Genome-wide association study and functional follow-up identify 14q12 as a candidate risk locus for cervical cancer.

Cervical cancer is among the leading causes of cancer-related death in females worldwide. Infection by human papillomavirus (HPV) is an established risk factor for cancer development. However, genetic factors contributing to disease risk remain largely unknown. We report on a genome-wide association study (GWAS) on 375 German cervical cancer patients and 866 healthy controls, followed by a replication study comprising 658 patients with invasive cervical cancer, 1361 with cervical dysplasia and 841 healthy controls. Functional validation was performed for the top GWAS variant on chromosome 14q12 (rs225902, close to PRKD1). After bioinformatic annotation and in silico predictions, we performed transcript analysis in a cervical tissue series of 317 samples and demonstrate rs225902 as an expression quantitative trait locus (eQTL) for FOXG1 and two tightly co-regulated long non-coding RNAs at this genomic region, CTD-2251F13 (lnc-PRKD1-1) and CTD-2503I6 (lnc-FOXG1-6). We also show allele-specific effects of the 14q12 variants via luciferase assays. We propose a combined effect of genotype, HPV status and gene expression at this locus on cervical cancer progression. Taken together, this work uncovers a potential candidate locus with regulatory functions and contributes to the understanding of genetic susceptibility to cervical cancer.

Safety, feasibility, and impact on the gut microbiome of kefir administration in critically ill adults.

BACKGROUND: Dysbiosis of the gut microbiome is frequent in the intensive care unit (ICU), potentially leading to a heightened risk of nosocomial infections. Enhancing the gut microbiome has been proposed as a strategic approach to mitigate potential adverse outcomes. While prior research on select probiotic supplements has not successfully shown to improve gut microbial diversity, fermented foods offer a promising alternative. In this open-label phase I safety and feasibility study, we examined the safety and feasibility of kefir as an initial step towards utilizing fermented foods to mitigate gut dysbiosis in critically ill patients. METHODS: We administered kefir in escalating doses (60 mL, followed by 120 mL after 12 h, then 240 mL daily) to 54 critically ill patients with an intact gastrointestinal tract. To evaluate kefir's safety, we monitored for gastrointestinal symptoms. Feasibility was determined by whether patients received a minimum of 75% of their assigned kefir doses. To assess changes in the gut microbiome composition following kefir administration, we collected two stool samples from 13 patients: one within 72 h of admission to the ICU and another at least 72 h after the first stool sample. RESULTS: After administering kefir, none of the 54 critically ill patients exhibited signs of kefir-related bacteremia. No side effects like bloating, vomiting, or aspiration were noted, except for diarrhea in two patients concurrently on laxatives. Out of the 393 kefir doses prescribed for all participants, 359 (91%) were successfully administered. We were able to collect an initial stool sample from 29 (54%) patients and a follow-up sample from 13 (24%) patients. Analysis of the 26 paired samples revealed no increase in gut microbial α-diversity between the two timepoints. However, there was a significant improvement in the Gut Microbiome Wellness Index (GMWI) by the second timepoint (P = 0.034, one-sided Wilcoxon signed-rank test); this finding supports our hypothesis that kefir administration can improve gut health in critically ill patients. Additionally, the known microbial species in kefir were found to exhibit varying levels of engraftment in patients' guts. CONCLUSIONS: Providing kefir to critically ill individuals is safe and feasible. Our findings warrant a larger evaluation of kefir's safety, tolerability, and impact on gut microbiome dysbiosis in patients admitted to the ICU. TRIAL REGISTRATION: NCT05416814; trial registered on June 13, 2022.

Downregulation of miR-1270 mediates endothelial progenitor cell function in preeclampsia: Role for ATM in the Src/VE-cadherin axis.

Preeclampsia, a pregnancy-related hypertensive disorder, is associated with endothelial dysfunction and increased cardiovascular risk of the offspring in adulthood. In preeclampsia, endothelial colony-forming cells (ECFC) are reduced in number and function. Recently, we have shown that miR-1270, which is involved in cancer in vitro proliferation, migration, and tumor progression, is downregulated in fetal ECFC from preeclamptic pregnancies. We now hypothesize that miR-1270 dysregulation contributes to vascular endothelial dysfunction occurring after preeclampsia via ATM (ataxia telangiectasia mutated) overexpression, the key kinase of DNA damage repair. Here, we show that miR-1270 silencing in normal ECFC and downregulation in preeclamptic ECFC are accompanied by an increase in the expression levels of ATM. Furthermore, ATM activation correlates with upregulated tyrosine kinase Src leading to phosphorylation and internalization of VE-cadherin (vascular endothelial-cadherin) which subsequently compromises endothelial barrier permeability and morphodynamic cell parameters. Treatment with specific ATM inhibitors reveals a novel role of ATM upstream of tyrosine kinase Src activation. Subsequently, Src phosphorylation and internalization of VE-cadherin compromise endothelial barrier permeability. Our findings suggest that downregulation of miR-1270 contributes to impaired ECFC function via the associated ATM overexpression, which further identifies ATM as a novel and critical factor for ECFC defects in preeclampsia. Our study provides new insights into the understanding of ECFC impairment associated with cardiovascular risk in preeclamptic offspring and identifies potential novel therapeutic targets.

Association of genomic variants at PAX8 and PBX2 with cervical cancer risk.

Cervical malignancy is triggered by human papillomavirus infection but the risk for cervical cancer has a hereditary component. From a recent Genome Wide Association Study meta-analysis, 2q14.1 (PAX8) and 6p21.32 (PBX2) have been proposed as novel cervical cancer susceptibility loci. We investigated the two main signals at these loci in an independent case-control series of 2578 cases with cervical dysplasia or carcinoma and 1483 healthy females. We find significant associations for both variants, rs10175462 at PAX8 and rs2856437 at PBX2, with overall cervical disease (rs10175462: odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74-0.91, P = 2.4 × 10-4 ; rs2856437: OR 1.52, 95% CI 1.14-2.02, P = .004). Both variants showed evidence of association with invasive squamous cervical cancer (rs10175462: OR 0.80, 95% CI 0.68-0.94, P = .006; rs2856437: OR 1.56, 95% CI 1.03-2.36, P = .036) and with high-grade dysplasia (rs10175462: OR 0.79, 95%CI 0.70-0.90, P = 1.9 × 10-4 ; rs2856437: OR 1.58, 95% CI 1.15-2.17, P = .005). A combined analysis of high-grade dysplasia and invasive cervical cancer also showed significant associations for both variants (rs10175462: OR 0.81, 95% CI 0.73-0.91, P = 2.4 × 10-4 ; rs2856437: OR 1.57, 95% CI 1.18-2.10, P = .002). No association was detected for rs2856437 with low-grade dysplasia, while rs10175462 showed weak evidence of association (P = .05). RNA analyses in cervical samples revealed that PAX8 transcripts were upregulated in HPV-positive lesions (P = .008) but this was not observed in the presence of the protective minor allele of rs10175462. The rs10175462 genotype also correlated with reduced levels of the lncRNA PAX8-AS1 (P < .001). Taken together, our results extend the evidence for a link between genomic risk variants at the HLA region (PBX2) with cervical disease and support PAX8 as the first consistent non-HLA cervical cancer susceptibility locus.

Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk, HPV status and gene expression levels.

The human leukocyte antigen (HLA) locus on chromosome 6 has been reported to be associated with cervical cancer. We investigated two independent single-nucleotide polymorphisms in a large case-control series of cervical dysplasia and carcinoma that has been newly established by the German Cervigen Consortium, comprising a total of 2481 cases and 1556 healthy females. We find significant associations for both variants, rs9272117 at HLA-DQA1 and rs2844511 at MICA and HCP5, with cervical disease. Both variants showed evidence of association with invasive cervical cancer (rs9272117: OR 0.89, 95% CI 0.79-0.99, P = .036; rs2844511: OR 1.17, 95% CI 1.04-1.31, P = .008) and with high-grade dysplasia (rs9272117: OR 0.78, 95% CI 0.70-0.87, P = 7.1 × 10-6 ; rs2844511: OR 1.13, 95% CI 1.01-1.26, P = .035), as well as in a combined analysis of both groups (rs9272117: OR 0.83, 95% CI 0.75-0.91, P = 6.9 × 10-5 ; rs2844511: OR 1.14, 95% CI 1.04-1.26, P = .005). Variant rs2844511, but not rs9272117, also showed modest evidence of association with low-grade dysplasia (OR 1.26, 95% CI 1.04-1.54, P = .019). In case-only analyses, rs2844511 tended to predict HPV status (P = .044) and rs9272117 tended to associate with HPV16 (P = .022). RNA studies in cervical samples showed a significant correlation in the transcript levels of MICA, HCP5 and HLA-DQA1, suggesting extensive co-regulation. All three genes were upregulated in HPV16-positive samples. In stratified analyses, rs9272117 was associated with HLA-DQA1 levels, specifically in HPV-positive samples, while rs2844511 was associated with MICA and HCP5 levels. The risk allele of rs2844511 was required for correlations between MICA or HCP5 with HLA-DQA1. Altogether, our results support 6p21.32-33 as the first consistent cervical cancer susceptibility locus and provide evidence for a link between genetic risk variants, HPV16 status and transcript levels of HLA-DQA1, HCP5 and MICA, which may contribute to tumor immune evasion.

TEM and AES investigations of the natural surface nano-oxide layer of an AISI 316L stainless steel microfibre.

The chemical composition, nanostructure and electronic structure of nanosized oxide scales naturally formed on the surface of AISI 316L stainless steel microfibres used for strengthening of composite materials have been characterised using a combination of scanning and transmission electron microscopy with energy-dispersive X-ray, electron energy loss and Auger spectroscopy. The analysis reveals the presence of three sublayers within the total surface oxide scale of 5.0-6.7 nm thick: an outer oxide layer rich in a mixture of FeO.Fe2 O3 , an intermediate layer rich in Cr2 O3 with a mixture of FeO.Fe2 O3 and an inner oxide layer rich in nickel.

Melamine-Formaldehyde Microcapsules: Micro- and Nanostructural Characterization with Electron Microscopy.

A systematic study has been carried out to compare the surface morphology, shell thickness, mechanical properties, and binding behavior of melamine-formaldehyde microcapsules of 5-30 µm diameter size with various amounts of core content by using scanning and transmission electron microscopy including electron tomography, in situ nanomechanical tensile testing, and electron energy-loss spectroscopy. It is found that porosities are present on the outside surface of the capsule shell, but not on the inner surface of the shell. Nanomechanical tensile tests on the capsule shells reveal that Young's modulus of the shell material is higher than that of bulk melamine-formaldehyde and that the shells exhibit a larger fracture strain compared with the bulk. Core-loss elemental analysis of microcapsules embedded in epoxy indicates that during the curing process, the microcapsule-matrix interface remains uniform and the epoxy matrix penetrates into the surface micro-porosities of the capsule shells.

Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects.

PURPOSE: The goal of this study was to identify the contribution of large copy-number variants to Down syndrome-associated atrioventricular septal defects, the risk for which in the trisomic population is 2,000-fold more as compared with that of the general disomic population. METHODS: Genome-wide copy-number variant analysis was performed on 452 individuals with Down syndrome (210 cases with complete atrioventricular septal defects; 242 controls with structurally normal hearts) using Affymetrix SNP 6.0 arrays, making this the largest heart study conducted to date on a trisomic background. RESULTS: Large, common copy-number variants with substantial effect sizes (OR > 2.0) do not account for the increased risk observed in Down syndrome-associated atrioventricular septal defects. By contrast, cases had a greater burden of large, rare deletions (P < 0.01) and intersected more genes (P < 0.007) as compared with controls. We also observed a suggestive enrichment of deletions intersecting ciliome genes in cases as compared with controls. CONCLUSION: Our data provide strong evidence that large, rare deletions increase the risk of Down syndrome-associated atrioventricular septal defects, whereas large, common copy-number variants do not appear to increase the risk of Down syndrome-associated atrioventricular septal defects. The genetic architecture of atrioventricular septal defects is complex and multifactorial in nature.

Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder.

Autism spectrum disorder (ASD) is a heterogeneous disorder with substantial heritability, most of which is unexplained. ASD has a population prevalence of one percent and affects four times as many males as females. Patients with fragile X E (FRAXE) intellectual disability, which is caused by a silencing of the X-linked gene AFF2, display a number of ASD-like phenotypes. Duplications and deletions at the AFF2 locus have also been reported in cases with moderate intellectual disability and ASD. We hypothesized that other rare X-linked sequence variants at the AFF2 locus might contribute to ASD. We sequenced the AFF2 genomic region in 202 male ASD probands and found that 2.5% of males sequenced had missense mutations at highly conserved evolutionary sites. When compared with the frequency of missense mutations in 5545 X chromosomes from unaffected controls, we saw a statistically significant enrichment in patients with ASD (OR: 4.9; P < 0.014). In addition, we identified rare AFF2 3' UTR variants at conserved sites which alter gene expression in a luciferase assay. These data suggest that rare variation in AFF2 may be a previously unrecognized ASD susceptibility locus and may help explain some of the male excess of ASD.

Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease.

OBJECTIVES: Inflammatory bowel disease (IBD) is heritable, but a total of 163 variants commonly implicated in IBD pathogenesis account for only 25% of the heritability. Rare, highly penetrant genetic variants may also explain mendelian forms of IBD and some of the missing heritability. To test the hypothesis that rare loss-of-function mutations can be causative, we performed whole exome sequencing (WES) on 5 members of a 2-generation family of European ancestry presenting with an early-onset and atypical form of IBD. METHODS: WES was performed for all of the 5 family members; the mother and 3 male offspring were affected, whereas the father was unaffected. Mapping, annotation, and filtering criteria were used to reduce candidate variants. For functional testing we performed forkhead box P3 (FOXP3) staining and a T-cell suppression assay. RESULTS: We identified a novel missense variant in exon 6 of the X-linked FOXP3 gene. The c.694A>C substitution in FOXP3 results in a cysteine-to-glycine change at the protein position 232 that is completely conserved among all vertebrates. This variant (heterozygous in the mother and hemizygous in all 3 affected sons) did not impair FOXP3 protein expression, but significantly reduced the ability of the host's T regulatory cells to suppress an inappropriate autoimmune response. The variant results in a milder immune dysregulation, polyendocrinopathy, enteropathy, and X-linked phenotype with early-onset IBD. CONCLUSIONS: Our study illustrates the successful application of WES for making a definitive molecular diagnosis in a case of multiply affected families, with atypical IBD-like phenotype. Our results also have important implications for disease biology and disease-directed therapeutic development.

Efficiency of moderately hypofractionated radiotherapy in NSCLC cell model.

Background: The current standard of radiotherapy for inoperable locally advanced NSCLCs with single fraction doses of 2.0 Gy, results in poor outcomes. Several fractionation schedules have been explored that developed over the past decades to increasingly more hypofractionated treatments. Moderate hypofractionated radiotherapy, as an alternative treatment, has gained clinical importance due to shorter duration and higher patient convenience. However, clinical trials show controversial results, adding to the need for pre-clinical radiobiological studies of this schedule. Methods: We examined in comparative analysis the efficiency of moderate hypofractionation and normofractionation in four different NSCLC cell lines and fibroblasts using several molecular-biological approaches. Cells were daily irradiated with 24x2.75 Gy (moderate hypofractionation) or with 30x2 Gy (normofractionation), imitating the clinical situation. Proliferation and growth rate via direct counting of cell numbers, MTT assay and measurements of DNA-synthesizing cells (EdU assay), DNA repair efficiency via immunocytochemical staining of residual γH2AX/53BP1 foci and cell surviving via clonogenic assay (CSA) were experimentally evaluated. Results: Overall, the four tumor cell lines and fibroblasts showed different sensitivity to both radiation regimes, indicating cell specificity of the effect. The absolute cell numbers and the CSA revealed significant differences between schedules (P < 0.0001 for all employed cell lines and both assays) with a stronger effect of moderate hypofractionation. Conclusion: Our results provide evidence for the similar effectiveness and toxicity of both regimes, with some favorable evidence towards a moderate hypofractionation. This indicates that increasing the dose per fraction may improve patient survival and therapy outcomes.

Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease.

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10-8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

Right Ventricular Systolic Dysfunction in Adults With Anatomic Repair of d-Transposition of Great Arteries.

The purpose of this study was to assess the prevalence of right ventricular (RV) systolic dysfunction in adults with anatomic repair of dextro-transposition of great arteries (d-TGAs), and to determine its relation to clinical outcomes across multiple domains (functional status, peak oxygen consumption, N-terminal pro-brain natriuretic peptide, and heart failure hospitalization). Adults with anatomic repair for d-TGA and with echocardiographic images for strain analysis were divided into 2 groups: (1) d-TGA status after an arterial switch operation (d-TGA-ASO group) and (2) d-TGA status after a Rastelli operation (d-TGA-Rastelli group). RV systolic function was assessed using RV global longitudinal strain (RVGLS), and RV systolic dysfunction was defined as RVGLS >-18%. We identified 151 patients (median age 21 years [19 to 28]; d-TGA-ASO group 89 [59%], and d-TGA-Rastelli group 62 [41%]). The mean RVGLS was -22 ± 4%, and 47 patients (31%) had RV systolic dysfunction. The d-TGA-Rastelli group had lower (less negative) RVGLS than that of the d-TGA-ASO group (-19 ± 3% vs -25 ± 3%, p <0.001) and higher prevalence of RV systolic dysfunction (48% vs 19%, p <0.001). RVGLS (absolute value) was associated with peak oxygen consumption (r = 0.58, p <0.001; adjusted R2 = 0.28), log-N-terminal pro-brain natriuretic peptide (r = -0.41, p = 0.004; adjusted R2 = 0.21), New York Heart Association class III/IV (odds ratio 2.29, 1.56 to 3.19, p = 0.01), and heart failure hospitalization (hazard ratio 0.93, 0.88 to 0.98, p = 0.009). RV systolic dysfunction was common in adults with d-TGA and anatomic repair and was associated with clinical outcomes. Longitudinal studies are required to determine the risk factors for progressive RV systolic dysfunction and to identify strategies for preventing RV systolic dysfunction in this population.

Plasma thrombin generation kinetics vary by injury pattern and resuscitation characteristics in pediatric and young adult trauma patients.

BACKGROUND: Thrombin generation kinetics are not well studied in children. This study aimed to assess how thrombin generation kinetics vary in pediatric and young adult (YA) trauma patients by clinical characteristics and injury pattern. METHODS: Prospective cohort study where plasma samples were obtained from pediatric (ages 0-17 years) and YA (ages 18-21 years) trauma patients upon emergency department arrival. Thrombin generation (calibrated automated thrombogram [CAT]) was quantified as lag time (LT, minutes), peak height (PH, nM), time to peak (ttPeak, minutes), and endogenous thrombin potential (ETP, nM × minute). Results are expressed as median and quartiles [Q1, Q3] and compared using Wilcoxon rank sum testing with p < 0.05 considered significant. RESULTS: We enrolled 47 pediatric (median age, 15 [14, 17] years, 78% male, 87% blunt, median Injury Severity Score, 12) and 49 YA (median age 20 [18, 21] years, 67% male, 84% blunt, median Injury Severity Score, 12) patients. Pediatric and YA patients had similar rates of operative intervention (51% vs. 57%), transfusion (25% vs. 20%), and traumatic brain injury (TBI) (53% vs. 49%). Pediatric patients who required an operation had accelerated initiation of thrombin generation, with shorter LT than those who did not (2.58 [2.33, 2.67]; 2.92 [2.54, 3.00], p = 0.034). Shorter LT (2.41 [2.22, 2.67]; 2.67 [2.53, 3.00]) and ttPeak (4.50 [4.23, 4.73]; 5.22 [4.69, 5.75], both p < 0.01) were noted in pediatric patients who required transfusion as compared with those who did not. The YA patients requiring transfusion had shorter LT (2.33 [2.19, 2.74]; 2.83 [2.67, 3.27]) and ttPeak (4.48 [4.33, 5.65]; 5.33 [4.85, 6.28] both p < 0.04) than those who were not transfused. Young adults with TBI had greater ETP than those without (1509 [1356, 1671]; 1284 [1154, 1471], p = 0.032). CONCLUSION: Thrombin generation kinetics in pediatric trauma patients prior to intervention vary with need for operation and transfusion, while thrombin generation kinetics in young adult patients are influenced by TBI and need for operation or transfusion. This is a promising tool for assessing coagulopathy in young trauma patients. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.

Risk of pulmonary artery dissection in adults with congenital heart disease.

BACKGROUND: There are limited data about the risk of pulmonary artery (PA) dissection in adults with congenital heart disease (CHD), and the purpose of this study was to estimate the incidence of PA dissection in this population. METHODS: Retrospective cohort study of adults with CHD that underwent cross-sectional imaging (2003-2020). PA aneurysm was defined as main or branch PA diameter > 40 mm or > 30 mm respectively, and severe PA aneurysm was defined as main or branch PA diameter > 50 mm. RESULTS: Of 1, 673 patients (41 ± 10 years; male 58%), 493 (24%), 286 (19%), and 306 (20%) had aneurysms of the main, right, and left PA respectively, while 66 (4%) had severe PA aneurysm. During a median follow-up of 8.2 (interquartile range 3.7-10.3) years, there was one PA dissection in a patient with Eisenmenger syndrome, thus the incidence of PA dissection was 14 per 100,000 patient-years. Of 779 females, 163 had one or more pregnancies during follow-up, and 41 (25%) of these patients had known PA aneurysm at the time of conception. There was no PA dissection during pregnancy. Of the 163 patients, 91 (56%) had cross-sectional imaging before and after pregnancy, there was no significant difference in PA dimension before versus after pregnancy (main PA 35 ± 5 versus 36 ± 4 mm, p = 0.6; right PA 21 ± 3 versus 33 ± 4 mm, p = 0.1; and left PA 23 ± 4 versus 22 ± 4 mm, p = 0.4). CONCLUSIONS: The risk of PA dissection was extremely low even in patients with severe PA aneurysm, or in patients with PA aneurysm that became pregnant. Collectively, these data suggest a benign natural history for patients without severe pulmonary hypertension and encourage and a conservative approach in managing patients with PA aneurysm.

TELOMERE LENGTH OF PERIPHERAL BLOOD MONONUCLEAR CELLS IS ASSOCIATED WITH DISCHARGE DISPOSITION IN OLDER TRAUMA PATIENTS.

Introduction: Little is known regarding peripheral blood mononuclear cell telomere length (PBMC-TL) and response to traumatic injury. The objective of this study was to characterize the role of PBMC-TL in coagulation and clinical outcomes after injury. Methods: Plasma and buffy coats were prospectively collected from trauma patients and healthy volunteers. DNA was purified and PBMC-TL quantified by quantitative polymerase chain reaction. Thrombin generation kinetics were expressed as lag time (in minutes), peak height (in nanometers), time to peak (in minutes), and endogenous thrombin potential (in nM × min). Results are in median and quartiles [Q1, Q3]. P < 0.05 was considered significant (Wilcoxon rank sum testing). Results: Forty-two younger patients (21 [20, 22] years, 69% were male) and 39 older patients (62 [61, 64] years, 79% were male) were included. There was no significant difference in Clinical Frailty Scores between groups. Younger patients had longer total PBMC-TL (0.40 Mb [0.30, 0.49] vs. 0.29 Mb [0.23, 0.33], P < 0.001) and longer average PBMC-TL per chromosome (4.3 kb [3.3, 5.3] vs. 3.2 kb [2.5, 3.7], P < 0.001). When older patients were stratified by 50th percentile of PBMC-TL, there were no differences in thrombin generation; however, those with shorter telomeres were less likely to be discharged home (29% vs. 77%, P = 0.004). Older patients in the bottom quartile of PBMC-TL had shorter lag time (2.78 min [2.33, 3.00] vs. 3.33 min [3.24, 3.89], P = 0.030) and were less likely to be discharged home (22% vs. 90%, P = 0.006) than those in the top quartile of PBMC-TL. Multivariable logistic regression models revealed both increased age and shorter PBMC-TL to be independent predictors of discharge disposition other than home. Conclusion: In older trauma patients, shorter PBMC-TL is associated with accelerated initiation of thrombin generation and lower likelihood of being discharged to home.

Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels.

To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression of CYP3A7, a gene involved in testosterone metabolism. Thus, our findings suggest opportunities for hormone therapy to prevent or treat endometrial cancer.

Estradiol and Dihydrotestosterone Levels in COVID-19 Patients.

OBJECTIVE: To determine differences in plasma sex hormone levels in male and female coronavirus disease 2019 (COVID-19) patients and healthy volunteers (HVs) because cell entry of severe acute respiratory syndrome coronavirus 2 occurs via the angiotensin-converting enzyme 2 receptor which is downregulated by 17ß-estradiol. PATIENTS AND METHODS: Citrated plasma samples were collected from 101 patients with COVID-19 upon presentation to the emergency department and from 40 HVs between November 1, 2020, and May 30, 2021. Plasma 17ß-estradiol and 5α-dihydrotestosterone (DHT) levels were measured using enzyme-linked immunosorbent assay (pg/mL). Data are presented as median and quartiles (IQR). Wilcoxon rank sum test with a P value less than .05 was considered significant. RESULTS: Patients with COVID-19 (median age, 49 years) included 51 males and 50 females (25 postmenopausal). Hospital admission was required for 58.8% of male patients (n = 30) and 48.0% of female patients (n = 24) (66.7% postmenopausal, n = 16) Healthy volunteers (median age, 41 years) included 20 males and 20 females (9 postmenopausal). Female patients with COVID-19 were found to have decreased 17ß-estradiol levels (18.5 [IQR, 10.5-32.3] pg/mL; 41.4 [IQR, 15.5-111.0] pg/mL, P=.025), and lower 17ß-estradiol to DHT ratios (0.073 [IQR, 0.052-0.159] pg/mL; 0.207 [IQR, 0.104-0.538] pg/mL, P=.015) than female HVs. Male patients with COVID-19 were found to have decreased DHT levels (302.8 [IQR, 249.9-470.8] pg/mL; 457.2 [IQR, 368.7-844.3] pg/mL, P=.005), compared with male HVs. Levels of DHT did not differ between female patients with COVID-19 and female HVs, whereas 17ß-estradiol levels did not differ between male patients with COVID-19 and male HVs. CONCLUSION: Sex hormone levels differ between patients with COVID-19 and HVs, with sex-specific patterns of hypogonadism in males and females. These alterations may be associated with disease development and severity.

Association of two genomic variants with HPV type-specific risk of cervical cancer.

PROBLEM: Human papillomavirus infection is integral to developing invasive cervical cancer in the majority of patients. In a recent genome-wide association study, rs9357152 and rs4243652 have been associated with seropositivity for HPV16 or HPV18, respectively. It is unknown whether these variants also associate with cervical cancer triggered by either HPV16 or HPV18. METHODS: We investigate whether the two HPV susceptibility variants show association with type-specific cervical cancer in a genetic case-control study with cases stratified by HPV16 or HPV18, respectively. We further tested whether rs9357152 modulates gene expression of any of 36 genes at the human leukocyte antigen locus in 256 cervical tissues. RESULTS: rs9357152 was associated with invasive HPV16-positive cervical cancer (OR 1.33, 95%CI 1.03-1.70, p = 0.03), and rs4243652 was associated with HPV18-positive adenocarcinomas (OR 2.96, 95%CI 1.18-7.41, p = 0.02). These associations remained borderline significant after testing against different sets of controls. rs9357152 was found to be an eQTL for HLA-DRB1 in HPV-positive cervical tissues (pANOVA = 0.0009), with the risk allele lowering mRNA levels. CONCLUSIONS: We find evidence that HPV seropositivity variants at chromosome 6 and 14 may modulate type-specific cervical cancer risk. rs9357152 may exert its effect through regulating HLA-DRB1 induction in the presence of HPV. In regard of multiple testing, these results need to be confirmed in larger studies.