Temporal Trends of Infant Mortality Secondary to Congenital Heart Disease: National CDC Cohort Analysis (1999-2020).

BACKGROUND: Infant mortality continues to be a significant problem for patients with congenital heart disease (CHD). Limited data exist on the recent trends of mortality in infants with CHD. METHODS: The CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research) was queried to identify deaths occurring within the United States with CHD listed as one of the causes of death between 1999 and 2020. Subsequently, trends were calculated using the Joinpoint regression program (version 4.9.1.0; National Cancer Institute). RESULTS: A total of 47,015 deaths occurred in infants due to CHD at the national level from the year 1999 to 2020. The overall proportional infant mortality (compared to all deaths) declined (47.3% to 37.1%, average annual percent change [AAPC]: -1.1 [95% CI -1.6 to -0.6, p < 0.001]). There was a significant decline in proportional mortality in both Black (45.3% to 34.3%, AAPC: -0.5 [-0.8 to -0.2, p = 0.002]) and White patients (55.6% to 48.6%, AAPC: -1.2 [-1.7 to -0.7, p = 0.001]), with a steeper decline among White than Black patients. A statistically significant decline in the proportional infant mortality in both non-Hispanic (43.3% to 33.0%, AAPC: -1.3% [95% CI -1.9 to -0.7, p < 0.001]) and Hispanic (67.6% to 57.7%, AAPC: -0.7 [95% CI -0.9 to -0.4, p < 0.001]) patients was observed, with a steeper decline among non-Hispanic infant population. The proportional infant mortality decreased in males (47.5% to 53.1%, AAPC: -1.4% [-1.9 to -0.9, p < 0.001]) and females (47.1% to 39.6%, AAPC: -0.9 [-1.9 to 0.0, p = 0.05]). A steady decline in for both females and males was noted. CONCLUSION: Our study showed a significant decrease in CHD-related mortality rate in infants and age-adjusted mortality rate (AAMR) between 1999 and 2020. However, sex-based, racial/ethnic disparities were noted, with female, Black, and Hispanic patients showing a lesser decline than male, White, and non-Hispanic patients.

A multi-state analysis on the effect of deprivation and race on PICU admission and mortality in children receiving Medicaid in United States (2007-2014).

INTRODUCTION: In the United States (US), racial and socioeconomic disparities have been implicated in pediatric intensive care unit (PICU) admissions and outcomes, with higher rates of critical illness in more deprived areas. The degree to which this persists despite insurance coverage is unknown. We investigated whether disparities exist in PICU admission and mortality according to socioeconomic position and race in children receiving Medicaid. METHODS: Using Medicaid data from 2007-2014 from 23 US states, we tested the association between area level deprivation and race on PICU admission (among hospitalized children) and mortality (among PICU admissions). Race was categorized as Black, White, other and missing. Patient-level ZIP Code was used to generate a multicomponent variable describing area-level social vulnerability index (SVI). Race and SVI were simultaneously tested for associations with PICU admission and mortality. RESULTS: The cohort contained 8,914,347 children (23·0% Black). There was no clear trend in odds of PICU admission by SVI; however, children residing in the most vulnerable quartile had increased PICU mortality (aOR 1·12 (95%CI 1·04-1·20; p = 0·0021). Black children had higher odds of PICU admission (aOR 1·04; 95% CI 1·03-1·05; p < 0·0001) and higher mortality (aOR 1·09; 95% CI 1·02-1·16; p = 0·0109) relative to White children. Substantial state-level variation was apparent, with the odds of mortality in Black children varying from 0·62 to 1·8. CONCLUSION: In a Medicaid cohort from 2007-2014, children with greater socioeconomic vulnerability had increased odds of PICU mortality. Black children were at increased risk of PICU admission and mortality, with substantial state-level variation. Our work highlights the persistence of sociodemographic disparities in outcomes even among insured children.

Do Racial and Ethnic Disparities Exist in Intensity of Intracranial Pressure-Directed Therapies and Outcomes Following Pediatric Severe Traumatic Brain Injury?

INTRODUCTION: Studies suggest disparities in outcomes in minoritized children after severe traumatic brain injury. We aimed to evaluate for disparities in intracranial pressure-directed therapies and outcomes after pediatric severe traumatic brain injury. METHODS: We conducted a secondary analysis of the Approaches and Decisions for Acute Pediatric TBI (ADAPT) Trial, which enrolled pediatric severe traumatic brain injury patients (Glasgow Coma Scale score ≤8) with an intracranial pressure monitor from 2014 to 2018. Patients admitted outside of the United States were excluded. Patients were categorized by race and ethnicity (Hispanic, non-Hispanic Black, non-Hispanic White, and "Other"). We evaluated outcomes by assessing mortality and 3-month Glasgow Outcome Score-Extended for Pediatrics. Our analysis involved parametric and nonparametric testing. MAIN RESULTS: A total of 671 children were analyzed. Significant associations included older age in non-Hispanic White patients (P < .001), more surgical evacuations in "Other" (P < .001), and differences in discharge location (P = .040). The "other" cohort received hyperventilation less frequently (P = .046), although clinical status during Paco2 measurement was not known. There were no other significant differences in intracranial pressure-directed therapies. Hispanic ethnicity was associated with lower mortality (P = .004) but did not differ in unfavorable outcome (P = .810). Glasgow Outcome Score-Extended for Pediatrics was less likely to be collected for non-Hispanic Black patients (69%; P = .011). CONCLUSIONS: Our analysis suggests a general lack of disparities in intracranial pressure-directed therapies and outcomes in children after severe traumatic brain injury. Lower mortality in Hispanic patients without a concurrent decrease in unfavorable outcomes, and lower availability of Glasgow Outcome Score-Extended for Pediatrics score for non-Hispanic Black patients merit further investigation.

The KDR Gene rs2071559 and the VEGF Gene rs6921438 May Be Associated with Diabetic Nephropathy in Caucasians with Type 2 Diabetes Mellitus.

The aim of our study was to investigate an association between polymorphisms of either the VEGF (vascular endothelial growth factor) gene (rs6921438) or the KDR (kinase insert domain receptor) gene (rs2071559, rs2305948) and DN (diabetic nephropathy) in Caucasians with T2DM (type 2 diabetes mellitus). The second aim was to investigate the effect of either the VEGF gene (rs6921438) or the KDR gene (rs2071559, rs2305948) on the immune expression of either VEGF or KDR in the renal tissues of T2DM subjects (to test the functional significance of tested polymorphisms). The study included 897 Caucasians with T2DM for at least ten years (344 patients with DN and 553 patients without DN). Each subject was genotyped and analyzed for KDR (rs1617640, rs2305948) and VEGF (rs6921438) polymorphisms. Kidney tissue samples taken from 15 subjects with T2DM (autopsy material) were immunohistochemically stained for the expression of VEGF and KDR. We found that the rs2071559 KDR gene was associated with an increased risk of DN. In addition, the GG genotype of the rs6921438 VEGF gene had a protective effect. We found a significantly higher numerical area density of VEGF-positive cells in T2DM subjects with the A allele of the rs6921438-VEGF compared to the homozygotes for wild type G allele (7.0 ± 2.4/0.1 mm2 vs. 1.24 ± 0.5/0.1 mm2, respectively; p < 0.001). Moreover, a significantly higher numerical area density of KDR-positive cells was found in T2DM subjects with the C allele of rs2071559 (CC + CT genotypes) compared to the homozygotes for wild type T allele (9.7± 3.2/0.1 mm2 vs. 1.14 ± 0.5/0.1 mm2, respectively; p < 0.001) To conclude, our study showed that the presence of the C allele of the rs2071559 KDR gene was associated with a higher risk of DN, while the G allele of the rs6921438-VEGF conferred protection against DN in Slovenian T2DM subjects.

Utility of Skin Tone on Pulse Oximetry in Critically Ill Patients: A Prospective Cohort Study.

OBJECTIVE: Pulse oximetry, a ubiquitous vital sign in modern medicine, has inequitable accuracy that disproportionately affects minority Black and Hispanic patients, with associated increases in mortality, organ dysfunction, and oxygen therapy. Previous retrospective studies used self-reported race or ethnicity as a surrogate for skin tone which is believed to be the root cause of the disparity. Our objective was to determine the utility of skin tone in explaining pulse oximetry discrepancies. DESIGN: Prospective cohort study. SETTING: Patients were eligible if they had pulse oximetry recorded up to 5 minutes before arterial blood gas (ABG) measurements. Skin tone was measured using administered visual scales, reflectance colorimetry, and reflectance spectrophotometry. PARTICIPANTS: Admitted hospital patients at Duke University Hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sao2-Spo2 bias, variation of bias, and accuracy root mean square, comparing pulse oximetry, and ABG measurements. Linear mixed-effects models were fitted to estimate Sao2-Spo2 bias while accounting for clinical confounders.One hundred twenty-eight patients (57 Black, 56 White) with 521 ABG-pulse oximetry pairs were recruited. Skin tone data were prospectively collected using six measurement methods, generating eight measurements. The collected skin tone measurements were shown to yield differences among each other and overlap with self-reported racial groups, suggesting that skin tone could potentially provide information beyond self-reported race. Among the eight skin tone measurements in this study, and compared with self-reported race, the Monk Scale had the best relationship with differences in pulse oximetry bias (point estimate: -2.40%; 95% CI, -4.32% to -0.48%; p = 0.01) when comparing patients with lighter and dark skin tones. CONCLUSIONS: We found clinical performance differences in pulse oximetry, especially in darker skin tones. Additional studies are needed to determine the relative contributions of skin tone measures and other potential factors on pulse oximetry discrepancies.

Utility of Skin Tone on Pulse Oximetry in Critically Ill Patients: A Prospective Cohort Study.

OBJECTIVE: Pulse oximetry, a ubiquitous vital sign in modern medicine, has inequitable accuracy that disproportionately affects minority Black and Hispanic patients, with associated increases in mortality, organ dysfunction, and oxygen therapy. Previous retrospective studies used self-reported race or ethnicity as a surrogate for skin tone which is believed to be the root cause of the disparity. Our objective was to determine the utility of skin tone in explaining pulse oximetry discrepancies. DESIGN: Prospective cohort study. SETTING: Patients were eligible if they had pulse oximetry recorded up to 5 minutes before arterial blood gas (ABG) measurements. Skin tone was measured using administered visual scales, reflectance colorimetry, and reflectance spectrophotometry. PARTICIPANTS: Admitted hospital patients at Duke University Hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sao2-Spo2 bias, variation of bias, and accuracy root mean square, comparing pulse oximetry, and ABG measurements. Linear mixed-effects models were fitted to estimate Sao2-Spo2 bias while accounting for clinical confounders.One hundred twenty-eight patients (57 Black, 56 White) with 521 ABG-pulse oximetry pairs were recruited. Skin tone data were prospectively collected using six measurement methods, generating eight measurements. The collected skin tone measurements were shown to yield differences among each other and overlap with self-reported racial groups, suggesting that skin tone could potentially provide information beyond self-reported race. Among the eight skin tone measurements in this study, and compared with self-reported race, the Monk Scale had the best relationship with differences in pulse oximetry bias (point estimate: -2.40%; 95% CI, -4.32% to -0.48%; p = 0.01) when comparing patients with lighter and dark skin tones. CONCLUSIONS: We found clinical performance differences in pulse oximetry, especially in darker skin tones. Additional studies are needed to determine the relative contributions of skin tone measures and other potential factors on pulse oximetry discrepancies.

Polygenic risk score portability for common diseases across genetically diverse populations.

BACKGROUND: Polygenic risk scores (PRS) derived from European individuals have reduced portability across global populations, limiting their clinical implementation at worldwide scale. Here, we investigate the performance of a wide range of PRS models across four ancestry groups (Africans, Europeans, East Asians, and South Asians) for 14 conditions of high-medical interest. METHODS: To select the best-performing model per trait, we first compared PRS performances for publicly available scores, and constructed new models using different methods (LDpred2, PRS-CSx and SNPnet). We used 285 K European individuals from the UK Biobank (UKBB) for training and 18 K, including diverse ancestries, for testing. We then evaluated PRS portability for the best models in Europeans and compared their accuracies with respect to the best PRS per ancestry. Finally, we validated the selected PRS models using an independent set of 8,417 individuals from Biobank of the Americas-Genomelink (BbofA-GL); and performed a PRS-Phewas. RESULTS: We confirmed a decay in PRS performances relative to Europeans when the evaluation was conducted using the best-PRS model for Europeans (51.3% for South Asians, 46.6% for East Asians and 39.4% for Africans). We observed an improvement in the PRS performances when specifically selecting ancestry specific PRS models (phenotype variance increase: 1.62 for Africans, 1.40 for South Asians and 0.96 for East Asians). Additionally, when we selected the optimal model conditional on ancestry for CAD, HDL-C and LDL-C, hypertension, hypothyroidism and T2D, PRS performance for studied populations was more comparable to what was observed in Europeans. Finally, we were able to independently validate tested models for Europeans, and conducted a PRS-Phewas, identifying cross-trait interplay between cardiometabolic conditions, and between immune-mediated components. CONCLUSION: Our work comprehensively evaluated PRS accuracy across a wide range of phenotypes, reducing the uncertainty with respect to which PRS model to choose and in which ancestry group. This evaluation has let us identify specific conditions where implementing risk-prioritization strategies could have practical utility across diverse ancestral groups, contributing to democratizing the implementation of PRS.

Risk of Parkinson's disease and depression severity in different populations: A two-sample Mendelian randomization analysis.

BACKGROUND: Depression is widely recognized as a common non-motor symptom of Parkinson's disease (PD). Across different studies, the reported prevalence of depression in PD varies widely, ranging from 2.7% to 90%, but it is unclear whether this association is due to genetic or acquired factors. Whether there is a causal relationship remains unknown. The aim of this study was to use a two-sample Mendelian randomization (MR) approach to investigate the causal effect of PD on depression. METHODS: Analyses were conducted separately for individuals of European and East Asian ancestry using publicly available summary data from genome-wide association studies. Depression was divided into two categories: ever depressed for a whole week and major depressive disorder (MDD). PD data were used as the exposure and were obtained from the International Parkinson's Disease Genomics Consortium and the BioBank Japan PheWeb, while depression data were used as the outcome and were obtained from the ntegrative Epidemiology Unit (IEU) Open GWAS Project(A public GWAS database） and the Psychiatric Genomics Consortium. The influence of PD on depression was assessed using inverse variance weighted (IVW), weighted median, MR-Egger, and weighted mode methods. Heterogeneity and pleiotropy were tested, and the results were validated using FinnGen GWAS data from version R9. RESULTS: In individuals of European ancestry, there was a causal relationship between PD and ever depressed for a whole week (IVW method, odds ratio [OR] = 0.990; 95% CI, 0.984-0.996; p = .002), but no causal relationship was observed between PD and MDD (IVW method, OR = 0.974; 95% CI, 0.942-1.009; p = .141). In individuals of East Asian ancestry, no causal relationship was observed between PD and ever depressed for a whole week (IVW method, OR = 1.001; 95% CI, 0.829-1.209; p = .990) and between PD and MDD (IVW method, OR = 1.017; 95% CI, 0.982-1.052; p = .342). The results of the three additional analysis methods were similar to those of the IVW method, and there was no heterogeneity according to Cochran's Q-test. There was no evidence of pleiotropy based on MR-Egger intercept test and MR-PRESSO. The FinnGen validation dataset supported these findings. The results are stable and reliable. CONCLUSION: The observed increase in depression among PD patients could potentially be attributed to modifiable acquired factors. Consequently, there is an urgent need to strengthen the management of PD patients in order to prevent the development of depression in the future.

Comparison of facial skin ageing in healthy Asian and Caucasian females quantified by in vivo line-field confocal optical coherence tomography 3D imaging.

BACKGROUND: Quantitative biomarkers of facial skin aging were investigated in 109 healthy Asian female volunteers, aged 20 to 70 years. MATERIALS AND METHODS: In vivo 3D Line-field Confocal Optical Coherence Tomography (LC-OCT) imaging, enhanced by Artificial Intelligence (AI)-based quantification algorithms, was utilized to compute various metrics, including stratum corneum thickness (SC), viable epidermal (VE) thickness, and Dermal-Epidermal Junction (DEJ) undulation along with cellular metrics for the temple, cheekbone, and mandible. RESULTS: Comparison with data from a cohort of healthy Caucasian volunteers revealed similarities in the variations of stratum corneum and viable epidermis layers, as well as cellular shape and size with age in both ethnic groups. However, specific findings emerged, such as larger, more heterogeneous nuclei in both layers, demonstrated by an increase in nuclei volume and their standard deviation, and increased network atypia, all showing significant age-related variations. Caucasian females exhibited a flatter and more homogeneous epidermis, evidenced by a decreased standard deviation of the number of layers, and a less dense cellular network with fewer cells per layer, indicated by a decrease in cell surface density. CONCLUSION: Ethnicity-wise comparisons highlighted distinct biological features specific to each population. Asian individuals showed significantly higher DEJ undulation, higher compactness, and lower cell network atypia compared to their Caucasian counterparts across age groups. Differences in stratum corneum and viable epidermal thickness on the cheekbone were also significant. LC-OCT 3D imaging provides valuable insights into the aging process in different populations and underscores inherent biological differences between Caucasian and Asian female volunteers.

Changes in the incidence of melanoma in Australia, 2006-2021, by age group and ancestry: a modelling study.

OBJECTIVES: To estimate the incidence of melanoma in Australia among people with ancestries associated with low, moderate, or high risk of melanoma, by sex and 5-year age group; to establish whether age-specific incidence rates by ancestry risk group have changed over time. STUDY DESIGN: Modelling study; United States (SEER database) melanoma incidence rates for representative ancestral populations and Australian census data (2006, 2011, 2016, 2021) used to estimate Australian melanoma incidence rates by ancestry-based risk. SETTING, PARTICIPANTS: Australia, 2006-2021. MAIN OUTCOME MEASURES: Age-specific invasive melanoma incidence rates, and average annual percentage change (AAPC) in age-specific melanoma rates, by ancestry-based risk group, sex, and 5-year age group. RESULTS: The proportion of people in Australia who reported high risk (European) ancestry declined from 85.3% in 2006 to 71.1% in 2021. The estimated age-standardised melanoma incidence rate was higher for people with high risk ancestry (2021: males, 82.2 [95% confidence interval {CI}, 80.5-83.8] cases per 100 000 population; females, 58.5 [95% CI, 57.0-59.9] cases per 100 000 population) than for all Australians (males, 67.8 [95% CI, 66.5-69.2] cases per 100 000 population; females, 45.4 [95% CI, 44.3-46.5] cases per 100 000 population). AAPCs were consistently positive for Australians aged 50 years or older, both overall and for people with high risk ancestry, but were statistically significant only for some age groups beyond 65 years. AAPCs were negative for people aged 34 years or younger, but were generally not statistically significant. CONCLUSIONS: Melanoma incidence has declined in some younger age groups in Australia, including among people with high risk ancestry. Social and behavioural changes over the same period that lead to lower levels of ultraviolet radiation exposure probably contributed to these changes.

The causality between use of glucocorticoids and risk of pancreatitis: a Mendelian randomization study.

Background and aim: To date, the association between glucocorticoid use and the risk of pancreatitis remains controversial. The aim of this study was the investigation of this possible relationship. Methods: We carried out a two-sample Mendelian randomization (MR) analysis using GWAS data from European ancestry, East Asian descendants and the FinnGen Biobank Consortium to evaluate this potential causal relationship. Genetic variants associated with glucocorticoid use were selected based on genome-wide significance (p < 5×10-8). Results: Our MR analysis of European ancestry data revealed no significant causal relationship between glucocorticoid use and AP (IVW: OR=1.084, 95% CI= 0.945-1.242, P=0.249; MR-Egger: OR=1.049, 95% CI= 0.686-1.603, P=0.828; weighted median: OR=1.026, 95% CI= 0.863-1.219, P=0.775) or CP (IVW: OR=1.027, 95% CI= 0.850-1.240, P=0.785; MR-Egger: OR= 1.625, 95% CI= 0.913-2.890, P= 0.111; weighted median: OR= 1.176, 95% CI= 0.909-1.523, P= 0.218). Sensitivity analyses, including MR-Egger and MR-PRESSO, indicated no evidence of pleiotropy or heterogeneity, confirming the robustness of our findings. Multivariable MR analysis adjusted for alcohol consumption, BMI, cholelithiasis and C-reactive protein levels supported these findings. Replicated analysis was performed on datasets from the FinnGen Biobank Consortium and East Asian descendants, and similar results were obtained. Conclusions: This MR analysis suggests that there is no causal association between glucocorticoid use and the risk of pancreatitis.

Association of Urinary Cadmium Concentration With Cognitive Impairment in US Adults: A Longitudinal Cohort Study.

BACKGROUND AND OBJECTIVES: Studies have indicated that cadmium (Cd) exposure is associated with neurotoxicity. However, data linking Cd exposure to cognitive impairment are sparse. We aimed to investigate the association between urinary Cd concentration and cognitive impairment in US adults. METHODS: The REasons for Geographic and Racial Differences in Stroke (REGARDS) study is an ongoing population-based prospective cohort study that enrolled 30,239 Black and White US adults aged 45 years or older at baseline (2003-2007). In a randomly selected subcohort of REGARDS participants who were free of cognitive impairment or stroke at baseline, certain trace element concentrations, including urinary creatinine-corrected Cd, were measured using biospecimens collected and stored at baseline. During an average of 10 years of follow-up, global cognitive impairment was assessed annually using the Six-Item Screener, and domain-based cognitive impairment, including verbal learning, memory, and executive function, was evaluated every other year using the Enhanced Cognitive Battery. Multivariable-adjusted logistic regression models were used to examine the association between urinary Cd concentration and the odds of global or domain-based cognitive impairment. RESULTS: A total of 2,172 participants (mean age: 64.1 ± 9.0 years; female: 54.8%; Black participants: 38.7%) with available data on urinary Cd concentration, including 195 cases of global cognitive impairment and 53 cases of domain-based cognitive impairment, were included in the analyses. While there was no association between Cd and cognitive impairment in the full sample, there was a significant positive association of urinary Cd concentration with global cognitive impairment among White but not Black participants. The odds of cognitive impairment for White participants in the high urinary Cd concentration group (≥median) were doubled compared with those in the low urinary Cd group (odds ratio 2.07, 95% CI 1.18-3.64). Sex, age, region, smoking pack-years, alcohol consumption, and other related metals did not materially modify the associations of interest. DISCUSSION: Findings from this prospective cohort study suggest that urinary Cd concentrations are associated with global cognitive impairment among White but not Black individuals. Further studies with repeatedly measured Cd exposure, larger sample sizes, and longer duration are needed to confirm our findings and explore the potential explanations for the observed racial discrepancy, such as the impact of smoking.

Causality between neuroticism personality clusters and female reproductive diseases in European population: a two-sample bidirectional mendelian randomization study.

BACKGROUND: The causality between neuroticism, a personality trait characterized by the tendency to experience negative emotions, and female reproductive diseases remains unclear. To provide evidence for the development of effective screening and prevention strategies, this study employed Mendelian randomization (MR) to investigate the causality between neuroticism clusters and female reproductive diseases. METHODS: Instrumental variables were obtained from large-scale genome-wide association studies of populations of European descent involving three neuroticism clusters (depressed affect, worry, sensitivity to environmental stress, and adversity [SESA]) in the Complex Trait Genetics database and six female reproductive diseases (infertility, polycystic ovary syndrome [PCOS], spontaneous abortion, recurrent spontaneous abortion, endometriosis, and uterine fibroids) in the FinnGen database. The bidirectional two-sample MR analysis was conducted using the inverse variance-weighted, weighted median, and MR-Egger methods, whereas the sensitivity analysis was conducted using the Cochran's Q-test, MR-Egger intercept, and leave-one-out analysis. RESULTS: In the forward analysis, genetically predicted depressed affect and worry components of neuroticism significantly increased the risk of infertility (depressed affect: odds ratio [OR] = 1.399, 95% confidence interval [CI]: 1.054-1.856, p = 0.020; worry: OR = 1.587, 95% CI: 1.229-2.049, p = 0.000) and endometriosis (depressed affect: OR = 1.611, 95% CI: 1.234-2.102, p = 0.000; worry: OR = 1.812, 95% CI: 1.405-2.338, p = 0.000). Genetically predicted SESA component of neuroticism increased only the risk of endometriosis (OR = 1.524, 95% CI: 1.104-2.103, p = 0.010). In the reverse analysis, genetically predicted PCOS was causally associated with an increased risk of the worry component of neuroticism (Beta = 0.009, 95% CI: 0.003-0.016, p = 0.003). CONCLUSIONS: The MR study showed that the three neuroticism personality clusters had definite causal effects on at least one specific female reproductive disease. Moreover, PCOS may increase the risk of the worry component of neuroticism. This finding suggests the need to screen for specific female reproductive diseases in populations with high neuroticism and assess the psychological status of patients with PCOS.

Identification of potential therapeutic targets for nonischemic cardiomyopathy in European ancestry: an integrated multiomics analysis.

BACKGROUND: Nonischemic cardiomyopathy (NISCM) is a clinical challenge with limited therapeutic targets. This study aims to identify promising drug targets for NISCM. METHODS: We utilized cis-pQTLs from the deCODE study, which includes data from 35,559 Icelanders, and SNPs from the FinnGen study, which includes data from 1,754 NISCM cases and 340,815 controls of Finnish ancestry. Mendelian randomization (MR) analysis was performed to estimate the causal relationship between circulating plasma protein levels and NISCM risk. Proteins with significant associations underwent false discovery rate (FDR) correction, followed by Bayesian colocalization analysis. The expression of top two proteins, LILRA5 and NELL1, was further analyzed using various NISCM datasets. Descriptions from the Human Protein Atlas (HPA) validated protein expression. The impact of environmental exposures on LILRA5 was assessed using the Comparative Toxicogenomics Database (CTD), and molecular docking identified the potential small molecule interactions. RESULTS: MR analysis identified 255 circulating plasma proteins associated with NISCM, with 16 remaining significant after FDR correction. Bayesian colocalization analysis identified LILRA5 and NELL1 as significant, with PP.H4 > 0.8. LILRA5 has a protective effect (OR = 0.758, 95% CI, 0.670-0.857) while NELL1 displays the risk effect (OR = 1.290, 95% CI, 1.199-1.387) in NISCM. Decreased LILRA5 expression was found in NISCM such as diabetic, hypertrophic, dilated, and inflammatory cardiomyopathy, while NELL1 expression increased in hypertrophic cardiomyopathy. HPA data indicated high LILRA5 expression in neutrophils, macrophages and endothelial cells within normal heart and limited NELL1 expression. Immune infiltration analysis revealed decreased neutrophil in diabetic cardiomyopathy. CTD analysis identified several small molecules that affect LILRA5 mRNA expression. Among these, Estradiol, Estradiol-3-benzoate, Gadodiamide, Topotecan, and Testosterone were found to stably bind to the LILRA5 protein at the conserved VAL-15 or THR-133 residues in the Ig-like C2 domain. CONCLUSION: Based on European Ancestry Cohort, this study reveals that LILRA5 and NELL1 are potential therapeutic targets for NISCM, with LILRA5 showing particularly promising prospects in diabetic cardiomyopathy. Several small molecules interact with LILRA5, implying potential clinical implication.

Neighborhood Child Opportunity and Preterm Birth Rates by Race and Ethnicity.

Importance: In the US, infants born to non-Hispanic Black birthing parents are 50% more likely to be born preterm than those born to non-Hispanic White birthing parents, and individual-level factors do not fully account for this inequity. Neighborhood context, rooted in historic patterns of structural racism, may facilitate understanding patterns of inequity in preterm birth. Objective: To estimate the association between neighborhood opportunity level, measured by the Child Opportunity Index (COI), and preterm birth among infants in Massachusetts. Design, Setting, and Participants: In this cross-sectional, population-based study, Massachusetts birth certificates from 3 large metropolitan areas (Boston, Springfield, and Worcester) were linked to US Census tract-level data from the COI, and log binomial regression models and generalized estimating equations were fit to examine associations of different levels of opportunity with preterm birth. Singleton infants born in Massachusetts between February 1, 2011, and December 31, 2015, were included. Analyses were originally conducted in 2019 and updated in 2024. Exposure: Level of child opportunity (measured by the COI) at the US Census tract level. Race and ethnicity were ascertained from the birth certificate, as reported by the birthing parent. Main Outcomes and Measures: Live birth before 37 completed weeks' gestation. Results: The analytic dataset included 267 553 infants, of whom 18.9% were born to Hispanic, 10.1% to non-Hispanic Asian or Pacific Islander, 10.1% to non-Hispanic Black, and 61.0% to non-Hispanic White birthing parents. More than half of infants born to non-Hispanic Black and Hispanic birthing parents were born into very low opportunity neighborhoods, and in crude models, this was associated with greater prevalence of preterm birth relative to very high opportunity neighborhoods (prevalence ratio, 1.44; 95% CI, 1.37-1.52). After adjustment for covariates, infants born into very low opportunity neighborhoods still had a greater prevalence of preterm birth (prevalence ratio, 1.16; 95% CI, 1.10-1.23). Conclusions and Relevance: In this cross-sectional study of neighborhood opportunity and preterm birth, elevated risk associated with exposure to a very low opportunity neighborhood, coupled with the disproportionate exposure by race and ethnicity, points to a modifiable factor that may contribute to racial and ethnic inequities in preterm birth. Future research should investigate interventions that seek to address neighborhood opportunity.

Mitochondrial reprogramming by activating OXPHOS via glutamine metabolism in African American patients with bladder cancer.

Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further demonstrate that knockdown of NDUFB8, one of the components of complex I in AA BLCA cells, resulted in reduced basal respiration, ATP production, GLS1 expression, and proliferation. Moreover, preclinical studies demonstrate the therapeutic potential of targeting complex I, as evidenced by decreased tumor growth in NDUFB8-depleted AA BLCA tumors. Additionally, genetic and pharmacological inhibition of GLS1 attenuated mitochondrial respiration rates and tumor growth potential in AA BLCA. Taken together, these findings provide insight into BLCA disparity for targeting GLS1-Complex I for future therapy.

Differences in the risk association of TERT-CLPTM1L rs4975616 (A>G) with lung cancer between Caucasian and Asian populations: A meta-analysis.

BACKGROUND: Although the G allele variant of TERT-CLPTM1L rs4975616 has been confirmed to be negatively associated to the risk of lung cancer (LC), some other studies haven't found this negative association. The purpose of this study is to clarify the association of the rs4975616 with the risk of developing LC and the differences of this association among patients with different ethnicities (Caucasians and Asians), different subtypes of LC, and different smoking status. METHODS: Relevant literatures published before July 20, 2023 in PubMed, EMbase, Web of Science, MEDLINE databases were searched through the Internet. Statistical analysis of data was performed in Revman5.3, including drawing forest plots, funnel plots and so on. Sensitivity and publication bias were performed in Stata 14.0. The stability of the results was assessed using Test Sequence Analysis (TSA) software. Registration number: CRD42024568348. RESULTS: The G allele variant of rs4975616 was negatively associated with the risk of LC ([OR] = 0.86, 95%CI [0.84, 0.88]), and that this negative association was present in both Caucasians ([OR] = 0.85, 95%CI [0.83, 0.87]) and Asians ([OR] = 0.91, 95%CI [0.86, 0.95]), and the strength of the negative association was higher in Caucasians than in Asians (subgroup differences: P = 0.02, I2 = 80.3%). Across LC subtypes, rs4975616[G] was negatively associated with the risk of NSCLC (LUAD, LUSC) in both Caucasians and Asians (P<0.05) and the strength of the association with NSCLC (LUAD) was higher in Caucasians than in Asians (Subgroup differences: I2>50%). In Caucasians, rs4975616[G] was negatively associated with the risk of LC in both smokers and non-smokers (P<0.05), and the strength of the association did not differ between smokers and non-smokers (Subgroup differences: P = 0.18, I2 = 45.0%). In Asians, rs4975616[G] was mainly negatively associated with the risk of LC in smokers (P<0.05) but not in non-smokers ([OR] = 0.97, 95%CI [0.78, 1.20]). Comparisons between the two populations showed that the strength of this negative association was higher in Caucasian non-smokers than in Asian non-smokers (Subgroup differences: P = 0.04, I2 = 75.3%), whereas the strength of this negative association was the same for Caucasian smokers as for Asian smokers (Subgroup differences: P = 0.42, I2 = 0%). Among the different LC subtypes, rs4975616[G] was negatively associated with the risk of NSCLC (LUAD) incidence in both Asian smokers and Caucasian non-smokers (P<0.05), whereas it was not associated with the risk of NSCLC development in Asian non-smokers (P>0.05). Comparisons between the two populations showed that the strength of the association was higher in Caucasian non-smokers than in Asian non-smokers (Subgroup differences: I2>50%). CONCLUSION: The G allele variant of rs4975616 is negatively associated with the risk of LC and NSCLC (LUAD, LUSC). Compared with Asians, Caucasians are more likely to have a higher risk of LC and NSCLC (LUAD) due to the rs4975616 variant. In Caucasians, smoking and other factors like non-smoking contribute to rs4975616 variations leading to LC, and other factors like non-smoking also induce rs4975616 variations leading to NSCLC (LUAD). In Asians, smoking is the major risk factor for the induction of rs4975616 variations leading to LC and NSCLC(LUAD).

Beneficial Effects of Cocoa Flavanols on Microvascular Responses in Young Men May Be Dependent on Ethnicity and Lifestyle.

Cocoa flavan-3-ols affect endothelium-dependent responses in resistance vessels and microcirculation has received little attention. We tested the effects of dark chocolate consumption (396 mg total flavanols/day for 3 days) in two Groups of 10 men (18-25 years; non-smokers) each comprising equal numbers of White European (WE) and South Asian (SA) ethnicity. In Group 1, dark chocolate did not affect reactive hyperaemia in forearm muscle, but augmented muscle dilatation evoked by acute mental stress, and reactive hyperaemia and acetylcholine (ACh)-evoked dilatation in cutaneous microcirculation. Conversely, in Group 2, chocolate did not affect cutaneous reactive hyperaemia or ACh-evoked dilatation, but these responses were blunted in Group 1 relative to Group 2. Further, when Groups 1 and 2 were combined, responses were blunted in SAs relative to WEs, augmented by chocolate in SAs only. In Group 2 individuals whose ACh-evoked dilatation was attenuated by nitric oxide synthase (NOS) inhibition, ACh-evoked dilatation was not altered after chocolate, but the attenuating effect of NOS inhibition was lost. Conversely, in Group 2 individuals whose ACh-evoked dilatation was enhanced by NOS inhibition, ACh-evoked dilatation was also augmented by chocolate. We propose that in resistance and microvessels of young men, cocoa flavan-3-ols preferentially augment endothelium-dependent dilator responses whose responses are depressed by familial and lifestyle factors more prevalent in SAs than Wes. Flavan-3-ols may facilitate the NOS pathway but also influence other endothelium-dependent dilators.

Optimal Pair Matching Combined with Machine Learning Predicts a Significant Reduction in Myocardial Infarction Risk in African Americans Following Omega-3 Fatty Acid Supplementation.

Conflicting clinical trial results on omega-3 highly unsaturated fatty acids (n-3 HUFA) have prompted uncertainty about their cardioprotective effects. While the VITAL trial found no overall cardiovascular benefit from n-3 HUFA supplementation, its substantial African American (AfAm) enrollment provided a unique opportunity to explore racial differences in response to n-3 HUFA supplementation. The current observational study aimed to simulate randomized clinical trial (RCT) conditions by matching 3766 AfAm and 15,553 non-Hispanic White (NHW) individuals from the VITAL trial utilizing propensity score matching to address the limitations related to differences in confounding variables between the two groups. Within matched groups (3766 AfAm and 3766 NHW), n-3 HUFA supplementation's impact on myocardial infarction (MI), stroke, and cardiovascular disease (CVD) mortality was assessed. A weighted decision tree analysis revealed belonging to the n-3 supplementation group as the most significant predictor of MI among AfAm but not NHW. Further logistic regression using the LASSO method and bootstrap estimation of standard errors indicated n-3 supplementation significantly lowered MI risk in AfAm (OR 0.17, 95% CI [0.048, 0.60]), with no such effect in NHW. This study underscores the critical need for future RCT to explore racial disparities in MI risk associated with n-3 HUFA supplementation and highlights potential causal differences between supplementation health outcomes in AfAm versus NHW populations.

Vanishing twins, spared cohorts, and the birthweight of periviable infants born to Black and white women in the United States.

Pregnancies ending before 26 weeks contribute 1% of births but 40% of infant deaths in the United States. The rate of these "periviable" births to non-Hispanic (NH) Black women exceeds four times that for NH whites. Small male periviable infants remain most likely to die. NH white periviable males weigh more than their NH Black counterparts. We argue that male infants born from twin gestations, in which one fetus died in utero (i.e., the vanishing twin syndrome), contribute to the disparity. We cannot directly test our argument because "vanishing" typically occurs before clinical recognition of pregnancy. We, however, describe and find associations that would emerge in vital statistics were our argument correct. Among male periviable singleton births from 288 monthly conception cohorts (January 1995 through December 2018), we found an average NH white advantage of 30 grams (759 grams versus 729 grams). Consistent with our argument, however, cohorts signaling relatively few survivors of the vanishing twin syndrome showed no disparity.