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Rationale: People with cystic fibrosis (CF) experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration. Objectives: To test differing durations of intravenous antimicrobials for CF exacerbations. Methods: STOP2 (Standardized Treatment of Pulmonary Exacerbations 2) was a multicenter, randomized, controlled clinical trial in exacerbations among adults with CF. After 7-10 days of treatment, participants exhibiting predefined lung function and symptom improvements were randomized to 10 or 14 days' total antimicrobial duration; all others were randomized to 14 or 21 days' duration. Measurements and Main Results: The primary outcome was percent predicted FEV1 (ppFEV1) change from treatment initiation to 2 weeks after cessation. Among early responders, noninferiority of 10 days to 14 days was tested; superiority of 21 days compared with 14 days was compared for the others. Symptoms, weight, and adverse events were secondary. Among 982 randomized people, 277 met improvement criteria and were randomized to 10 or 14 days of treatment; the remaining 705 received 21 or 14 days of treatment. Mean ppFEV1 change was 12.8 and 13.4 for 10 and 14 days, respectively, a ‒0.65 difference (95% CI [‒3.3 to 2.0]), excluding the predefined noninferiority margin. The 21- and 14-day arms experienced 3.3 and 3.4 mean ppFEV1 changes, a difference of ‒0.10 (‒1.3 to 1.1). Secondary endpoints and sensitivity analyses were supportive. Conclusions: Among adults with CF with early treatment improvement during exacerbation, ppFEV1 after 10 days of intravenous antimicrobials is not inferior to 14 days. For those with less improvement after one week, 21 days is not superior to 14 days. Clinical trial registered with www.clinicaltrials.gov (NCT02781610). [ABSTRACT FROM AUTHOR]

Background: Remimazolam is a new benzodiazepine for procedural sedation and general anaesthesia. The aim of this study was to characterise its pharmacokinetic properties and safety in renally and hepatically impaired subjects.Methods: Two separate trials were conducted in patients with hepatic (n=11) or renal impairment (n=11) compared with matched healthy subjects (n=9 and n=12, respectively). The hepatic impairment trial was an open-label adaptive 'Reduced Design' trial, using a single bolus of remimazolam 0.1 mg kg-1 i.v., whereas the renal impairment trial was an open-label trial of a single bolus dose of remimazolam 1.5 mg i.v. Remimazolam plasma concentrations over time were analysed by population pharmacokinetic modelling.Results: Remimazolam pharmacokinetic properties were adequately described by a three-compartment, recirculatory model. Exposure in subjects with severe hepatic impairment was 38.1% higher (i.e. clearance was 38.1% lower) compared with healthy volunteers. This increase caused a slightly delayed recovery (8.0 min for healthy, 12.1 min for moderate, and 16.7 min for severe hepatic impairment). With renal impairment, plasma clearance was comparable with that measured in healthy subjects. Simulations of Cmax after a bolus dose of 10 mg showed no relevant impact of hepatic or renal impairment. The overall incidence of adverse events was low, and all adverse events were mild.Conclusions: As Cmax after a remimazolam bolus i.v. was not affected by hepatic or renal impairment, no dose adjustments are required. No unexpected adverse events related to remimazolam were seen in subjects with renal or hepatic impairment.Clinical Trial Registration: Hepatic impairment trial: ClinicalTrials.gov, NCT01790607 (https://clinicaltrials.gov/ct2/show/NCT01790607). Renal impairment trial: EudraCT Number: 2014-004575-23. [ABSTRACT FROM AUTHOR]

Introduction: Anemia is one of the most common complications of chronic kidney disease (CKD). As a result of the side effects of high doses of recombinant human erythropoietin (rhEPO) and the differences in the standard dose of the injectable iron, this study aimed to evaluate the effect of high and low intravenous iron supplementation on hematinic parameters and EPO requirements in patients under hemodialysis.Methods: This multicenter, randomized, double-blind clinical trial was conducted on 60 patients with CKD admitted to Sina and 29 Bahman hospitals in Tabriz, Iran in 2019-2020 to undergo hemodialysis. In the two studied groups, low (100 mg/week) and high (400 mg/week) doses of iron were administered and subjects were followed up for 6 months. The incidence of acute myocardial ischemia, stroke, and mortality during 6 months was recorded.Results: The required rhEPO dosage (mg/week) to maintain hemoglobin levels between 10 and 12 g/dL in the high-dose iron group was significantly decreased during the follow-up period (52,129.03 ± 23,810 vs. 45,760 ± 20,978.71, P ≤ 0.028). Transferrin saturation (TSAT) index had a significant upward trend after iron injection and significant correlations with the serum levels of Fe (r ≥ 0.353, P ≤ 0.007), ferritin (r ≥ 0.315, P ≤ 0.016), and total iron binding capacity (r ≥ 0.219, P < 0.050) during the follow-up period in the studied groups.Conclusion: High-dose intravenous iron (400 mg/week) can reduce the mean dose of rhEPO requirements and increase the TSAT index over a period of 6 months in hemodialysis patients. High-dose IV iron administration can decrease cardiovascular events in hemodialysis patients with iron deficiency anemia. [ABSTRACT FROM AUTHOR]

Background: The anterior approach to the cervical spine is commonly used to treat cervical pathology. It is, however, associated with high rates of dysphagia, which may be associated with substantial patient morbidity. Perioperative corticosteroid administration has been advocated to decrease dysphagia rates; its efficacy, however, remains uncertain. We conducted a meta-analysis of randomized trials to determine the efficacy of perioperative corticosteroid administration in reducing postoperative dysphagia as well as any adverse effects, such as pseudarthrosis and infection.Methods: We conducted a systematic search of electronic databases (MEDLINE, Embase, CENTRAL [Cochrane Central Register of Controlled Trials], ClinicalTrials.gov) to identify randomized controlled trials (RCTs) that evaluated corticosteroids versus any comparator for prevention of postoperative dysphagia after anterior cervical spine procedures. Two independent reviewers used the GRADE (Grades of Recommendation Assessment, Development and Evaluation) criteria to assess eligibility and risk of bias, perform data extraction, and rate the quality of evidence. The primary outcome was severity of postoperative dysphagia. We conducted meta-analyses of dysphagia (both overall and by delivery method), pseudarthrosis, and postoperative infection.Results: After screening of 927 articles, a total of 7 studies were eligible for final inclusion. These included 431 patients, of whom 247 received corticosteroids and 184 received placebo or a control treatment. Moderate-quality evidence demonstrated a significant improvement in postoperative dysphagia rates (odds ratio, 0.35; 95% confidence interval, 0.20 to 0.63; p < 0.001), and this finding was robust to both permutation analyses and sensitivity analyses removing the studies with a high risk of bias. There was no significant difference between intravenous and local steroid administration (p = 0.16). There were no documented infections. There was no significantly increased risk of pseudarthrosis in those receiving steroids compared with placebo or a control treatment (p = 0.13).Conclusions: This meta-analysis found moderate-quality evidence supporting the use of perioperative corticosteroid administration as an adjunct to anterior cervical spinal procedures. Patients treated with corticosteroids intravenously or locally had significantly decreased severity of dysphagia.Level Of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Background: IV pushes of phenylephrine may be used for patients with septic shock with the intent of rapidly achieving mean arterial pressure (MAP) goals. However, the clinical effectiveness and safety of this approach are unclear.Research Question: In patients with septic shock, is administration of a phenylephrine push before norepinephrine initiation associated with a higher incidence of hemodynamic stability?Methods: This retrospective, multicenter cohort study included adult patients with septic shock initiated on norepinephrine. Propensity scores for initial phenylephrine push receipt were generated, and patients receiving an initial phenylephrine push were propensity score-matched 1:2 to those not receiving an initial phenylephrine push. The primary outcome was achievement of hemodynamic stability (defined as maintaining MAP of ≥ 65 mm Hg for at least 6 h without an increase in continuous infusion vasoactive agent dosage) within 3 and 12 h of norepinephrine initiation.Results: Of 1,317 included patients, 181 received an initial phenylephrine push; 141 phenylephrine push patients were matched to 282 patients not receiving a phenylephrine push. More patients who received a phenylephrine push achieved hemodynamic stability at hour 3 than those who did not receive a phenylephrine push (28.4% vs 18.8%; risk difference, 10%; 95% CI, 0.9%-18%). Phenylephrine push receipt was associated independently with hemodynamic stability within 3 h (adjusted OR, 1.8; 95% CI, 1.09-2.97), but not at 12 h (adjusted OR, 1.42; 95% CI, 0.93-2.16). Phenylephrine push receipt was associated independently with higher ICU mortality (adjusted OR, 1.88; 95% CI, 1.1-3.21).Interpretation: Phenylephrine pushes were associated with a higher incidence of early, but not sustained, hemodynamic stability and were associated independently with higher ICU mortality. Caution is warranted when clinicians are considering the use of phenylephrine pushes in patients with septic shock. [ABSTRACT FROM AUTHOR]

Background: Guillian--Barre' Syndrome (GBS) has been shown to be associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The aim of our study was to study the clinical profile and outcomes of GBS in COVID-19 from the Western region of India, the State of Maharashtra. Methods: This was a retrospective, multicenter observation study from different hospitals in Maharashtra beginning from March 2020 until November 2020. Results: We report 42 patients with COVID-19 GBS. Mean age was 59 years (range, 24--85 years). 31/42 (73.8%) were men. GBS was the presenting symptom in 14/42 (33%), while six of them remained asymptomatic for COVID-19 despite positive SARS-CoV-2 on nasopharyngeal swab reverse transcriptase polymerase chain reaction. The median interval between COVID-19 and GBS was 14 days (SD + 11), with minimum of 1 and maximum 40 days. Clinical presentation was like that of typical GBS. Electrophysiological studies showed a predominant demyelinating pattern in 25/42 (59.5%). Inflammatory markers were elevated in 35/42 (83.3%) and 38/42 (90.5%) had an Abnormal high-resolution CT (HRCT) chest. 14/42 (33.3%) patients required a ventilator, with nine deaths. Intravenous immunoglobulin was the mainstay of treatment for GBS. Majority had a good outcome and were walking independently or with minimal support at discharge. In subgroup analysis, the postinfectious group had a better outcome than the parainfectious group. Conclusion: GBS in COVID-19 occurs as both parainfectious and postinfectious GBS. Parainfectious GBS needs more rigorous monitoring and may benefit from COVID-19 specific treatment. Routine screening for SARS-CoV-2 should be implemented in patients with GBS in view of the ongoing pandemic. [ABSTRACT FROM AUTHOR]

In this study (trial registration: NCT02166021), we aimed to evaluate the optimal way of administration, the safety and the clinical efficacy of mesenchymal stem cell (MSC) transplantation in patients with active and progressive multiple sclerosis. Forty-eight patients (28 males and 20 females) with progressive multiple sclerosis (Expanded Disability Status Scale: 3.0-6.5, mean : 5.6 ± 0.8, mean age: 47.5 ± 12.3) and evidence of either clinical worsening or activity during the previous year, were enrolled (between 2015 and 2018). Patients were randomized into three groups and treated intrathecally (IT) or intravenously (IV) with autologous MSCs (1 × 106/kg) or sham injections. After 6 months, half of the patients from the MSC-IT and MSC-IV groups were retreated with MSCs, and the other half with sham injections. Patients initially assigned to sham treatment were divided into two subgroups and treated with either MSC-IT or MSC-IV. The study duration was 14 months. No serious treatment-related safety issues were detected. Significantly fewer patients experienced treatment failure in the MSC-IT and MSC-IV groups compared with those in the sham-treated group (6.7%, 9.7%, and 41.9%, respectively, P = 0.0003 and P = 0.0008). During the 1-year follow-up, 58.6% and 40.6% of patients treated with MSC-IT and MSC-IV, respectively, exhibited no evidence of disease activity compared with 9.7% in the sham-treated group (P < 0.0001 and P < 0.0048, respectively). MSC-IT transplantation induced additional benefits on the relapse rate, on the monthly changes of the T2 lesion load on MRI, and on the timed 25-foot walking test, 9-hole peg test, optical coherence tomography, functional MRI and cognitive tests. Treatment with MSCs was well-tolerated in progressive multiple sclerosis and induced short-term beneficial effects regarding the primary end points, especially in the patients with active disease. The intrathecal administration was more efficacious than the intravenous in several parameters of the disease. A phase III trial is warranted to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Recent studies show activity of ketamine metabolites, such as hydroxynorketamine, in producing rapid relief of depression-related symptoms and analgesia. To improve our understanding of the pharmacokinetics of ketamine and metabolites norketamine, dehydronorketamine, and hydroxynorketamine, we developed a population pharmacokinetic model of ketamine and metabolites after i.v. administration of racemic ketamine and the S-isomer (esketamine). Pharmacokinetic data were derived from an RCT on the efficacy of sodium nitroprusside (SNP) in reducing the psychotomimetic side-effects of ketamine in human volunteers.Methods: Three increasing i.v. doses of esketamine and racemic ketamine were administered to 20 healthy volunteers, and arterial plasma samples were obtained for measurement of ketamine and metabolites. Subjects were randomised to receive esketamine/SNP, esketamine/placebo, racemic ketamine/SNP, and racemic ketamine/placebo on four separate occasions. The time-plasma concentration data of ketamine and metabolites were analysed using a population compartmental model approach.Results: The pharmacokinetics of ketamine and metabolites were adequately described by a seven-compartment model with two ketamine, norketamine, and hydroxynorketamine compartments and one dehydronorketamine compartment with metabolic compartments in-between ketamine and norketamine, and norketamine and dehydronorketamine main compartments. Significant differences were found between S- and R-ketamine enantiomer pharmacokinetics, with up to 50% lower clearances for the R-enantiomers, irrespective of formulation. Whilst SNP had a significant effect on ketamine clearances, simulations showed only minor effects of SNP on total ketamine pharmacokinetics.Conclusions: The model is of adequate quality for use in future pharmacokinetic and pharmacodynamic studies into the efficacy and side-effects of ketamine and metabolites.Clinical Trial Registration: Dutch Cochrane Center 5359. [ABSTRACT FROM AUTHOR]

Background: Factor VIII replacement products have improved the care of patients with hemophilia A, but the short half-life of these products affects the patients' quality of life. The half-life of recombinant factor VIII ranges from 15 to 19 hours because of the von Willebrand factor chaperone effect. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein designed to overcome this half-life ceiling and maintain high sustained factor VIII activity levels. Data are lacking on the safety and pharmacokinetics of single-dose BIVV001.Methods: In this phase 1-2a open-label trial, we consecutively assigned 16 previously treated men (18 to 65 years of age) with severe hemophilia A (factor VIII activity, <1%) to receive a single intravenous injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight (lower-dose group) or 65 IU per kilogram (higher-dose group). This injection was followed by a washout period of at least 3 days. The patients then received a single intravenous injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram. Adverse events and pharmacokinetic measurements were assessed.Results: No inhibitors to factor VIII were detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. The geometric mean half-life of BIVV001 was three to four times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group); the area under the curve (AUC) for product exposure was six to seven times as great in the two dose groups (4470 hours vs. 638 hours × IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours × IU per deciliter in the higher-dose group). After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for 4 days and 17% at day 7, which suggested the possibility of a weekly interval between treatments.Conclusions: In a small, early-phase study involving men with severe hemophilia A, a single intravenous injection of BIVV001 resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII, an increase that could signal a new class of factor VIII replacement therapy with a weekly treatment interval. No safety concerns were reported during the 28-day period after administration. (Funded by Sanofi and Sobi; ClinicalTrials.gov number, NCT03205163.). [ABSTRACT FROM AUTHOR]

No known therapies can prevent anaphylaxis. Bruton's tyrosine kinase (BTK) is an enzyme thought to be essential for high-affinity IgE receptor (FcεRI) signaling in human cells. We tested the hypothesis that FDA-approved BTK inhibitors (BTKis) would prevent IgE-mediated responses including anaphylaxis. We showed that irreversible BTKis broadly prevented IgE-mediated degranulation and cytokine production in primary human mast cells and blocked allergen-induced contraction of isolated human bronchi. To address their efficacy in vivo, we created and used what we believe to be a novel humanized mouse model of anaphylaxis that does not require marrow ablation or human tissue implantation. After a single intravenous injection of human CD34+ cells, NSG-SGM3 mice supported the population of mature human tissue-resident mast cells and basophils. These mice showed excellent responses during passive systemic anaphylaxis using human IgE to selectively evoke human mast cell and basophil activation, and response severity was controllable by alteration of the amount of allergen used for challenge. Remarkably, pretreatment with just 2 oral doses of the BTKi acalabrutinib completely prevented moderate IgE-mediated anaphylaxis in these mice and also significantly protected against death during severe anaphylaxis. Our data suggest that BTKis may be able to prevent anaphylaxis in humans by inhibiting FcεRI-mediated signaling. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the feasibility of using indocyanine green (ICG) to estimate the vascularization of the resected zone during a laparoscopic rectal shaving.Design: Indocyanine green can highlight blood vascularization when injected intravenously. There is no relevant, objective, intraoperative method to assess the vascularity of the resected zone during a laparoscopic rectal shaving for deep infiltrating endometriosis (DIE) to prevent fistula. We conducted a registered clinical trial examining the feasibility of the use of ICG to evaluate the bowel vascularization after endometriosis rectal shaving (Institutional Review Board number 2016-002773-35).Setting: Tertiary university hospital.Patient(s): Twenty-one patients underwent laparoscopic surgery for DIE with a rectal shaving.Intervention(s): Patients undergoing laparoscopic surgery for DIE received ICG intravenously at the end of the endometriosis resection.Main Outcome Measure(s): The main evaluation criteria was the fluorescence degree in the operated rectal area and in the vaginal suture. We used a visual assessment with a Likert-type scale from 0 to 4 (0 = no fluorescence; 4 = very good fluorescence).Result(s): No adverse reaction was recorded. Most of the patients (81%) showed very good fluorescence levels at the rectal shaving area. The protocol did not increase the operating time. In one patient we changed the surgical strategy making two stitches to bring the rectal muscularis closer together, which improved the degree of fluorescence. There was no case of digestive fistula.Conclusion: Indocyanine green fluorescent imaging is feasible in endometriosis surgery and may be considered as a potential candidate to further enhance patient safety in endometriosis bowel surgery.Clinical Trial Registration Number: NCT03080558. [ABSTRACT FROM AUTHOR]

Background: Iron deficiency can result in hyporetinolemia and hepatic vitamin A (VA) sequestration.Objectives: We used model-based compartmental analysis to determine the impact of iron repletion on VA metabolism and kinetics in iron-deficient rats.Methods: At weaning, Sprague-Dawley rats were assigned to either a VA-marginal diet (0.35 mg retinol equivalent/kg) with adequate iron (35 ppm, control group [CN]) or reduced iron (3 ppm, iron-deficient group [ID-]), with an equivalent average body weight for each group. After 5 wk, n = 4 rats from each group were euthanized for baseline measurements of VA and iron indices, and the remaining rats (n = 6 CN, n = 10 ID-) received an intravenous injection of 3H-labeled retinol in an emulsion as tracer to initiate the kinetic study. On day 21 after dosing, half of the ID- rats were switched to the CN diet to initiate iron repletion, referred to as the iron-repletion group (ID+). From the time of dosing, 34 serial blood samples were collected from each rat over a 92-d time course. Plasma tracer and tissue tracee data were fitted to 6- and 4-compartment models, respectively, to analyze the kinetic behavior of VA in all groups.Results: Our mathematical model indicated that ID- rats exhibited a nearly 6-fold decrease in liver VA secretion and >4-fold reduction in whole-body VA utilization, compared with CN rats, whereas these perturbed kinetic behaviors were notably corrected in ID+ rats, close to those from the CN group.Conclusions: Iron repletion can remove the inhibitory effect that iron deficiency exerts on hepatic mobilization of VA and restore retinol kinetic parameters to values similar to that of never-deficient CN rats. Together with improvements in iron and VA indices, our results suggest that restoration of an iron-adequate diet is sufficient to improve VA kinetics after a previous state of iron deficiency. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the impact on cost, time, resource use, and clinic workflow of converting the route of drug administration from a neurokinin-1 receptor antagonist (NK-1 RA) 30-min intravenous (IV) infusion to aprepitant IV, and more specifically to IV push, within a multicenter community oncology practice.Methods: This was a retrospective, multicenter time, motion, and resource/cost evaluation study. Conversion to aprepitant IV was determined by calculating number of doses of aprepitant IV versus fosaprepitant administered in patients receiving moderately or highly emetogenic chemotherapy regimens. Operational advantages (i.e., supply costs, time saved) of switching from fosaprepitant IV infusion to aprepitant administered as a 2-min IV push were assessed.Results: A total of 12,908 doses of aprepitant IV 130 mg were administered at 13 Rocky Mountain Cancer Centers clinics over an 18-month period. Conversion from fosaprepitant to aprepitant IV reached 90% after 9 months of aprepitant IV initiation. Supply costs per administration were reduced ($2.51 to $0.52) when aprepitant was prepared as an IV push versus an NK-1 RA infusion. The overall time savings per administration of aprepitant was reduced by 90% (from 36.5 to 3.5 min, 33 min saved) as an IV push rather than an infusion. Most of the time saved per administration (30 min) pertained to the infusion nurse, and 3 min was saved by the pharmacy technician.Conclusion: Successful conversion to aprepitant, and specifically to a 2-min IV push, provides time, cost, and resource savings, improves operational efficiency, and avoids the negative impact of potential future IV fluid shortages. [ABSTRACT FROM AUTHOR]

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding.Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124.Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82-1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98).Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial.Funding: UK National Institute for Health Research Health Technology Assessment Programme. [ABSTRACT FROM AUTHOR]

Aims: This trial was conducted to determine the efficacy of umbilical vein injection of 400 versus 800 μg misoprostol to deliver retained placenta and to compare both regimens regarding the time of placental delivery and amount of vaginal blood loss. Methods: A double‐blind, multicenter randomized clinical trial was undertaken in four teaching hospitals in the North of Iraq and Al‐Azhar University Hospital in Egypt, from March 2016 to May 2019. Group I (274 women) received 400 μg misoprostol and group II (249 women) received 800 μg misoprostol. Data regarding the time of placental separation and amount of vaginal blood loss were analyzed and proportions were compared between groups using Chi‐squared test. Mean values were compared using the Student's t‐test. The Mann–Whitney test was used to determine the median of vaginal blood loss. Results: The proportion of placental separation was 84.3% among women in group I and 86.7% of women in group II. The mean time of placental separation was 18.86 ± 234.2 and 17.86 ± 213.09 min in groups I and II, respectively (P < 0.05).The mean hemoglobin levels on admission and 24 h after placental deliveries were significantly higher in group I than group II. Conclusions: Intra‐umbilical injection of 400 and 800 μg misoprostol were both safe and effective methods for delivery of retained placenta. [ABSTRACT FROM AUTHOR]

Robot-assisted radical prostatectomy causes discomfort in the immediate postoperative period. This randomised controlled trial investigated if intrathecal bupivacaine/morphine, in addition to general anaesthesia, could be beneficial for the postoperative quality of recovery. One hundred and fifty-five patients were randomly allocated to an intervention group that received intrathecal 12.5 mg bupivacaine/300 μg morphine (20% dose reduction in patients > 75 years) or a control group receiving a subcutaneous sham injection and an intravenous loading dose of 0.1 mg.kg-1 morphine. Both groups received standardised general anaesthesia and the same postoperative analgesic regimen. The primary outcome was a decrease in the Quality of Recovery-15 (QoR-15) questionnaire score on postoperative day 1. The intervention group (n = 76) had less reduction in QoR-15 on postoperative day 1; median (IQR [range]) 10% (1-8 [-60% to 50%]) vs. 13% (5-24 [-6% to 50%]), p = 0.019, and used less morphine during the admission; 2 mg (1-7 [0-41 mg]) vs. 15 mg (12-20 [8-61 mg]), p < 0.001. Furthermore, they perceived lower pain scores during exertion; numeric rating scale (NRS) 3 (1-6 [0-9]) vs. 5 (3-7 [0-9]), p = 0.001; less bladder spasms (NRS 1 (0-2 [0-10]) vs. 2 (0-5 [0-10]), p = 0.001 and less sedation; NRS 2 (0-3 [0-10]) vs. 3 (2-6 [0-10]), p = 0.005. Moreover, the intervention group used less rescue medication. Pruritus was more severe in the intervention group; NRS 4 (1-7 [0-10]) vs. 0 (0-1 [0-10]), p = 0.000. We conclude that despite a modest increase in the incidence of pruritus, multimodal pain management with intrathecal bupivacaine/morphine remains a viable option for robot-assisted radical prostatectomy. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the feasibility and safety of power injection of contrast media through totally implantable venous power ports during computed tomography scans in oncologic patients. Methods: The study population consisted of 417 patients who underwent computed tomography scan through a totally implantable venous power port. Clinical data were examined. Logistic regression analysis was used to assess the associations between clinical covariables and computed tomography scan failure. Results: Successful computed tomography scans were achieved in 534 of 540 examinations (98.9%). Logistic regression analysis showed that contrast media above a 350 concentration was significantly associated with computed tomography scan failure (95% confidence interval: 1.01–1.13, p = 0.012). No major complications were noted. Conclusions: Power injection of contrast media through a totally implantable venous power port for computed tomography examination is feasible and safe. This procedure provides an acceptable alternative in oncologic patients with inadequate peripheral intravenous access when computed tomography examination with contrast enhancement is needed. [ABSTRACT FROM AUTHOR]

Background: Peritoneal carcinomatosis (PC) from pancreatic ductal adenocarcinoma (PDAC) is fatal. Our preclinical study presents an effective treatment against PDAC PC using a novel oncolytic viral agent, CF33-hNIS-antiPDL1.Study Design: CF33-hNIS-antiPDL1 is a genetically engineered chimeric orthopoxvirus, CF33, armed with the human Sodium Iodide Symporter (hNIS) and anti-PD-L1 antibody (anti-PD-L1). The in vitro cytotoxic ability of this virus against 5 PDAC cell lines was tested at various doses (multiplicity of infection [MOI] = 0.01, 0.1, 1, 10). Production and blockade function of virus-encoded anti-PD-L1 antibody were verified using immunoblot, immunoprecipitation, and PD-1/PD-L1 bioassay. In vivo mouse models of PC, with or without subcutaneous (SC) tumors, created by injecting AsPC-1-ffluc cells into nude mice, were treated with PBS or a single dose (1×105 plaque-forming units) of either intraperitoneal (IP) or IV injection of CF33-hNIS-antiPDL1. Mice with PC tumors were treated on days 0, 2, or 14 after tumor implantation.Results: CF33-hNIS-antiPDL1 killed PDAC cells in a dose-dependent manner, achieving >90% cell killing by day 8. Cells infected with CF33-hNIS-antiPDL1 produced bioactive anti-PD-L1 antibody, which blocked PD-1/PD-L1 interaction. In vivo, a single dose of virus reduced tumor burden and prolonged survival of treated mice. It was observed that IP administration of CF33-hNIS-antiPDL1 was more effective than IV administration.Conclusions: CF33-hNIS-antiPDL1 virus is effective in infecting and killing human PDACs and producing functional anti-PD-L1 antibody. Intraperitoneal delivery of CF33-hNIS-antiPDL1 effectively reduces peritoneal tumor burden and improves survival after only 1 dose and is superior to IV delivery. [ABSTRACT FROM AUTHOR]

Purpose: [18F]MK-6240 is a selective, high-affinity positron emission tomography tracer for imaging neurofibrillary tangles, a key pathological signature that correlates with cognitive decline in Alzheimer disease. This report provides safety information from preclinical toxicology studies and first-in-human whole-body biodistribution and dosimetry studies of [18F]MK-6240 for its potential application in human brain imaging studies.Procedures: MK-6240 was administered intravenously (IV) in a 7-day rat toxicity study at × 50, × 100, and × 1000 dose margins relative to projected highest clinical dose of 0.333 μg/kg. The IV formulation of MK-6240 for clinical use and the formulation used in the 7-day rat toxicity study was tested for hemolysis potential in human and Wistar rat whole blood. Sequential whole-body positron emission tomography scans were performed in three healthy young subjects after IV bolus injection of 180 ± 0.3 MBq [18F]MK-6240 to characterize organ biodistribution and estimate whole-body radiation exposure (effective dose).Results: MK-6240 administered IV in a 7-day rat toxicity study did not show any test article-related changes. The no-observed-adverse-effect level in rats was ≥ 333 μg/kg/day which provides a margin 1000-fold over an anticipated maximum clinical dose of 0.333 μg/kg. Additionally, the MK-6240 formulation was not hemolytic in human or Wistar rat blood. [18F]MK-6240 activity was widely distributed to the brain and the rest of the body, with organ absorbed doses largest for the gall bladder (202 μGy/MBq). The average (±SD) effective dose was 29.4 ± 0.6 μSv/MBq, which is in the typical range for F-18 radiolabeled ligands.Conclusions: Microdoses of [18F]MK-6240 are safe for clinical positron emission tomography imaging studies. Single IV administration of 185 MBq (5 mCi) [18F]MK-6240 is anticipated to result in a total human effective dose of 5.4 mSv and thus allows multiple positron emission tomography scans of the same subject per year. [ABSTRACT FROM AUTHOR]

Background and Purpose: Fentanyl overdose deaths have reached "epidemic" levels in North America. Death in opioid overdose invariably results from respiratory depression. In the present work, we have characterized how fentanyl depresses respiration, and by comparing fentanyl with heroin and morphine, the active breakdown product of heroin, we have sought to determine the factors, in addition to high potency, that contribute to the lethality of fentanyl.Experimental Approach: Respiration (rate and tidal volume) was measured in awake, freely moving mice by whole body plethysmography.Key Results: Intravenously administered fentanyl produced more rapid depression of respiration than equipotent doses of heroin or morphine. Fentanyl depressed both respiratory rate and tidal volume. Fentanyl did not depress respiration in μ-opioid receptor knockout mice. Naloxone, the opioid antagonist widely used to treat opioid overdose, reversed the depression of respiration by morphine more readily than that by fentanyl, whereas diprenorphine, a more lipophilic antagonist, was equipotent in reversing fentanyl and morphine depression of respiration. Prolonged treatment with morphine induced tolerance to respiratory depression, but the degree of cross tolerance to fentanyl was less than the tolerance to morphine itself.Conclusion and Implications: We propose that several factors (potency, rate of onset, lowered sensitivity to naloxone, and lowered cross tolerance to heroin) combine to make fentanyl more likely to cause opioid overdose deaths than other commonly abused opioids. Lipophilic antagonists such as diprenorphine may be better antidotes than naloxone to treat fentanyl overdose. [ABSTRACT FROM AUTHOR]

Objective: To assess whether metoclopramide is effective in shortening the duration of the first stage of labor in primiparous women.Methods: The present randomized, double-blind, placebo-controlled trial was conducted at King Faisal Hospital, Saudi Arabia (between July 30, 2013, and September 1, 2016), and sequentially recruited young nulliparous women admitted in spontaneous active labor with or without ruptured membranes. Eligible participants were randomly assigned to receive a slow intravenous injection of either metoclopramide or placebo and consistently managed according to the local institutional intrapartum protocol and received identical monitoring and supportive care. The primary outcome was the cervical dilatation rate.Results: Fifty-nine women were included in the metoclopramide group and 52 in the placebo group. The first stage of labor was significantly shorter in the metoclopramide group (203 minutes vs 230 minutes in the placebo group, P=0.019), with a faster cervical dilatation rate (2.4 ± 0.4 cm/h vs 1.9 ± 0.5 cm/h in the placebo group, P<0.001) and shorter interval from treatment administration until full cervical dilatation. There was a significantly higher probability of faster delivery among women who were treated with metoclopramide (log-rank test, χ2 =5.997, P=0.014).Conclusion: Metoclopramide safely reduced the duration of the first stage of labor and was not associated with major maternal or neonatal adverse outcomes. CLINICALTRIALS.GOV: NCT01937234. [ABSTRACT FROM AUTHOR]

Introduction: Severe hypersensitivity reactions (HSRs) such as anaphylaxis are of great clinical concern because of their life-threatening potential. The adverse events attributable to intravenous iron products include HSRs. An investigation by the European Medicines Agency presented in late 2013 resulted in the implementation of risk minimization measures (RMMs).Objective: This study evaluated the number of severe HSRs reported for intravenous iron substances related to exposure for the 4-year periods before and after this implementation.Methods: This was a retrospective pharmacoepidemiologic study with a case-population design. We obtained information from the safety surveillance database EudraVigilance on spontaneously reported severe HSRs using the Medical Dictionary for Regulatory Activities preferred terms "anaphylactic reaction/shock" and "anaphylactoid reaction/shock". Exposure was estimated using IQVIA MIDAS sales data in European economic area countries.Results: Reporting rates for individual products were heterogenous, and the implementation of RMMs appeared to have no clear impact. Reporting rates remained low for the full study period for iron sucrose (0.03-0.20) and ferric gluconate (0.02-0.14) and were higher at the beginning and lower at the end of the study period for ferric carboxymaltose (1.47-0.18). No clear trend was detected for iron dextran (range 0.22-2.80) and iron (III) isomaltoside 1000 (range 0-7.94).Conclusions: Future research is needed to investigate whether the wide variability in reporting rates for severe HSRs associated with these intravenous iron products are due to potential differences in the safety profiles of these substances. [ABSTRACT FROM AUTHOR]

Oral VRL offers easier administration, better quality of life, and cost saving. This study aimed to evaluate the treatment efficacy in terms of tumor response of the two formulations of vinorelbine (VRL, oral and IV) in combination with epirubicin (EPI); and the effect of EPI co-administration on VRL pharmacokinetics (PK) in Chinese patients with metastatic breast cancer (MBC) using a phase 2, open label, randomized trial. Patients were aged 18-70 years, had histologically confirmed MBC, Karnofsky Performance Status ≥ 70%, and life expectancy ≥ 12 weeks. The treatment consisted of 6 cycles of 3 weeks each. VRL dose was: (Oral-VRL) 60 mg/m2 for cycle 1, 80 mg/m2 for cycles 2-6, and (IV-VRL) 25 mg/m2 for cycle 1 and 30 mg/m2 for cycles 2-6. EPI dose of 75 mg/m2 was given on day 1 in both arms for all cycles. 133 patients were enrolled: 66 in Oral-VRL and 67 in IV-VRL arms. The median age for Oral-VRL and IV-VRL arms was 48.4 and 50.0 years, respectively. Objective response rates were 50.0% (95% CI 37.4-62.6%) for Oral-VRL and 53.7% (95% CI 41.1-66.0%) for IV-VRL. Both treatment arms met the efficacy objective target of at least 31 responses, demonstrating efficacy as first-line treatment for MBC. Similar blood PK profiles, exposures, and VRL clearance were observed between VRL + EPI vs VRL-only modalities for both arms. Oral VRL is comparable to IV VRL and an effective first-line treatment for Chinese patients with MBC. The activity of VRL + EPI combination is unaltered when VRL is given orally at recommended doses. [ABSTRACT FROM AUTHOR]

Objective: To assess whether oxytocin administered before clamping the umbilical cord modifies the volume of placental transfusion.Design: Randomised controlled trial.Methods: Mothers of term infants born vigorous by vaginal delivery with informed consent provided in early labour were randomly assigned to oxytocin (10 IU) given intravenously within 15 s of birth (group 1) or after clamping the umbilical cord 3 min after delivery (group 2). Soon after birth, all infants were weighed using a 1 g precision scale and subsequently placed on the mother's abdomen or chest. At 3 min, in both groups, the cord was clamped and cut, and the weight was again obtained. The primary outcome (volume of placental transfusion) was estimated by the difference in weights.Results: 144 patients were included. There were no differences in the primary outcome: infants in group 1 (n=70) gained a mean weight of 85.9 g (SD 48.3), and in group 2 (n=74) 86.7 g (SD 49.6) (p=0.92). No differences were found in secondary outcomes, including newborns' haematocrit and bilirubin concentrations and severe maternal postpartum haemorrhage. On the advice of the Data and Safety Monitoring Committee, the trial was stopped due to futility at 25% of the planned sample size.Conclusions: When umbilical cord clamping is delayed for 3 min, term newborn infants born vigorous receive a clinically significant placental transfusion which is not modified by the administration of intravenous oxytocin immediately after birth.Trial Registration Number: NCT02618499. [ABSTRACT FROM AUTHOR]

Objective: To compare the effect of contrast medium iodine concentration on contrast enhancement, heart rate, and injection pressure when injected at a constant iodine delivery rate in coronary CT angiography (CTA).Methods: One thousand twenty-four patients scheduled for coronary CTA were prospectively randomized to receive one of four contrast media: iopromide 300 mg I/ml, iohexol 350 mg I/ml, iopromide 370 mg I/ml, or iomeprol 400 mg I/ml. Contrast media were delivered at an equivalent iodine delivery rate of 2.0 g I/s. Intracoronary attenuation was measured and compared (per vessel and per segment). Heart rate before and after contrast media injection was documented. Injection pressure was recorded (n = 403) during contrast medium injection and compared between groups.Results: Intracoronary attenuation values were similar for the different contrast groups. The mean attenuation over all segments ranged between 384 HU for 350 mg I/ml and 395 HU for 400 mg I/ml (p = 0.079). Dose-length product (p = 0.8424), signal-to-noise ratio (all p > 0.05), time to peak (p = 0.324), and changes in heart rate (p = 0.974) were comparable between groups. The peak pressures differed: 197.4 psi for 300 mg I/ml (viscosity 4.6 mPa s), 229.8 psi for 350 mg I/ml (10.4 mPa s), 216.1 psi for 370 mg I/ml (9.5 mPa s), and 243.7 psi for 400 mg I/ml (12.6 mPa s) (p < 0.0001).Conclusion: Intravascular attenuation and changes in heart rate are independent of iodine concentration when contrast media are injected at the same iodine delivery rate. Differences in injection pressures are associated with the viscosity of the contrast media.Key Points: • The contrast enhancement in coronary CT angiography is independent of the iodine concentration when contrast media are injected at body temperature (37 °C) with the same iodine delivery rate. • Iodine concentration does not influence the change in heart rate when contrast media are injected at identical iodine delivery rates. • For a fixed iodine delivery rate and contrast temperature, the viscosity of the contrast medium affects the injection pressure. [ABSTRACT FROM AUTHOR]

Purpose: To describe clinical features and outcome in bilateral acute retinal necrosis (BARN). Methods: Observational retrospective longitudinal review of ocular findings. Results: Thirty eyes of 15 patients (age 44.1 ± 15.8). Delay of involvement between eyes was 57.2 ± 105.2 months (median 3, range 0.5-360). Herpes simplex virus (HSV)-1 was the most frequent (20 eyes, 66.6%), followed by HSV-2 (five eyes, 16.7%) and varicella zoster virus (VZV, four eyes, 13.3%). Visual acuity worsened in 7 (23%) eyes, improved in 4 (13%), and remained stable in 19 (63%). Major complications included retinal detachment (11 eyes, 36%), optic atrophy (11 eyes, 33%), proliferative vitreoretinopathy (four eyes, 13.3%), neovascular glaucoma (four eyes, 13.3%), phthisis bulbi (three eyes, 10%). Symptoms-to-referral average time was 2.7 ± 1.0 weeks (range 1-4). Conclusions: In our study BARN was associated with severe visual outcome and high rate of ocular complications. Although BARN is a rare disease, the course is aggressive, regardless prompt referral in tertiary-care uveitis centers. [ABSTRACT FROM AUTHOR]

Background and Purpose: d-Amino acid oxidase (DAAO) is a flavine adenine dinucleotide-containing flavoenzyme and specifically catalyses oxidative deamination of d-amino acids. This study aimed to explore the association between increased cerebral DAAO expression or enzymic activity and the development of cerebral ischaemia.Experimental Approach: A mouse model of transient (90 min) middle cerebral artery occlusion (MCAO) was established, and western blotting, enzymic activity assay, and fluorescent immunostaining techniques were used.Key Results: The expression and enzymic activity of DAAO increased over time in the cortical peri-infarct area of the mice subjected to transient MCAO. The DAAO was specifically expressed in astrocytes, and its double immunostaining with the astrocytic intracellular marker, glial fibrillary acidic protein, in the cortical peri-infarct area was up-regulated following ischaemic insult, with peak increase on Day 5 after MCAO. Single intravenous injection of the specific and potent DAAO inhibitor Compound SUN reduced the cerebral DAAO enzymic activity and attenuated neuronal infarction and neurobehavioural deficits with optimal improvement apparent immediately after the MCAO procedure. The neuroprotective effect was dose dependent, with ED50 values of 3.9-4.5 mg·kg-1 . Intracerebroventricular injection of the DAAO gene silencer siRNA/DAAO significantly reduced cerebral DAAO expression and attenuated MCAO-induced neuronal infarction and behavioural deficits.Conclusions and Implications: Our results, for the first time, demonstrated that increased cerebral astrocytic DAAO expression and enzymic activity were causally associated with the development of neuronal destruction following ischaemic insults, suggesting that targeting cerebral DAAO could be a potential approach for treatment of neurological conditions following cerebral ischaemia. [ABSTRACT FROM AUTHOR]

Importance: Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy.Objective: To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy.Design, Setting, and Participants: The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 109/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019.Interventions: Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d [maximum, 6 mg/d]; n = 395) or matching placebo (n = 405) once daily for 6 days.Main Outcome and Measures: The primary end point was 28-day all-cause mortality.Results: Among 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P = .32). The absolute risk difference was 2.55% (95% CI, -3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group.Conclusions and Relevance: Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality.Trial Registration: ClinicalTrials.gov Identifier: NCT01598831. [ABSTRACT FROM AUTHOR]

Rhabdomyosarcoma (RMS) is a pediatric soft tissue tumor classified in two major subtypes namely embryonal and alveolar, which have distinctive histopathological and genetic signatures and worse outcomes in the presence of metastases. Here, in order to evaluate the role of Caveolin-1 (Cav-1) in embryonal RMS dissemination, we employed an experimental in vivo metastasis assay using immunodeficient NOD/SCID mice. We found that the intravenous injection of human RD cells engineered for Cav-1 overexpression promoted the formation of lung metastases compared to parental cells. The arisen metastases were isolated and cultured in vitro to establish two derivative lines that showed greater metastatic capacity, as detected by performing in vivo metastasis and tumor spheroid invasion assays. Compared to parental cells, all metastatic lines were characterized by an increase in cell proliferation, migration and invasiveness that were downregulated by synthetic inhibition of Erk pathway. The metastatic cells showed a marked cell apoptosis induced by nutrient deprivation and consistent loss of differentiation characterized by depletion of MyoD and Myogenin factors. Furthermore, they showed marked changes in cell size, a re-organization of the three-dimensional cytoskeleton characterized by an increased actin stress fiber content, and increased adhesion and angiogenic properties. Collectively, these data provide new insights into Cav-1-driven metastatic process of embryonal RMS through cooperation of the Erk signaling pathway. Furthermore, our derivative metastatic lines represent useful tools for identifying genes or molecular pathways that regulate the metastatic progression of embryonal RMS. [ABSTRACT FROM AUTHOR]

Purpose: To compare the efficacy of a single perioperative bolus dose of intravenous antibiotic versus postoperative oral antibiotic prophylaxis for prevention of surgical site infection (SSI) in external dacryocystorhinostomy (DCR) for primary acquired nasolacrimal duct obstruction (PANDO).Methods: This was a prospective randomized controlled study with a noninferiority design. Patients undergoing external DCR surgery were randomized into two groups A and B. Patients in group A received a single bolus dose of intravenous cefazolin 1 g at surgery, whereas those in group B received oral cephalexin 500 mg postoperatively twice a day for 5 days. Allocation concealment was ensured by sequentially numbered opaque sealed envelopes (SNOSEs). Both groups were advised identical postoperative local wound care regimens. Any clinical evidence of SSI at 4 weeks of follow-up in either group was the main outcome measure.Results: In all, 338 patients randomized into two groups of 169 patients each participated in this study. At follow-up of 4 weeks, only one patient in group B developed postoperative SSI. None in group A developed postoperative SSI. Other potential risk factors for postoperative SSI were also analyzed by univariate and multivariate analyses but none achieved statistical significance in either group.Conclusion: Our results demonstrate that a single bolus dose of perioperative intravenous antibiotic offers adequate prophylaxis against postoperative SSI and compares favorably with the more commonly used oral antibiotic prophylaxis in external DCR for PANDO in our population and our practice scenario. [ABSTRACT FROM AUTHOR]

Background: Although antiemetics are commonly used to prevent postoperative nausea or vomiting, the failure rate is appreciable and there is currently no generally accepted standard for rescue treatment of postoperative nausea or vomiting after failed prophylaxis. This prospective, randomized, double-blind, parallel-group, placebo-controlled, multicenter study was designed to test the hypothesis that intravenous amisulpride, a dopamine D2/D3-antagonist, is superior to placebo at treating established postoperative nausea or vomiting after failed prophylaxis.Methods: A total of 2,285 adult patients undergoing surgery under general inhalational anesthesia and receiving standard antiemetic prophylaxis were enrolled at 23 sites in Canada, France, Germany, and the United States. Of these, 702 patients experienced postoperative nausea or vomiting in the 24-h period after surgery and were randomized to receive a single dose of 5 or 10 mg intravenous amisulpride or matching placebo. The primary endpoint was complete response, defined as no emesis or rescue antiemetic use for 24 h after study drug administration, excluding emesis in the first 30 min. Secondary endpoints included incidence of emesis and rescue medication use, nausea burden, time to treatment failure, and length of stay in postanesthesia care unit and hospital.Results: Complete response occurred in significantly more patients receiving 10 mg amisulpride (96 of 230, 41.7%) than placebo (67 of 235, 28.5%), a 13.2% difference (95% CI, 4.6 to 21.8; odds ratio, 1.80; P = 0.006). A 5-mg dose of amisulpride did not show a significant benefit (80 of 237, 33.8%); the difference from placebo was 5.2% (95% CI, 3.1 to 13.6; odds ratio, 1.24; P = 0.109). The total number of adverse events recorded and proportion of patients with at least one adverse event were comparable between the placebo and amisulpride groups. No clinically relevant toxicities were observed.Conclusions: A single 10-mg dose of intravenous amisulpride was safe and more effective than placebo at treating established postoperative nausea or vomiting in patients failing postoperative nausea or vomiting prophylaxis. [ABSTRACT FROM AUTHOR]

Background: Phenylephrine is the first-line vasoactive drug in the cesarean section under spinal anesthesia. The rate of hypotension remains high after intravenous preventive use of phenylephrine. However, few studies have investigated the effect of preventive intramuscular phenylephrine via a longer period of usage on fetal and maternal outcomes.Methods: A total of 99 healthy parturients undergoing elective cesarean delivery were randomly allocated into three groups: M group (preventive intramuscular use of 5 mg phenylephrine), V group (preventive intravenous use of 100 μg phenylephrine), and P group (0.9% normal saline placebo). Rescue phenylephrine, ephedrine and atropine were used intraoperatively to adjust blood pressure and heart rate. The primary outcome was umbilical artery pH.Results: Significant differences in umbilical artery pH (M group: 7.32 ± 0.05 versus V group: 7.25 ± 0.04 versus P group: 7.21 ± 0.03, P < 0.05), fetal acidosis (M group: 3% [n = 33] versus V group: 15% [n = 33] versus P group: 30% [n = 33], P = 0.01) and maternal intraoperative hypotension (M group: 12% [33] versus V group: 39% [33] versus P group: 73% [33], P < 0.0001) were identified among the groups. Multiple linear regression analysis demonstrated that treating arms, neonatal birthweight and the interval from the end of anesthesia to baby delivery were associated with umbilical artery pH.Conclusion: Compared with the preventive intravenous use of phenylephrine and placebo, preventive intramuscular phenylephrine exhibited a better neonatal acid-base status and more stable maternal hemodynamics in elective cesarean under spinal anesthesia. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the frequency, outcome, and risk factors of intravenous contrast media (CM) extravasation during contrast-enhanced CT scans in a large population.Methods: After institutional review board approval, 142,651 patients (72,976 males and 69,675 females; mean age, 59.9 ± 13.0 years) who underwent contrast-enhanced CT scans with intravenous CM between January 2015 and April 2017 were retrospectively included. The frequency of CM extravasations and their clinical outcomes were investigated. Risk factors of CM extravasation were evaluated using logistic regression with generalized estimating equation analyses. In addition, the frequency and risk factors of large-volume (≥100 ml) CM extravasation were also investigated.Results: CM extravasation occurred in 0.23% (321/142,651) of patients, all of which were of mild degree and resolved without any sequelae through conservative management. Multivariate analysis revealed that female gender [odds ratio (OR) = 1.61; p < 0.001], 60 < age ≤ 70 years (OR = 1.71; p = 0.004) or age > 70 years (OR = 2.49; p < 0.001), patients in general wards (OR = 2.71; p < 0.001) or ICUs (OR = 4.76; p < 0.001), 9.4 < CM viscosity ≤ 10.0 (OR = 1.65; p = 0.015), 10.0 < CM viscosity ≤ 10.6 (OR = 1.60; p = 0.002), and CM viscosity > 16.0 (OR = 2.55, p < 0.001) were independent risk factors for CM extravasation.Conclusion: CM extravasation during contrast-enhanced CT scans was uncommon with no substantial clinical consequences. Several risk factors that may have the potential to reduce the occurrence of CM extravasation were identified.Key Points: • The observed frequency of contrast media extravasation during contrast-enhanced CT scans was 0.23% (321/142,651). • Significant risk factors for contrast media extravasation were female gender, age older than 60 years, patients in general wards or ICUs, and the viscosity of contrast media greater than 9.4 mPa∙s. • The main preventive action for contrast media extravasation would be to lower the viscosity of contrast media. [ABSTRACT FROM AUTHOR]

Objective: To assess the effect of hyoscine butylbromide (HBB) on duration of the first stage of labor in primigravdae.Methods: A case-control study conducted on 120 primigravida at term admitted in active labor were divided into three equal groups. A single dose of the drug (placebo or HBB 20 mg or HBB 40 mg) was injected intravenously slowly to groups A, B, and C. The duration of the first stage was calculated from the time of cervical dilatation of three to four centimeters in active labor until a fully dilated cervix was observed.Results: The duration of first stage was significantly shorter in women receiving 20 and 40 mg of HBB when controlled to control women (187.73 ± 20.92, 186.41 ± 19.40 versus 231.39 ± 33.14 min). There was no significant difference between the three study groups regarding duration of the second stage (36.76 ± 9.98, 35.72 ± 9.97 and 37.55 ± 10.57, respectively, p > .05), number of cases delivered by cesarean section (12.5%, 12.5%, and 15%, respectively, p > .05) and Apgar score of the neonates (p > .05). There was no significant difference between the three study groups regarding occurrence of side effects named dry mouth (7.5%, 12.5%, and 5%, p > .05), flushing (2.5%, 5% and 0%, p > .05), tachycardia (2.5%, 2.5%, and 2.5%, p > .05), or urinary retention (2.5%, 0%, and 0%, p > .05).Conclusion: Intravenous injection of HBB decreases the duration of active phase of labor in primigravidae with no side effects. [ABSTRACT FROM AUTHOR]

Background and Purpose: Acid-sensing ion channels (ASICs) are neuronal proton sensors emerging as potential therapeutic targets in pain of the orofacial region. Amiloride, a non-specific ASIC blocker, has been shown to exert beneficial effects in animal models of migraine and in patients. We explored the involvement of the ASIC1-subtype in cutaneous allodynia, a hallmark of migraine affecting cephalic and extra-cephalic regions in about 70% of migrainers.Experimental Approach: We investigated the effects of systemic injections of amiloride and mambalgin-1, a specific inhibitor of ASIC1a- and ASIC1b-containing channels, on cephalic and extra-cephalic mechanical sensitivity in a rodent model of acute and chronic migraine induced by i.p. injections of isosorbide dinitrate.Key Results: I.v. injections of these inhibitors reversed cephalic and extra-cephalic acute cutaneous mechanical allodynia in rats, a single injection inducing a delay in the subsequent establishment of chronic allodynia. Both mambalgin-1 and amiloride also reversed established chronic allodynia. The anti-allodynic effects of mambalgin-1 were not altered in ASIC1a-knockout mice, showing the ASIC1a subtype is not involved in these effects which were comparable to those of the anti-migraine drug sumatriptan and of the preventive drug topiramate on acute and chronic allodynia respectively. A single daily injection of mambalgin-1 also had a significant preventive effect on allodynia chronification.Conclusions and Implications: These pharmacological data support the involvement of peripheral ASIC1-containing channels in migraine cutaneous allodynia as well as in its chronification. They highlight the therapeutic potential of ASIC1 inhibitors as both an acute and prophylactic treatment for migraine. [ABSTRACT FROM AUTHOR]

Objective: To explore the use of two consecutive axial scans in triple-rule-out (TRO) examination on a 16 cm wide-detector CT for radiation dose reduction.Materials and Methods: Sixty TRO patients were assigned to either study group (Group A, n = 30) or control group (Group B, n = 30). Group A used a two-phasic contrast injection: 25mgI/kg/s for 12 s in 1st and at 3.0 ml/s injection rate for 7 s in 2nd phase. The pulmonary artery, coronary artery and aorta were scanned in succession with two axial scans using smart-coverage technique. Group B used the conventional protocol of scanning pulmonary arteries first in helical, followed by coronary arteries in axial and aorta in helical mode with contrast injection of 25mgI/kg/s for 14 s. All images were reconstructed with 80% ASIR-V. The qualitative and quantitative image assessment and effective dose of the two groups were statistically compared.Results: The demographic data and quantitative measurements and qualitative image scores between the two groups were statistically the same (p > 0.05). However, Group A reduced radiation dose by 52% (2.67 ± 0.98 mSv vs. 5.65 ± 1.37 mSv) (p < 0.001).Conclusion: Using two consecutive axial scans in triple-rule-out on a 16 cm wide-detector CT reduces radiation dose while maintaining image quality compared with the conventional TRO protocol.Key Points: • Triple-rule-out can be performed with two-axial scans on a wide-detector CT system. • TRO with two-axial scans maintain image quality compared with conventional protocol. • TRO with two-axial scans reduces 52% radiation dose over conventional protocol. [ABSTRACT FROM AUTHOR]

Background: Ketamine has been shown to produce a rapid and potent antidepressant response in patients with treatment-resistant depression. Currently ketamine is most commonly administered as a 40-minute intravenous infusion, though it is unknown whether this is the optimal route of administration.Aims: To determine the plasma concentration time course of the R- and S-enantiomers of ketamine and norketamine following administration of ketamine by four different routes of administration.Methods: Plasma from conscious non-anaesthetised rats was collected following administration of ketamine by either subcutaneous (SC), intramuscular (IM), intravenous infusion (IVI) or intravenous bolus (IVB) routes of administration. Concentrations of the enantiomers of ketamine and norketamine were determined by LC/MS.Results: Administration by the SC, IM and IVI routes produced an overall similar drug exposure. In contrast, administration by the IVB route produced approximately 15-fold higher peak plasma concentrations for the enantiomers of ketamine and an approximately four-fold lower AUC for the enantiomers of norketamine.Conclusions: Route of administration can significantly influence ketamine and norketamine exposures. These differences may influence safety and tolerability, and potentially drug efficacy in humans. This knowledge adds to current research into the optimisation of the use of ketamine for the treatment of depression. [ABSTRACT FROM AUTHOR]

Background: Post-partum depression is associated with substantial morbidity, and improved pharmacological treatment options are urgently needed. We assessed brexanolone injection (formerly SAGE-547 injection), a positive allosteric modulator of γ-aminobutyric-acid type A (GABAA) receptors, for the treatment of moderate to severe post-partum depression.Methods: We did two double-blind, randomised, placebo-controlled, phase 3 trials, at 30 clinical research centres and specialised psychiatric units in the USA. Eligible women were aged 18-45 years, 6 months post partum or less at screening, with post-partum depression and a qualifying 17-item Hamilton Rating Scale for Depression (HAM-D) score (≥26 for study 1; 20-25 for study 2). Women with renal failure requiring dialysis, anaemia, known allergy to allopregnanolone or to progesterone, or medical history of schizophrenia, bipolar disorder, or schizoaffective disorder were excluded. Patients were randomly assigned (1:1:1) to receive a single intravenous injection of either brexanolone 90 μg/kg per h (BRX90), brexanolone 60 μg/kg per h (BRX60), or matching placebo for 60 h in study 1, or (1:1) BRX90 or matching placebo for 60 h in study 2. Patients, the study team, site staff, and the principal investigator were masked to treatment allocation. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all patients who started infusion of study drug or placebo, had a valid HAM-D baseline assessment, and had at least one post-baseline HAM-D assessment. The safety population included all randomised patients who started infusion of study drug or placebo. Patients were followed up until day 30. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT02942004 (study 1) and NCT02942017 (study 2).Findings: Participants were enrolled between Aug 1, 2016, and Oct 19, 2017, in study 1, and between July 25, 2016, and Oct 11, 2017, in study 2. We screened 375 women simultaneously across both studies, of whom 138 were randomly assigned to receive either BRX90 (n=45), BRX60 (n=47), or placebo (n=46) in study 1, and 108 were randomly assigned to receive BRX90 (n=54) or placebo (n=54) in study 2. In study 1, at 60 h, the least-squares (LS) mean reduction in HAM-D total score from baseline was 19·5 points (SE 1·2) in the BRX60 group and 17·7 points (1·2) in the BRX90 group compared with 14·0 points (1·1) in the placebo group (difference -5·5 [95% CI -8·8 to -2·2], p=0·0013 for the BRX60 group; -3·7 [95% CI -6·9 to -0·5], p=0·0252 for the BRX90 group). In study 2, at 60 h, the LS mean reduction in HAM-D total score from baseline was 14·6 points (SE 0·8) in the BRX90 group compared with 12·1 points (SE 0·8) for the placebo group (difference -2·5 [95% CI -4·5 to -0·5], p=0·0160). In study 1, 19 patients in the BRX60 group and 22 patients in the BRX90 group had adverse events compared with 22 patients in the placebo group. In study 2, 25 patients in the BRX90 group had adverse events compared with 24 patients in the placebo group. The most common treatment-emergent adverse events in the brexanolone groups were headache (n=7 BRX60 group and n=6 BRX90 group vs n=7 placebo group for study 1; n=9 BRX90 group vs n=6 placebo group for study 2), dizziness (n=6 BRX60 group and n=6 BRX90 group vs n=1 placebo group for study 1; n=5 BRX90 group vs n=4 placebo group for study 2), and somnolence (n=7 BRX60 group and n=2 BRX90 group vs n=3 placebo group for study 1; n=4 BRX90 group vs n=2 placebo group for study 2). In study 1, one patient in the BRX60 group had two serious adverse events (suicidal ideation and intentional overdose attempt during follow-up). In study 2, one patient in the BRX90 group had two serious adverse events (altered state of consciousness and syncope), which were considered to be treatment related.Interpretation: Administration of brexanolone injection for post-partum depression resulted in significant and clinically meaningful reductions in HAM-D total score at 60 h compared with placebo, with rapid onset of action and durable treatment response during the study period. Our results suggest that brexanolone injection is a novel therapeutic drug for post-partum depression that has the potential to improve treatment options for women with this disorder.Funding: Sage Therapeutics, Inc. [ABSTRACT FROM AUTHOR]

Individuals with limited health literacy (HL) are less likely to obtain preventive care. We designed a study to compare adherence to weekly oral and quarterly intravenous bisphosphonates among patients with low HL. The study enrolled a total of 432 female patients who presented with a distal radius fracture caused by low-energy trauma. Participant HL was measured using the Newest Vital Sign tool, and patients were randomized to weekly oral or quarterly intravenous bisphosphonate groups. Subjects in the intravenous bisphosphonate group received intravenous injections of 3 mg ibandronate every 3 months, and those in the oral bisphosphonate group self-administered 70 mg alendronate orally once each week for 12 months. The adherence to weekly oral or quarterly intravenous bisphosphonates was analyzed by HL level. The rate of adherence to quarterly intravenous bisphosphonates was significantly higher than that for weekly oral bisphosphonates in patients with inadequate HL (73 vs. 46%, p = 0.001), whereas no significant differences were observed between HL groups in adherence to intravenous bisphosphonate. Conversely, the rate of adherence to orally administered bisphosphonates was significantly lower in patients with inadequate HL than in those with appropriate HL (46 vs. 65%, p = 0.005). After controlling for confounding variables, inadequate HL, the presence of comorbidities, and weekly oral bisphosphonates were associated with a higher likelihood of nonadherence to osteoporosis treatment. Thus patients with limited health literacy can achieve rates of adherence to quarterly intravenous bisphosphonates, as opposed to weekly oral bisphosphonates, similar to rates among patients with appropriate literacy. [ABSTRACT FROM AUTHOR]

Neostigmine reverses non-depolarising neuromuscular blockade, but may cause muscle weakness when administered after full recovery of neuromuscular function. We hypothesised that neostigmine in therapeutic doses impairs muscle strength and respiratory function in awake healthy volunteers. Twenty-one volunteers were randomised to receive two doses of either intravenous (i.v.) neostigmine 2.5 mg with glycopyrrolate 450 μg (neostigmine group, n = 14) or normal saline 0.9% (placebo group, n = 7). The first dose was administered immediately after obtaining baseline measurements, and the second dose was administered 15 min later. All 14 volunteers in the neostigmine group received the first dose, mean (SD) 35 (5.8) μg.kg-1 , but only nine of these volunteers agreed to receive the second dose, 34 (3.5) ?g.kg-1 . The primary outcome was hand grip strength. Secondary outcomes were train-of-four ratio, single twitch height, forced expiratory volume in 1 s, forced vital capacity, forced expiratory volume in 1 s/forced vital capacity ratio, oxygen saturation, heart rate and mean arterial pressure. The first dose of intravenous neostigmine with glycopyrrolate resulted in reduced grip strength compared with placebo, -20 (20) % vs. +4.3 (9.9) %, p = 0.0016; depolarising neuromuscular blockade with decreased single twitch height, -14 (11) % vs. -3.8 (5.6) %, p = 0.0077; a restrictive spirometry pattern with decreased predicted forced expiratory volume in 1 s, -15 (12) % vs. -0.47 (3.4) %, p = 0.0011; and predicted forced vital capacity, -20 (12) % vs. -0.59 (3.2) %, p < 0.0001 at 5 min after administration. The second dose of neostigmine with glycopyrrolate further decreased grip strength mean (SD) -41 (23) % vs. +1.0 (15) %, p = 0.0004; single twitch height -25 (15) % vs. -2.5 (6.6) %, p = 0.0030; predicted forced expiratory volume in 1 s -23 (24) % vs. -0.7 (4.4) %, p = 0.0063; and predicted forced vital capacity, -27.1 (22.0) % vs. -0.66 (3.9) %, p = 0.0010. Train-of-four ratio remained unchanged (p = 0.22). In healthy volunteers, therapeutic doses of neostigmine induced significant and dose-dependent muscle weakness, demonstrated by a decrease in maximum voluntary hand grip strength and a restrictive spirometry pattern secondary to depolarising neuromuscular blockade. [ABSTRACT FROM AUTHOR]

Background: Ibalizumab, a humanized IgG4 monoclonal antibody, blocks the entry of human immunodeficiency virus type 1 (HIV-1) by noncompetitive binding to CD4.Methods: In this single-group, open-label, phase 3 study, we enrolled 40 adults with multidrug-resistant (MDR) HIV-1 infection in whom multiple antiretroviral therapies had failed. All the patients had a viral load of more than 1000 copies of HIV-1 RNA per milliliter. After a 7-day control period in which patients continued to receive their current therapy, a loading dose of 2000 mg of ibalizumab was infused; the viral load was quantified 7 days later. Through week 25 of the study, patients received 800 mg of ibalizumab every 14 days, combined with an individually optimized background regimen including at least one fully active agent. The primary end point was the proportion of patients with a decrease in viral load of at least 0.5 log10 copies per milliliter from baseline (day 7) to day 14.Results: A total of 31 patients completed the study. The mean baseline viral load was 4.5 log10 copies per milliliter, and the mean CD4 count was 150 per microliter. Of the 40 patients in the intention-to-treat population, 33 (83%) had a decrease in viral load of at least 0.5 log10 copies per milliliter from baseline (P<0.001 for the comparison with the control period). The mean viral-load decrease was 1.1 log10 copies per milliliter. During the control period, 1 patient, who received the optimized background regimen prematurely, had a decrease in viral load of 0.5 log10 copies per milliliter. At week 25, patients who had received ibalizumab plus an optimized background regimen had a mean decrease of 1.6 log10 copies per milliliter from baseline; 43% of the patients had a viral load of less than 50 copies per milliliter, and 50% had a viral load of less than 200 copies per milliliter. Among 10 patients who had virologic failure or rebound, in vitro testing identified 9 who had a lower degree of susceptibility to ibalizumab than at baseline. The most common adverse event was diarrhea (in 20% of patients). Four patients died from causes related to underlying illnesses; 1 had a serious adverse event (the immune reconstitution inflammatory syndrome) that was deemed to be related to ibalizumab therapy.Conclusions: In patients with MDR HIV-1 infection who had advanced disease and limited treatment options, ibalizumab had significant antiviral activity during a 25-week study. Evidence of the emergence of diminished ibalizumab susceptibility was observed in vitro in patients who had virologic failure. (Funded by the Orphan Products Clinical Trials Grants Program of the Food and Drug Administration and TaiMed Biologics; TMB-301 ClinicalTrials.gov number, NCT02475629 .). [ABSTRACT FROM AUTHOR]

Aims: Mechanical ultrafiltration (UF) involves the removal of an iso-osmotic filtrate from the blood. Its benefit in acute decompensated heart failure, however, remains inconclusive. We sought to better understand the direct effects of UF in comparison to an aggressive, urine output-guided pharmacological protocol for decongestion on fluid loss, renal function, and neurohormonal activation.Methods and Results: A per-protocol analysis of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial (n = 188) was performed. Participants were included if randomized to UF and had UF output collected, or if randomized to the pharmacological arm and had urine but not UF output collected. Using these definitions, there were 163 participants at 24 h, 156 at 48 h, 129 at 72 h, and 106 at 96 h. UF was associated with higher cumulative fluid loss (P = 0.003), net fluid loss (P = 0.001), and relative reduction in weight (P = 0.02). UF was also associated with higher serum creatinine and blood urea nitrogen by 72 h (P-interaction <0.05 for both), lower serum sodium by 48 h (P-interaction <0.01) and increased plasma renin activity by 96 h (P = 0.04). The pharmacological arm was associated with higher serum bicarbonate after 24 h (P-interaction <0.002). There were no differences in 60-day outcomes between the UF and pharmacological arms.Conclusions: Ultrafiltration vs. pharmacological therapy was associated with more fluid removal but also rise in serum creatinine and neurohormonal activation. Additionally, loop diuretic use vs. UF was associated with an increase in serum bicarbonate despite less decongestion, data which question the commonly held conception of a 'contraction alkalosis'. [ABSTRACT FROM AUTHOR]

Background: The value of intravenous acetaminophen in postoperative pain management remains debated. The authors tested the hypothesis that intravenous acetaminophen use, in isolation and in comparison to oral, would be associated with decreased opioid utilization (clinically significant reduction defined as 25%) and opioid-related adverse effects in open colectomy patients.Methods: Using national claims data from open colectomy patients (Premier Healthcare Database, Premier Healthcare Solutions, Inc., USA; 2011 to 2016; n = 181,640; 602 hospitals), we separately categorized oral and intravenous acetaminophen use: 1 (1,000 mg) or more than 1 dose on the day of surgery, postoperative day 1, or later. Multilevel models measured associations between intravenous or oral acetaminophen and (1) opioid utilization and (2) opioid-related adverse effects. Percent change and multiplicity-adjusted 99.5% CI are reported.Results: Overall, 25.1% of patients received intravenous acetaminophen, of whom 48.0% (n = 21,878) received 1 dose on the day of surgery. In adjusted analyses, particularly more than 1 dose of intravenous acetaminophen (versus nonuse) on postoperative day 1 was associated with a -12.4% (99.5% CI, -15.2 to -9.4%) change in opioid utilization. In comparison, a stronger reduction was seen in those receiving more than 1 oral acetaminophen dose: -22.6% (99.5% CI, -26.2 to -18.9%). Unadjusted group medians were 550 and 490 oral morphine equivalents, respectively. Intravenous versus oral differences were less pronounced among those receiving more than 1 acetaminophen dose on the day of surgery: -8.0% (99.5% CI, -11.0 to -4.9%) median 499 oral morphine equivalents versus -8.7% (99.5% CI, -14.4 to -2.7%) median 445 oral morphine equivalents, respectively; all statistically significant, but none clinically significant. Comparable outcome patterns existed for opioid-related adverse effects.Conclusions: The demonstrated marginal effects do not support routine use of intravenous acetaminophen given alternative nonopioid analgesic options. [ABSTRACT FROM AUTHOR]

Purpose: Much of the volume of solid tumors typically exists in a chronically hypoxic microenvironment that has been shown to result in both chemotherapy and radiation therapy resistance. The purpose of this study was to use localized microbubble delivery to overcome hypoxia prior to therapy.Materials and Methods: In this study, surfactant-shelled oxygen microbubbles were fabricated and injected intravenously to locally elevate tumor oxygen levels when triggered by noninvasive ultrasound in mice with human breast cancer tumors. Changes in oxygen and sensitivity to radiation therapy were then measured.Results: In this work, we show that oxygen-filled microbubbles successfully and consistently increase breast tumor oxygenation levels in a murine model by 20 mmHg, significantly more than control injections of saline solution or untriggered oxygen microbubbles (P < .001). Using photoacoustic imaging, we also show that oxygen delivery is independent of hemoglobin transport, enabling oxygen delivery to avascular regions of the tumor. Finally, we show that overcoming hypoxia by this method immediately prior to radiation therapy nearly triples radiosensitivity. This improvement in radiosensitivity results in roughly 30 days of improved tumor control, providing statistically significant improvements in tumor growth and animal survival (P < .03).Conclusions: Our findings demonstrate the potential advantages of ultrasound-triggered oxygen delivery to solid tumors and warrant future efforts into clinical translation of the microbubble platform. [ABSTRACT FROM AUTHOR]

BACKGROUND AND STUDY AIMS : The present study aimed to determine the type of intravenous hydration that is best suited to reducing the incidence of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis.Patients and Methods: In a prospective randomized multicenter trial, average-to-high risk patients who underwent first-time ERCP were randomly assigned to three groups (1:1:1) who received: aggressive intravenous hydration (3 mL/kg/h during ERCP, a 20-mL/kg bolus and 3 mL/kg/h for 8 hours after ERCP) with either lactated Ringer's solution (LRS) or normal saline solution (NSS), or standard intravenous hydration with LRS (1.5 mL/kg/h during and for 8 hours after ERCP). The primary end point was post-ERCP pancreatitis (PEP).Results: 395 patients were enrolled, and 385 completed the protocols. The three groups showed no significant differences in demographic characteristics. There was a significant difference in the intention-to-treat (ITT) PEP rate between the aggressive LRS group (3.0 %, 95 % confidence interval [CI] 0.1 % - 5.9 %; 4 /132), the aggressive NSS group (6.7 %, 95 %CI 2.5 % - 10.9 %; 9 /134) and the standard LRS group (11.6 %, 95 %CI 6.1 % - 17.2 %; 15 /129; P = 0.03). In the two-group comparisons, the ITT PEP rate was significantly lower for the aggressive LRS group than for the standard LRS group (relative risk [RR] 0.26, 95 %CI 0.08 - 0.76; P = 0.008). There was no significant difference in the ITT PEP rate between the aggressive NSS group and the standard LRS group (RR 0.57, 95 %CI 0.26 - 1.27; P = 0.17).Conclusion: Aggressive hydration with LRS is the best approach to intravenous hydration for the prevention of PEP in average-to-high risk patients. [ABSTRACT FROM AUTHOR]

Superantigens (SAgs) are extremely potent bacterial toxins, which evoke a virulent immune response, inducing nonspecific T-cell proliferation, rapid cytokine release, and lethal toxic shock, for which there is no effective treatment. We previously developed a small molecule, S101, which potently inhibits proliferating T cells. In a severe mouse model of toxic shock, a single injection of S101 given together with superantigen challenge rescued 100% of the mice. Even when given 2 hours after challenge, S101 rescued 40% of the mice. S101 targets the T-cell receptor, inflammatory response, and actin cytoskeleton pathways. S101 inhibits the aryl hydrocarbon receptor, a ligand-activated transcription factor that is involved in the differentiation of T-helper cells, especially Th17, and regulatory T cells. Our results provide the rationale for developing S101 to treat superantigen-induced toxic shock and other pathologies characterized by T-cell activation and proliferation. [ABSTRACT FROM AUTHOR]

Background: Injecting drugs safely almost always includes the presence of one's social network, especially for the prevention of overdose. Yet, the systematic analysis of users' social networks has yet to be established as a focal method in harm reduction research, and interventions.Methods: This study draws from 200 interviews with persons who inject drugs recruited from North America's first sanctioned supervised injection facility and a drug user's advocacy group. Respondents were asked about the individuals they personally considered as facilitators of harm reduction, and the relations between them. Collectively, these 200 respondents provided over 900 individuals whom they considered as members of their harm reduction network. The aim was to locate individuals that would potentially make the network denser (harm reduction champions) and users that were situated in the "periphery" of the network, and in practice, further away from the harm reduction core.Results: Of the 1135 network members, 63 individuals formed the "core" of the harm reduction network, collectively reaching approximately 70% of individuals in the network. We also uncovered 31 individuals that acted as "articulation points"- these individuals were not as connected, but were more effective at reaching peripheral individuals.Conclusion: Former or current injecting drug users that were sampled were surrounded by a relatively rich harm reduction network, but the network approach showed that only a minority of individuals were true harm reduction "champions". Recruitment of a combination of well-connected harm reduction champions, and strategically connected articulation points, would be most effective in planning network interventions that encourage harm reduction behaviors among this population. [ABSTRACT FROM AUTHOR]

Background: Tourniquet use during primary total knee arthroplasty is thought to reduce intraoperative blood loss and improve visibility. Our goal was to investigate whether tourniquet use is necessary for controlling intraoperative blood loss when alternatives such as tranexamic acid (TXA) are available.Methods: One hundred and fifty patients were equally randomized to 3 groups. Group A was treated with a tourniquet as well as multiple doses of intravenous TXA (20 mg/kg 5 to 10 minutes before the skin incision and 10 mg/kg 3, 6, 12, and 24 hours later) along with 1 g of topical TXA, Group B was treated the same as Group A but without the tourniquet, and Group C was treated with the tourniquet only.Results: The amount of intraoperative blood loss was similar for the 3 groups. Group B had significantly less hidden blood loss than Group A (p = 0.018) and Group C (p < 0.001). No significant differences (p > 0.05) were observed between Group A and Group B with regard to total blood loss, drainage volume, intraoperative blood loss, transfusion rate, or maximum change in the hemoglobin (Hb) level. We also found significantly more benefits for Group B compared with Groups A and C with regard to postoperative swelling ratio, levels of inflammatory biomarkers, visual analog scale (VAS) pain scores, range of motion at discharge, Hospital for Special Surgery (HSS) score, and patient satisfaction. There were no significant differences (p > 0.05) in the deep venous thrombosis or pulmonary embolus rates among the 3 groups. More wound secretion was observed in the groups in which a tourniquet was used.Conclusions: Patients treated with multiple doses of intravenous and topical TXA without a tourniquet had less hidden blood loss, a lower ratio of postoperative knee swelling, less postoperative knee pain, lower levels of inflammatory biomarkers, better early knee function, and even better early satisfaction than those treated with a tourniquet. Long-term follow-up should be performed to evaluate the effects on prosthetic fixation and long-term survival of total knee arthroplasty performed without a tourniquet.Level Of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Background: Norepinephrine has been investigated as a potential alterative to phenylephrine for maintaining blood pressure during spinal anesthesia for cesarean delivery with the advantage of less depression of maternal heart rate and cardiac output. However, the relative potencies of these two vasopressors have not been fully determined in this context.Methods: In a random-allocation, graded dose-response study, 180 healthy patients undergoing spinal anesthesia for elective cesarean delivery received a single bolus of norepinephrine in one of six different doses ranging from 4 to 12 µg or phenylephrine in one of six different doses ranging from 60 to 200 µg to treat the first episode of hypotension. The magnitude of response was measured as the percentage of full restoration of systolic blood pressure to the baseline value. Dose-response analysis was performed using nonlinear regression to derive four-parameter logistic dose-response curves, which were compared to determine relative potency.Results: Data were analyzed for 180 patients. The estimated ED50 values (dose giving a 50% response) were norepinephrine 10 µg (95% CI, 6 to 17 µg) and phenylephrine 137 µg (95% CI, 79 to 236 µg). The estimated relative potency ratio for the two drugs was 13.1 µg (95% CI, 10.4 to 15.8 µg).Conclusions: Comparative dose-response analysis was completed for norepinephrine and phenylephrine given as a bolus to treat the first episode of hypotension in patients undergoing spinal anesthesia for cesarean delivery. The estimated dose equivalent to phenylephrine 100 µg was norepinephrine 8 µg (95% CI, 6 to 10 µg). These results may be useful to inform the design of future comparative studies. [ABSTRACT FROM AUTHOR]