Genome-Wide Association Studies of the PR Interval in African Americans

The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p<2.5×10−8) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta  = 5.1 msec per minor allele, 95% CI  = 4.1–6.1, p = 3×10−23). This SNP was also associated with PR interval (beta = 2.4 msec per minor allele, 95% CI = 1.8–3.0, p = 3×10−16) in individuals of European ancestry (n = 14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p = 0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans

Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer

<p>Abstract</p> <p>Background</p> <p>Ovarian cancer (OvCa) most often derives from ovarian surface epithelial (OSE) cells. Several lines of evidence strongly suggest that increased exposure to progesterone (P4) protects women against developing OvCa. However, the underlying mechanisms of this protection are incompletely understood.</p> <p>Methods</p> <p>To determine downstream gene targets of P4, we established short term <it>in vitro </it>cultures of non-neoplastic OSE cells from six subjects, exposed the cells to P4 (10^-6M) for five days and performed transcriptional profiling with oligonucleotide microarrays containing over 22,000 transcripts.</p> <p>Results</p> <p>We identified concordant but modest gene expression changes in cholesterol/lipid homeostasis genes in three of six samples (responders), whereas the other three samples (non-responders) showed no expressional response to P4. The most up-regulated gene was <it>TMEM97 </it>which encodes a transmembrane protein of unknown function (MAC30). Analyses of outlier transcripts, whose expression levels changed most significantly upon P4 exposure, uncovered coordinate up-regulation of 14 cholesterol biosynthesis enzymes, insulin-induced gene 1, low density lipoprotein receptor, <it>ABCG1</it>, endothelial lipase, stearoyl- CoA and fatty acid desaturases, long-chain fatty-acyl elongase, and down-regulation of steroidogenic acute regulatory protein and <it>ABCC6</it>. Highly correlated tissue-specific expression patterns of <it>TMEM97 </it>and the cholesterol biosynthesis genes were confirmed by analysis of the GNF Atlas 2 universal gene expression database. Real-time quantitative RT-PCR analyses revealed 2.4-fold suppression of the <it>TMEM97 </it>gene expression in short-term cultures of OvCa relative to the normal OSE cells.</p> <p>Conclusion</p> <p>These findings suggest that a co-regulated transcript network of cholesterol/lipid homeostasis genes and <it>TMEM97 </it>are downstream targets of P4 in normal OSE cells and that <it>TMEM97 </it>plays a role in cholesterol and lipid metabolism. The P4-induced alterations in cholesterol and lipid metabolism in OSE cells might play a role in conferring protection against OvCa.</p

Endometrial cancer

Endometrial cancer is the most common gynecological malignancy in well-developed countries. Biologically and clinicopathologically, endometrial carcinomas are divided into two types: type 1 or estrogen-dependent carcinomas and type 2 or estrogen-independent carcinomas. Type 1 cancers correspond mainly to endometrioid carcinomas and account for approximately 90 % of endometrial cancers, whereas type 2 cancers correspond to the majority of the other histopathological subtypes. The vast majority of endometrial cancers present as abnormal vaginal bleedings in postmenopausal women. Therefore, 75 % of cancers are diagnosed at an early stage, which makes the overall prognosis favorable. The first diagnostic step to evaluate women with an abnormal vaginal bleeding is the measurement of the endometrial thickness with transvaginal ultrasound. If endometrial thickening or heterogeneity is confirmed, a biopsy should be performed to establish a definite histopathological diagnosis. Magnetic resonance imaging is not considered in the International Federation of Gynaecology and Obstetrics staging system. Nonetheless it plays a relevant role in the preoperative staging of endometrial carcinoma, helping to define the best therapeutic management. Moreover, it is important in the diagnosis of treatment complications, in the surveillance of therapy response, and in the assessment of recurrent disease.info:eu-repo/semantics/publishedVersio

Group membership and racial bias modulate the temporal estimation of in-group/out-group body movements

Social group categorization has been mainly studied in relation to ownership manipulations involving highly-salient multisensory cues. Here, we propose a novel paradigm that can implicitly activate the embodiment process in the presence of group affiliation information, whilst participants complete a task irrelevant to social categorization. Ethnically White participants watched videos of White- and Black-skinned models writing a proverb. The writing was interrupted 7, 4 or 1 s before completion. Participants were tasked with estimating the residual duration following interruption. A video showing only hand kinematic traces acted as a control condition. Residual duration estimates for out-group and control videos were significantly lower than those for in-group videos only for the longest duration. Moreover, stronger implicit racial bias was negatively correlated to estimates of residual duration for out-group videos. The underestimation bias for the out-group condition might be mediated by implicit embodiment, affective and attentional processes, and finalized to a rapid out-group categorization

Awareness and preparedness of healthcare workers against the first wave of the COVID-19 pandemic: A cross-sectional survey across 57 countries.

BACKGROUND: Since the COVID-19 pandemic began, there have been concerns related to the preparedness of healthcare workers (HCWs). This study aimed to describe the level of awareness and preparedness of hospital HCWs at the time of the first wave. METHODS: This multinational, multicenter, cross-sectional survey was conducted among hospital HCWs from February to May 2020. We used a hierarchical logistic regression multivariate analysis to adjust the influence of variables based on awareness and preparedness. We then used association rule mining to identify relationships between HCW confidence in handling suspected COVID-19 patients and prior COVID-19 case-management training. RESULTS: We surveyed 24,653 HCWs from 371 hospitals across 57 countries and received 17,302 responses from 70.2% HCWs overall. The median COVID-19 preparedness score was 11.0 (interquartile range [IQR] = 6.0-14.0) and the median awareness score was 29.6 (IQR = 26.6-32.6). HCWs at COVID-19 designated facilities with previous outbreak experience, or HCWs who were trained for dealing with the SARS-CoV-2 outbreak, had significantly higher levels of preparedness and awareness (p<0.001). Association rule mining suggests that nurses and doctors who had a 'great-extent-of-confidence' in handling suspected COVID-19 patients had participated in COVID-19 training courses. Male participants (mean difference = 0.34; 95% CI = 0.22, 0.46; p<0.001) and nurses (mean difference = 0.67; 95% CI = 0.53, 0.81; p<0.001) had higher preparedness scores compared to women participants and doctors. INTERPRETATION: There was an unsurprising high level of awareness and preparedness among HCWs who participated in COVID-19 training courses. However, disparity existed along the lines of gender and type of HCW. It is unknown whether the difference in COVID-19 preparedness that we detected early in the pandemic may have translated into disproportionate SARS-CoV-2 burden of disease by gender or HCW type

Pediatric DXA: clinical applications

Normal bone mineral accrual requires adequate dietary intake of calcium, vitamin D and other nutrients; hepatic and renal activation of vitamin D; normal hormone levels (thyroid, parathyroid, reproductive and growth hormones); and neuromuscular functioning with sufficient stress upon the skeleton to induce bone deposition. The presence of genetic or acquired diseases and the therapies that are used to treat them can also impact bone health. Since the introduction of clinical DXA in pediatrics in the early 1990s, there has been considerable investigation into the causes of low bone mineral density (BMD) in children. Pediatricians have also become aware of the role adequate bone mass accrual in childhood has in preventing osteoporotic fractures in late adulthood. Additionally, the availability of medications to improve BMD has increased with the development of bisphosphonates. These factors have led to the increased utilization of DXA in pediatrics. This review summarizes much of the previous research regarding BMD in children and is meant to assist radiologists and clinicians with DXA utilization and interpretation