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The New England Journal of Medicine Apr 2019Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors.
BACKGROUND
Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors.
METHODS
We evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti-factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin).
RESULTS
Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti-factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti-factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage.
CONCLUSIONS
In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti-factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327.).
Topics: Acute Disease; Aged; Aged, 80 and over; Atrial Fibrillation; Coagulants; Factor Xa; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Intracranial Hemorrhages; Male; ROC Curve; Recombinant Proteins
PubMed: 30730782
DOI: 10.1056/NEJMoa1814051 -
The New England Journal of Medicine Feb 2004The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor...
BACKGROUND
The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role.
METHODS
We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia.
RESULTS
During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant.
CONCLUSIONS
Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia.
Topics: Adult; Biomarkers; Body Mass Index; Case-Control Studies; Cross-Sectional Studies; Female; Gestational Age; Humans; Logistic Models; Odds Ratio; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Pregnancy Proteins; Risk Factors; Statistics, Nonparametric; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1
PubMed: 14764923
DOI: 10.1056/NEJMoa031884 -
The New England Journal of Medicine May 2004The optimal upper limit of the normal range for prostate-specific antigen (PSA) is unknown. We investigated the prevalence of prostate cancer among men in the Prostate... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
The optimal upper limit of the normal range for prostate-specific antigen (PSA) is unknown. We investigated the prevalence of prostate cancer among men in the Prostate Cancer Prevention Trial who had a PSA level of 4.0 ng per milliliter or less.
METHODS
Of 18,882 men enrolled in the prevention trial, 9459 were randomly assigned to receive placebo and had an annual measurement of PSA and a digital rectal examination. Among these 9459 men, 2950 men never had a PSA level of more than 4.0 ng per milliliter or an abnormal digital rectal examination, had a final PSA determination, and underwent a prostate biopsy after being in the study for seven years.
RESULTS
Among the 2950 men (age range, 62 to 91 years), prostate cancer was diagnosed in 449 (15.2 percent); 67 of these 449 cancers (14.9 percent) had a Gleason score of 7 or higher. The prevalence of prostate cancer was 6.6 percent among men with a PSA level of up to 0.5 ng per milliliter, 10.1 percent among those with values of 0.6 to 1.0 ng per milliliter, 17.0 percent among those with values of 1.1 to 2.0 ng per milliliter, 23.9 percent among those with values of 2.1 to 3.0 ng per milliliter, and 26.9 percent among those with values of 3.1 to 4.0 ng per milliliter. The prevalence of high-grade cancers increased from 12.5 percent of cancers associated with a PSA level of 0.5 ng per milliliter or less to 25.0 percent of cancers associated with a PSA level of 3.1 to 4.0 ng per milliliter.
CONCLUSIONS
Biopsy-detected prostate cancer, including high-grade cancers, is not rare among men with PSA levels of 4.0 ng per milliliter or less--levels generally thought to be in the normal range.
Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Biopsy; Finasteride; Humans; Male; Middle Aged; Prevalence; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Risk
PubMed: 15163773
DOI: 10.1056/NEJMoa031918 -
The New England Journal of Medicine Jul 2018Smallpox was declared eradicated in 1980, but variola virus (VARV), which causes smallpox, still exists. There is no known effective treatment for smallpox; therefore,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Smallpox was declared eradicated in 1980, but variola virus (VARV), which causes smallpox, still exists. There is no known effective treatment for smallpox; therefore, tecovirimat is being developed as an oral smallpox therapy. Because clinical trials in a context of natural disease are not possible, an alternative developmental path to evaluate efficacy and safety was needed.
METHODS
We investigated the efficacy of tecovirimat in nonhuman primate (monkeypox) and rabbit (rabbitpox) models in accordance with the Food and Drug Administration (FDA) Animal Efficacy Rule, which was interpreted for smallpox therapeutics by an expert advisory committee. We also conducted a placebo-controlled pharmacokinetic and safety trial involving 449 adult volunteers.
RESULTS
The minimum dose of tecovirimat required in order to achieve more than 90% survival in the monkeypox model was 10 mg per kilogram of body weight for 14 days, and a dose of 40 mg per kilogram for 14 days was similarly efficacious in the rabbitpox model. Although the effective dose per kilogram was higher in rabbits, exposure was lower, with a mean steady-state maximum, minimum, and average (mean) concentration (C, C, and C, respectively) of 374, 25, and 138 ng per milliliter, respectively, in rabbits and 1444, 169, and 598 ng per milliliter in nonhuman primates, as well as an area under the concentration-time curve over 24 hours (AUC) of 3318 ng×hours per milliliter in rabbits and 14,352 ng×hours per milliliter in nonhuman primates. These findings suggested that the nonhuman primate was the more conservative model for the estimation of the required drug exposure in humans. A dose of 600 mg twice daily for 14 days was selected for testing in humans and provided exposures in excess of those in nonhuman primates (mean steady-state C, C, and C of 2209, 690, and 1270 ng per milliliter and AUC of 30,632 ng×hours per milliliter). No pattern of troubling adverse events was observed.
CONCLUSIONS
On the basis of its efficacy in two animal models and pharmacokinetic and safety data in humans, tecovirimat is being advanced as a therapy for smallpox in accordance with the FDA Animal Rule. (Funded by the National Institutes of Health and the Biomedical Advanced Research and Development Authority; ClinicalTrials.gov number, NCT02474589 .).
Topics: Administration, Oral; Adolescent; Adult; Aged; Animals; Antiviral Agents; Benzamides; Disease Models, Animal; Dose-Response Relationship, Drug; Double-Blind Method; Female; Healthy Volunteers; Humans; Isoindoles; Macaca fascicularis; Male; Middle Aged; Mpox (monkeypox); Monkeypox virus; Poxviridae Infections; Rabbits; Vaccinia virus; Young Adult
PubMed: 29972742
DOI: 10.1056/NEJMoa1705688 -
Saudi Journal of Biological Sciences Jan 2021Microbial surfactants are amphipathic molecules that consist of hydrophilic and hydrophobic domains, which allow partition of two fluid phases of varying degree of... (Review)
Review
Microbial surfactants are amphipathic molecules that consist of hydrophilic and hydrophobic domains, which allow partition of two fluid phases of varying degree of polarity. They are classified into two main groups: bioemulsifier and biosurfactant, depending on their molecular weight. Microbial surfactants occur in various categories according to their chemical nature and producing organisms. These biomolecules are produced by diverse groups of microorganisms including fungi, bacteria, and yeasts. Their production is significantly influenced by substrate type, fermentation technology and microbial strains. Owing to inherent multifunctional properties and assorted synthetic aptitude of the microbes, microbial surfactants are mostly preferred than their chemical counterparts for various industrial and biomedical applications including bioremediation, oil recovery; as supplements in laundry formulations and as emulsion-stabilizers in food and cosmetic industries as well as therapeutic agents in medicine. The present review discusses on production of microbial surfactants as promising and alternative broad-functional biomolecules for various biotechnological applications.
PubMed: 33424354
DOI: 10.1016/j.sjbs.2020.10.058 -
Academic Pediatrics 2018A recent American Academy of Pediatrics policy statement recommends milliliter-exclusive dosing for pediatric liquid medications. Little is known about parent...
BACKGROUND AND OBJECTIVES
A recent American Academy of Pediatrics policy statement recommends milliliter-exclusive dosing for pediatric liquid medications. Little is known about parent preferences regarding units, perceptions about moving to milliliters only, and the role of health literacy and prior milliliter-dosing experience.
METHODS
Cross-sectional analysis of data collected as part of a randomized controlled study in 3 urban pediatric clinics (SAFE Rx for Kids study). English- and Spanish-speaking parents (n = 493) of children aged ≤8 years were randomized to 1 of 4 study arms and given labels and dosing tools which varied in label instruction format (text plus pictogram, text only) and units (milliliter only ["mL"], milliliter/teaspoon ["mL"/"tsp"]). Outcomes included teaspoon preference in dosing instructions and perceived difficulty with milliliter-only dosing. The predictor variable was health literacy (Newest Vital Sign; low [0-1], marginal [2-3], adequate [4-6]). The mediating variable was prior milliliter-dosing experience.
RESULTS
Over two-thirds of parents had low or marginal health literacy. The majority (>70%) preferred to use milliliters, perceived milliliter-only dosing to be easy, and had prior milliliter-dosing experience; 11.5% had a teaspoon preference, 18.1% perceived milliliter-only dosing will be difficult, and 17.7% had no prior milliliter-dosing experience. Parents with lower health literacy had a higher odds of having a teaspoon preference (low vs adequate: adjusted odds ratio [AOR] = 2.9 [95% confidence interval [CI] 1.3-6.2]), and greater odds of perceiving difficulty with milliliter-only dosing (low vs adequate: AOR = 13.9 [95% CI 4.8-40.6], marginal vs adequate: AOR = 7.1 [95% CI 2.5-20.4]). Lack of experience with milliliter dosing partially mediated the impact of health literacy.
CONCLUSIONS
Most parents were comfortable with milliliter-only dosing. Parents with low health literacy were more likely to perceive milliliter-only dosing to be difficult; educational efforts will need to target this group to ensure safe medication use.
Topics: Adult; Child; Child, Preschool; Cross-Sectional Studies; Drug Dosage Calculations; Female; Health Literacy; Humans; Infant; Infant, Newborn; Logistic Models; Male; Odds Ratio; Parents; Patient Preference; Pharmaceutical Preparations; Young Adult
PubMed: 28400304
DOI: 10.1016/j.acap.2017.04.001 -
FEMS Microbiology Letters Jan 2019A global census of marine microbial life has been underway over the past several decades. During this period, there have been scientific breakthroughs in estimating... (Review)
Review
A global census of marine microbial life has been underway over the past several decades. During this period, there have been scientific breakthroughs in estimating microbial diversity and understanding microbial functioning and ecology. It is estimated that the ocean, covering 71% of the earth's surface with its estimated volume of about 2 × 1018 m3 and an average depth of 3800 m, hosts the largest population of microbes on Earth. More than 2 million eukaryotic and prokaryotic species are thought to thrive both in the ocean and on its surface. Prokaryotic cell abundances can reach densities of up to 1012 cells per millilitre, exceeding eukaryotic densities of around 106 cells per millilitre of seawater. Besides their large numbers and abundance, marine microbial assemblages and their organic catalysts (enzymes) have a largely underestimated value for their use in the development of industrial products and processes. In this perspective article, we identified critical gaps in knowledge and technology to fast-track this development. We provided a general overview of the presumptive microbial assemblages in oceans, and an estimation of what is known and the enzymes that have been currently retrieved. We also discussed recent advances made in this area by the collaborative European Horizon 2020 project 'INMARE'.
Topics: Aquatic Organisms; Bacteria; Biodiversity; Oceans and Seas; Water Microbiology
PubMed: 30534987
DOI: 10.1093/femsle/fny285 -
Journal of Family & Reproductive Health Sep 2022To investigate the effect of cold plasma on Staphylococcus aureus destruction at different treatment times. Staphylococcus aureus was cultured on 4 plates of LB Agar...
To investigate the effect of cold plasma on Staphylococcus aureus destruction at different treatment times. Staphylococcus aureus was cultured on 4 plates of LB Agar medium each at 1.5 × 103 CFU / mL (colony-forming unit per milliliter) and one group was selected as the control group and the other 3 groups were treated with plasma for 5, 7 and 10 minutes. They were incubated for 24 hours at 37 °C. Finally, the number of colonies formed was counted. It was shown that treatment with cold atmospheric plasma significantly reduced bacterial colonies and in comparison to the control plate with a colony count of 1.5 × 10 CFU/mL treatment with air plasma for 10 minutes decreased the Pseudomonas colony count to zero. It was observed that the cold atmospheric plasma jet device manufactured in atomic Energy Organization of Iran can significantly kill bacteria in a short time. Increasing the duration of treatment significantly reduces bacterial colonies.
PubMed: 36569254
DOI: 10.18502/jfrh.v16i3.10583 -
Bulletin of the National Research Centre 2022COVID-19 outbreak has engulfed different parts of the world, affecting more than 163 million people and causing more than 3 million deaths worldwide due to human... (Review)
Review
BACKGROUND
COVID-19 outbreak has engulfed different parts of the world, affecting more than 163 million people and causing more than 3 million deaths worldwide due to human transmission. Thus, it has become critical to identify the risk factors and laboratory parameters to identify patients who have high chances of worsening clinical symptoms or poor clinical outcomes. Therefore, the study aims to identify inflammatory markers that can help identify patients at increased risk for progression to critical illness, thus decreasing the risk of any mortality. Our study focussed on the predictive utility of C-reactive protein, Interleukin-6, D-dimer and Procalcitonin in assisting the management of COVID-19 patients with adverse clinical effects. Through literature search in electronic databases, we included the retrospective studies that evaluated the biomarkers among confirmed COVID-19 patients before initiation of treatment and who had a definite outcome (dead or discharged). Biomarkers were expressed in standardized difference in mean value, calculated based on study sizes and mean values between survivors and non-survivors considered the effect size. We carried out a meta-regression analysis to identify the causes of the heterogeneity between the studies.
RESULTS
Number of studies eligible for C-reactive protein, D-dimer and Interleukin-6 markers were eight, seven and four, respectively. Using random effect model revealed that the overall effect size with 95% confidence interval (CI) for C-reactive protein, D-dimer and Interleukin-6 were 1.45 (0.79-2.12) milligrams/litre, 1.12 (0.64-1.59) micrograms/millilitre Fibrinogen Equivalent Units and 1.34 (0.43-2.24) picograms/millilitre respectively was statistically significant ( < 0.05) inferring that the mean scores of these marker were significantly higher among the non-survivors compared to the survivors. Two studies were eligible for Procalcitonin marker and there was no heterogeniety ( -statistics = 0) between these studies. Therefore, fixed-effect model revealed that the overall effect size (95% CI) for Procalcitonin was 0.75 (0.30-1.21) Nanograms/millilitre was also high among non-survivors.
CONCLUSIONS
The study found that serum levels of C-reactive protein, Interleukin-6 and D-dimer showed significant elevation in non-survivors compared to survivors. Raised inflammatory markers aid in the risk stratification of COVID-19 patients and their proper management.
PubMed: 35261542
DOI: 10.1186/s42269-022-00733-z -
Medicine Jul 2018To compare the transperitoneal approach with extraperitoneal approach in laparoscopic radical prostatectomy (LRP) (including pure and robotic-assisted LRP) using... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
To compare the transperitoneal approach with extraperitoneal approach in laparoscopic radical prostatectomy (LRP) (including pure and robotic-assisted LRP) using meta-analytic techniques.
METHODS
Medline (PubMed), Embase, Ovid, CMB, and Cochrane databases were searched for studies that compared the transperitoneal and extraperitoneal approaches in LRP from January 2000 to January 2017. Outcomes included were operative time, operative bloods joss (milliliters), rate of transfusion, rate of open conversion, rate of intraoperative complications, rate of postoperative complications, and time of postoperative catheterization.
RESULTS
Thirteen studies including 1674 patients were selected for the meta-analysis. 850 (50.8%) cases had undergone transperitoneal LRP (TLRP) and 824 (49.2%) cases had undergone the extraperitoneal LRP (ELRP). Comparison of operative time between the TLRP group and the ELRP group showed no significant differences (weighted mean difference [WMD] = 21.21,95%CI = -1.16-43.57, P = .06). No significant differences were observed in blood loss (WMD = -6.04, 95%CI = -43.38-31.29, P = .75) and the rate of transfusion (odds ratio [OR] = 1.03, 95%CI = 0.55-1.96, P = .92) between the 2 groups. No significant differences were observed for the rate of intraoperative complications (OR = 1.25, 95%CI = 0.57-2.21, P = .75) and the rate of open conversion (OR = 1.12, 95%CI = 0.32-4.97, P = .75). Significant differences were observed in the TLRP group compared with the ELRP group (OR = 1.69, 95%CI: 1.23-2.32, P = .001) regarding the rate of postoperative complications.
CONCLUSIONS
Our meta-analysis findings revealed that the TLRP group showed no significant differences in most important indicators compared with ELRP. Moreover, TLRP showed higher rate of postoperative complications compared with ELRP.
Topics: Blood Transfusion; Catheterization; Humans; Laparoscopy; Male; Operative Time; Peritoneum; Postoperative Complications; Prostate; Prostatectomy; Prostatic Neoplasms; Reoperation
PubMed: 30024501
DOI: 10.1097/MD.0000000000011176