Dose-response Fashion Research Articles

A cross-sectional study of the association between blood metal mixtures exposure and hyperuricemia.

To determine the association between blood metal mixture and HUA risk. A cross-sectional study was performed based on the populations from Kailuan cohort trial in China. Inductively coupled plasma mass spectrometry was utilized to detect the blood concentrations of iron (Fe), lead (Pb), calcium (Ca), copper (Cu), magnesium (Mg), zinc (Zn), selenium (Se), and manganese (Mn). Multivariate logistic regression (MLR) models and weighted quantile sum (WQS) regression models were employed to assess the relationships. There were 3706 participants included in this study, and 464 (12.52%) were with HUA. The mean level of uric acid was 485.60μmol/L in the subjects with HUA, which was remarkably increased compared to those without HUA (293.10μmol/L). The multivariate-adjusted odds ratios (95% confidence intervals) of HUA were 2.15 (1.40, 3.29) for Pb, 3.42 (2.24, 5.23) for Fe, 1.61 (1.15, 2.25) for Ca, 3.06 (2.04, 4.59) for Mg, and 1.69 (1.26, 2.28) for Zn by comparing the highest and lowest metal quartiles using the single-metal logistic regression model. Meanwhile, the WQS regression models demonstrated a positive association between metal mixtures and HUA risk, to which, Fe, Mg, Pb, and Zn were the major contributors. Pb, Fe, and Zn were still robust in multiple-metal models. Age, gender, weight, smoking, and drinking status could modify these relationships with significant interactions. Co-exposure to Fe, Pb, Ca, Cu, Zn, Mg, Se, and Mn were related to increased HUA risk in Chinese adults, of with, Pb, Fe, and Zn appeared to have greater impacts. These relationships were more obvious in adults aged < 60years, or women, or overweight, or non-smoking, or drinking with significant interactions. Key Points • Increased Fe, Pb, Mg, Ca, and Zn were related to increased HUA risk in dose-response fashion among Chinese adults. • The metal mixture dominated by Fe, Mg, Pb, and Zn was positively associated with HUA risk. Fe, Pb, and Zn were still robust in MM model. • Such association was stronger showed in adults aged < 60years, or women, or overweight, or non-smoking, or drinking with significant interactions.

Symptoms and Diabetes among Chinese Middle-Aged and Elderly Adults with Prediabetes: A National Cohort Study.

We aimed to assess the association between depressive symptoms and the risk of transition from prediabetes to diabetes. We included 3,956 adults with prediabetes aged 45 years and above in 2011. Participants with a ten-item Center for Epidemiologic Studies Depression (CES-D) score of 10 or higher were classified as having depressive symptoms. Incident diabetes was defined as a self-reported physician diagnosis of diabetes, or treatment with glucose-lowering medication in 2013, 2015, or 2018. Among 3, 956 participants (mean age was 59.53 years old and 53.29% were female), the proportion of depressive symptoms was 36.50% in 2011. During the 24,831 person-years of follow-up, 458 participants developed diabetes and the incidence rate was 18.44 (95% CI 16.83 to 20.21) per 1000 person-years. Depressive symptoms were significantly associated with a higher risk of incident diabetes (HR, 1.31; 95% CI, 1.07 to 1.59). In addition, the association was in a dose-response fashion (P trend < 0.001). Compared with the CES-D <10 group, the HRs (95% CI) were 1.21 (0.98 to 1.49) in the 10≤ CES-D <21 group, and 1.95 (1.38 to 2.75) in the CES-D ≥ 21 group. Depressive symptoms were shown as an independent risk factor for the progression from prediabetes to diabetes.

Intratumoral vitamin D signaling and lethal prostate cancer.

High circulating vitamin D levels and supplementation may lower prostate cancer mortality. To probe for direct effects of vitamin D signaling in the primary tumor, we assessed how activation of intratumoral vitamin D signaling in prostate cancer is associated with lethal prostate cancer during long-term follow-up. Among 404 participants with primary prostate cancer in the Health Professionals Follow-up Study and the Physicians' Health Study, we defined a gene score of expected activated intratumoral vitamin D signaling consisting of transcriptionally upregulated (CYP27A1, CYP2R1, RXRA, RXRB, and VDR) and downregulated genes (CYP24A1 and DHCR7). We contrasted vitamin D signaling in tumors that progressed to lethal disease (metastases/prostate cancer-specific death, n = 119) over up to three decades of follow-up with indolent tumors that remained nonmetastatic for >8 years post-diagnosis (n = 285). The gene score was downregulated in tumor tissue compared with tumor-adjacent histologically normal tissue of the same men. Higher vitamin D gene scores were inversely associated with lethal prostate cancer (odds ratio for highest versus lowest quartile: 0.46, 95% confidence interval: 0.21-0.99) in a dose-response fashion and after adjusting for clinical and pathologic factors. This association appeared strongest among men with high predicted plasma 25-hydroxyvitamin D3 and men with body mass index ≥25 kg/m2. Findings were replicated with broader gene sets. These data support the hypothesis that active intratumoral vitamin D signaling is associated with better prostate cancer outcomes and provide further rationale for testing how vitamin D-related interventions after diagnosis could improve prostate cancer survival through effects on the tumor.

Physical, mental, and behavioral health after adverse and benevolent childhood experiences: A comparison of two adversity conceptualizations.

Adverse and benevolent childhood experiences (ACEs and BCEs) impact health across the lifespan. No known study has investigated these associations across different health domains using a representative adult sample. This study examined the associations between adult physical, mental, and behavioral health with ACEs and BCEs based on two ACEs conceptualizations. A cross-sectional population-based survey was conducted in Hong Kong. Thirteen ACEs were measured and conceptualized as cumulative ACE scores and ACE patterns. Self-reports of BCEs; 10 physical health problems; current mental health; posttraumatic stress; history of diagnosed mental illness; suicidal thought and suicide attempt; and engagement in three health risk behaviors (smoking, illicit substance misuse, binge drinking) were also included. A series of regression analyses were conducted to examine the association between childhood experiences and health. In a random sample of 1,070 Hong Kong adults (Mage = 41.78 years; 53.93% female; mean ACEs = 1.64), 649 (60.65%) reported at least one ACE. Four ACE patterns were identified (Low ACEs, Household Instability, Household Violence, and High ACEs). Higher ACE scores associated with poorer health in a dose-response fashion. Two ACE patterns shared similar average ACE scores but differentially linked with outcomes across health domains. High BCEs negatively associated with mental and behavioral health problems. Public health responses to ACEs should consider both the accumulation and co-occurrence of ACE exposure. Schools, neighborhoods, and the wider community should take an active role in helping children and families create more positive experiences as a universal prevention strategy to safeguard population health. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Associations of activity, sedentary and sleep behaviors with prevalent steatotic liver disease in middle-aged and older adults: the ELSA-Brasil study

BackgroundSteatotic liver disease (SLD) is a prevalent metabolic disease. While single component movement behaviors have been related to its development, comprehensive assessments of their joint associations are scarce.ObjectiveTo investigate the single-component and multi-component associations of moderate and vigorous physical activity (MVPA), light physical activity (LPA), sedentary behavior (SB), and sleep with prevalent SLD in Brazilian adults.MethodsA cross-sectional analysis using data from the third wave of the ELSA-Brasil cohort (2017–2019). Participants wore an ActiGraph wGT3X-BT in the waist for seven days and completed a sleep diary. SLD was defined by a Fatty Liver Index ≥ 60. To investigate single-component and multi-component associations, we used three exposure modeling approaches based on Poisson models: multivariable-adjusted regression, restricted cubic splines, and compositional data analysis.ResultsAmong 8569 participants (55.7% women, mean age 59.2 ± 8.60), 43.9% had SLD. Total activity volume adjusted for covariates was inversely associated with prevalent SLD. Every 1 mg/day increase in total activity volume was associated with a PR of 0.95 in individuals sleeping < 7 h/day (95% CI 0.94–0.97) and 0.95 (95% CI 0.93–0.96) in those sleeping ≥ 7 h/day. Increasing 30 min/day of MVPA was associated with decreasing prevalence of SLD (sleep ≥ 7 h/day [PR 0.83; 95% CI 0.77–0.89]; sleep ≥ 7 h/day [PR 0.78; 95% CI 0.74–0.83]). Sleep, SB, and LPA were not associated with SLD. Associations of total activity volume and MVPA were more pronounced among females. Adjustment with adiposity markers attenuated the associations.ConclusionsIn adults, total activity volume and MVPA were inversely associated with SLD in a dose–response fashion. Substituting lower-intensity behaviors with MVPA was associated with a lower prevalence of SLD independent of sleep duration, sex, and age.

A study of inflammatory biomarkers in crystalline silica exposed rock drillers

BackgroundCrystalline silica (CS) exposure can cause serious lung disease in humans, but mechanisms of pulmonary toxicity have not been completely elucidated.AimsTo assess pro-inflammatory and anti-inflammatory biomarkers and biomarkers related to the development of chronic obstructive pulmonary disease and fibrosis in serum of rock drillers exposed to CS.MethodsRock drillers (N = 123) exposed to CS and non-specified particulate matter (PM) were compared to 48 referents without current or past exposure to PM in a cross-sectional study.ResultsThe rock drillers had been exposed to CS for 10.7 years on average. Geometric mean (GM) current exposure was estimated to 36 µg/m3. Their GM concentration of matrix metalloproteinase 12 (MMP-12) was significantly higher (16 vs. 13 ng/L; p = 0.04), while interleukin (IL) 6 and IL-8 were significantly lower compared to the referents. Also pentraxin 3 was significantly lower (3558 vs. 4592 ng/L; p = 0.01) in the rock drillers. A dose-response relationship was observed between cumulative exposure to CS and MMP-12, the highest exposed subgroup having significantly higher MMP-12 concentrations than the referents.ConclusionExposure to CS may increase circulating MMP-12 concentrations in a dose-response related fashion. The results may also suggest a down-regulation of pro-inflammatory pathways.

Midlife diseases of despair and cardiometabolic risk: testing shared origins in adolescent psychopathology.

Rising midlife mortality in the United States is largely attributable to 'deaths of despair' (deaths from suicide, drug poisonings, and alcohol-related diseases) and deaths from cardiometabolic conditions. Although despair- and cardiometabolic-related mortality are increasing concurrently, it is unclear whether they share common developmental origins. We tested adolescent psychopathology as a potential common origin of midlife diseases of despair and cardiometabolic risk. Participants (N = 4578) were from the National Longitudinal Study of Adolescent to Adult Health, a nationally representative cohort followed from adolescence to early midlife. Adolescent psychopathology included depression, anxiety, eating disorders, PTSD, conduct disorder, and ADHD at ages 11-18. Diseases of despair (suicidality, substance misuse, pain, and sleep problems) and cardiometabolic risk (hypertension, hyperlipidemia, high-risk waist circumference, diabetes, and cardiovascular conditions) were multi-modally measured at ages 33-43. At midlife, adolescents who experienced psychopathology exhibited more indicators of despair-related diseases and cardiometabolic risk (IRRs = 1.67 [1.46-1.87] and 1.13 [1.04-1.21], respectively), even after accounting for demographics, adolescent SES, and adolescent cognitive ability. Associations were evident for internalizing and externalizing conditions, and in a dose-response fashion. In mediation analyses, low education explained little of these associations, but early-adult substance use explained 21.5% of psychopathology's association with despair-related diseases. Midlife despair-related diseases and cardiometabolic risk co-occurred within individuals (IRR = 1.12 [1.08-1.16]). Adolescent psychopathology accounted for 8.3% of this co-occurrence, and 16.7% together with adolescent SES and cognitive ability. Adolescent psychopathology precedes both diseases of despair and cardiometabolic risk. Prevention and treatment of psychopathology may mitigate multiple causes of poor midlife health, reducing premature mortality.

The dynamic responses of mood and sleep physiology to chronic sleep restriction and subsequent recovery sleep.

Healthy sleep of sufficient duration preserves mood and disturbed sleep is a risk factor for a range of psychiatric disorders. As adults commonly experience chronic sleep restriction (SR), an enhanced understanding of the dynamic relationship between sleep and mood is needed, including whether susceptibility to SR-induced mood disturbance differs between sexes. To address these gaps, data from N = 221 healthy adults who completed one of the two multi-day laboratory studies with identical 9-day SR protocols were analyzed. Participants randomized to the SR (n = 205) condition underwent 5 nights of SR to 4 hours of time-in-bed and were then randomized to one of the seven sleep doses that ranged from 0 to 12 hours in 2 hours increments; participants randomized to the control (n = 16) condition received 10 hours time-in-bed on all study nights. The Profile of Mood States (POMS) was used to assess mood every 2 hours during wakefulness and markers of sleep homeostasis (EEG slow-wave activity (SWA)) were derived via polysomnography. Mood progressively deteriorated across SR with marked disturbances in somatic mood components. Altered sleep physiology contributed to mood disturbance whereby increased EEG SWA was associated with increased POMS Total Mood Disturbance scores, a finding specific to males. The mood was restored in a dose-response fashion where improvements were greater with longer sleep doses. These findings suggest that when lifestyle and environmental factors are inhibited in the laboratory, the affective consequences of chronic sleep loss are primarily somatic mood disturbances. Altered sleep homeostasis may contribute to mood disturbance, yet sleep-dependent mechanisms may be sex-specific.

Long-term night shift work, genetic predisposition and risk of incident asthma: a prospective cohort study.

Evidence about a potential link between current and lifetime night shift work and risk of incident asthma is insufficient. To investigate the association of current and lifetime night shift work with risk of incident asthma, and the modified effect of genetic susceptibility on this association. We included 253773 individuals with complete night shift work information in the UK biobank. We calculated the standard polygenetic risk score (PRS) for asthma. The Cox proportional hazard models were conducted to estimate hazard ratios and 95% CIs. After multivariable adjustments, we found that current night shift work was associated with an increased risk of incident asthma in a dose-response fashion (P for trend < 0.001). Compared with day workers, those working usual/permanent night shifts had a 17% (95% CI: 1.04-1.33) higher risk of asthma incidence. In addition, we observed significant dose-dependent relationships of longer lifetime duration or frequency of night shift work with elevated risk of asthma incidence (all P for trend < 0.05). Compared with never night shift workers, those with a duration (≥5 years) or frequency (≥8 nights/month) of night shift work exhibited a 20% (95% CI: 1.03-1.39) or 22% (95% CI: 1.03-1.44) higher risk of incident asthma, respectively. Moreover, the elevated risk of incident asthma related to current and lifetime night shift work exposure was strengthened by high PRS, although no significant shift work-PRS interactions were detected. Both current and lifetime night shift work may increase the risk of incident asthma, regardless of genetic predisposition to asthma.

Adverse Childhood Experiences and Truancy in High School: An Analysis of Florida Adolescents

ABSTRACT Previous research links exposure to adverse childhood experiences (ACEs) with a host of negative outcomes, including negative school outcomes. For instance, some studies link exposure to ACEs with weak school attachment, school misbehavior, suspension, negative academic performance, and absenteeism. The current study extends the previous literature by examining the association between exposure to ACEs and truancy using self-reports from a representative sample of Florida high-school students. The findings reveal that exposure to ACEs is associated with truancy in a dose–response fashion. In addition, the findings provide some evidence that the association between ACEs and truancy is partially attenuated by school- and parenting-related variables.

A high-content screen of FDA approved drugs to enhance CAR T cell function: ingenol-3-angelate improves B7-H3-CAR T cell activity by upregulating B7-H3 on the target cell surface via PKCα activation

BackgroundCAR T cell therapy is a promising approach to improve outcomes and decrease toxicities for patients with cancer. While extraordinary success has been achieved using CAR T cells to treat patients with CD19-positive malignancies, multiple obstacles have so far limited the benefit of CAR T cell therapy for patients with solid tumors. Novel manufacturing and engineering approaches show great promise to enhance CAR T cell function against solid tumors. However, similar to single agent chemotherapy approaches, CAR T cell monotherapy may be unable to achieve high cure rates for patients with difficult to treat solid tumors. Thus, combinatorial drug plus CAR T cell approaches are likely required to achieve widespread clinical success.MethodsWe developed a novel, confocal microscopy based, high-content screen to evaluate 1114 FDA approved drugs for the potential to increase expression of the solid tumor antigen B7-H3 on the surface of osteosarcoma cells. Western blot, RT-qPCR, siRNA knockdown and flow cytometry assays were used to validate screening results and identify mechanisms of drug-induced B7-H3 upregulation. Cytokine and cytotoxicity assays were used to determine if drug pre-treatment enhanced B7-H3-CAR T cell effector function.ResultsFifty-five drugs were identified to increase B7-H3 expression on the surface of LM7 osteosarcoma cells using a novel high-content, high-throughput screen. One drug, ingenol-3-angelate (I3A), increased B7-H3 expression by up to 100%, and was evaluated in downstream experiments. Validation assays confirmed I3A increased B7-H3 expression in a biphasic dose response and cell dependent fashion. Mechanistic studies demonstrated that I3A increased B7-H3 (CD276) mRNA, total protein, and cell surface expression via protein kinase C alpha activation. Functionally, I3A induced B7-H3 expression enhanced B7-H3-CAR T cell function in cytokine production and cytotoxicity assays.ConclusionsThis study demonstrates a novel high-content and high-throughput screen can identify drugs to enhance CAR T cell activity. This and other high-content technologies will pave the way to develop clinical trials implementing rational drug plus CAR T cell combinatorial therapies. Importantly, the technique could also be repurposed for an array of basic and translational research applications where drugs are needed to modulate cell surface protein expression.

Dose-dependent alteration in hepatic and cerebral glucose metabolism following exposure to polystyrene microplastic in Wistar rats

Background: Recently, microplastics (MPs) with dimensions less than 5 mm have gained more attention due to their adverse impact on the environment and living creatures. Polystyrene (PS) particle is a key element of primary microplastics, which are causing numerous health issues such as interruption of energy metabolism, oxidative stress, neurotoxicity, immunotoxicity, digestive gland disorders, reproductive disruption, and genotoxicity in marine living organisms. Method: Alteration in carbohydrate metabolism was evaluated in male Wistar rats (six weeks of age) after four weeks of oral exposure to polystyrene microplastic (PS-MP) at three different doses (0.5mg/L, 5mg/L and 50 mg/L via drinking water). Results: Polystyrene exposure caused a significant decrease in blood glucose, liver glycogen, and pyruvic acid content in liver and cerebral tissue. Free amino nitrogen content significantly altered in the liver and cerebrum in a dose-specific manner. The LDH activity was found to be decreased in the liver, whereas it increased in the cerebral cortex of rats in a dose-responsive fashion. Enzymes like glucose 6-phosphatase, GOT, GPT, and succinate dehydrogenase activities demonstrated differential effects on the liver and cerebrum of rats in terms of energy metabolism. Conclusion: It is suggested that sub-acute polystyrene exposure significantly perturbs glucose metabolism by inducing hypoglycemia associated with decreased glycolysis and increased TCA cycle enzyme function in rat liver in a dose-dependent manner. Gluconeogenesis is also affected differentially by metabolic adjustment in the studied organs.

Abstract 3373: Protein kinase D1 alleviate etoposide induced DNA damage through up regulation of alpha-catenin

Abstract Interaction between E-cadherin and β-catenin at cell-cell adherens junctions is pivotal in cell adhesion, and dysregulation of these genes is associated with disease progression in various solid tumors, notably in prostate cancer. α-catenin acts as a physical linker between the cadherin/β-catenin complex and actin cytoskeleton, through its mechanosensory properties has potential to modify interactions between cadherins and cytoskeleton and results in sensitivity of cells to DNA damage and toxicity. Membranous β-catenin interacts with the cellular cytoskeleton through threonine 120 (T120) phosphorylation and its association with α-catenin. We want to investigate the role of protein Kinase D1 (PrKD1) in DNA damage response, using various prostate cancer cell lines; PrKD1-silenced cells (LNCaP sh-PrKD1) and overexpression of PrKD1 (C4-2 PrKD1). PrKD1 silence and overexpress cells were treated with PrKD1 inhibitor and Etoposide to observe the effect of DNA damage repair altering various genes in prostate cancer cells. Silencing α-Catenin increased p-γH2AX (ser-139) expression in C4-2 PrKD1 cells. Conversely silenced PrKD1 (LNCaP sh-PrKD1) cells represented decreased α-Catenin expression, and increased p-γH2AX (ser-139). Overexpression of PrKD1 in prostate cancer cells increased α-catenin levels and conferred resistance to etoposide-induced DNA damage. Silencing PrKD1 compromised DNA damage protective effect. Furthermore, we elucidate the role of Protein kinase D1 (PrKD1), a unique serine-threonine kinase that phosphorylates β-catenin at T120, in this interaction. We treated C4-2 and C4-2 PrKD1 cells with PrKD1 inhibitor and immuno-precipitated β-Catenin complex represented decrease in β-Catenin (T-120) and α-Catenin than untreated C4-2 PrKD1 cells. We observed crosstalk between α-catenin and PrKD1 in DNA damage repair. In-silico analysis affirmed that the loss of T120 phosphorylation disrupts β- and α-catenin interaction. PrKD1 inhibitor decreased cell viability in dose response fashion, and also decrease the p-γH2AX (ser-139) in C4-2 PrKD1 cells than C4-2 cells. In vitro findings were corroborated in a mouse prostate cancer PDX xenograft model by inhibiting PrKD1 kinase activity, resulting in reduced β-catenin T120 phosphorylation and α-catenin levels. In vivo experiments with PrKD1 inhibitor represented tolerability in mice and its efficacy in modulating α-catenin and PrKD1 expression to inhibit tumor progression. Study for the first time provides a mechanistic basis of the protective role of PrKD1 against DNA damage. Citation Format: Sanjeev Shukla, Samuel Serrano, Mohammed Al-Toubat, Teruko Osumi, K.C. Balaji. Protein kinase D1 alleviate etoposide induced DNA damage through up regulation of alpha-catenin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3373.

Abstract 7320: Expression of circadian rhythm genes and lethal prostate cancer

Abstract Background: The circadian rhythm regulates diverse physiological and oncologic processes. We have previously shown in epidemiology studies that disruption of the circadian rhythm may be associated with increased risk of aggressive prostate cancer, including germline polymorphisms in certain circadian rhythm genes. This study sought to investigate the relationship between tumor circadian rhythm gene expression and lethal prostate cancer. Methods: We studied patients with primary prostate cancer in the Health Professionals Follow-up Study (HPFS) and Physicians’ Health Study (PHS). We created a composite score of mRNA expression using principal components that incorporated 11 circadian rhythm genes: AANAT, ARNTL, CLOCK, CRY1, CSNK1E, MTNR1A, MTNR1B, NPAS2, PER1, PER2, PER3. An age-stratified analysis was performed, and the mean differences of the score both by Gleason score and compared to normal tissue were calculated. The relationship between the score in prostate tumor tissue and lethal prostate cancer (metastases/prostate cancer-specific death) vs. indolent disease (no metastases after &amp;gt;8 years of follow-up) was assessed using logistic regression. The contribution of each gene was evaluated by leave-one-out analysis, generating scores leaving out one gene and assessing the relationship between the modified score and lethal disease. Results: Among 404 cancer patients in HPFS/PHS, there were 119 lethal events over 30 years of follow-up (median: 17 years). The circadian rhythm gene score was lower in tumor tissue compared to tumor-adjacent, histologically normal tissue (mean difference in units of standard deviation [SD] of gene score: -0.31, 95% confidence interval [CI]: -0.48 to -0.15). In addition, the score was lower in Gleason 9-10 compared to Gleason 6 tumors (mean difference in SD units: -1.05, 95% CI: -1.55 to -0.54). The three PER genes were the most strongly correlated with each other and with the score (Spearman correlation coefficients from 0.52-0.88 for the score and 0.31-0.63 between PER genes). Higher circadian rhythm gene scores were inversely associated with lethal prostate cancer (odds ratio [OR] for highest vs. lowest quartile: 0.43, 95% CI: 0.20 to 0.90) in a dose-response fashion and after adjusting for clinical and pathologic factors. The association appeared to be stronger in patients aged ≥65 years (OR for highest vs. lowest quartile: 0.21, 95% CI: 0.08 to 0.47) compared to &amp;lt;65 years at diagnosis (OR: 0.78, 95% CI: 0.29, 2.17). Results were consistent in the leave-one-out analysis for all genes except PER2 (OR for highest vs. lowest quartile: 1.00, 95% CI: 0.55 to 1.83) and PER1 (OR: 0.55, 95% CI: 0.30 to 1). Conclusion: This study examining intratumoral circadian rhythm gene expression contributes further evidence in support of the relationship between circadian rhythm disruption and aggressive prostate cancer. Tumor expression of PER1 and PER2 may be a predominant factor in the association. Citation Format: Jane Bailey Vaselkiv, Sarah C. Markt, Hannah E. Guard, Anqi Wang, Kathryn L. Penney, Konrad H. Stopsack, Lorelei A. Mucci. Expression of circadian rhythm genes and lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7320.

Pregnancy History at 40 Years of Age as a Marker of Cardiovascular Risk.

Individual pregnancy complications are associated with increased maternal risk of cardiovascular disease. We assessed the link between a woman's total pregnancy history at 40 years of age and her relative risk of dying from atherosclerotic cardiovascular disease (ASCVD). This population-based prospective study combined several Norwegian registries covering the period 1967 to 2020. We identified 854 442 women born after 1944 or registered with a pregnancy in 1967 or later, and surviving to 40 years of age. The main outcome was the time to ASCVD mortality through age 69 years. The exposure was a woman's number of recorded pregnancies (0, 1, 2, 3, or 4) and the number of those with complications (preterm delivery <35 gestational weeks, preeclampsia, placental abruption, perinatal death, and term or near-term birth weight <2700 g). Cox models provided estimates of hazard ratios across exposure categories. The group with the lowest ASCVD mortality was that with 3 pregnancies and no complications, which served as the reference group. Among women reaching 40 years of age, risk of ASCVD mortality through 69 years of age increased with the number of complicated pregnancies in a strong dose-response fashion, reaching 23-fold increased risk (95% CI, 10-51) for women with 4 complicated pregnancies. Based on pregnancy history alone, 19% of women at 40 years of age (including nulliparous women) had an increased ASCVD mortality risk in the range of 2.5- to 5-fold. Pregnancy history at 40 years of age is strongly associated with ASCVD mortality. Further research should explore how much pregnancy history at 40 years of age adds to established cardiovascular disease risk factors in predicting cardiovascular disease mortality.

The effect of PM2.5 on acute sinusitis: A population-based study.

PM2.5 exposure is a risk factor for the development of acute sinusitis. PM2.5 exposure affects acute sinusitis in a dose response fashion.

Dose-Response Effect of Mental Health Diagnoses on Concussion Recovery in Children and Adolescents.

Pre-existing mental health diagnoses may contribute to greater emotional symptom burden and prolonged recovery after concussion. Youth with pre-existing mental health diagnoses will have greater emotional symptom burden, greater risk for delayed return to exercise, and more prolonged recovery from concussion than those without those diagnoses. Prospective cohort. Level 3. A prospective registry of youth concussion was examined for differences in emotional symptom burden after injury to develop a predictive risk model for prolonged recovery. The impact of individual and total number of pre-existing mental health diagnoses (0, 1, 2, and 3+) was assessed, and multivariable logistic regression was performed to identify factors associated with prolonged recovery. Among a cohort of 3105 youth with concussion, those with a history of mental health diagnoses, in a dose-response fashion, had greater postinjury emotional symptom burden (7 emotional symptoms vs 4; P < 0.01), visio-vestibular dysfunction (65% abnormal vs 56% abnormal; P < 0.01), later return to symptom-limited exercise (23 vs 21 days; P < 0.01), and overall longer concussion recovery (38 days, interquartile range [IQR] 18, 80) versus 25 days (IQR 13, 54; P < 0.01). Boys with prolonged recovery after concussion had greater emotional symptom burden than girls (5 emotional symptoms vs 3; P < 0.01). Pre-existing mental health diagnoses are associated with greater postinjury emotional symptom burden and longer concussion recovery in a dose-response fashion. Visiovestibular deficits and delayed return to exercise are also associated with pre-existing mental health diagnoses and prolonged recovery. Boys with prolonged recovery from concussion experience greater emotional symptom burden than girls. Addressing pre-existing mental health diagnoses is essential to concussion management. Boys with prolonged recovery from concussion may particularly benefit from interventions to address their higher emotional symptom burden. Interventions, including a home visio-vestibular exercise program and symptom-limited exercise, may contribute to improving time to concussion recovery.

Dose-response association between physical activity and blood pressure among Chinese adults: a nationwide cross-sectional study.

The aim of this study was to examine the dose-response associations of physical activity with blood pressure (BP) and hypertension risk among Chinese adults. Derived from the national community-based China Hypertension Survey database during 2012--2015, a total of 203 108 residents aged at least 18 years were included. Individual-level physical activity was evaluated using a standardized questionnaire, and minutes of metabolic equivalent tasks per week (MET-min/week) were calculated, integrating domain, intensity, frequency, and duration. Multivariable linear and logistic regressions were used to estimate associations of physical activity with BP and hypertension risk, and restricted cubic spline regressions were performed for their nonlinear dose-response relationships. Overall, the median total physical activity (TPA) was 3213.0 MET-min/week and the prevalence of physical inactivity was 14.8%. TPA was negatively associated with BP. Increasing TPA levels was related to a steep decrease in systolic BP, up to approximately 2500 MET-min/week, with more modest benefits above that level of TPA. Higher levels of domain-specific and intensity-specific physical activity were found to be associated with lower BP levels and hypertension risk, except for the association between vigorous-intensity physical activity and systolic BP. We found that TPA within the range of 2000--4000 MET-min/week, a higher frequency and shorter duration were inversely associated with diastolic BP levels. Total, domain-specific, and intensity-specific physical activity were inversely related to BP levels, respectively, in a dose-response fashion. Of a given amount, higher-frequency, shorter-duration, and lower-intensity physical activity produced more beneficial effects.

The Relative Risk of Alcohol-Involved Crashes as a Function of Time of Day.

Epidemiological research has repeatedly found that alcohol-impaired driving is associated with elevated risk of crash involvement in a dose-response fashion. Although experimental studies show that alcohol impairment of cognitive and psychomotor driving skills is exacerbated by sleep deprivation, there is less evidence that the combination of drowsiness and alcohol predicts actual motor vehicle crashes. We explored this by reanalyzing data from the National Highway Traffic Safety Administration Drug and Alcohol Crash Risk Study, constructing separate risk curves for daytime and nighttime hours. Controlling for driver demographics and driving exposure, and excluding other impairing drugs, we observed significantly greater risk of crash during the night versus the day at blood alcohol concentrations (BACs) between approximately .04 and .12 g/dl. Based on fitted point estimates, at .08 g/dl, the risk of crash at night was three times the risk of crash during the day. The association between BACs and crash risk was markedly different during daytime versus nighttime hours. Increased daytime risk was not observed until BACs exceeded the .08 g/dl per se legal limit. Results are interpreted as emphasizing the sedating role of alcohol. Implications are discussed.

Differential Viral Dynamics by Sex and Body Mass Index During Acute SARS-CoV-2 Infection: Results From a Longitudinal Cohort Study.

There is evidence of an association of severe coroanavirus disease (COVID-19) outcomes with increased body mass index (BMI) and male sex. However, few studies have examined the interaction between sex and BMI on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral dynamics. Participants conducted RT-PCR testing every 24-48 hours over a 15-day period. Sex and BMI were self-reported, and Ct values from E-gene were used to quantify viral load. Three distinct outcomes were examined using mixed-effects generalized linear models, linear models, and logistic models, respectively: all Ct values (model 1), nadir Ct value (model 2), and strongly detectable infection (at least 1 Ct value ≤28 during their infection) (model 3). An interaction term between BMI and sex was included, and inverse logit transformations were applied to quantify the differences by BMI and sex using marginal predictions. In total, 7988 participants enrolled in this study and 439 participants (model 1) and 309 (models 2 and 3) were eligible for these analyses. Among males, increasing BMI was associated with lower Ct values in a dose-response fashion. For participants with BMIs greater than 29 kg/m2, males had significantly lower Ct values and nadir Ct values than females. In total, 67.8% of males and 55.3% of females recorded a strongly detectable infection; increasing proportions of men had Ct values <28 with BMIs of 35 and 40 kg/m2. We observed sex-based dimorphism in relation to BMI and COVID-19 viral load. Further investigation is needed to determine the cause, clinical impact, and transmission implications of this sex-differential effect of BMI on viral load.