aObjectives To evaluate triple tourniquets in controlled conditions and for the first time to investigate the hypothesis that leaving a semi-permanent tourniquet around the uterine artery reduces post-operative bleeding from the uterine incisions. Design A randomised controlled trial.Setting Two University teaching hospitals.Population Twenty-eight patients with symptomatic fibroids and uterine sizes ranging from 14 to 24 weeks of gestation undergoing open myomectomy. Methods A number 1 polyglactin suture was tied around the cervix to occlude the uterine arteries, and polythene tourniquets were tied around the infundibulopelvic ligament to obstruct the ovarian vessels. At the end of the procedure, the ovarian ties were released but the uterine artery suture remained in situ. Main outcome measures Intra-operative blood loss, post-operative blood loss, blood transfusion rates, operative morbidity, uterine blood flow and ovarian function. Results There was significantly less blood lost in the tourniquet group than in the control group (difference between means 1870 mL, 95% CI 1159 -2580 mL, P < 0.0001; transfusion rates of 7% and 79%, P ¼ 0.0003). The volume in the pelvic drain 20 min post-operatively and after 48 hours failed to reach statistical significance between the two groups (P ¼ 0.10 and P ¼ 0.165). There were no differences in uterine artery Doppler resistance indices at five days (P ¼ 0.54), six weeks (P ¼ 0.47), three months (P ¼ 0.49) and at six months (P ¼ 0.18). Day two serum FSH concentrations after surgery were unchanged (P ¼ 0.45), compared with baseline values. Conclusions Triple tourniquets are effective in reducing bleeding and transfusion rates. There appears no obvious adverse effect on uterine perfusion or ovarian function.

Reactivation of fetal hemoglobin remains a critical goal in the treatment of patients with sickle cell disease and β-thalassemia. Previously, we discovered that silencing of the fetal γ-globin gene requires the erythroid-specific eIF2α kinase heme-regulated inhibitor (HRI), suggesting that HRI might present a pharmacologic target for raising fetal hemoglobin levels. Here, via a CRISPR-Cas9–guided loss-of-function screen in human erythroblasts, we identify transcription factor ATF4, a known HRI-regulated protein, as a novel γ-globin regulator. ATF4 directly stimulates transcription of BCL11A, a repressor of γ-globin transcription, by binding to its enhancer and fostering enhancer-promoter contacts. Notably, HRI-deficient mice display normal Bcl11a levels, suggesting species-selective regulation, which we explain here by demonstrating that the analogous ATF4 motif at the murine Bcl11a enhancer is largely dispensable. Our studies uncover a linear signaling pathway from HRI to ATF4 to BCL11A to γ-globin and illustrate potential limits of murine models of globin gene regulation.

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Objective To assess whether outpatient hysteroscopy using the 'no-touch' technique confers any advantages in terms of patient discomfort over the traditional technique. Design Prospective randomised controlled study.Setting Outpatient hysteroscopy clinic in a large university undergraduate teaching hospital.Population All women referred for outpatient hysteroscopy in a 12-month period.Interventions Women were randomised to undergo either traditional saline hysteroscopy requiring the use of a speculum and tenaculum, or a 'no-touch' vaginoscopic hysteroscopy which does not require a speculum or tenaculum. Each group was further subdivided to have hysteroscopy with either a 2.9-mm or 4-mm hysteroscope. Patients were asked to complete pre-and postprocedure questionnaires ranking pain scores. Main outcome measures The relative success of each of these techniques, requirement for local anaesthetic and pain scores at different times during the hysteroscopy were recorded at the end of the procedure. The time taken to carry out each procedure was also measured. Results One hundred and twenty women were recruited in this study: 60 were randomised to traditional hysteroscopy and 60 to 'no-touch' hysteroscopy. The overall success rate for hysteroscopy was 99%. There was no significant difference in the requirement for local anaesthetic between the two groups, but those who underwent 'no-touch' hysteroscopy with a 2.9-mm hysteroscope had the lowest requirement of local anaesthetic (10% compared with 27% in the no-touch hysteroscopy with a 4-mm hysteroscope group). The time taken to perform hysteroscopy and biopsy was significantly shorter with 'no-touch' hysteroscopy (5.9 vs 7.8 min; difference 1.9, 95% CI 0.7 -3.1). There were no differences in pain scores between the groups at different times during hysteroscopy. Conclusions 'No-touch' or vaginoscopic hysteroscopy is significantly faster to perform than the traditional technique. Although there was no difference in pain scores between the two techniques, local anaesthetic requirements were least in those who underwent 'no-touch' hysteroscopy with a narrow bore hysteroscope.

Animal chromosomes are partitioned into contact domains. Pathogenic domain disruptions can result from chromosomal rearrangements or perturbation of architectural factors. However, such broad-scale alterations are insufficient to define the minimal requirements for domain formation. Moreover, to what extent domains can be engineered is only beginning to be explored. In an attempt to create contact domains, we inserted a 2-kb DNA sequence underlying a tissue-invariant domain boundary—containing a CTCF binding site (CBS) and a transcription start site (TSS)—into 16 ectopic loci across 11 chromosomes, and characterized its architectural impact. Depending on local constraints, this fragment variably formed new domains, partitioned existing ones, altered compartmentalization, and initiated contacts reflective of chromatin loop extrusion. Deletions of the CBS or the TSS individually or in combination within inserts revealed their distinct contributions to genome folding. Altogether, short DNA insertions can suffice to shape the spatial genome in a manner influenced by chromatin context.