversity Scale: A Feasibility Study Using Cross-Sectional and Longitudinal Data.

This study assessed the feasibility of a multi-domain measure of the occurrence, impact, and timing of childhood/adolescent psychological adversity exposure, the Subjective Impact and Timing of Adversity Scale (SITA). Participants were from among those who had previously participated in two waves of data collection when aged approximately 14 and 21 years. Internal consistency estimates at both online and interview stages were acceptable for all SITA domains (with the exception of parental loss). SITA domain scores correlated meaningfully with scores on other scales and psychological measures, supporting convergent validity. Those with lifetime psychiatric diagnoses scored significantly higher on SITA domains than those not meeting diagnostic threshold. There was evidence of the importance of both the subjective impact and timing of adversity with regard to psychiatric diagnoses. The study demonstrates the viability of the SITA; however, further studies are required to substantiate these findings in larger samples.

Adversity Exposure, Syntax, and Specific Language Impairment: An Exploratory Study.

Children exposed to adversity (e.g., chronic poverty, traumatic events, and maltreatment) are at increased risk for performing below age expectations on norm-referenced language assessments, but it is unknown whether the risk is higher for specific language impairment (SLI). This exploratory study investigated whether adversity exposure is associated with reduced grammar knowledge and SLI. The syntax subtest of the Diagnostic Evaluation of Language Variation-Norm-Referenced (DELV-NR) assessment was administered to 30 school-age children with known histories of adversity exposure. Their primary caregiver also completed a comprehensive adversity exposure measure, which captured adverse event type, frequency, chronicity, and severity. Analyses included t tests, correlations, Mann-Whitney U tests, and chi-square. Overall, the sample performed below age expectations on the DELV-NR Syntax subtest, and a higher percentage of participants (20%) met diagnostic criteria for SLI than expected. The SLI and typical language (TL) groups did not significantly differ in adversity dosage, frequency, chronicity, or severity; however, participants in the SLI group were 1.46 times more likely to have experienced physical trauma than the participants in the TL group. Children with known histories of adversity exposure presented with grammatical deficits and SLI more often than expected based on the DELV-NR normative sample; however, features of the adverse event did not associate with SLI status except for exposure to physical trauma (e.g., physical abuse and victimization). Future research is needed to investigate the prevalence and potential causal pathways of SLI in this population. https://doi.org/10.23641/asha.20483706.

Racial residential segregation shapes the relationship between early childhood lead exposure and fourth-grade standardized test scores

Racial/ethnic disparities in academic performance may result from a confluence of adverse exposures that arise from structural racism and accrue to specific subpopulations. This study investigates childhood lead exposure, racial residential segregation, and early educational outcomes. Geocoded North Carolina birth data is linked to blood lead surveillance data and fourth-grade standardized test scores (n = 25,699). We constructed a census tract-level measure of racial isolation (RI) of the non-Hispanic Black (NHB) population. We fit generalized additive models of reading and mathematics test scores regressed on individual-level blood lead level (BLL) and neighborhood RI of NHB (RINHB). Models included an interaction term between BLL and RINHB. BLL and RINHB were associated with lower reading scores; among NHB children, an interaction was observed between BLL and RINHB. Reading scores for NHB children with BLLs of 1 to 3 µg/dL were similar across the range of RINHB values. For NHB children with BLLs of 4 µg/dL, reading scores were similar to those of NHB children with BLLs of 1 to 3 µg/dL at lower RINHB values (less racial isolation/segregation). At higher RINHB levels (greater racial isolation/segregation), children with BLLs of 4 µg/dL had lower reading scores than children with BLLs of 1 to 3 µg/dL. This pattern becomes more marked at higher BLLs. Higher BLL was associated with lower mathematics test scores among NHB and non-Hispanic White (NHW) children, but there was no evidence of an interaction. In conclusion, NHB children with high BLLs residing in high RINHB neighborhoods had worse reading scores.

Adversity and child body mass index in Fragile Families over 15 years: Do type and timing matter?

BackgroundWeight status has been linked to adverse childhood experiences. Existing research, however, is limited to unidimensional assessments of cumulative risk and does not account for the complex nature of adversity experienced by children in high-risk settings. We fill existing gaps by assessing how four subtypes of adversity across two primary dimensions of threat and deprivation-based adversity are associated with changes in body mass index (BMI) across child ages 3 through 15 years. MethodU.S. mothers and fathers (n = 2412) in the Fragile Families and Child Wellbeing Study were interviewed when children were born, and again at ages 1, 3, 5, 9, and 15 years. Independent variables include interpersonal (e.g., domestic violence), family (e.g., mental health), economic (e.g., housing insecurity), and community (e.g., witness/victim of violence) adversity from ages 1 through 9 years. Path analysis regressed changes in BMIz from ages 3 through 15 on past adversity exposures. ResultsIncreased interpersonal and community adversity subtypes from ages 3 to 5 were associated with decreased BMIz from ages 5–9 years. Increased economic adversity from age 3 to 5 was associated with increased BMIz from ages 5 to 9, adjusted for mother age, race, and education. ConclusionFindings highlight the differential influence of past adversity type and timing on child BMI. Interpersonal and community adversity were associated with decreased BMIz, and economic adversity with increased BMIz. Differences in directionality of associations suggest research should capture multiple dimensions of adversity in early childhood and possible positive and negative trends in effects on child weight as children grow from early to mid-childhood.

Efficacy and Safety of Single-dose OC-02 (Simpinicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease: The PEARL Phase II Randomized Trial

PurposeDry eye disease is a multifactorial disorder that affects the ocular surface, with symptoms including ocular irritation, impaired vision, and pain. Nicotinic acetylcholine receptor (nAChR) agonists are novel treatments for dry eye disease; this study investigates the nAChR agonist OC-02 (simpinicline solution) as an aqueous nasal spray. MethodsPEARL (Clinical Trial to Evaluate the Efficacy of OC-02 Nasal Spray on Signs and Symptoms of Dry Eye Disease) was a Phase II study that evaluated the efficacy and safety of OC-02 (simpinicline solution) nasal spray (OC-02 SNS) in adult patients with dry eye disease. Patients ≥22 years of age were eligible if they had an Ocular Surface Disease Index score ≥23, corneal fluorescein staining score ≥2 in >1 region or ≥4 for all regions, or Schirmer test score (STS) ≤10 mm; there were no restrictions on eye dryness score (EDS). Patients (N = 165) were randomly assigned 1:1:1:1 to vehicle (control; n = 42) or OC-02 SNS (0.11 mg, 0.55 mg, or 1.1 mg; n = 41 per group) and received a single dose of study drug (100 µL using a nasal spray atomizer) at visit 1 and visit 2 (15–19 days after visit 1). Primary efficacy outcomes were change in the STS from baseline to immediately after treatment administration (visit 1) and change in the EDS from before to 5 minutes after treatment during controlled adverse environment exposure (visit 2). FindingsBaseline demographic and ocular clinical characteristics were similar across all groups. Single-dose OC-02 SNS improved the signs and symptoms of dry eye disease. For the STS, statistically significant and dose-dependent improvements were found from before to after treatment with OC-02 SNS versus vehicle (least-squares mean change from baseline: vehicle, 3.0 mm; 0.11 mg OC-02 SNS, 9.0 mm; 0.55 mg, 17.5 mm; and 1.1 mg, 19.6 mm). For EDS, statistically significant and dose-dependent improvements were found from before to 5 minutes after treatment with higher doses of OC-02 SNS versus vehicle (least-squares mean change from baseline: vehicle, –6.5; 0.11 mg OC-02 SNS, –9.4; 0.55 mg, –17.4; and 1.1 mg, –20.7). OC-02 SNS was well tolerated: only 2 ocular adverse events were reported (eye pruritis and keratitis), and the most common nonocular events were cough and throat irritation. ImplicationsSingle-dose OC-02 SNS over a range of doses immediately and significantly increased tear production and improved eye dryness. Together with previous studies of OC-01 (varenicline solution) nasal spray, our findings suggest that agonist stimulation of nAChRs in the nasal cavity is a valid and effective mechanism to elicit natural tear production in patients with dry eye disease. ClinicalTrials.gov identifier: NCT03452397.

Health Outcomes in Children Associated with Prenatal and Early-Life Exposures to Air Pollution: A Narrative Review.

(1) Background: The developmental origins of health and disease (DOHaD) hypothesis links adverse fetal exposures with developmental mal-adaptations and morbidity later in life. Short- and long-term exposures to air pollutants are known contributors to health outcomes; however, the potential for developmental health effects of air pollution exposures during gestation or early-childhood have yet to be reviewed and synthesized from a DOHaD lens. The objective of this study is to summarize the literature on cardiovascular and metabolic, respiratory, allergic, and neuropsychological health outcomes, from prenatal development through early childhood, associated with early-life exposures to outdoor air pollutants, including traffic-related and wildfire-generated air pollutants. (2) Methods: We conducted a search using PubMed and the references of articles previously known to the authors. We selected papers that investigated health outcomes during fetal or childhood development in association with early-life ambient or source-specific air pollution exposure. (3) Results: The current literature reports that prenatal and early-childhood exposures to ambient and traffic-related air pollutants are associated with a range of adverse outcomes in early life, including cardiovascular and metabolic, respiratory and allergic, and neurodevelopmental outcomes. Very few studies have investigated associations between wildfire-related air pollution exposure and health outcomes during prenatal, postnatal, or childhood development. (4) Conclusion: Evidence from January 2000 to January 2022 supports a role for prenatal and early-childhood air pollution exposures adversely affecting health outcomes during development. Future studies are needed to identify both detrimental air pollutants from the exposure mixture and critical exposure time periods, investigate emerging exposure sources such as wildfire, and develop feasible interventional tools.

Predicting Sensitivity to Adverse Lifestyle Risk Factors for Cardiometabolic Morbidity and Mortality.

People appear to vary in their susceptibility to lifestyle risk factors for cardiometabolic disease; determining a priori who is most sensitive may help optimize the timing, design, and delivery of preventative interventions. We aimed to ascertain a person’s degree of resilience or sensitivity to adverse lifestyle exposures and determine whether these classifications help predict cardiometabolic disease later in life; we pooled data from two population-based Swedish prospective cohort studies (n = 53,507), and we contrasted an individual’s cardiometabolic biomarker profile with the profile predicted for them given their lifestyle exposure characteristics using a quantile random forest approach. People who were classed as ‘sensitive’ to hypertension- and dyslipidemia-related lifestyle exposures were at higher risk of developing cardiovascular disease (CVD, hazards ratio 1.6 (95% CI: 1.3, 1.91)), compared with the general population. No differences were observed for type 2 diabetes (T2D) risk. Here, we report a novel approach to identify individuals who are especially sensitive to adverse lifestyle exposures and who are at higher risk of subsequent cardiovascular events. Early preventive interventions may be needed in this subgroup.

Cosmetic Ingredient: Metabolism and Mechanism

As additives, scents, preservatives, stabilizers, surfactants, stains, and shine, a variety of chemical substances have been added into the creation of cosmetic, beauty, and personal care products. Many of these compounds, on the other hand, are bioactive, ecologically persistent, and have the potential to bioaccumulate, posing a major hazard to the environment and human health. To genuinely address this issue, new techniques and approaches are necessary. This review summarizes the use of preservatives, pigments, and UV filters in cosmetics. The mechanisms of toxicities of preservative, such as parabens, benzalkonium chloride, and chlorphenesin are illustrated. Parabens have non-cutaneous adverse health effects, including infertility, spermatogenesis, adipogenesis, and perinatal exposure effects. Benzalkonium chloride in preservative decreased cell viability and caused apoptotic cell death in vitro. Pigment also played an important role in cosmetics and, some pigmentations in cosmetics are made by heavy metal or have heavy metal as ingredients. Cadmium and Chromium are two commonly used heavy metal in cosmetics. UV filters absorb UV energy and transform it chemically, which can lead to breakdown and the formation of photo-unstable reactive intermediates. Future research may focus on the safety assessment of specific substance in the application of cosmetics.

Fetal and Childhood Exposure to Parental Tobacco Smoking and Arterial Health at Age 10 Years.

BACKGROUNDExposure to parental tobacco smoking during fetal life and childhood is associated with adverse cardiovascular health outcomes. It is not known whether these adverse parental lifestyle exposures are also associated with changes in the structure and function of the carotid arteries in children aged 10 years.METHODSIn a population-based prospective cohort study among 4,639 healthy children, we examined the associations of fetal exposure to maternal (no, first trimester only, continued), paternal (no, yes), and combined parental tobacco smoking (nonsmoking parents, mother only, father only, both parents smoked) with carotid intima-media thickness and distensibility at 10 years. We also assessed the associations of exposure to any parental tobacco smoking at ages 6 and 10 years with these outcomes.RESULTSCompared with no exposure, fetal exposure to continued maternal smoking was not associated with carotid intima-media thickness (−0.04 standard deviation score (SDS); 95% confidence interval (CI): −0.13, 0.05); and distensibility (0 SDS, 95% CI: −0.09, 0.09) at age 10 years. Fetal exposure to two smoking parents was also not associated with carotid intima-media thickness (−0.07 SDS, 95% CI: −0.16, 0.02) and distensibility (0 SDS, 95% CI: −0.09, 0.10) at this age. Exposure to any parental smoking during childhood also was not associated with these outcomes at age 10 years.CONCLUSIONSExposure to parental tobacco smoking during fetal life and childhood was not associated with markers of arterial health in children aged 10 years. Prevention strategies aiming at minimizing smoke exposure later in life are still relevant regarding arterial health.

The Effect of High and Low Ambient Temperature on Infant Health: A Systematic Review.

Children, and particularly infants, have physiological, anatomic, and social factors that increase vulnerability to temperature extremes. We performed a systematic review to explore the association between acute adverse infant outcomes (children 0–1 years) and exposure to high and low ambient temperatures. MEDLINE (Pubmed), Embase, CINAHL Plus, and Global Health were searched alongside the reference lists of key papers. We included published journal papers in English that assessed adverse infant outcomes related to short-term weather-related temperature exposure. Twenty-six studies met our inclusion criteria. Outcomes assessed included: infant mortality (n = 9), sudden infant death syndrome (n = 5), hospital visits or admissions (n = 5), infectious disease outcomes (n = 5), and neonatal conditions such as jaundice (n = 2). Higher temperatures were associated with increased risk of acute infant mortality, hospital admissions, and hand, foot, and mouth disease. Several studies identified low temperature impacts on infant mortality and episodes of respiratory disease. Findings on temperature risks for sudden infant death syndrome were inconsistent. Only five studies were conducted in low- or middle-income countries, and evidence on subpopulations and temperature-sensitive infectious diseases was limited. Public health measures are required to reduce the impacts of heat and cold on infant health.

An Osimertinib-Perfluorocarbon Nanoemulsion with Excellent Targeted Therapeutic Efficacy in Non-small Cell Lung Cancer: Achieving Intratracheal and Intravenous Administration.

Low accumulation of anticancer drugs in tumors and serious systemic toxicity remain the main challenges to the clinical efficiency of pharmaceuticals. Pulmonary delivery of nanoscale-based drug delivery systems offered a strategy to increase antitumor activity with minimal adverse exposure. Herein, we report an osimertinib-loaded perfluoro-15-crown-5-ether (AZD9291-PFCE) nanoemulsion, through intratracheal and intravenous delivery, synergizes with 19F magnetic resonance imaging (19F MRI)-guided low-intensity focused ultrasound (LIFU) for lung cancer therapy. Pulmonary delivery of AZD9291-PFCE nanoemulsion in orthotopic lung carcinoma models achieves quick distribution of the nanoemulsion in lung tissues and tumors without short-term and long-term toxic effects. Furthermore, LIFU can trigger drug release from the AZD9291-PFCE nanoemulsion and specifically increases tumor vascular and tumor tissue permeability. 19F MRI was applied to quantify nanoemulsion accumulation in tumors in real time after LIFU irradiation. We validate the treatment effect of AZD9291-PFCE nanoemulsion in resected human lung cancer tissues, proving the translational potential to enhance clinical outcomes of lung cancer therapy. Thus, this work presents a promising pulmonary nanoemulsion delivery system of osimertinib (AZD9291) for targeted therapy of lung cancer without severe side effects.

Characterization and Toxicity Analysis of Lab-Created Respirable Coal Mine Dust from the Appalachians and Rocky Mountains Regions

Coal mine workers are continuously exposed to respirable coal mine dust (RCMD) in workplaces, causing severe lung diseases. RCMD characteristics and their relations with dust toxicity need further research to understand the adverse exposure effects to RCMD. The geographic clustering of coal workers’ pneumoconiosis (CWP) suggests that RCMD in the Appalachian region may exhibit more toxicity than other geographic regions such as the Rocky Mountains. This study investigates the RCMD characteristics and toxicity based on geographic location. Dissolution experiments in simulated lung fluids (SLFs) and in vitro responses were conducted to determine the toxicity level of samples collected from five mines in the Rocky Mountains and Appalachian regions. Dust characteristics were investigated using Fourier-transform infrared spectroscopy, scanning electron microscopy, the BET method, total microwave digestion, X-ray diffraction, and X-ray photoelectron spectroscopy. Inductively coupled plasma mass spectrometry was conducted to determine the concentration of metals dissolved in the SLFs. Finer particle sizes and higher mineral and elemental contents were found in samples from the Appalachian regions. Si, Al, Fe, Cu, Sr, and Pb were found in dissolution experiments, but no trends were found indicating higher dissolutions in the Appalachian region. In vitro studies indicated a proinflammatory response in epithelial and macrophage cells, suggesting their possible participation in pneumoconiosis and lung diseases development.

P666: ACALABRUTINIB ± OBINUTUZUMAB VS OBINUTUZUMAB + CHLORAMBUCIL IN TREATMENT-NAIVE CHRONIC LYMPHOCYTIC LEUKEMIA: 5-YEAR FOLLOW-UP OF ELEVATE-TN

Background: For ELEVATE-TN (NCT02475681), we previously reported superior efficacy of acalabrutinib (A) ± obinutuzumab (O) vs O + chlorambucil (Clb) in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) at 28.3 and 46.9 months median follow-up. Aims: To report the updated efficacy and safety results from the ELEVATE-TN study after a median follow-up of 5 years. Methods: Patients were randomized to A+O, A, or O+Clb after informed consent was obtained. Patients who progressed on O+Clb could cross over to A monotherapy. Investigator-assessed (INV) progression-free survival (PFS), INV overall response rate (ORR), overall survival (OS), and safety were evaluated. Results: A total of 535 patients (A+O, n=179; A, n=179; O+Clb, n=177) had a median age of 70 years; 63% had unmutated IGHV and 9% had del(17p). At a median follow-up of 58.2 months (range, 0.0–72.0; data cutoff Oct 1, 2021), median PFS was not reached (NR) (hazard ratio [HR]: 0.11) for A+O and A (HR: 0.21) vs 27.8 months for O+Clb (both P<0.0001). The estimated 60-month PFS rates were 84% (A+O), 72% (A), and 21% (O+Clb). In patients with unmutated IGHV, the median PFS was NR for A+O and A vs 22.2 months among patients in the O+Clb arm (HR: 0.06 [A+O] and 0.12 [A]; both P<0.0001); estimated 60-month PFS rates were 82% (A+O), 72% (A), and 6% (O+Clb). In patients with del(17p), the median PFS was NR and 64.1 months for A+O and A vs 17.7 months for O+Clb (HR: 0.21, P=0.0031 [A+O]; HR: 0.29, P=0.0130 [A]); estimated 60-month PFS rates were 75% (A+O), 71% (A), and 27% (O+Clb). Median OS was NR in any treatment arm, and significantly longer in the A+O vs O+Clb arms (HR: 0.55; P=0.0474); estimated 60-month OS rates were 90% (A+O), 84% (A), and 82% (O+Clb). ORR was significantly higher with A+O (96%; 95% CI 92–98) and A (90%; 85–94) vs O+Clb (83%; 77–88; P<0.0001 [A+O], P=0.0499 [A]). Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were higher with A+O (29%/3%) vs O+Clb (13%/1%); 13%/1% had CR/CRi with A; CR increased since the interim analysis (previously 21% [A+O] and 7% [A]). Adverse events (AEs) and treatment exposure are shown in the Table. Treatment is ongoing in 65% (A+O) and 60% (A) of patients; the most common reasons for treatment discontinuation were AEs (17% [A+O], 16% [A], 14% [O+Clb]) and progressive disease (6%, 10%, 2%, respectively). Crossover from O+Clb to A occurred in 72 (41%) patients; 25% of these patients discontinued A (10% due to AEs and 11% due to progressive disease). Image:Summary/Conclusion: After 5 years of follow-up, efficacy and safety of A+O and A monotherapy were maintained, with significantly longer OS in the A+O arm compared with O+Clb.

MiR-195-5p facilitates the proliferation, migration, and invasion of human trophoblast cells by targeting FGF2.

Preeclampsia (PE), the most significant adverse exposure to cardiovascular risk during pregnancy, is one of the three major factors contributing to maternal and fetal mortality and the leading cause of preterm birth. Recently, various miRNAs have been reported to participate in PE occurrence and development. Nevertheless, the regulatory impact of miR-195-5p in PE is still indistinct. Quantitative realtime-PCR (qRT-PCR), western blot, and fluorescence in situ hybridization (FISH) assay were performed to examine miR-195-5p and FGF2 expressions in PE serum samples or HTR-8/SVneo and TEV-1 cells. CCK8, flow cytometry, wound scratch, and transwell assays were conducted to determine cell viability, cycle, apoptosis, migration, and invasion. Dual-luciferase reporter assay unveiled the relationship between miR-195-5p and FGF2. Migration-related and invasion-related protein expressions were measured by western blot assay. miR-195-5p was prominently downregulated while FGF2 was increased in serum samples from PE patients and hypoxia-treated human trophoblast cells. FGF2 was predicted as a downstream target of miR-195-5p and targeted association was verified by dual-luciferase reporter assay. Functional experiments elaborated that miR-195-5p could facilitate trophoblast cell proliferation and metastasis but hinder cell cycle and apoptosis. Inversely, overexpressing of FGF2 could reverse the effects of miR-195-5p on trophoblast cell growth. miR-195-5p was decreased in PE serum samples and cell lines, serving as a potential biomarker in protecting PE exacerbation by targeting FGF2.