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The relationship between cortisol and perceived stress is poorly understood. We sought to determine whether perceived stress is associated with cortisol biomarkers in adolescents. In a sample of 229 adolescents (mean age = 15.8 years) we measured perceived stress with the 14-item Perceived Stress Scale (PSS) questionnaire, serum cortisol (sCOR), salivary Cortisol Awakening Response (CAR: 30-minute post-awakening - awakening), salivary Diurnal Cortisol Slope (DCS: evening-awakening), and total daily salivary cortisol (TDC). Multivariable linear regression was used to estimate baseline associations between PSS, TDC, and sCOR Mixed effects linear regression was used to estimate baseline associations between PSS and CAR and DCS. A twelve-week longitudinal association between PSS and cortisol biomarkers using random effects regression was tested. Analyses were adjusted for age, gender, and BMI. There were statistically significant associations between PSS and TDC (beta= -104.36 ± 34.3; p = 0.002) at baseline and between PSS and DCS at 12 weeks (beta= -0.058 ± 0.02; p = 0.01), but no association between PSS and sCOR or CAR (p > 0.26 for all) at baseline or 12-weeks. There were no associations between change in PSS and change in cortisol biomarkers longitudinally. In adolescents, perceived stress, measured by the PSS, was inconsistently associated with TDC and DCS, and consistently unassociated with CAR and sCOR. Studies reporting on PSS outcomes should exercise caution when making conclusions about cortisol biomarkers. There is a need for greater specificity of psychological stress to understand their relationship with biomarkers of stress.

PurposeTo determine whether a history of conception by assisted reproductive technology (ART) is associated with occurrence of one or more imprinting disorders of either maternal or paternal origin.MethodsWe implemented a systematic review of scholarly literature followed by comprehensive meta-analysis to quantitatively synthesize data from reports relating to use of ART to occurrence of any imprinting disorder of humans, including Beckwith-Wiedemann (BWS), Angelman (AS), Prader-Willi (PWS), and Silver-Russell (SRS) syndromes, as well as transient neonatal diabetes mellitus (TNDB) and sporadic retinoblasoma (RB).ResultsThe systematic review identified 13 reports presenting unique data from 23 studies that related conception following ART to occurrence of imprinting disorders. Multiple studies of four disorder were identified, for which meta-analysis yielded the following summary estimates of associations with a history of ART: AS, summary odds ratio (sOR) = 4.7 (95% confidence interval (CI) 2.6–8.5, 4 studies); BWS, sOR = 5.8 (95% CI 3.1–11.1, 8 studies); PWS, sOR = 2.2 (95% CI 1.6–3.0, 6 studies); SRS, sOR = 11.3 (95% CI 4.5–28.5, 3 studies). Only one study reported on each of TNDB and RB.ConclusionPublished data reveal positive associations between history of ART conception and each of four imprinting disorders. Reasons for these associations warrant further investigation.

Changes in epigenetic marks such as DNA methylation and histone acetylation are associated with a broad range of disease traits, including cancer, asthma, metabolic disorders, and various reproductive conditions. It seems plausible that changes in epigenetic state may be induced by environmental exposures such as malnutrition, tobacco smoke, air pollutants, metals, organic chemicals, other sources of oxidative stress, and the microbiome, particularly if the exposure occurs during key periods of development. Thus, epigenetic changes could represent an important pathway by which environmental factors influence disease risks, both within individuals and across generations. We discuss some of the challenges in studying epigenetic mediation of pathogenesis and describe some unique opportunities for exploring these phenomena.

Male-factor infertility is a common condition, and etiology is unknown for a high proportion of cases. Abnormal epigenetic programming of the germline is proposed as a possible mechanism compromising spermatogenesis of some men currently diagnosed with idiopathic infertility. During germ cell maturation and gametogenesis, cells of the germ line undergo extensive epigenetic reprogramming. This process involves widespread erasure of somatic-like patterns of DNA methylation followed by establishment of sex-specific patterns by de novo DNA methylation. Incomplete reprogramming of the male germ line could, in theory, result in both altered sperm DNA methylation and compromised spermatogenesis. We determined concentration, motility and morphology of sperm in semen samples collected by male members of couples attending an infertility clinic. Using MethyLight and Illumina assays we measured methylation of DNA isolated from purified sperm from the same samples. Methylation at numerous sequences was elevated in DNA from poor quality sperm. This is the first report of a broad epigenetic defect associated with abnormal semen parameters. Our results suggest that the underlying mechanism for these epigenetic changes may be improper erasure of DNA methylation during epigenetic reprogramming of the male germ line.

Background Preterm birth is a leading cause of infant morbidity and mortality worldwide. The burden of prematurity underscores the need for effective risk reduction strategies. The purpose of this study is to evaluate the efficacy of progesterone therapy, both intramuscular 17-α-hydroxyprogesterone caproate (IM 17-OHPC) and vaginal progesterone, in the prevention of recurrent spontaneous preterm birth (sPTB). The co-primary outcomes included: recurrent spontaneous PTB < 37 and < 34 weeks’ gestation. Methods This retrospective cohort study included 637 pregnant patients that delivered at any of the three hospitals within the Los Angeles County healthcare system between October 2015 and June 2021. We compared frequencies of measured variables between each of the progesterone treated groups to no treatment using Pearson chi-squared tests and independent t-tests for categorical and continuous variables, respectively. We estimated crude and adjusted associations between each specific treatment (versus no treatment) and primary outcomes using logistic regression. Results Recurrent sPTB < 37 weeks’ gestation occurred in 22.3% ( n  = 64) of those in the no treatment group, 29.1% ( n  = 86, p  = .077) in the 17-OHPC group, and 14.3% ( n  = 6, p  = 0.325) in the vaginal progesterone group. Recurrent sPTB < 34 weeks’ gestation was 6.6% ( n  = 19) in the no treatment group, 11.8% ( n  = 35, p  = .043) in the 17-OHPC group, and 7.1% ( n  = 3, p  = 1) in the vaginal progesterone group. Among all participants, neither 17-OHPC nor vaginal progesterone was significantly associated with a reduction in recurrent sPTB at any time point. Among those with a short cervix, IM 17-OHPC was positively associated with recurrent sPTB < 37 weeks’ gestation (aOR 5.61; 95% CI 1.16, 42.9). Conclusions Progesterone therapy of any type did not reduce the risk of recurrent sPTB < 34 or < 37 weeks’ gestation compared to no progesterone therapy.

Background/Objectives: Legal access to cannabinoids is increasing, and patients with chronic pelvic pain from endometriosis were hypothesized to explore and find benefit from the use of marijuana for symptom management. A survey of women with endometriosis was conducted with the objective of characterizing their experience with marijuana for management of pelvic pain: exploring symptom benefit, characteristics of use, and factors contributing to use and discontinuation. Methods: A descriptive cross-sectional survey was undertaken using an anonymous online questionnaire. Participants were recruited from an outpatient gynecology clinic using endometriosis ICD-10 diagnostic codes, and from the Endometriosis Association mailing list. Results: Marijuana use for symptom relief was reported by 78 (32.2%) Endometriosis Association participants, and 58 (46.8%) clinic participants. Within both populations, marijuana was considered very or moderately effective by most users (68.0 to 75.9%). Legality of recreational and medicinal marijuana in the state of residence was strongly associated with use (OR 7.13 [95% CI: 2.57–19.8]). Among users specifying current or past use, discontinuation was reported by 45% (54 of 121), and most frequently attributed to non-clinical factors of legal/employment risk and obstacles to marijuana access; 64.8% of former users attributed discontinuation to non-clinical factors only. Lack of symptom relief from other clinical management was the most cited motivation for initiation (55.1% clinic, 39.7% EA users). Conclusions: Marijuana use is common among women with endometriosis and chronic, refractory pelvic pain. Legality and access appear to impact use and discontinuation. While legal access to marijuana is associated with increased use, marijuana obtained outside of legal routes is also commonly being used for symptom relief.

Gestational trophoblastic diseases (GTDs) have not been investigated for their epigenetic marks and consequent transcriptomic changes. Here, we analyzed genome-wide DNA methylation and transcriptome data to reveal the epigenetic basis of disease pathways that may lead to benign or malignant GTDs. RNA-Seq, mRNA microarray, and Human Methylation 450 BeadChip data from complete moles and choriocarcinoma cells were bioinformatically analyzed. Paraffin-embedded tissues from complete moles and control placentas were used for tissue microarray construction, DNMT3B immunostaining and immunoscoring. We found that DNA methylation increases with disease severity in GTDs. Differentially expressed genes are mainly upregulated in moles while predominantly downregulated in choriocarcinoma. DNA methylation principally influences the gene expression of villous trophoblast differentiation-related or predominantly placenta-expressed genes in moles and choriocarcinoma cells. Affected genes in these subsets shared focal adhesion and actin cytoskeleton pathways in moles and choriocarcinoma. In moles, cell cycle and differentiation regulatory pathways, essential for trophoblast/placental development, were enriched. In choriocarcinoma cells, hormone biosynthetic, extracellular matrix-related, hypoxic gene regulatory, and differentiation-related signaling pathways were enriched. In moles, we found slight upregulation of DNMT3B protein, a developmentally important de novo DNA methylase, which is strongly overexpressed in choriocarcinoma cells that may partly be responsible for the large DNA methylation differences. Our findings provide new insights into the shared and disparate molecular pathways of disease in GTDs and may help in designing new diagnostic and therapeutic tools.

Katherine Nathanson and colleagues report four new susceptibility loci for testicular germ cell tumor identified through a meta-analysis of genome-wide association studies with follow-up replication. The newly discovered risk regions include genes important for male germ cell development, chromosomal segregation and the DNA damage response. We conducted a meta-analysis to identify new susceptibility loci for testicular germ cell tumor (TGCT). In the discovery phase, we analyzed 931 affected individuals and 1,975 controls from 3 genome-wide association studies (GWAS). We conducted replication in 6 independent sample sets comprising 3,211 affected individuals and 7,591 controls. In the combined analysis, risk of TGCT was significantly associated with markers at four previously unreported loci: 4q22.2 in HPGDS (per-allele odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.12–1.26; P = 1.11 × 10 −8 ), 7p22.3 in MAD1L1 (OR = 1.21, 95% CI = 1.14–1.29; P = 5.59 × 10 −9 ), 16q22.3 in RFWD3 (OR = 1.26, 95% CI = 1.18–1.34; P = 5.15 × 10 −12 ) and 17q22 (rs9905704: OR = 1.27, 95% CI = 1.18–1.33; P = 4.32 × 10 −13 and rs7221274: OR = 1.20, 95% CI = 1.12–1.28; P = 4.04 × 10 −9 ), a locus that includes TEX14 , RAD51C and PPM1E . These new TGCT susceptibility loci contain biologically plausible genes encoding proteins important for male germ cell development, chromosomal segregation and the DNA damage response.

ObjectiveTo compare the frequency and severity of neonatal hypoglycemia in pregnancies treated with and without late preterm antenatal corticosteroids.Study designWe conducted a retrospective cohort study of late preterm deliveries at LAC + USC (2015–2018). Neonatal outcomes were compared between pregnancies treated with and without corticosteroids.Results93 pregnancies (39.9%) received corticosteroids and 140 (60.1%) did not. Neonates born to women given corticosteroids were more likely to be hypoglycemic (47.3 vs. 29.3%, ORadj 2.25, padj = 0.01). The mean initial glucose (45.6 mg/dL vs. 51.9 mg/dL, p = 0.01) and glucose nadir (39.1 mg/dL vs. 45.4 mg/dL, p < 0.001) were significantly lower if the neonates received corticosteroids. Neonates admitted to the NICU solely for hypoglycemia were more likely to be born to women treated with corticosteroids (ORadj 4.71, padj = 0.01).ConclusionAdministration of late preterm corticosteroids was associated with an increased incidence and severity of neonatal hypoglycemia.

Gene expression studies of molar pregnancy have been limited to a small number of candidate loci. We analyzed high-dimensional RNA and protein data to characterize molecular features of complete hydatidiform moles (CHMs) and corresponding pathologic pathways. CHMs and first trimester placentas were collected, histopathologically examined, then flash-frozen or paraffin-embedded. Frozen CHMs and control placentas were subjected to RNA-Seq, with resulting data and published placental RNA-Seq data subjected to bioinformatics analyses. Paraffin-embedded tissues from CHMs and control placentas were used for tissue microarray (TMA) construction, immunohistochemistry, and immunoscoring for galectin-14. Of the 14,022 protein-coding genes expressed in all samples, 3,729 were differentially expressed (DE) in CHMs, of which 72% were up-regulated. DE genes were enriched in placenta-specific genes (OR = 1.88, p = 0.0001), of which 79% were down-regulated, imprinted genes (OR = 2.38, p = 1.54 × 10−6), and immune genes (OR = 1.82, p = 7.34 × 10−18), of which 73% were up-regulated. DNA methylation-related enzymes and histone demethylases were dysregulated. “Cytokine–cytokine receptor interaction” was the most impacted of 38 dysregulated pathways, among which 17 were immune-related pathways. TMA-based immunoscoring validated the lower expression of galectin-14 in CHM. In conclusion, placental functions were down-regulated, imprinted gene expression was altered, and immune pathways were activated, indicating complex dysregulation of placental developmental and immune processes in CHMs.