Mechanical and surgical interventions for treating primary postpartum haemorrhage.

BACKGROUND:Primary postpartum haemorrhage (PPH) is commonly defined as bleeding from the genital tract of 500 mL or more within 24 hours of birth. It is one of the most common causes of maternal mortality worldwide and causes significant physical and psychological morbidity. An earlier Cochrane Review considering any treatments for the management of primary PPH, has been split into separate reviews. This review considers treatment with mechanical and surgical interventions. OBJECTIVES:To determine the effectiveness and safety of mechanical and surgical interventions used for the treatment of primary PPH. SEARCH METHODS:We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (26 July 2019) and reference lists of retrieved studies. SELECTION CRITERIA:Randomised controlled trials (RCTs) of mechanical/surgical methods for the treatment of primary PPH compared with standard care or another mechanical/surgical method. Interventions could include uterine packing, intrauterine balloon insertion, artery ligation/embolism, or uterine compression (either with sutures or manually). We included studies reported in abstract form if there was sufficient information to permit risk of bias assessment. Trials using a cluster-RCT design were eligible for inclusion, but quasi-RCTs or cross-over studies were not. DATA COLLECTION AND ANALYSIS:Two review authors independently assessed studies for inclusion and risk of bias, independently extracted data and checked data for accuracy. We used GRADE to assess the certainty of the evidence. MAIN RESULTS:We included nine small trials (944 women) conducted in Pakistan, Turkey, Thailand, Egypt (four trials), Saudi Arabia, Benin and Mali. Overall, included trials were at an unclear risk of bias. Due to substantial differences between the studies, it was not possible to combine any trials in meta-analysis. Many of this review's important outcomes were not reported. GRADE assessments ranged from very low to low, with the majority of outcome results rated as very low certainty. Downgrading decisions were mainly based on study design limitations and imprecision; one study was also downgraded for indirectness. External uterine compression versus normal care (1 trial, 64 women) Very low-certainty evidence means that we are unclear about the effect on blood transfusion (risk ratio (RR) 2.33, 95% confidence interval (CI) 0.66 to 8.23). Uterine arterial embolisation versus surgical devascularisation plus B-Lynch (1 trial, 23 women) The available evidence for hysterectomy to control bleeding (RR 0.73, 95% CI 0.15 to 3.57) is unclear due to very low-certainty evidence. The available evidence for intervention side effects is also unclear because the evidence was very low certainty (RR 1.09; 95% CI 0.08 to 15.41). Intrauterine Tamponade Studies included various methods of intrauterine tamponade: the commercial Bakri balloon, a fluid-filled condom-loaded latex catheter ('condom catheter'), an air-filled latex balloon-loaded catheter ('latex balloon catheter'), or traditional packing with gauze. Balloon tamponade versus normal care (2 trials, 356 women) One study(116 women) used the condom catheter. This study found that it may increase blood loss of 1000 mL or more (RR 1.52, 95% CI 1.15 to 2.00; 113 women), very low-certainty evidence. For other outcomes the results are unclear and graded as very low-certainty evidence: mortality due to bleeding (RR 6.21, 95% CI 0.77 to 49.98); hysterectomy to control bleeding (RR 4.14, 95% CI 0.48 to 35.93); total blood transfusion (RR 1.49, 95% CI 0.88 to 2.51); and side effects. A second study of 240 women used the latex balloon catheter together with cervical cerclage. Very low-certainty evidence means we are unclear about the effect on hysterectomy (RR 0.14, 95% CI 0.01 to 2.74) and additional surgical interventions to control bleeding (RR 0.20, 95% CI 0.01 to 4.12). Bakri balloon tamponade versus haemostatic square suturing of the uterus (1 trial, 13 women) In this small trial there was no mortality due to bleeding, serious maternal morbidity or side effects of the intervention, and the results are unclear for blood transfusion (RR 0.57, 95% CI 0.14 to 2.36; very low certainty). Bakri balloon tamponade may reduce mean 'intraoperative' blood loss (mean difference (MD) -426 mL, 95% CI -631.28 to -220.72), very low-certainty evidence. Comparison of intrauterine tamponade methods (3 trials, 328 women) One study (66 women) compared the Bakri balloon and the condom catheter, but it was uncertain whether the Bakri balloon reduces the risk of hysterectomy to control bleeding due to very low-certainty evidence (RR 0.50, 95% CI 0.05 to 5.25). Very low-certainty evidence also means we are unclear about the results for the risk of blood transfusion (RR 0.97, 95% CI 0.88 to 1.06). A second study (50 women) compared Bakri balloon, with and without a traction stitch. Very low-certainty evidence means we are unclear about the results for hysterectomy to control bleeding (RR 0.20, 95% CI 0.01 to 3.97). A third study (212 women) compared the condom catheter to gauze packing and found that it may reduce fever (RR 0.47, 95% CI 0.38 to 0.59), but again the evidence was very low certainty. Modified B-Lynch compression suture versus standard B-Lynch compression suture (1 trial, 160 women) Low-certainty evidence suggests that a modified B-Lynch compression suture may reduce the risk of hysterectomy to control bleeding (RR 0.33, 95% CI 0.11 to 0.99) and postoperative blood loss (MD -244.00 mL, 95% CI -295.25 to -192.75). AUTHORS' CONCLUSIONS:There is currently insufficient evidence from RCTs to determine the relative effectiveness and safety of mechanical and surgical interventions for treating primary PPH. High-quality randomised trials are urgently needed, and new emergency consent pathways should facilitate recruitment. The finding that intrauterine tamponade may increase total blood loss > 1000 mL suggests that introducing condom-balloon tamponade into low-resource settings on its own without multi-system quality improvement does not reduce PPH deaths or morbidity. The suggestion that modified B-Lynch suture may be superior to the original requires further research before the revised technique is adopted. In high-resource settings, uterine artery embolisation has become popular as the equipment and skills become more widely available. However, there is little randomised trial evidence regarding efficacy and this requires further research. We urge new trial authors to adopt PPH core outcomes to facilitate consistency between primary studies and subsequent meta-analysis

Publisher Correction: The long non-coding RNA HOXB-AS3 regulates ribosomal RNA transcription in NPM1-mutated acute myeloid leukemia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Author Correction: The long non-coding RNA HOXB-AS3 regulates ribosomal RNA transcription in NPM1-mutated acute myeloid leukemia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial.

BACKGROUND: Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. METHODS: In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. FINDINGS: Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). INTERPRETATION: Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. FUNDING: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level