Cross-product Terms Research Articles

Comparison of the Three Types of Central Composite Designs Over Subsets of Reduced Models by Design Optimality Criteria

The purpose of this article is to compare the 3 important types of central composite designs (CCDs) consisting of central composite circumscribed design (CCCD), central composite inscribed design (CCID), and central composite face-centroid design (CCFD) in response surface methodology (RSM). The difference among these designs is the distance from the center design to the axial points. The comparison was performed across the full second-order response surface model and across a set of reduced models for 3, 4, and 5 design factors ( 3, 4, and 5) including 1, 3, and 5 center runs ( 1, 3, and 5). This study used D-, A-, and G- optimality criteria to evaluate the performance of CCDs by presenting the design optimality criteria comparison ranking throughout the reduced-model subsets of 43, 224, and 839 models for 3, 4, and 5 design variables, respectively. The results showed that CCCD was superior to CCID and CCFD according to A- and D- optimality criteria, while CCCD and CCID performed better than CCFD based on G- optimality criterion over a set of reduced models for 3, 4, and 5 design factors. It was observed that D-, A-, and G- optimality efficiencies were robust to changes in the linear and cross-product terms and sensitive to deviation in the square terms. The study will provide recommendations to assist the experimenters in the choice of the best design among the candidate designs for practice applications when some model effects may be insignificant. HIGHLIGHTS Comparison of 3 classifications of CCD. Assessment by using D-, A-, and G- optimality criteria over the reduced-model subsets for the full second-order response surface model. Generated the reduced models by using weak heredity. CCCD was superior to CCID and CCFD according to A- and D- optimality criteria, while CCCD and CCID performed better than CCFD based on G- optimality criterion over a set of reduced models for 3, 4, and 5 design factors. GRAPHICAL ABSTRACT

Group peer mentoring is effective for different demographic groups of biomedical research faculty: A controlled trial.

Improved mentoring of midcareer researchers in medical schools has been identified as an important potential avenue for addressing low vitality and high burnout rates in faculty, and the scarcity of both underrepresented minority (URM) faculty and women in biomedical research. To address the need for widescale effective mentoring, we sought to determine whether a group peer mentoring intervention (C-Change Mentoring and Leadership Institute) for early midcareer research faculty was effective for different demographic groups in a controlled trial. Thirty-five diverse early midcareer faculty and 70 propensity-matched (PM) control subjects matched to intervention subjects on a) study inclusion criteria; b) gender, race, and ethnicity, degree, rank, years of experience, publications, grants; and c) pretest survey outcome variables, participated in the intervention. The C-Change Participant Survey assessed vitality, self-efficacy in career advancement, research success, mentoring others, valuing diversity, cognitive empathy, and anti-sexism/anti-racism skills at pretest and intervention completion. Analysis using multiple regression models included outcome pretest values and indicator variables for intervention, gender, URM status, and MD vs. PhD. Hypotheses regarding differential effectiveness of the intervention by demographic group were tested by including cross-product terms between the demographic indicator variables and the intervention indicator. Missing data were addressed using chained equations to create 100 data sets. The intervention participants had significantly higher (favorable) scores than PM controls for: self-assessed change in vitality; self-efficacy for career advancement, research, and mentoring others; cognitive empathy; and anti-sexism/racism skills. The benefits of the intervention were nearly identical across: gender, URM vs non-URM faculty, and degree MD/PhD, except vitality significantly increased for non-URM subjects, and not for URM faculty. Self-assessed change in vitality increased for URM and non-URM. The intervention worked successfully for enhancing vitality, self-efficacy and cross-cultural engagement across different demographic groups of biomedical research faculty.

Maternal prenatal lead levels and neonatal brain volumes: Testing moderations by maternal depressive symptoms and family income

There is considerable evidence that prenatal lead exposure is detrimental to child cognitive and socio-emotional development. Further evidence suggests that the effects of prenatal lead on developmental outcomes may be conditional upon exposure to social stressors, such as maternal depression and low socioeconomic status. However, no studies have examined associations between these co-occurring stressors during pregnancy and neonatal brain volumes. Leveraging a sample of 101 mother-infant dyads followed beginning in mid-pregnancy, we examined the main effects of prenatal urinary lead levels on neonatal lateralized brain volumes (left and right hippocampus, amygdala, cerebellum, frontal lobes) and total gray matter. We additionally tested for moderations between lead and depressive symptoms and between lead and family income relative to the federal poverty level (FPL) on the same neurodevelopmental outcomes. Analyses of main effects indicated that prenatal lead was significantly (ps < 0.05) associated with reduced right and left amygdala volumes (βs = −0.23- -0.20). The testing and probing of cross-product interaction terms using simple slopes indicated that the negative effect of lead on the left amygdala was conditional upon mothers having low depressive symptoms or high income relative to the FPL. We interpret the results in the context of trajectories of prenatal and postnatal brain development and susceptibility to low levels of prenatal lead in the context of other social stressors.

Abstract B144: Associations between experiences of discrimination and quality of life in a cohort of Black/African American breast cancer survivors

Abstract Introduction: Racism and discrimination have been associated with poorer mental and physical health, and decreased health-related quality of life (QoL) in the general population, however; there are limited studies examining the impact of discrimination in cancer survivors. We examined the relationship between experiences of discrimination and QoL in Black women diagnosed with breast cancer. Methods: Data were obtained from women enrolled in the Women’s Circle of Health Follow-up Study, a population-based cohort study of Black breast cancer survivors in New Jersey, enrolled within 10 months of diagnosis. Women included in these analyses were diagnosed between 2015-2019. Self-reported experiences of discrimination along with information on potential covariates and effect modifiers were collected during baseline in-person interviews. QoL was assessed at follow-up visits approximately 24 months post-diagnosis using a validated self-reported QoL of measure, the Functional Assessment of Cancer Therapy – Breast (FACT-B), which consists of 5 individual domains (emotional, functional, social/family, and physical wellbeing, as well as a disease specific domain for breast cancer). We examined the association of experiences of discrimination (none, low (&amp;lt;median 43%), high (≥ median 43%)) with continuous total QoL score using linear regression, adjusted for age at diagnosis, tumor stage, educational attainment, household income, smoking status, insurance, and body mass index. We also examined statistical interaction by neighborhood socioeconomic index (nSES), coping strategy (assessed using the Brief Resilient Coping Scale), and spirituality (assessed using the Functional Assessment of Chronic Illness Therapy - Spiritual Well-Being (FACIT-Sp-12) scale) using cross-product terms with experiences of discrimination. Results: Of 220 study participants, 73% of participants reported experiencing any discrimination. In age adjusted models, women who reported the highest experiences of discrimination had lower QoL for overall FACT-B scores and the subscale scores (no discrimination, mean overall FACT-B:117.7, 95% confidence interval (CI): 112.4, 122.9; high discrimination, mean overall FACT-B: 106.8, 95% CI: 102.1, 111.5). Similar associations were observed in fully adjusted models, where women who reported the highest experiences of discrimination had lower QoL. For example, for women who reported no discrimination the mean overall FACT-B score was 114.7 (95% CI: 107.9, 121.4) and 100.8 (95% CI: 94.2, 107.5) for women who reported the highest level of discrimination. No evidence of statistically significant interaction was observed for nSES, spirituality, or coping strategy. Conclusions: In a population-based study of Black breast cancer survivors, experiences of discrimination were associated with poorer QoL, as measured by FACT-B. Citation Format: Nur Zeinomar, Marley M. Perlstein, Bo Qin, Hari S. Iyer, Jesse J. Plascak, Christine B. Ambrosone, Kitaw Demissie, Chi-Chen Hong, Elisa V. Bandera. Associations between experiences of discrimination and quality of life in a cohort of Black/African American breast cancer survivors [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B144.

Abstract B114: Population differences in the associations between chromosomal abnormalities and overall survival among Blacks and Whites with multiple myeloma

Abstract Background: Several primary and secondary cytogenetic abnormalities (e.g., translocation t(4;14) and 1q copy number changes) are associated with poor prognosis and worse survival of multiple myeloma (MM). Some of the aberrations (e.g., t(11;14), t(14;16), and t(14;20)) have been suggested, albeit inconclusively, to be enriched in Blacks. However, whether the associations between chromosomal abnormalities and overall survival (OS) of MM differ by race/ethnicity remains largely unknown. Methods: We prospectively enrolled 586 patients with newly diagnosed MM between 2010-2019 at the University of Chicago Medical Center. Of the 561 subjects identified as Black or White, 181 had chromosomal abnormalities determined by fluorescence in situ hybridization (FISH), which used CD138+ plasma cells enriched from bone marrow aspirates collected within 180 days of diagnosis. We analyzed data for 19 aberrations, including IGH/FGFR3 fusion [t(4;14)(p16,q32)]; IGH/CCND1 fusion [t(11;14)(q13,q32)]; IGH/MAF [t(14;16)(q32,q23)]; IGH/MAFB [t(14;20)(q32,q12)]; trisomies of chromosome 3, 7, 9, and 12; chromosome 13 deletion; loss of ATM [11q22.3]; gain of ATM; loss of TP53 [17p13.1]; gain of TP53; loss of CDKN2C [1p32.3]; gain of CKS1B [1q21]; IGH translocation with uncommon chromosome partners; IGH locus rearrangement; loss of IGH; and tetraploidy. Vital status was ascertained using the National Death Index. Baseline clinical and laboratory data were retrieved from electronic medical records. We used proportions and Chi-square tests to compare the distributions of cytogenetic abnormalities in Blacks and Whites. In each population, we evaluated the associations between cytogenetic abnormalities and OS using hazard ratios (HRs) and 95% confidence interval (CIs) from Cox proportional hazards models, adjusting for prognostic factors including age, international staging system, elevated lactate dehydrogenase, and estimated glomerular filtration rate. We used the Wald test of the cross-product terms to assess potential heterogeneity of effect in the HRs by race. Results: Of the 181 MM patients, 55 (30.39%) were Black and 126 (69.61%) were White. The median follow-up was 69 months. The frequencies of the 19 cytogenetic abnormalities did not differ between Blacks and Whites. However, we observed population differences in the associations between two chromosomal abnormalities and OS: the presence of t(4;14) was associated with worse OS in Blacks (HR=14.34 [2.17-94.58]; N=38) but not Whites (HR=2.04 [0.70-5.88]; N=99, p-heterogeneity = 0.08), whereas gain of 1q was associated with poorer OS in Whites (HR: 3.38, 95% CI: [1.25- 9.09], N=77), but not Blacks (HR=1.32 [0.31-5.68]; N=32; p-heterogeneity=0.02). Conclusions: Although we found similar frequencies of primary and secondary chromosomal abnormalities between Blacks and Whites, our data show population differences in the associations between two established high-risk cytogenetic abnormalities and the OS of MM. Our findings suggest that cytogenetic features may have varying impacts on the OS of MM based on race. Citation Format: Bei Wang, Benjamin A. Derman, Jason Cheung, Wei Zhang, Andrzej Jakubowiak, Brian C. Chiu. Population differences in the associations between chromosomal abnormalities and overall survival among Blacks and Whites with multiple myeloma [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B114.

Gender-specific moderating role of abdominal obesity in the relationship between handgrip strength and cognitive impairment

Both low handgrip strength (HGS) and abdominal obesity (AO) are associated with cognitive impairment. However, it remains unclear whether low HGS and AO interact to affect cognition, and whether the synergistic effect varies by gender. This study aimed to examine whether the association between low HGS and incident cognitive impairment was moderated by AO among Chinese older men and women. We used the data of participants (≥60 years) from four waves (2011-2018) of the China Health and Retirement Longitudinal Study. We defined low HGS as the maximal HGS of <28kg in men and <18kg in women, and AO as waist circumference of ≥90cm for men and ≥80cm for women. Cognitive impairment was defined as a global cognitive score in the lowest 10th percentile. For each gender, we used subdistribution hazards model to estimate subdistribution hazard ratios (SHRs) for the association of low HGS and AO with incident cognitive impairment, treating mortality as the competing event and controlling for other covariates. Multiplicative interaction was assessed through a cross-product interaction term of low HGS and AO in the model. Additive interaction between low HGS and AO was evaluated by calculating the relative excess risk due to interaction (RERI) and attributable proportion due to interaction (AP). We included 3704 participants (Mean age: 66.9±5.81; 54.9% male). During the 7-year follow-up, 1133 events of interest occurred (731 cognitive impairments and 402 deaths). Incidence rates of cognitive impairment and mortality were 4.1 (95% CI: 3.8 to 4.4) and 2.2 (95% CI: 2.0 to 2.5) per 100 person-years. There were positive multiplicative (SHR for the product term=1.974, 95% CI: 1.114 to 3.500) and additive interactions (RERI=1.056, 95% CI: 0.027 to 2.086, AP=0.454, 95% CI: 0.158 to 0.750) of low HGS and AO on the risk of cognitive impairment among older men. Male participants with both low HGS and AO showed an increased risk of cognitive impairment (SHR=2.325, 95% CI: 1.498 to 3.609) compared with those without either. There was no evidence of interaction among older women (SHR for the product term=1.151, 95% CI: 0.725 to 1.825; RERI=0.044, 95% CI:-0.524 to 0.613; AP=0.039, 95% CI:-0.458 to 0.536). Low HGS and AO may interact to synergistically increase the risk of cognitive impairment among Chinese older men. Screening the highest-risk subpopulation, who may benefit most from neurocognitive prevention strategies, may maximize potential public health gains.

Analysis of Novel 4D Rabinovich-Fabrikant Continuous Dynamical System with Coexistence Attractors

In this paper a new Rabinovitch-Fabrikant (R-F) four dimensional (4D) continuous time dynamical system was generated from three dimensional (3D) Rabinovitch-Fabrikant dynamical system using the state augmentation technique by adding new state variables u. The system employs thirteen terms includes five cross-product terms and one irreversible function. The dynamical behaviors of the system were investigated which include equilibrium points, stability analysis, wave form analysis, phase space analysis, multistability, Hopf-bifurcation, the Lyapunov exponent and Lyapunov dimension. The values of Lyapunov exponents are:L1 = 14.025946, L2 = 0.295151, L3 = −2.854401, L4 = −13.736833. and Lyapunov dimension is (3.83474), so the system is unstable and hyperchaotic with coexistence attractors. Chaos was handled in two ways: adaptive control and adaptive synchronization, it was found that the new system is stable and achieved good results.

Prenatal exposure to polybrominated diphenyl ethers and inattention/hyperactivity symptoms in mid to late adolescents.

Prenatal exposure to polybrominated diphenyl ethers (PBDEs) has been associated with increased symptoms of attention deficit/hyperactivity disorder (ADHD) in early to middle childhood, as well as early adolescence. However, data are limited for the long-lasting impact of exposure on outcomes assessed across the entire adolescent period and the sex-specificity of such associations. We investigated the association between continuous natural-log-transformed cord plasma PBDE concentrations and ADHD rating scale 4th edition (ADHD-RS-IV) score from mid adolescence (approximately 11 years old) to late adolescence (approximately 17 years old). The study sample includes a subset (n = 219) of the African American and Dominican children enrolled in the Columbia Center for Children's Environmental Health Mothers and Newborns birth cohort. We used generalized estimating equations to account for the repeated measure of ADHD-RS scores. We examined interactions between exposure to PBDE and sex using cross-product terms and sex-stratified models. In addition, we used linear regression using an age-stratified sample as a sensitivity analysis. Associations between prenatal exposure and parents' reports of ADHD symptoms varied by sex (p-interaction <0.20), with positive relationships observed among girls but not boys from sex-stratified models. Our finding suggests prenatal exposure to PBDE may affect ADHD symptoms assessed during middle to late adolescence and the sex-specificity of such impact. Our results can be confirmed by future studies with larger and more diverse samples.

Investigating a Paradox: Toward a Better Understanding of the Relationships Between Racial Group Membership, Stress, and Major Depressive Disorder.

Epidemiologic studies in the United States routinely report a lower or equal prevalence of major depressive disorder (MDD) for Black people relative to White people. Within racial groups, individuals with greater life stressor exposure experience greater prevalence of MDD; however, between racial groups this pattern does not hold. Informed by theoretical and empirical literature seeking to explain this "Black-White depression paradox," we outline 2 proposed models for the relationships between racial group membership, life stressor exposure, and MDD: an effect modification model and an inconsistent mediator model. Either model could explain the paradoxical within- and between-racial group patterns of life stressor exposure and MDD. We empirically estimated associations under each of the proposed models using data from 26,960 self-identified Black and White participants in the National Epidemiologic Survey on Alcohol and Related Conditions III (United States, 2012-2013). Under the effect modification model, we estimated relative risk effect modification using parametric regression with a cross-product term, and under the inconsistent mediation model, we estimated interventional direct and indirect effects using targeted minimum loss-based estimation. We found evidence of inconsistent mediation (i.e., direct and indirect effects operating in opposite directions), suggesting a need for greater consideration of explanations for racial patterns in MDD that operate independent of life stressor exposure. This article is part of a Special Collection on Mental Health.

Secondhand smoke, genetic susceptibility, and incident chronic kidney disease in never smokers: A prospective study of a selected population from the UK Biobank.

A large number of people around the world are exposed to the risks of passive smoking. This prospective study aimed to examine the association between secondhand smoke exposure, exposure time, and the incidence of chronic kidney disease (CKD) and determine whether this association was influenced by genetic susceptibility. The study included 214244 participants of the UK Biobank who were initially free of CKD. Cox proportional hazards model was used to estimate the associations between secondhand smoke exposure time and the risks of CKD in people who have never smoked. The genetic risk score for CKD was calculated by a weighted method. The likelihood ratio test comparing models was used to examine the cross-product term between secondhand smoke exposure and genetic susceptibility to CKD outcomes. During a median of 11.9 years of follow-up, 6583 incidents of CKD were documented. Secondhand smoke exposure increased the risk of CKD (HR=1.09; 95% CI: 1.03-1.16, p<0.01), and a dose-response relationship between CKD prevalence and secondhand smoke exposure time was found (p for trend<0.01). Secondhand smoke exposure increases the risk of CKD even in people who never smoke and have a low genetic risk (HR=1.13; 95% CI: 1.02-1.26, p=0.02). There was no statistically significant interaction between secondhand smoke exposure and genetic susceptibility to CKD (p for interaction=0.80). Secondhand smoke exposure is associated with higher risk of CKD, even in people with low genetic risk, and the relationship is dose dependent. These findings change the belief that people with low genetic susceptibility and without direct participation in smoking activities are not prone to CKD, emphasizing the need to avoid the harm of secondhand smoke in public places.

The association of cortisol/testosterone ratio and sleep quality with coronary heart disease: A case-control study in Chinese rural population.

There were limited studies that have probed into the combined effect of the cortisol/testosterone (C/T) ratio as a biomarker of stress and Pittsburgh Sleep Quality Index (PSQI) on coronary heart disease (CHD). This research aimed to explore the association of C/T ratio and PSQI with the risk of CHD in a rural Chinese population, as well as the interaction and combined effect between C/T ratio and PSQI on CHD. A case-control study was performed including 307 individuals without CHD and 307 patients drawn from Henan Rural Cohort. Logistic regression was utilized to survey the independent and joint effects of the C/T ratio and PSQI on CHD. To estimate the interaction impact of the C/T ratio and sleep quality (PSQI) on CHD, a cross-product term was introduced in the generalized linear model. Higher C/T ratio and PSQI index scores are related to increased odds ratio for CHD (Odds ratios (ORs) and 95% confidence interval (CI) were 1.17 (1.07, 1.29), p-trend<0.001; 1.16 (1.09, 1.22), respectively). The odds ratio of C/T ratio for CHD increased with increasing PSQI in women (pinteraction=0.018) and total population (pinteraction=0.033). The combined group of high C/T ratio and high PSQI had the highest risk of CHD (Total: OR=7.53, 95% CI: 4.12-13.76). The risk of CHD was associated with low testosterone levels, high C/T ratios, and high PSQI scores. Additionally, poor sleep quality aggravated the effect of high C/T ratio on coronary heart disease.

KCNQ1 rs2237892 polymorphism modify the association between short-term ambient particulate matter exposure and fasting blood glucose: A family-based study

BackgroundThe association between particulate matter and fasting blood glucose (FBG) has shown conflicting results. Genome-wide association studies have shown that KCNQ1 rs2237892 polymorphism is associated with the risk of diabetes. Whether KCNQ1 rs2237892 polymorphism might modify the association between particulate matter and FBG is still uncertain. MethodsData collected from a family-based cohort study in Northern China, were used to perform the analysis. A generalized additive Gaussian model was used to examine the short-term effects of air pollutants on FBG. We further conducted interaction analyses by including a cross-product term of air pollutants by rs2237892 within KCNQ1 gene. ResultsA total of 4418 participants were included in the study. In the single pollutant model, the FBG level increased 0.0031 mmol/L with per 10 μg/m3 elevation in fine particular matter (PM2.5) for lag 0 day. After additional adjustments for nitrogen dioxide (NO2) and sulfur dioxide (SO2), similar results were observed for lag 0–2 days. As for particulate matter with particle size below 10 μm (PM10), the significant association between the daily average concentration of the pollutant and FBG level was observed for lag 0–3 days. Additionally, rs2237892 in KCNQ1 gene modified the association between PM and FBG level. The higher risk of FBG levels associated with elevations in PM10 and PM2.5 were more evident as the number of risk allele C increased. Individuals with a CC genotype had the highest risk of elevation in FBG levels. ConclusionShort-term exposures to PM2.5 and PM10 were associated with higher FBG levels. Additionally, rs2237892 in KCNQ1 gene might modify the association between the air pollutants and FBG levels.

Neighborhood disinvestment and severe maternal morbidity in the state of California

Social determinants of health, including neighborhood context, may be a key driver of severe maternal morbidity and its related racial and ethnic inequities; however, investigations remain limited. This study aimed to examine the associations between neighborhood socioeconomic characteristics and severe maternal morbidity, as well as whether the associations between neighborhood socioeconomic characteristics and severe maternal morbidity were modified by race and ethnicity. This study leveraged a California statewide data resource on all hospital births at ≥20 weeks of gestation (1997-2018). Severe maternal morbidity was defined as having at least 1 of 21 diagnoses and procedures (eg, blood transfusion or hysterectomy) as outlined by the Centers for Disease Control and Prevention. Neighborhoods were defined as residential census tracts (n=8022; an average of 1295 births per neighborhood), and the neighborhood deprivation index was a summary measure of 8 census indicators (eg, percentage of poverty, unemployment, and public assistance). Mixed-effects logistic regression models (individuals nested within neighborhoods) were used to compare odds of severe maternal morbidity across quartiles (quartile 1 [the least deprived] to quartile 4 [the most deprived]) of the neighborhood deprivation index before and after adjustments for maternal sociodemographic and pregnancy-related factors and comorbidities. Moreover, cross-product terms were created to determine whether associations were modified by race and ethnicity. Of 10,384,976 births, the prevalence of severe maternal morbidity was 1.2% (N=120,487). In fully adjusted mixed-effects models, the odds of severe maternal morbidity increased with increasing neighborhood deprivation index (odds ratios: quartile 1, reference; quartile 4, 1.23 [95% confidence interval, 1.20-1.26]; quartile 3, 1.13 [95% confidence interval, 1.10-1.16]; quartile 2, 1.06 [95% confidence interval, 1.03-1.08]). The associations were modified by race and ethnicity such that associations (quartile 4 vs quartile 1) were the strongest among individuals in the "other" racial and ethnic category (1.39; 95% confidence interval, 1.03-1.86) and the weakest among Black individuals (1.07; 95% confidence interval, 0.98-1.16). Study findings suggest that neighborhood deprivation contributes to an increased risk of severe maternal morbidity. Future research should examine which aspects of neighborhood environments matter most across racial and ethnic groups.

Sepsis-related coagulopathy treatment based on the disseminated intravascular coagulation diagnostic criteria: a post-hoc analysis of a prospective multicenter observational study

BackgroundThe development of disseminated intravascular coagulation (DIC) in patients with sepsis has been repeatedly confirmed as a factor associated with poor prognosis. Anticoagulant therapy has been expected to improve sepsis patient outcomes, whereas no randomized controlled trials have demonstrated the survival benefit of anticoagulant therapies in non-specific overall sepsis. Patient selection based on the component of “high disease severity” in addition to “sepsis with DIC” has recently proved important in identifying appropriate targets for anticoagulant therapy. The aims of this study were to characterize “severe” sepsis DIC patients and to identify the patient population benefiting from anticoagulant therapy.MethodsThis retrospective sub-analysis of a prospective multicenter study included 1,178 adult patients with severe sepsis from 59 intensive care units in Japan from January 2016 to March 2017. We examined the association of patient outcomes, including organ dysfunction and in-hospital mortality, with the DIC score and prothrombin time-international normalized ratio (PT-INR), one of the components of the DIC score, using multivariable regression models including the cross-product term between these indicators. Multivariate Cox proportional hazard regression analysis with non-linear restricted cubic spline including a three-way interaction term (anticoagulant therapy × the DIC score × PT-INR) was also performed. Anticoagulant therapy was defined as the administration of antithrombin, recombinant human thrombomodulin, or their combination.ResultsIn total, we analyzed 1013 patients. The regression model showed that organ dysfunction and in-hospital mortality deteriorated with higher PT-INR values in the range of < 1.5 and that this trend was more pronounced with higher DIC scores. Three-way interaction analysis demonstrated that anticoagulant therapy was associated with better survival outcome in patients with a high DIC score and high PT-INR. Furthermore, we identified a DIC score ≥ 5 and PT-INR ≥ 1.5 as the clinical threshold for identification of optimal targets for anticoagulant therapy.ConclusionsThe combined use of the DIC score and PT-INR helps in selecting the optimal patient population for anticoagulant therapy in sepsis-induced DIC. The results obtained from this study will provide valuable information regarding the study design of randomized controlled trials examining the effects of anticoagulant therapy for sepsis.Trial registration: UMIN-CTR, UMIN000019742. Registered on November 16, 2015.

Gene–environment interactions in the associations of PFAS exposure with insulin sensitivity and beta-cell function in a Faroese cohort followed from birth to adulthood

BackgroundExposure to perfluoroalkyl substances (PFAS) has been associated with changes in insulin sensitivity and pancreatic beta-cell function in humans. Genetic predisposition to diabetes may modify these associations; however, this hypothesis has not been yet studied. ObjectivesTo evaluate genetic heterogeneity as a modifier in the PFAS association with insulin sensitivity and pancreatic beta-cell function, using a targeted gene–environment (GxE) approach. MethodsWe studied 85 single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes, in 665 Faroese adults born in 1986–1987. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were measured in cord whole blood at birth and in participants’ serum from age 28 years. We calculated the Matsuda-insulin sensitivity index (ISI) and the insulinogenic index (IGI) based on a 2 h-oral glucose tolerance test performed at age 28. Effect modification was evaluated in linear regression models adjusted for cross-product terms (PFAS*SNP) and important covariates. ResultsPrenatal and adult PFOS exposures were significantly associated with decreased insulin sensitivity and increased beta-cell function. PFOA associations were in the same direction but attenuated compared to PFOS. A total of 58 SNPs were associated with at least one PFAS exposure variable and/or Matsuda-ISI or IGI in the Faroese population and were subsequently tested as modifiers in the PFAS-clinical outcome associations. Eighteen SNPs showed interaction p-values (PGxE) < 0.05 in at least one PFAS-clinical outcome association, five of which passed False Discovery Rate (FDR) correction (PGxE-FDR<0.20). SNPs for which we found stronger evidence for GxE interactions included ABCA1 rs3890182, FTO rs9939609, FTO rs3751812, PPARG rs170036314 and SLC12A3 rs2289116 and were more clearly shown to modify the PFAS associations with insulin sensitivity, rather than with beta-cell function. DiscussionFindings from this study suggest that PFAS-associated changes in insulin sensitivity could vary between individuals as a result of genetic predisposition and warrant replication in independent larger populations.

Long-term exposure to ambient air pollutants and their interaction with physical activity on insomnia: A prospective cohort study

Exposure to air pollution or lack of physical activity (PA) increases the risk of insomnia. However, evidence on joint exposure to air pollutants is limited, and the interaction of joint air pollutants and PA on insomnia is unknown. This prospective cohort study included 40,315 participants with related data from the UK Biobank, which recruited participants from 2006 to 2010. Insomnia was assessed by self-reported symptoms. The annual average air pollutant concentrations of particulate matter (PM2.5, PM10), nitrogen oxides (NO2, NOX), sulfur dioxide (SO2) and carbon monoxide (CO) were calculated based on participants' addresses. We applied a weighted Cox regression model to evaluate the correlation between air pollutants and insomnia and newly proposed an air pollution score to assess joint air pollutants effect using a weighted concentration summation after obtaining the weights of each pollutant in the Weighted-quantile sum regression. With a median follow-up of 8.7 years, 8511 participants developed insomnia. For each 10 μg/m³ increase in NO2, NOX, PM10, SO2, the average hazard ratios (AHRs) and 95% confidence interval (CI) of insomnia were 1.10 (1.06, 1.14), 1.06 (1.04, 1.08), 1.35 (1.25, 1.45) and 2.58 (2.31, 2.89), respectively; For each 5 μg/m³ increase in PM2.5 and each 1 mg/m³ increase in CO, the corresponding AHRs (95%CI) were 1.27 (1.21, 1.34) and 1.83 (1.10, 3.04), respectively. The AHR (95%CI) for insomnia associated with per interquartile range (IQR) increase in air pollution scores were 1.20 (1.15, 1.23). In addition, potential interactions were examined by setting cross-product terms of air pollution score with PA in the models. We observed an interaction between air pollution scores and PA (P = 0.032). The associations between joint air pollutants and insomnia were attenuated among participants with higher PA. Our study provides evidence on developing strategies for improving healthy sleep by promoting PA and reducing air pollution.

Indefinite Backward Stochastic Linear-Quadratic Optimal Control Problems

This paper is concerned with a backward stochastic linear-quadratic (LQ, for short) optimal control problem with deterministic coefficients. The weighting matrices are allowed to be indefinite, and cross-product terms in the control and state processes are presented in the cost functional. Based on a Hilbert space method, necessary and sufficient conditions are derived for the solvability of the problem, and a general approach for constructing optimal controls is developed. The crucial step in this construction is to establish the solvability of a Riccati-type equation, which is accomplished under a fairly weak condition by investigating the connection with forward stochastic LQ optimal control problems.

Synergism of cell adhesion regulatory genes and instant air pollutants on blood pressure elevation

Accumulating evidence suggests that an instant exposure to particulate matter (PM) may elevate blood pressure (BP), where cell-adhesion regulatory genes may be involved in the interplay. However, few studies to date critically examined their interaction, and it remained unclear whether these genes modified the association. To assess the association between instant PM exposure and BP, and to examine whether single-nucleotide polymorphisms (SNPs) mapped in four cell adhesion regulatory genes modify the relationship, a cross-sectional study was performed, based on the baseline of an ongoing family-based cohort in Beijing, China. A total of 4418 persons from 2089 families in Northern China were included in the analysis. Four tagged SNPs in cell adhesion regulatory genes were selected among ZFHX3, CXCL12, RASGRP1 and MIR146A. A generalized additive model (GAM) with a Gaussian link was adopted to estimate the change in blood pressure after instant PM2.5 or PM10 exposure. A cross-product term of PM2.5/PM10 and genotype was incorporated into the GAM model to test for interaction. The study observed that an instant exposure to either PM2.5 or PM10 was found to be associated with elevated systolic blood pressure (SBP). On average, a 10 μg/m3 increase in instant exposure to PM2.5 and PM10 concentration corresponded to 0.140% (95% CI: 0.014%–0.265%, P = 0.029) and 0.173% (95% CI: 0.080%–0.266%, P < 0.001) higher SBP. However, diastolic blood pressure (DBP) was not elevated as the PM2.5 or PM10 concentration increased (P > 0.05). A synergetic interaction on SBP was observed between SNPs in four cell adhesion regulatory genes (rs2910164 in MIR146A, rs2297630 in CXCL12, rs7403531 in RASGRP1, and rs7193343 in ZFHX3) and instant PM2.5 exposure (Pfor interaction <0.05). Briefly, as carriers of risk alleles in each of these four genes increased, an enhanced association was found between instant PM2.5 exposure and SBP.

The impact of prolonged exposure to air pollution on the incidence of chronic non-communicable disease based on a cohort in Tianjin

Evidence on the associations of prolonged ambient pollutants exposure with chronic non-communicable diseases among middle-aged and elderly residents is still limited. This prospective cohort study intends to investigate the long-term effects of ambient pollution on hypertension and diabetes incidence among relatively older residents in China. Individual particulate matter exposure levels were estimated by satellite-based model. Individual gaseous pollutants exposure levels were estimated by Inverse Distance Weighted model. A Cox regression model was employed to assess the risks of hypertension and diabetes morbidity linked to air pollutants exposures. The cross-product term of ambient pollutants exposure and covariates was further added into the regression model to test whether covariates would modify these air pollution-morbidity associations. During the period from 2014 to 2018, a total of 97,982 subjects completed follow-up. 12,371 incidents of hypertension and 2034 of diabetes occurred. In the multi-covariates model, the hazard ratios (HR) and 95% confidence interval (CI) were 1.49 (1.45–1.52), 1.28 (1.26–1.30), 1.17 (1.15–1.18), 1.21 (1.17–1.25) and 1.33 (1.31–1.35) for hypertension morbidity per 10 μg/m3 increment in PM1, PM2.5, PM10, NO2 and SO2, respectively. For diabetes onsets, the HR (95% CI) were 1.17 (1.11–1.23), 1.09 (1.04–1.13), 1.06 (1.02–1.09), 1.02 (0.95–1.10), and 1.24 (1.19–1.29), respectively. In addition, for hypertension analyses, the effect estimates were more pronounced in the participants with age <60 years old, BMI ≥24 kg/m2, and frequent alcohol drinking. These findings provided the evidence on elevated risks of morbidity of hypertension and diabetes associated with prolonged ambient pollutants exposure at relatively high levels.

Ambient air pollution, healthy diet and vegetable intakes, and mortality: a prospective UK Biobank study.

Recent studies suggest potential interactions of air pollutants with dietary factors and genetic susceptibility on mortality risk; however, evidence from prospective studies is still lacking. We aimed to assess the association between air pollution and mortality, and investigate the modification effects of a healthy diet and genetic susceptibility. A total of 386 937 participants were enrolled from 2006 to 2010 and followed up to 2018 in the UK Biobank study. The annual average air pollutant concentrations of particulate matter (PM) with diameters ≤2.5 (PM2.5), ≤10 (PM10) and between 2.5 and 10 µm (PM2.5-10) and nitrogen oxides (NO2 and NOx) were calculated and linked to participants' residential addresses. Healthy dietary patterns were evaluated by a healthy diet score (HDS) based on intakes of vegetables, fruit, fish, unprocessed red meat and processed meat. We also calculated genetic risk score (GRS) of the lifespan. We examined potential interactions by setting variable cross-product terms of air pollutants with diets or GRS in the models. We identified 11 881 deaths [2426 from cardiovascular diseases (CVD), 1211 from coronary heart disease (CHD) and 466 from stroke] during a median follow-up of 8.9 years. We found that PM2.5 [hazard ratio (HR), 1.27; 95% CI, 1.05-1.55], PM10 (HR, 1.18; 95% CI, 1.04-1.34), NO2 (HR, 1.05; 95% CI, 1.01-1.08), and NOx (HR, 1.02; 95% CI, 1.01-1.03) were associated with all-cause mortality. PM2.5 was also associated with increased risks of CVD mortality (HR, 1.68; 95% CI, 1.10-2.56) and CHD mortality (HR, 2.08; 95% CI, 1.16-3.75). In addition, we found that adherence to healthy dietary patterns modified associations of PM2.5, NO2 and NOx with all-cause mortality (P-interaction = 0.006, 0.006 and 0.02, respectively). Among the individual dietary components, vegetable intakes showed interactions with PM2.5, NO2 and NOx (P-interaction = 0.007, 0.004 and 0.02, respectively). The associations between air pollutants and increased risks of all-cause mortality were attenuated among participants with higher vegetable intakes. We did not observe interactions between air pollutants and HDS on CVD, CHD or stroke mortality (P-interaction > 0.05). Besides, we did not find interactions between air pollutants and genetic risk for lifespan on mortality risk. This study provides evidence linking long-term exposure to various air pollutants to the risk of all-cause, CVD and CHD mortality, and the potential attenuation of a healthy diet, especially high vegetable intakes, on such relations. Our findings highlight the importance of adherence to a healthy diet in lowering ambient air-pollution-related mortality risk.