Postpartum haemorrhage (PPH) can be exacerbated by haemostatic failure. We hypothesized that early fibrinogen replacement, guided by viscoelastometric testing, reduces blood product usage and bleed ...size.
Women with PPH 1000–1500 ml were enrolled. If Fibtem A5 was ≤15 mm and bleeding continued, subjects were randomized to fibrinogen concentrate or placebo. The primary outcome compared the number of units of red blood cells, plasma, cryoprecipitate and platelets transfused.
Of 663 women enrolled 55 were randomized. The adjusted incidence rate ratio (IRR) (95% CI) for the number of allogeneic units transfused in the fibrinogen group compared with placebo was 0.72 (0.3–1.7), P=0.45. In pre-specified subgroup analyses, subjects who had a Fibtem A5 ≤12 mm at the time of randomization and who received fibrinogen concentrate received a median (25th–75th centile) of 1 (0–4.5) unit of allogeneic blood products and had an additional 300 (100–350) ml blood loss whereas those who received placebo also received 3 (0–6) units of allogeneic blood products and had 700 (200–1550) ml additional blood loss; these differences were not statistically significantly different. There was one thrombotic event in each group.
Infusion of fibrinogen concentrate triggered by Fibtem A5 ≤15 mm did not improve outcomes in PPH. Pre-specified subgroup analyses suggest that fibrinogen replacement is not required if the Fibtem A5 is > 12 mm or Clauss fibrinogen >2 g litre−1, but an effect below these levels cannot be excluded. The raised fibrinogen at term appears to be a physiological buffer rather than required for haemostasis.
ISRCTN46295339 (http://www.isrctn.com/ISRCTN46295339, last accessed 5 July 2017), EudraCT 2012-005511-11 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-005511-11, last accessed 5 July 2017).
Summary Background Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with ...oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. Methods 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2–3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. Results After a median follow-up of 55·7 months (range 0–89·7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0·76 (95% CI 0·66–0·88, p=0·0001) in favour of exemestane, absolute benefit 3·3% (95% CI 1·6–4·9) by end of treatment (ie, 2·5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0·85 (95% CI 0·71–1·02, p=0·08), 0·83 (0·69–1·00, p=0·05) when 122 patients with oestrogen-receptor-negative disease were excluded. Conclusions Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2–3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.
Escalating environmental threats to coral reefs coincides with global advancements in coral restoration programs. To improve long-term efficacy, practitioners must consider incorporating genotypes ...resilient to ocean warming and disease while maintaining genetic diversity. Identifying such genotypes typically occurs under long-term exposures that mimic natural stressors, but these experiments can be time-consuming, costly, and introduce tank effects, hindering scalability for hundreds of nursery genotypes used for outplanting. Here, we evaluated the efficacy of the acute Coral Bleaching Automated Stress System (CBASS) against long-term exposures on the bleaching response of Acropora cervicornis, the dominant restoration species in Florida's Coral Reef. Comparing bleaching metrics, F
/F
, chlorophyll, and host protein, we observed similar responses between the long-term heat and the CBASS treatment of 34.3 °C, which was also the calculated bleaching threshold. This suggests the potential of CBASS as a rapid screening tool, with 90% of restoration genotypes exhibiting similar bleaching tolerances. However, variations in acute bleaching phenotypes arose from measurement timing and experiment heat accumulation, cautioning against generalizations solely based on metrics like F
/F
. These findings identify the need to better refine the tools necessary to quickly and effectively screen coral restoration genotypes and determine their relative tolerance for restoration interventions.
The All of Us (AoU) initiative aims to sequence the genomes of over one million Americans from diverse ethnic backgrounds to improve personalized medical care. In a recent technical pilot, we compare ...the performance of traditional short-read sequencing with long-read sequencing in a small cohort of samples from the HapMap project and two AoU control samples representing eight datasets. Our analysis reveals substantial differences in the ability of these technologies to accurately sequence complex medically relevant genes, particularly in terms of gene coverage and pathogenic variant identification. We also consider the advantages and challenges of using low coverage sequencing to increase sample numbers in large cohort analysis. Our results show that HiFi reads produce the most accurate results for both small and large variants. Further, we present a cloud-based pipeline to optimize SNV, indel and SV calling at scale for long-reads analysis. These results lead to widespread improvements across AoU.
A plethora of drug molecules and agrochemicals contain the sulfonamide functional group. However, sulfonamides are seldom viewed as synthetically useful functional groups. To confront this ...limitation, a late-stage functionalization strategy is described, which allows sulfonamides to be converted to pivotal sulfonyl radical intermediates. This methodology exploits a metal-free photocatalytic approach to access radical chemistry, which is harnessed by combining pharmaceutically relevant sulfonamides with an assortment of alkene fragments. Additionally, the sulfinate anion can be readily obtained, further broadening the options for sulfonamide functionalization. Mechanistic studies suggest that energy-transfer catalysis (EnT) is in operation.
Results for the solar heating rates in ambient air due to absorption by black-carbon (BC) containing particles and ozone are presented as calculated from airborne observations made in the tropical ...tropopause layer (TTL) in January-February 2006. The method uses airborne in situ observations of BC particles, ozone and actinic flux. Total BC mass is obtained along the flight track by summing the masses of individually detected BC particles in the range 90 to 600-nm volume-equivalent diameter, which includes most of the BC mass. Ozone mixing ratios and upwelling and partial downwelling solar actinic fluxes were measured concurrently with BC mass. Two estimates used for the BC wavelength-dependent absorption cross section yielded similar heating rates. For mean altitudes of 16.5, 17.5, and 18.5 km (0.5 km) in the tropics, average BC heating rates were near 0.0002 K/d. Observed BC coatings on individual particles approximately double derived BC heating rates. Ozone heating rates exceeded BC heating rates by approximately a factor of 100 on average and at least a factor of 4, suggesting that BC heating rates in this region are negligible in comparison.
Our previous laboratory and clinical data suggested that one mechanism underlying the development of platinum resistance in ovarian cancer is the acquisition of DNA methylation. We therefore tested ...the hypothesis that the DNA hypomethylating agent 5-aza-2'-deoxycytodine (decitabine) can reverse resistance to carboplatin in women with relapsed ovarian cancer.
Patients progressing 6-12 months after previous platinum therapy were randomised to decitabine on day 1 and carboplatin (AUC 6) on day 8, every 28 days or carboplatin alone. The primary objective was response rate in patients with methylated hMLH1 tumour DNA in plasma.
After a pre-defined interim analysis, the study closed due to lack of efficacy and poor treatment deliverability in 15 patients treated with the combination. Responses by GCIG criteria were 9 out of 14 vs 3 out of 15 and by RECIST were 6 out of 13 vs 1 out of 12 for carboplatin and carboplatin/decitabine, respectively. Grade 3/4 neutropenia was more common with the combination (60% vs 15.4%) as was G2/3 carboplatin hypersensitivity (47% vs 21%).
With this schedule, the addition of decitabine appears to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to deliver. Patient-selection strategies, different schedules and other demethylating agents should be considered in future combination studies.
Abdominal radiotherapy for testicular cancer (TC) increases risk for second stomach cancer, although data on the radiation dose-response relationship are sparse.
In a cohort of 22,269 5-year TC ...survivors diagnosed during 1959-1987, doses to stomach subsites were estimated for 92 patients who developed stomach cancer and 180 matched controls. Chemotherapy details were recorded. Odds ratios (ORs) were estimated using logistic regression.
Cumulative incidence of second primary stomach cancer was 1.45% at 30 years after TC diagnosis. The TC survivors who received radiotherapy (87 (95%) cases, 151 (84%) controls) had a 5.9-fold (95% confidence interval (CI) 1.7-20.7) increased risk of stomach cancer. Risk increased with increasing stomach dose (P-trend<0.001), with an OR of 20.5 (3.7-114.3) for ⩾50.0 Gy compared with <10 Gy. Radiation-related risks remained elevated ⩾20 years after exposure (P<0.001). Risk after any chemotherapy was not elevated (OR=1.1; 95% CI 0.5-2.5; 14 cases and 23 controls).
Radiotherapy for TC involving parts of the stomach increased gastric cancer risk for several decades, with the highest risks after stomach doses of ⩾30 Gy. Clinicians should be aware of these excesses when previously irradiated TC survivors present with gastrointestinal symptoms and when any radiotherapy is considered in newly diagnosed TC patients.
. Wilhelm‐Leen ER, Hall YN, deBoer IH, Chertow GM. (Stanford University School of Medicine; University of Washington; Stanford University School of Medicine, Palo Alto, CA, USA). Vitamin D ...deficiency and frailty in older Americans. J Intern Med 2010; 268: 171–180.
Objective. To explore the relation between 25‐hydroxyvitamin D deficiency and frailty. Frailty is a multidimensional phenotype that describes declining physical function and a vulnerability to adverse outcomes in the setting of physical stress such as illness or hospitalization. Low serum concentrations of 25‐hydroxyvitamin D are known to be associated with multiple chronic diseases such as cardiovascular disease and diabetes, in addition to all cause mortality.
Design. Using data from the Third National Health and Nutrition Survey (NHANES III), we evaluated the association between low serum 25‐hydroxyvitamin D concentration and frailty, defined according to a set of criteria derived from a definition previously described and validated.
Subjects. Nationally representative survey of noninstitutionalized US residents collected between 1988 and 1994.
Results. 25‐Hydroxyvitamin D deficiency, defined as a serum concentration <15 ng mL−1, was associated with a 3.7‐fold increase in the odds of frailty amongst whites and a fourfold increase in the odds of frailty amongst non‐whites. This association persisted after sensitivity analyses adjusting for season of the year and latitude of residence, intended to reduce misclassification of persons as 25‐hydroxyvitamin D deficient or insufficient.
Conclusion. Low serum 25‐hydroxyvitamin D concentrations are associated with frailty amongst older adults.
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