Glucocorticoid stimulation induces regionalized gene responses within topologically associating domains.

Transcription-factor binding to cis-regulatory regions regulates the gene expression program of a cell, but occupancy is often a poor predictor of the gene response. Here, we show that glucocorticoid stimulation led to the reorganization of transcriptional coregulators MED1 and BRD4 within topologically associating domains (TADs), resulting in active or repressive gene environments. Indeed, we observed a bias toward the activation or repression of a TAD when their activities were defined by the number of regions gaining and losing MED1 and BRD4 following dexamethasone (Dex) stimulation. Variations in Dex-responsive genes at the RNA levels were consistent with the redistribution of MED1 and BRD4 at the associated cis-regulatory regions. Interestingly, Dex-responsive genes without the differential recruitment of MED1 and BRD4 or binding by the glucocorticoid receptor were found within TADs, which gained or lost MED1 and BRD4, suggesting a role of the surrounding environment in gene regulation. However, the amplitude of the response of Dex-regulated genes was higher when the differential recruitment of the glucocorticoid receptor and transcriptional coregulators was observed, reaffirming the role of transcription factor-driven gene regulation and attributing a lesser role to the TAD environment. These results support a model where a signal-induced transcription factor induces a regionalized effect throughout the TAD, redefining the notion of direct and indirect effects of transcription factors on target genes.

Impact of a Pozzi tenaculum forceps use on the success rate of intrauterine insemination (IUI) : protocol for a randomised control trial.

INTRODUCTION: A therapeutic option frequently proposed for infertility is to proceed first with intrauterine insemination (IUI) cycles. Little is known on the effect of uterine contractions on IUI success rates. We postulated that uterine contractions may help with sperm migration in the women's genital tract. Our objective is to compare the efficacy of IUI when performed with and without a tenaculum forceps on the cervix. METHODS AND ANALYSIS: We are conducting a randomised controlled trial with women aged 18-40 years old, diagnosed with primary or secondary infertility due to endometriosis, mild to moderate male factor, unexplained infertility or ovulatory dysfunction, receiving IUI treatments. On the day of their IUI, women will receive standard care treatment plus or minus the planned use of a Pozzi tenaculum forceps on the cervix. Each of the 800 women will be randomised only once for their first three IUI. They will be randomised in one of the following sequences: tenaculum-no tenaculum-tenaculum or, no tenaculum-tenaculum-no tenaculum. We will compare the live birth rate (primary outcome) and the clinical pregnancy rate (secondary outcome) after IUI treatment. We also plan on assessing global satisfaction of women, pain levels felt during IUI and discrepancies in primary and secondary outcomes in interventions performed by attendings compared with trainees. ETHICS AND DISSEMINATION: This research project was approved by the Centre Hospitalier Universitaire de Québec's ethics review board (no 2018-4084). Pozzi tenaculum application is associated with mild pain, estimated at 33 on a Visual Analogue Scale ranging from 0 to 100. We plan on publishing an article to present our findings in a peer-reviewed journal as well as presenting the research abstract at conferences. TRIAL REGISTRATION NUMBER: NCT03435809.

Modulating HSF1 levels impacts expression of the estrogen receptor α and antiestrogen response.

Master transcription factors control the transcriptional program and are essential to maintain cellular functions. Among them, steroid nuclear receptors, such as the estrogen receptor α (ERα), are central to the etiology of hormone-dependent cancers which are accordingly treated with corresponding endocrine therapies. However, resistance invariably arises. Here, we show that high levels of the stress response master regulator, the heat shock factor 1 (HSF1), are associated with antiestrogen resistance in breast cancer cells. Indeed, overexpression of HSF1 leads to ERα degradation, decreased expression of ERα-activated genes, and antiestrogen resistance. Furthermore, we demonstrate that reducing HSF1 levels reinstates expression of the ERα and restores response to antiestrogens. Last, our results establish a proof of concept that inhibition of HSF1, in combination with antiestrogens, is a valid strategy to tackle resistant breast cancers. Taken together, we are proposing a mechanism where high HSF1 levels interfere with the ERα-dependent transcriptional program leading to endocrine resistance in breast cancer.

Describing adverse events in Swiss hospitalized oncology patients using the Global Trigger Tool.

BACKGROUND AND AIMS: The occurrence rate of adverse events (AEs) related to care among hospitalized oncology patients in Switzerland remains unknown. The primary objective of this study was to describe, for the first time, the occurrence rate, type, severity of harm, and preventability of AEs related to care, reported in health records of hospitalized hematological and solid-tumor cancer patients in three Swiss hospitals. METHODS: Using an adapted version of the validated Global Trigger Tool (GTT) from the Institute for Healthcare Improvement, we conducted a retrospective record review of patients discharged from oncology units over a 6-week period during 2018. Our convenience sample included all records from adult patients (≥18 years of age), diagnosed with cancer, and hospitalized (>24 hours). Per the GTT method, two trained nurses independently assessed patient records to identify AEs using triggers, and physicians from the included units analyzed the consensus of the two nurses. Together, they assessed the severity and preventability of each AE. RESULTS: From the sample of 224 reviewed records, we identified 661 triggers and 169 AEs in 94 of them (42%). Pain related to care was the most frequent AE (n = 29), followed by constipation (n = 17). AEs rates were 75.4 per 100 admissions and 106.6 per 1000 patient days. Most of the identified AEs (78%) caused temporary harm to the patient and required an intervention. Among AEs during hospitalization (n = 125), 76 (61%) were considered not preventable, 28 (22%) preventable, and 21 (17%) undetermined. CONCLUSION: About half of the hospitalized oncology patients suffered from at least one AE related to care during their hospitalization. Pain, constipation, and nosocomial infections were the most frequent AEs. It is, therefore, essential to identify AEs to guide future clinical practice initiatives to ensure patient safety.

First Trimester Mean Arterial Pressure Measured Manually Versus Using an Automated Device and the Prediction of Preeclampsia: A Case-Cohort Study.

OBJECTIVE: First trimester mean arterial blood pressure (MAP) can be used to predict preeclampsia. This study aimed to compare the performance of first trimester MAP measured with an automated device using a standardized technique versus MAP taken manually in a typical clinical setting. METHODS: A case-cohort study niched into a prospective cohort of pregnant women recruited at 11-14 weeks was performed. MAP was measured with an automated device on both arms until stability was reached. These results were compared with the MAP measured with a manual device at the closest medical visit (between 10 and 15 weeks gestation) and noted in the medical charts. Receiver-operator characteristics curve analyses were used to estimate the predictive values of MAP measured by both techniques. RESULTS: Forty-one women with preeclampsia and 167 control patients were used for the comparisons. MAP measured with an automated device decreased significantly between 11 and 14 weeks gestation (P < 0.001). Moreover, MAP measured with an automated device was a better predictor of preeclampsia (area under the curve 0.70; 95% confidence interval 0.61-0.79) than MAP measured with a manual device in a clinical setting (area under the curve 0.60; 95% confidence interval 0.50-0.70). Taken alone, MAP measured with an automated device was associated with a detection rate of preeclampsia of 34%, for a false-positive rate of 10%. CONCLUSION: First trimester MAP can predict preeclampsia. This study demonstrated that MAP measured with an automated device using a standardized technique is a better predictor than MAP measured with a manual device.

First-trimester mean arterial blood pressure and the risk of preeclampsia: The Great Obstetrical Syndromes (GOS) study.

OBJECTIVE: To estimate the predictive value of first-trimester mean arterial pressure (MAP) for the hypertensive disorders of pregnancy (HDP). STUDY METHODS: We performed a prospective cohort study of nulliparous women recruited at 110/7-136/7 weeks. MAP was calculated from blood pressure measured on both arms simultaneously using an automated device taking a series of recordings until blood pressure stability was reached. MAP was reported as multiples of the median adjusted for gestational age. Participants were followed for development of gestational hypertension (GH), preeclampsia (PE), preterm PE (<37 weeks) and early-onset (EO) PE (<34 weeks). Receiver operating characteristic curves and the area under the curve (AUC) were used to estimate the predictive values of MAP. Multivariate logistic regressions were used to develop predictive models combining MAP and maternal characteristics. RESULTS: We obtained complete follow-up in 4700 (99%) out of 4749 eligible participants. GH without PE was observed in 250 (5.3%) participants, and PE in 241 (5.1%), including 33 (0.7%) preterm PE and 10 (0.2%) EO-PE. First-trimester MAP was associated with GH (AUC: 0.77; 95%CI: 0.74-0.80); term PE (0.73; 95%CI: 0.70-0.76), preterm PE (0.80; 95%CI: 0.73-0.87) and EO-PE (0.79; 95%CI: 0.62-0.96). At a 10% false-positive rate, first-trimester MAP could have predicted 39% of GH, 34% of term PE, 48% of preterm PE and 60% of EO-PE. The addition of maternal characteristics improved the predictive values (to 40%, 37%, 55% and 70%, respectively). CONCLUSION: First-trimester MAP is a strong predictor of GH and PE in nulliparous women.

FOXA and master transcription factors recruit Mediator and Cohesin to the core transcriptional regulatory circuitry of cancer cells.

Controlling the transcriptional program is essential to maintain the identity and the biological functions of a cell. The Mediator and Cohesin complexes have been established as central cofactors controlling the transcriptional program in normal cells. However, the distribution, recruitment and importance of these complexes in cancer cells have not been fully investigated. Here we show that FOXA and master transcription factors are part of the core transcriptional regulatory circuitry of cancer cells and are essential to recruit M ediator and Cohesin. Indeed, Mediator and Cohesin occupied the enhancer and promoter regions of actively transcribed genes and maintained the proliferation and colony forming potential. Through integration of publically available ChIP-Seq datasets, we predicted the core transcriptional regulatory circuitry of each cancer cell. Unexpectedly, for all cells investigated, the pioneer transcription factors FOXA1 and/or FOXA2 were identified in addition to cell-specific master transcription factors. Loss of both types of transcription factors phenocopied the loss of Mediator and Cohesin. Lastly, the master and pioneer transcription factors were essential to recruit Mediator and Cohesin to regulatory regions of actively transcribed genes. Our study proposes that maintenance of the cancer cell state is dependent on recruitment of Mediator and Cohesin through FOXA and master transcription factors.

Posterior tibial nerve sensory blockade duration prolonged by adding dexmedetomidine to ropivacaine.

BACKGROUND: Dexmedetomidine, an α(2)-receptor agonist, prolongs analgesia when used in neuraxial and IV blocks. We evaluated the effect of dexmedetomidine added to ropivacaine for tibial nerve block on the duration of the sensory blockade. METHODS: For this prospective, randomized, controlled, double-blind, crossover trial, 14 healthy volunteers were allocated to 2 groups. All volunteers received an ultrasound-guided tibial nerve block 4 to 5 cm proximally to the medial malleolus. In group R, 10 mL of 0.5% ropivacaine was injected for the block; in group RD, 10 mL of a solution containing 0.5% ropivacaine with 1 µg/kg of dexmedetomidine was administered. After the injection, monitoring of vital signs, evaluation of onset and resolution of sensory block, and level of sedation (Observer's Assessment of Alertness/Sedation scale) were performed. Three weeks later, the same procedure was repeated, but the study subjects were allocated to the other group in a crossover fashion. The primary end point was the duration of sensory blockade. The time and carryover effects were also evaluated. Secondary outcomes were the onset time and the presence of adverse effects such as hypotension, bradycardia, hypoxia, and sedation. RESULTS: Sensory blocks lasted longer in group RD than in group R (21.5 vs 16.2 hours; mean pairwise difference 5.3 hours [95% confidence interval: 3.9-6.7 hours]; P < 0.0001). Onset times were similar between groups. The mean systolic and diastolic blood pressure levels were stable throughout the study period in group R. In group RD, a noticeable decrease in systolic and diastolic blood pressure was observed between 60 and 480 minutes (P < 0.05); 2 volunteers experienced a 30% decrease in systolic blood pressure when compared with the baseline value as compared with none in group R. Heart rate was similar between groups except at 60 minutes (P < 0.01). CONCLUSION: Dexmedetomidine added to ropivacaine for tibial nerve block prolongs the duration of sensory blockade with similar onset time. However, patients should be monitored for potential adverse effects such as hypotension, bradycardia, and sedation.

The impact of anesthesia on glycine absorption in operative hysteroscopy: a randomized controlled trial.

BACKGROUND: Operative hysteroscopy requires the use of a distension medium and its absorption can lead to serious consequences from intravascular volume overload and water intoxication. We compared the impact of 2 types of anesthesia (general anesthesia and local anesthesia with sedation) on the absorption of glycine solution in operative hysteroscopy. METHODS: A randomized controlled trial was conducted over a 17-month period. Eligible patients undergoing operative hysteroscopy for abnormal uterine bleeding were randomized in 2 groups: a general anesthesia group and a local anesthesia with sedation group. The primary outcome was the median absorption of the glycine solution (10th-90th percentile) measured with an automated tandem canister system. Secondary outcomes included incidence of absorption >1000 mL, discontinued surgery because of excessive absorption, median change in serum sodium, postoperative hyponatremia, and patients' postoperative quality of life at 24 hours (8-item Short Form Health Survey questionnaire). Nonparametric analyses (Mann-Whitney U test, χ(2) test, and Fisher exact test) were used. RESULTS: Of 142 eligible patients, 95 agreed to participate and were randomized. Women who underwent general anesthesia had a higher median absorption of the glycine solution (10th-90th percentile) compared with women who underwent local anesthesia with sedation (480 mL [76-1300 mL] vs 253 mL [70-728 mL]; P = 0.005). General anesthesia was also associated with a higher rate of glycine solution absorption (>1000 mL [20% vs 4%; P = 0.009]) and a more rapid rate of decrease in serum sodium (≥10 mEq/L [8% vs 0%; P = 0.005]) than local anesthesia with sedation. Postoperative quality of life measures as rated by the patients were comparable between the 2 groups. CONCLUSION: Compared with general anesthesia, local anesthesia with sedation is associated with less glycine absorption and should be considered the preferred method of anesthesia for operative hysteroscopy.

Regulation of vascular endothelial growth factor-induced endothelial cell migration by LIM kinase 1-mediated phosphorylation of annexin 1.

In this study, we obtained evidence indicating that annexin 1 is a new target of the p38/MAPKAP kinase-2 pathway and that it regulates endothelial cell migration in response to vascular endothelial growth factor (VEGF). These conclusions are supported by a series of substantiating experiments. First, by two-dimensional gel electrophoresis and mass spectrometry, we identified annexin 1 as a protein whose phosphorylation is induced by VEGF and is impaired by inhibiting p38. Second, using in vitro kinase assays and in vivo phosphorylation assays, we found that VEGF-mediated activation of LIM kinase 1 downstream of the p38 pathway triggers the phosphorylation of annexin 1. Third, VEGF-induced cell migration and tube formation in Matrigel are inhibited following small interfering RNA-mediated knockdown of annexin 1. Fourth, both processes are rescued in cells expressing an annexin 1 construct insensitive to the small interfering RNA knockdown. Finally, the VEGF/annexin 1-mediated cell migration is impaired by inhibiting p38. We therefore conclude that phosphorylation of annexin 1 regulates the angiogenic effect that is associated with the activation of the p38/LIM kinase 1 axis by VEGF.

The burden of hospitalized hip fractures: patterns of admissions in a level I trauma center over 20 years.

BACKGROUND: To describe trends over 20 years in (1) number of admissions for hip fracture, (2) patients' demographics, type of fractures sustained by the patients, and their health status at admission, (3) surgical delays, and (4) acute care outcomes. METHODS: This trend was a study conducted in a Level I trauma center in Quebec, Canada. All patients (n = 3174) aged 65 and older, admitted with a hip fracture between 1985 and 2005 were included. Outcome measures were: number of admissions, age, gender, comorbidities at admission, surgical delays, postsurgical complications, inpatient mortality, discharge destinations. RESULTS: From 1985 to 2005, the number of admissions increased from 56 to 271, age at admission has increased by 2 years both in men and women (p < 0.01), women/men proportion has remained stable (3.2) over time. The adjusted proportions of minor and severe comorbidities at admission increased by 13% and 5% yearly (p < 0.01). Surgical delays decreased from 4.7 days +/- 16.5 days to 0.9 days +/- 1.9 days (p < 0.01). Acute care length of stay has drastically decreased from 37.0 days +/- 70.9 days to 16.7 days +/- 14.2 days (p < 0.01). Although severe postsurgical complications did not increase over time, the proportion of patients suffering from minor postsurgical complications increased by 22%. Inpatient death has decreased by 4% each year. CONCLUSION: The tremendous increase in the volume of older and sicker patients admitted for hip fracture has put an enormous demand on our Level I trauma center. The changes in clinical management implemented to face this challenge have helped improve acute care outcomes.