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In magnesium alloys with aluminum as an alloying component, zirconium loses its grain refinement effect as a grain refiner. Instead of zirconium, Mg3N2 can be used, and promising results have already been obtained. However, the duration of action of Mg3N2 has not been elucidated yet. The aim of this work is therefore to determine the grain size of the AZ80 alloy as a function of the duration of action of Mg3N2 and thus the economically reasonable duration of use. It was found that the Mg3N2 reaches its full effect from 30 min after a complete remelting and does not lose this grain refinement effect even after 90 min. It thus proves to be a stable and reliable grain refiner. A grain size of 146.3 ± 10.3 µm was achieved. Furthermore, a minimum tensile strength of 205 MPa with a break elongation of 5.99% was achieved.

Metallic Zn alloys have recently gained interest as potential candidates for developing platforms of bioresorbable vascular stents (BVS). Previous studies revealed that Mg alloys used for BVS can degrade too early, whereas PLLA materials may fail to provide effective scaffolding properties. Here we report on results of a new bioresorbable, metallic stent made from a Zn-Ag alloy studied in a porcine animal model of thrombosis and restenosis. While the tensile strength (MPa) of Zn-3Ag was higher than that of PLLA and resembled Mg's (WE43), fracture elongation (%) of Zn-3Ag was much greater (18-fold) than the PLLA's or Mg alloy's (WE43). Zn-3Ag exposed to HAoSMC culture medium for 30 days revealed degradation elements consisting of Zn, O, N, C, P, and Na at a 6 nm surface depth. Platelet adhesion rates and blood biocompatibility did not differ between Zn-3Ag, PLLA, Mg (WE43), and non-resorbable Nitinol (NiTi) stent materials. Balloon-expandable Zn-3Ag alloy BVS implanted into iliofemoral arteries of 15 juvenile domestic pigs were easily visible fluoroscopically at implantation, and their bioresorption was readily detectable via X-ray over time. Histologically, arteries with Zn-3Ag BVS were completely endothelialized, covered with neointima, and were patent at 1, 3, and 6 months follow-up with no signs of stent thrombosis. Zn-3Ag alloy appears to be a promising material platform for the fabrication of a new generation of bioresorbable vascular stents.

ARTIKLAR Anders Nygren: Missionens plats i kristendomens centrum Ernst Newman: Svenska fromhets- och predikoriktningar i den romantiska kulturidealismens tidevarv TEOLOGISK LITTERATUR Henrik Sandblad: De eskatologiska föreställningarna i Sverige under reformation och motreformation. Anm. av Carl-Martin Edsman V. Schou Pedersen: Bidrag til en analyse af de mandaeiske skrifter med henblik paa bestemmelsen af mandaeernas forhold til jødedom og kristendom. Anm. av Ernst Percy Coniectanea Neotestamentica edenda curavit A. Fridrichsen, Fasc. IV–VII. Anm. av Werner Georg Kümmel E. Lohmeyer: Kultus und Evangelium. Anm. av Erik Sjöberg G. Rudberg: Frihet – studium – tro. Anm. av Erik Sjöberg A. Fridrichsen: Våra evangeliers historiska värde. Anm. av Erik Sjöberg Gösta Nelson: Tio skriftetal. Anm. av H. B. Hammar En bok om kyrkan av svenska teologer. Anm. av Martin Lindström Sigfrid Blomstrand: Tidskriften Kristen gemenskap DISKUSSIONSINLÄGG Anton Fridrichsen: Skriften och tron. Radanmärkningar till D:r Barnekow

ARTIKLAR Edv. Rodhe: Nutida tendenser inom den svenska systematiska teologien Anders Nygren: Tvenne frälsningsvägar Ernst Newman: Kring den Waldenströmska försoningsläran Joh. Lindblom: Erik Stave och hans plats inom svensk teologi FRÅN DEN TEOLOGISKA SAMTIDEN TEOLOGISK LITTERATUR Hannah Arendt: Der Liebesbegriff bei Augustin. Versuch einer philosophischen Interpretation. Anm. av Anders Nygren Harald Eklund: Evangelisches und Katholisches in Max Schelers Ethik. Anm. av Anders Nygren Georg Wünsch: Evangelische Wirtschaftsethik. Anm. av Anders Nygren Wilhelm Bartelheimer: Schleiermacher und die gegenwärtige Schleiermacherkritik. Eine Untersuchung über den Subjektivismus. Robert Brunner: Schleiermachers Lehre vom Gefühl schlechthiniger Abhängigkeit mit besonderer Berücksichtigung seiner theologischen Methode. Anm. av A. Hjalmar J. Lindroth J. P. Bang: Gyllingproesten Otto Möller. Liv og forfatterskab. Anm. av Hilding Pleijel Johannes von Walter: Die Geschichte des Christentums, 1. Das Altertum. Anm. av Gustaf Aulén Ur tidskrifterna

ARTIKLAR Jens Nørregaard: Tre Augustin-ord Hugo Odeberg: Gamla testamentet i våra dagar Ernst Newman: Tegnér och prästmötet i Växjö 1836 Yngve Brilioth: Isolering och gemenskap i kyrkans liv TEOLOGISK LITTERATUR Wolfgang Schmidt: Die Kirche bei Irenäus. Anm. av Olof Linton Toni Schmid: Sveriges kristnande. Från verklighet till dikt. Anm. av Yngve Brilioth Sigurd Normann: Vilje frihet og forutbestemmelse i den lutherske reformasjon inntil 1525. Anm. av Gustaf Ljunggren Gåva och krav. Till Manfred Björkquist på hans femtioårsdag. Anm. av Ragnar Bring Johannes Sundwall: Die Zusammensetzung des Markusevangeliums. Anm. av Hugo Odeberg Einar Molland: Das Paulinische Euangelion, das Wort und die Sache. Anm. av Hugo Odeberg

ARTIKLAR Edv. Rodhe: Hava de kristna kyrkorna och de enskilda kristna något ansvar för de politiska frågorna? Folke Holmström: Nathan Söderbloms självbiografiska uttalanden om ungdomsårens avgörande kriser Ernst Newman: Den »frikyrkliga» strömningen bland de bildade i Finland på 1880-talet TEOLOGISK LITTERATUR Edvard Rodhe: Den religiösa liberalismen. Nils Ignell, Viktor Rydberg, Pontus Wikner. Isak Krook: Viktor Rydbergs lära om Kristus. Anm. av Gustaf Aulén Hjalmar Sundén: Wilfred Monod om det godas problem. Joh. Lindblom: Den gammaltestamentliga religionens egenart. En metodologisk och exegetisk studie. Anm. av Erik Sjöberg H. Odeberg: Nyutkommen engelsk litteratur till Nya testamentets exegetik G. L. Prestige: The Life of Charles Gore. A great Englishman. Anm. av Yngve Brilioth

Cellulose nanofibril-silver (CNF-Ag) hybrid and ultralight silver-infused aerogel were produced using cotton gin trash (CGT), an abundant agro-waste material. This repurposing of CGT was achieved by exploiting its potential for CNF extraction and the in situ synthesis of silver nanoparticles (Ag NPs). CNFs were extracted from CGT through a mechanical shearing process. These CNFs served as a multifunctional nanotemplate for the controlled reduction of Ag ions, efficient nucleation, and stabilization of NPs, resulting in the production of a high concentration of Ag NPs (ca. 19 wt %) within the CNFs. Transmission electron microscopy images of cross-sectioned CNFs confirmed the uniform dispersion of NPs (ca. 18 nm diameter) inside the CNFs. Rietveld refinement analysis of X-ray diffraction patterns revealed that CNFs produced smaller Ag crystallites compared to CGT microparticles. The CNF-Ag hybrid was then fabricated into an aerogel using freeze-drying, with its weight being light enough to rest on a cotton flower's stamen. The infusion of Ag NPs led to approximately 20% reductions in the specific surface area and pore volume of the aerogel., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Objectives: Determine percentage of subglottic stenosis using current endotracheal tube (ETT) cross-sectional areas as actual, compared with previously published ETT cross-sectional areas as expected, and determine if style of ETT could result in a change in percentage of stenosis or Myer-Cotton grade., Study Type: Cross-sectional study., Design: Prospective analysis., Methods: Eight styles of uncuffed pediatric ETT from four manufacturers ranging from 2.0 to 6.0 inner diameter (ID) were evaluated. ID and outer diameter (OD) measurements were obtained from each company's specification sheets. Cross-sectional area was calculated for each ETT using the formula (Area = πr 2 ). The cross-sectional areas of each current ETT (actual) were compared with those of previously published ETTs (expected) based on age, and the degree of stenosis was calculated using the formula [1- (Area actual /Area expected )] × 100%. Ranges of percentage for each style of ETT were calculated., Results: There was an increase in range of OD and area with increasing size of ETT ID, with the largest range in OD being 0.8 mm, and the largest range in area being 10.55 mm 2 . The median interquartile range (IQR), range of percentage stenoses was 11 (5%), ranging from 0% to 21%. Seven of 28 (25%) ranges were found to span two Myer-Cotton grades., Conclusions: The Myer-Cotton grade of subglottic stenosis depends on the style of ETT used. Using updated values from currently available ETTs aims to keep this grading system valid with respect to surgical approach and outcomes following surgery., Level of Evidence: NA Laryngoscope, 133:2808-2812, 2023., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Andexanet alfa (andexanet) is the only FDA-approved medication for reversal of apixaban and rivaroxaban anticoagulation for life-threatening or uncontrolled bleeding. Infusion modifications may be required in surgical patients undergoing prolonged operative intervention but have not previously been described. Case Report: A 78-year-old woman on rivaroxaban for atrial fibrillation was admitted to the trauma service for a mechanical fall, sustaining a T4 burst fracture with severe canal stenosis and spinal cord edema resulting in loss of strength and sensation in her legs. Clinically relevant rivaroxaban activity was verified with an elevated low molecular weight heparin anti-factor Xa assay, and laboratory confirmed coagulopathy was demonstrated by a prolonged prothrombin time, thromboelastography (TEG) R-time, and activated clotting time (ACT). The patient required urgent surgical intervention for spinal fixation. Given the expected prolonged duration of the procedure, standard dose andexanet was initiated with a prolonged infusion at half the standard rate during the operation. The procedure was successful and intraoperative TEGs demonstrated normalization of R-time and ACT throughout the procedure. The patient did not experience any complications postoperatively and successfully discharged to inpatient rehabilitation. Conclusion: Modifications to the andexanet infusion may be required in surgical patients requiring rivaroxaban reversal for a prolonged procedure. Further data are needed to determine the optimal approach to infusion modification.

Background: Altered drug and nutrient absorption presents a unique challenge in critically ill patients. Performing an acetaminophen absorption test (AAT) has been used as a marker for gastric motility and upper small bowel absorption; thus, it may provide objective data regarding enteral absorptive ability in critically ill patients., Study Question: What is the clinical experience with AAT when used as a surrogate marker for enteral absorption in critically ill patients?, Study Design: This single-center, retrospective, cohort study evaluated serum acetaminophen concentrations within 180 minutes following 1-time enteral administration of an AAT. Patients admitted to the surgical and medical intensive care units and medical intensive care units over a 7-year period were evaluated. Groups were defined as positive (acetaminophen concentration of ≥10 mg/L) or negative (acetaminophen concentration of <10 mg/L) AAT., Measures and Outcomes: The outcomes were to describe the clinical experience, characteristics, and performance of AAT., Results: Forty-eight patients were included. Patients were 58.5 ± 14 years of age, mostly male (58.3%), and admitted to the surgical intensive care unit (66.7%). Median hospital length of stay was 47.5 (27-78.8) days. Thirty-four patients (70.8%) had a positive AAT [median concentration, 14 (12-18) mg/L]. Median time to first detectable concentration was 37 (33-64) minutes. AAT characteristics were similar between the groups including total dose, weight-based dose, time to first and second assays, drug formulation, and site of administration between groups. There were no independent risk factors identified on regression analysis for negative AAT., Conclusions: An acetaminophen dose of 15 mg/kg with 2 coordinated serum concentrations approximately 30 and 60 minutes after administration is a reasonable construct for AAT. Future research is needed to assess AAT utility, safety, and clinical outcomes for predicting patient ability to absorb enteral feeds and medications., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The COVID-19 pandemic impacted profoundly on the wellbeing and social interactions of the world population, and all dimensions of sexual health were potentially affected by globally implemented preventive measures., Objectives: The scoping review aimed to compile existing research investigating possible effects of COVID-19 lockdowns on adult sexual health, that is, sexual behavior, functioning, and satisfaction. Further, studies on the interplay between mental health and sexual well-being during the pandemic were reviewed., Methods: The review was conducted in accordance with guidelines established by the Joanna Briggs Institute and the Extension for Scoping Reviews (PRISMA-ScR) Checklist. On October 11-12, 2021, PubMed, Embase, PsycInfo, Cinahl, Cochrane, Sociological Abstracts and Scopus were systematically searched for relevant peer-reviewed papers employing quantitative methodology. Additionally, unpublished ("grey") research studies on the subject were retrieved. The screening, data extraction, and analysis of evidence were conducted by 4 independent reviewers using an iterative approach., Results: Based on 107 studies included, the scoping review showed that the pandemic had had a wide impact on all dimensions of sexual health. Except for solo sex activities, mainly negative COVID-19 implications were identified, although findings were, in sum, characterized by complexity and unpredictability. Thus, sexual behavior, functioning, and satisfaction during the pandemic appeared to be mitigated by a broad range of sociodemographic and contextual factors. Finally, sexual health seemed deeply entwined with overall mental health., Conclusion: The scoping review revealed a broad range of COVID-19-related effects on sexual health, including an overall decline in partnered sex and a concurrent increase in solo sex activities. It also emphasized a need for future research to shed light on possible long-term consequences of the pandemic in various population groups and on all aspects of sexual health. Toldam NE, Graugaard C, Meyer R, et al. Sexual Health During COVID-19: A Scoping Review. Sex Med Rev 2022;10:714-753., (Copyright © 2022 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Outcomes following andexanet alfa reversal of factor Xa inhibitors in patients requiring urgent or emergent invasive procedures are lacking. This study aimed to describe efficacy and safety outcomes following andexanet alfa administration within 24 h of an invasive procedure., Methods: This single-center, observational, retrospective study included patients who received andexanet alfa within 24 h of an invasive or surgical procedure. The primary outcome was hemostatic efficacy graded as excellent, good, or poor using similar definitions to the ANNEXA-4 criteria. Secondary outcomes included hospital discharge disposition, intensive care unit (ICU) and hospital length of stay, 30-day mortality, 30-day thromboischemic event rates, and serum coagulation assay changes pre- and postreversal., Results: Forty-four patients met inclusion criteria; of these, 27 (62.8%) received apixaban and 16 (37.2%) were treated with rivaroxaban prior to admission. The indications for reversal were categorized as intracranial (n = 20 [45.5%]) or extracranial (n = 24 [54.5%]) sites. Majority of patients required emergent operative procedures (18 [40.9%]), followed by invasive device placement (10 [22.7%]) or arterial embolization (9 [20.5%]). Thirty-eight (86.4%) patients were able to be adequately graded for hemostatic efficacy. Overall, 30 (78.9%) patients achieved excellent or good hemostasis within 24 h after periprocedural administration of andexanet alfa (19 [82.6%] apixaban vs. 11 [78.6%] rivaroxaban; 12 [80.0%] intracranial events vs. 18 [78.3%] extracranial events). Discharge disposition was most often to a short- or long-term care facilities (27 [61.4%]). Thirty-day mortality and thromboischemic complications occurred in 15 (34.1%) and 12 (27.3%) patients, respectively. Prothrombin time and antifactor Xa assay results were significantly decreased after andexanet alfa administration (p < 0.05) while thromboelastogram assay values (reaction time, kinetic time, and activated clotting time) showed nonsignificant changes pre- versus postreversal., Conclusion: Andexanet alfa may be used for urgent or emergent reversal of apixaban and rivaroxaban peri-procedurally with promising hemostatic outcomes. Further prospective, comparative clinical research is warranted., (© 2022 The Authors. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

The complexity of macromolecular surfaces means that there are still many open questions regarding how specific areas are solvated and how this might affect the complexation of guests. Contributing to the identification and classification of the different possible mechanisms of complexation events in aqueous solution, and as part of the recent SAMPL8 exercise, we report here on the synthesis and conformational properties of TEEtOA 2 , a cavitand with conformationally flexible ethyl groups at its portal. Using a combination of ITC and NMR spectroscopy, we report the binding affinities of a series of carboxylates to 2 and compare it to a related cavitand TEMOA 1 . Additionally, we report MD simulations revealing how the wetting of the pocket of 2 is controlled by the conformation of its rim ethyl groups and, correspondingly, a novel triggered wetting, guest complexation mechanism, whereby the approaching guest opens up the pocket of the host, inducing its wetting and ultimately allows the formation of a hydrated host-guest complex (H·G·H 2 O). A general classification of complexation mechanisms is also suggested.

Background: Inhaled tobramycin can be used for empiric or definitive therapy of ventilator-associated pneumonia (VAP) in mechanically ventilated patients. This is believed to minimize systemic exposure and potential adverse drug toxicities including acute kidney injury (AKI). However, detectable serum tobramycin concentrations have been reported after inhaled tobramycin therapy with AKI., Methods: This retrospective, observational study evaluated mechanically ventilated adult subjects admitted to ICUs at a large, urban academic medical center that received empiric inhaled tobramycin for VAP. Subjects were separated into detectable (ie, ≥ 0.6 mg/L) or undetectable serum tobramycin concentration groups, and characteristics were compared. Independent predictors for detectable serum tobramycin concentration and new onset AKI during or within 48 h of therapy discontinuation were assessed., Results: Fifty-nine inhaled tobramycin courses in 53 subjects were included in the analysis, of which 39 (66.1%) courses administered to 35 (66.0%) subjects had detectable serum tobramycin concentrations. Subjects with detectable serum tobramycin concentrations were older (57.1 y ± 11.4 vs 45.9 ±15.0, P = .004), had higher PEEP (9.2 cm H 2 O [7.0-11.0] vs 8.0 [5.6-8.9] , P = .049), chronic kidney disease stage ≥ 2 (10 [29.4%] vs 0 [0%], P = .009), and higher serum creatinine before inhaled tobramycin therapy (1.26 mg/dL [0.84-2.18] vs 0.76 [0.47-1.28] , P = .004). Age (odds ratio 1.09 [95% CI 1.02-1.16], P = .009) and PEEP (odds ratio 1.47 [95% CI 1.08-2.0], P =.01) were independent predictors for detectable serum tobramycin concentration. Thirty-seven subjects had no previous renal disease or injury, of which 9 (24.3%) developed an AKI. Sequential Organ Failure Assessment score (odds ratio 1.72 [95% CI 1.07-2.76], P = .03) was the only independent predictor for AKI., Conclusions: Detectable serum tobramycin concentrations were frequently observed in critically ill, mechanically ventilated subjects receiving empiric inhaled tobramycin for VAP. Subject age and PEEP were independent predictors for detectable serum tobramycin concentration. Serum monitoring and empiric dose reductions should be considered in older patients and those requiring higher PEEP., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2022 by Daedalus Enterprises.)

Objective: Define the length of the subglottis and trachea in children to predict a safe intubation depth., Methods: Patients <18 years undergoing rigid bronchoscopy from 2013 to 2020 were included. The carina and inferior borders of the cricoid and true vocal folds were marked on a bronchoscope and distances were measured. Patient age, weight, height, and chest height were recorded. Four styles of cuffed pediatric endotracheal tubes (ETT) were measured and potential positions of each cuff and tip were calculated within each trachea using five depth of intubation scenarios. Multivariate linear regression was performed to identify predictors of subglottic and tracheal length., Results: Measurements were obtained from 210 children (141 male, 69 female), mean (SD) age 3.21 (3.66) years. Patient height was the best predictor of subglottic length (R 2 : 0.418): Length sg (mm) = 0.058 * height (cm) + 2.8, and tracheal length (R 2 : 0.733): Length t (mm) = 0.485 * height (cm) + 21.3. None of the depth of intubation scenarios maintained a cuff-free subglottis for all ETT styles investigated. A formula for depth of intubation: Length di (mm) = 0.06 * height (cm) + 8.8 found that no ETT cuffs would be in the subglottis and all tips would be above the carina., Conclusion: Current strategies for determining appropriate depth of intubation pose a high risk of subglottic ETT cuff placement. Placing the inferior border of the vocal cords 0.06 * height (cm) + 8.8 from the superior border of the inflated ETT cuff may prevent subglottic cuff placement and endobronchial intubation., Level of Evidence: 4 Laryngoscope, 132:S1-S10, 2022., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

The impact of antithrombin III activity (AT-III) on prophylactic enoxaparin anti-factor Xa concentration (anti-Xa) is unknown in high-risk trauma patients. So too is the optimal anti-Xa-adjusted enoxaparin dosage. This prospective, randomized, pilot study sought to explore the association between AT-III and anti-Xa goal attainment and to preliminarily evaluate two enoxaparin dosage adjustment strategies in patients with subprophylactic anti-Xa. Adult trauma patients with Risk Assessment Profile (RAP) ≥ 5 prescribed enoxaparin 30 mg subcutaneously every 12 h were eligible. AT-III and anti-Xa were drawn 8 h after the third enoxaparin dose and compared between patients with anti-Xa ≥ 0.1 IU/mL (goal; control group) or anti-Xa < 0.1 IU/mL (subprophylactic; intervention group). The primary outcome was difference in baseline AT-III. Subsequently, intervention group patients underwent 1:1 randomization to either enoxaparin 40 mg every 12 h (up to 50 mg every 12 h if repeat anti-Xa < 0.1 IU/mL) (enox12) or enoxaparin 30 mg every 8 h (enox8) with repeat anti-Xa assessments. The proportion of patients achieving goal anti-Xa after dosage adjustment were compared. A total of 103 patients were included. Anti-Xa was subprophylactic in 50.5%. Baseline AT-III (median [IQR]) was 87% [80-98%] in control patients versus 82% [71-96%] in intervention patients (p = 0.092). Goal trough anti-Xa was achieved on first assessment in 38.1% enox12 versus 50% enox8 patients (p = 0.67), 84.6% versus 53.3% on second assessment (p = 0.11), and 100% vs. 54.5% on third trough assessment (p = 0.045). AT-III activity did not differ between high-risk trauma patients with goal and subprophylactic enoxaparin anti-Xa concentrations, although future investigation is warranted. Enoxaparin dose adjustment rather than frequency adjustment may be associated with a higher proportion of patients achieving goal anti-Xa over time., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Induction of antibiotic resistance is associated with increased morbidity and mortality in AmpC β-lactamase producing Enterobacteriaceae. The use of ceftriaxone is controversial for treatment of these organisms due to concerns for inducible resistance. This study was designed to compare treatment failure rates between ceftriaxone and antipseudomonal β-lactam antibiotics when used as definitive therapy for organisms most commonly associated with chromosomal AmpC β-lactamase production. Methods: A retrospective, single-center cohort study was performed enrolling patients hospitalized with monomicrobial Enterobacter, Citrobacter , or Serratia spp. infections. The primary objective compared proportion of treatment failure between groups. All patients received either ceftriaxone or an antipseudomonal β-lactam alone within 24 hours of culture finalization, and with a duration of at least 72 hours for definitive treatment. Treatment failure was defined as either clinical failure (abnormal white blood cell count or temperature on day 7 or 14 post-antibiotics) or microbiologic failure (regrowth of the same organism at same site within 14 or 21 days). Results: Of 192 total patients, treatment failure was observed in 24/71 patients (34%) receiving ceftriaxone and in 42/121 patients (35%) receiving antipseudomonal β-lactam ( P  = .98). No difference was observed between clinical or microbiologic failure rates between groups. The ceftriaxone group had significantly more patients undergoing treatment for urinary tract infections (51% vs 17%, P  < .001), but treatment failure rates remained similar between groups when comparing infections of all other sources. Conclusion: Ceftriaxone has comparable treatment failure rates to antipseudomonal β-lactams for susceptible Enterobacteriaceae infections and may be considered as a therapeutic option. Further, prospective research is needed to validate optimal dosing and application in all sites of infection., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Serum anti-factor Xa (anti-Xa) concentration may guide low molecular weight heparin chemoprophylaxis in trauma patients. Higher total body weight (TBW) is a risk factor for subprophylactic anti-Xa and venous thromboembolism (VTE). The purpose of this study was to evaluate TBW differences in patients with subprophylactic versus prophylactic trough anti-Xa., Methods: This retrospective study included adults admitted to the trauma service who received enoxaparin chemoprophylaxis, trough anti-Xa assessment, and screening duplex ultrasound. Initial enoxaparin dose was determined per trauma team weight-tiered protocol with subsequent 10 mg increase if anti-Xa was subprophylactic. Patients were stratified into subprophylactic (anti-Xa <0.1 IU/ml) and prophylactic (anti-Xa ≥0.1 IU/mL) groups. The primary outcome was difference in TBW. Secondary outcomes were weight-adjusted enoxaparin dose (mg/kg), VTE, red blood cell (pRBC) transfusions., Results: A total of 887 patients were included with 681 (76.8%) having subprophylactic anti-Xa. The subprophylactic group had significantly younger age, higher proportion male sex, higher Injury Severity Score (ISS), higher BMI, and longer length of hospital stay. The subprophylactic group had higher TBW (median [IQR], 87.8 [74-102] kg vs. 78.9 [68-91.8] kg; P < 0.001) which equated to a lower weight-adjusted dose (0.34 [0.3-0.41] mg/kg vs. 0.38 (0.33-0.44) mg/kg; P < 0.001). There were no differences in VTE (10.4% vs. 9.2%; P = 0.71) or pRBC administration (17.0% vs. 16.0%; P = 0.81)., Conclusions: TBW is higher and weight-adjusted enoxaparin dose is lower in high-risk trauma patients with subprophylactic anti-Xa concentrations. These data suggest TBW should be considered when determining the optimal prophylactic enoxaparin dose in high-risk trauma patients., (Copyright © 2021. Published by Elsevier Inc.)

Sepsis causes half of acute kidney injuries in the intensive care unit (ICU). ICU patients may need continuous renal replacement therapy (CRRT), which will affect their antimicrobial exposure. We aimed to build a cefepime population pharmacokinetic (PK) model in CRRT ICU patients and perform simulations to assess target attainment. Patients who were ≥18 years old, were admitted to the ICU, and received cefepime 2 g every 8 h as a 4-h infusion while on CRRT were enrolled prospectively. Samples were collected from the predialyzer ports, postdialyzer ports, and effluent fluid at 1, 2, 3, 4, and 8 h after the first dose and at steady state. Age, sex, weight, urine output, and CRRT parameters were recorded. Pmetrics was used for population PK and simulations. The target exposure was 100% of the dosing interval during which the free beta-lactam concentration is above the MIC ( fT >MIC ). Ten patients were included; their mean age was 53 years, and mean weight was 119 kg. Seventy percent were males. Cefepime was described by a five-compartment model. The downtime was applied to the CRRT flow rates, which were used to describe the rates of transfer between the compartments. At MICs of ≤8 mg/liter, intermittent infusion of 2 g cefepime every 8 h achieved good target attainment both early in therapy and at steady state. Only extended- and continuous-infusion regimens achieved good target attainment at MICs of 16 mg/liter. In conclusion, 2 g cefepime infused over 30 min followed by extended infusion of 2 g every 8 h achieved good target attainment at MICs of ≤16 mg/liter with different CRRT flow rates and may be considered in resistant bacterial infections., (Copyright © 2021 American Society for Microbiology.)

Objective: Evaluate patterns and predictors of spread to the neck in pediatric metastatic differentiated thyroid carcinoma (DTC)., Methods: Patients <18 years old undergoing thyroidectomy by a single surgeon from January 2015 to December 2019 were included. Neck sublevels were removed separately according to AJCC boundaries. Clinical outcomes included nerve injury, hypocalcemia, hematoma, and residual tumor., Results: Forty-eight children underwent thyroid surgery. Thirty (63%) were for malignancy, 27 (90%) of which were DTC. Nineteen (70%) patients with DTC underwent 24 neck dissections; 19 central plus lateral and 5 central alone. The female to male ratio increased from 1:1 to 3:1 with age. Two children with lateral neck involvement had sub-centimeter primaries. Patients requiring neck dissection were more likely to have 1) diffuse sclerosing or tall cell variant, 2) T3 or T4 disease, 3) genetic mutation, 4) lymphatic invasion, 5) extracapsular extension, 6) positive resection margin. Levels IIA (79%), III (89%), IV (84%), VI (100%) were most commonly involved. Levels IB (16%), IIB (16%), VB (16%) were also involved, often without involvement of adjacent levels. Permanent injuries included one unilateral recurrent laryngeal nerve, one mild marginal mandibular nerve and one mild accessory nerve. Hypocalcemia was highest following neck dissection for malignant disease. One patient was re-operated for a mediastinal node. Most patients with N1 disease received radioactive iodine. Most patients have no evidence or indeterminate disease on long-term follow-up., Conclusion: Children with lateral nodal spread from DTC should be considered for neck dissection including Levels IB, IIA, IIB, III, IV, VB, bilateral VI., Level of Evidence: 4 Laryngoscope, 131:E1002-E1009, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To prospectively evaluate 1) use of endotracheal tube (ETT) surface electrodes for recurrent laryngeal nerve (RLN) monitoring in thyroid surgery in children, and 2) effects of thyroid surgery on the RLN in children., Methods: Patients <18 years old undergoing thyroidectomy were included. Vocal cord mobility was assessed pre- and postoperatively. RLNs were monitored using adhesive or integrated electrodes. Recordings were made before and after dissection, and area under the curve and latency were compared using mixed models., Results: Twenty-five children (44 nerves at risk), mean (standard deviation) age 13.1 (3.4) years (range 4.5-17.4 years), underwent thyroidectomy. Twelve (46%) monitors were adhesive. One nerve had unobtainable responses. Nerveäna Power Index (NPI) (Neurovision Medical Products, Ventura, CA) decreased, and latency increased pre- versus postdissection at all amplitudes (P < 0.0001), with change in slope of NPI affected by tumor size (P < 0.05). Postdissection, the NPI was lower, and the latency was longer when stimulating low in the neck versus near the cricothyroid joint at all stimulating amplitudes (P < 0.0001), with change in NPI related to tumor size (P < 0.0001). Changes were not associated with decreased vocal cord mobility, aspiration, or voice change. One patient had a temporary unilateral paresis that resolved by 7 weeks, and another had normal movement 3 weeks postoperatively and developed a paresis 2 months postoperatively., Conclusion: ETT surface electrodes are reliable for RLN monitoring in thyroid surgery in children. Thyroid surgery is associated with a decrease in RLN stimulability that is related to tumor size. The site of RLN stimulation matters when evaluating the nerve., Level of Evidence: 4 Laryngoscope, 130:1583-1589, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Venous thromboembolism (VTE) risk increases with age. Scarce data exist for patients age ≥65 y. This study evaluated VTE incidence in elderly, high-risk trauma patients receiving unfractionated heparin (UFH) or enoxaparin chemoprophylaxis., Materials and Methods: This retrospective, single-center, cohort study included trauma patients age ≥ 65 y with risk assessment profile (RAP) ≥ 5 who received UFH or enoxaparin chemoprophylaxis. The primary outcome was VTE incidence requiring therapeutic anticoagulation. An age-modified RAP (RAP-AM) was calculated as RAP without age distribution points. Logistic regression analyses were performed to identify independent predictors for VTE development and chemoprophylactic agent selection. Bleeding incidence compared packed red blood cells utilized., Results: A total of 1090 patients were included (UFH, n = 655; enoxaparin, n = 435). VTE occurred in 39 (3.6%) patients with no difference between groups in proximal deep vein thrombosis (2.1% versus 3.0%, P = 0.52) or pulmonary embolism (1.2% versus 1.4%, P = 0.96). Weight ≥125 kg (OR 4.12, 95% CI 1.06-16.11) and RAP-AM ≥ 5 (OR 6.52, 95% CI 2.65-16.03) were independently associated with VTE development. Increasing age (OR 1.04, 95% CI 1.03-1.06), initiation ≤ 24 h (OR 2.17, 95% CI 1.66-2.84) and creatinine clearance ≤ 30 mL/min (OR 1.61, 95% CI 1.17-2.21) were independent predictors of receiving UFH whereas increasing ISS (OR 0.97, 95% CI 0.95-0.99) was associated with receiving enoxaparin., Conclusions: VTE incidence may be similar for high-risk, elderly trauma patients receiving UFH and enoxaparin chemoprophylaxis. Further research is necessary to determine noninferiority of UFH to enoxaparin in this patient population., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Enoxaparin is used as chemoprophylaxis to reduce incidence of venous thromboembolism and its complications following trauma. Serum anti-Xa monitoring is used to assess efficacy but requires several doses to be administered. Thrombelastography assesses hypercoagulability and may have utility identifying high-risk patients for venous thromboembolism. The objective was to evaluate whether thrombelastography parameters could identify trauma patients requiring enoxaparin dose adjustment earlier than serum anti-Xa concentrations., Methods: A single-center, retrospective medical record review evaluated patients admitted to a regional level I trauma center that received an admission thrombelastography and a dose of enoxaparin with a serum trough anti-Xa concentration drawn. Patients were divided into standard-dose or dose-adjusted enoxaparin. Venous thromboembolism incidence between groups and risk factors for enoxaparin dose adjustment and venous thromboembolism development were evaluated., Results: A total of 204 patients were included. Differences observed between groups included age (standard-dose enoxaparin, 48.5 [29.3-72] vs dose-adjusted enoxaparin, 38.5 [25-55.7] years; P  = .005), admission creatinine clearance (standard-dose enoxaparin, 92.9 [67.4-113.4] vs dose-adjusted enoxaparin, 102.1 [83.8-129.2] mL/min; P  = .017), and time to venous thromboembolism prophylaxis initiation (standard-dose enoxaparin, 23.8 [11.2-36.4] vs dose-adjusted enoxaparin, 34.5 [18.3-52.7] hours; P  = .004). No differences in thrombelastography parameters or venous thromboembolism incidence were observed. No independent risk factors for enoxaparin dose adjustment were identified; however, risk assessment profile score > 10 was an independent risk factor for venous thromboembolism development., Conclusion: No relationship between admission thrombelastography and need for enoxaparin dose adjustment in trauma patients was observed. As thrombelastography continues growing in clinical use, it is prudent to investigate other potential applications. Currently, thrombelastography should not be used to guide enoxaparin dosing., (© 2020 The Authors.)

Science still does not have the ability to accurately predict the affinity that ligands have for proteins. In an attempt to address this, the Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) series of blind predictive challenges is a community-wide exercise aimed at advancing computational techniques as standard predictive tools in rational drug design. In each cycle, a range of biologically relevant systems of different levels of complexity are selected to test the latest modeling methods. As part of this on-going exercise, and as a step towards understanding the important factors in context dependent guest binding, we challenged the computational community to determine the affinity of a series of negatively and positively charged guests to two constitutionally isomeric cavitand hosts: octa-acid 1 , and exo -octa acid 2 . Our affinity determinations, combined with molecular dynamics simulations, reveal asymmetries in affinities between host-guest pairs that cannot alone be explained by simple coulombic interactions, but also point to the importance of host-water interactions. Our work reveals the key facets of molecular recognition in water, emphasizes where improvements need to be made in modelling, and shed light on the complex problem of ligand-protein binding in the aqueous realm., (This journal is © The Royal Society of Chemistry 2020.)

Study Objective: To evaluate extended-infusion (EI) cefepime pharmacokinetics (PK) and pharmacodynamic target attainment in critically ill patients receiving continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodialysis (CVVHD)., Design: Prospective, open-label, PK study., Setting: Intensive care units at a large, academic, tertiary-care medical center., Patients: Ten critically ill adults who were receiving cefepime 2 g intravenously every 8 hours as a 4-hour infusion while receiving CVVH (eight patients) or CVVHD (two patients)., Intervention: Two sets of five serum cefepime concentrations were collected for each patient to assess pharmacokinetics before and during presumed steady state. Concurrent serum and CRRT effluent samples were collected at hours 1, 2, 3, 4, and 8 after the first cefepime dose and after either the fourth, fifth, or sixth (steady-state) cefepime doses., Measurements and Main Results: Reversed-phase high-performance liquid chromatography was used to determine free cefepime concentrations. PK analyses included CRRT clearance, half-life, and sieving coefficient or saturation coefficient. Cefepime peak (4 hrs) concentrations, trough (8 hrs) concentrations (C min ), and minimum inhibitory concentration breakpoint of 8 µg/ml for the pathogen (MIC 8 ) were used to evaluate attainment of pharmacodynamic targets: 100% of the dosing interval that free drug remains above MIC 8 (100% fT > MIC 8 ), 100% fT > 4 × MIC 8 (optimal), percentage of time fT > 4 × MIC 8 (%fT > 4 × MIC 8 ) at steady state, and ratio of C min to MIC 8 (fC min /MIC 8 ). Total CRRT effluent flow rate was a mean ± SD of 30.1 ± 5.4 ml/kg/hr, CRRT clearance was 39.6 ± 9.9 ml/min, and half-life was 5.3 ± 1.7 hours. Sieving coefficient or saturation coefficient were 0.83 ± 0.13 and 0.69 ± 0.22, respectively. First and steady-state dose C min were 23.4 ± 10.1 µg/ml and 45.2 ± 14.6 µg/ml, respectively. All patients achieved 100% fT > MIC 8 on first and steady-state doses. First and steady-state dose 100% fT > 4 × MIC 8 were achieved in 22% (2/9 patients) and 87.5% (7/8 patients) of patients, respectively. The mean %fT > 4 × MIC 8 at steady state was 97.5%. The fC min /MIC 8 was 2.92 ± 1.26 for the first dose and 5.65 ± 1.83 at steady state., Conclusion: Extended-infusion cefepime dosing in critically ill patients receiving CRRT successfully attained 100% fT > MIC 8 in all patients and an appropriate fC min /MIC 8 for both first and steady-state doses. All but one patient achieved 100% fT > 4 × MIC 8 at steady state. No significant differences were observed in PK properties between first and steady-state doses among or between patients. It may be reasonable to initiate an empiric or definitive regimen of EI cefepime in critically ill patients receiving concurrent CRRT who are at risk for resistant organisms. Further research is needed to identify the optimal dosing regimen of EI cefepime in this patient population., (© 2019 Pharmacotherapy Publications, Inc.)

Alcohol withdrawal syndrome (AWS) is a complex neurologic disorder that develops after an acute reduction in or cessation of chronic alcohol consumption that alters neurotransmitter conduction. The incidence of AWS in the intensive care unit varies, but has been associated with poor outcomes. This is primarily driven by downregulation of gamma-aminobutyric acid (GABA) leading to autonomic excitability and psychomotor agitation. No clinical assessment tools have been validated to assess for AWS in the intensive care unit, particularly for patients requiring mechanical ventilation. The Clinical Institute Withdrawal Assessment for Alcohol Scale, Revised, may be considered to gauge the extent of withdrawal, but is not particular with acute presentations in this population. Symptom-triggered use of GABA agonist such as benzodiazepines remains the mainstay of pharmacotherapeutic intervention. Nonbenzodiazepine GABA agonists such as barbiturates and propofol as well as non-GABA adjunctive agents such as dexmedetomidine, ketamine, and antipsychotic agents may help reduce the need for symptom-triggered benzodiazepine dosing, but lack robust data. Agent selection should be based on patient-specific factors such as renal and hepatic metabolism, duration of action, and clearance. Institution-specific protocols directing GABA-acting medications and adjunctive medications for excitatory, adrenergic, and delirium assessments could be considered to improve patient outcomes and caregiver satisfaction.

Background: Continuous renal replacement therapy (CRRT) may be associated with thrombocytopenia in critically ill patients. A confounding factor is concomitant use of unfractionated heparin (UFH) and suspicion for heparin-induced thrombocytopenia (HIT)., Objective: To determine the impact of CRRT on platelet count and development of thrombocytopenia., Methods: Retrospective analyses evaluated the intrapatient change in platelet count following CRRT initiation. Critically ill adult patients who received CRRT for at least 48 hours were included. The primary outcome was intrapatient change in platelet count from CRRT initiation through the first 5 days of therapy. Secondary outcomes included thrombocytopenia incidence, identification of concomitant factors associated with thrombocytopenia, and frequency of HIT., Results: 80 patients were included. Median platelet count at CRRT initiation (D0) was 128000/µL (81500-212500/µL), which was higher than those on subsequent post-CRRT days (D1: 104500/µL [63000-166750/µL]; D2: 88500/µL [53500-136750/µL]; D3: 91000/µL [49000-138000/µL]; D4: 93000/µL [46000-134000/µL]; and D5: 76000/µL [45500-151000/µL]; P < 0.05 for all). Twenty-five (35%) patients had thrombocytopenia on CRRT D0 compared with D2 (56.3%), D3 (58.7%), and D5 (59.1%); P < 0.05 for all. Controlling for potential confounders, Sequential Organ Failure Assessment score at the time of CRRT initiation was the only independent factor associated with thrombocytopenia. One (1.3%) patient had confirmed HIT. Conclusion and Relevance: This study is the first to demonstrate serial decreases in platelet count across multiple days after CRRT initiation. These data may provide additional insight to thrombocytopenia development in critically ill patients receiving heparin while on CRRT that is not associated with HIT.

Obesity presents a growing challenge in critically ill patients because of variable medication pharmacokinetics and pharmacodynamics. Vasopressors used in the treatment of septic shock, including norepinephrine, are dosed using weight-based (WB) or non-weight-based (NWB) strategies. Retrospective research has evaluated the effect of total body weight and body mass index on vasopressor requirements, consequently finding that obese patients require less total vasopressor per kilogram to obtain clinical end points such as mean arterial pressure. Although this effect is not completely understood, this may suggest that a NWB dosing strategy is preferred over a WB strategy in obese patients to minimize potential for error.

Introduction: Long acting muscarinic receptor antagonists (LAMA) reverse airflow obstruction by antagonizing para-sympathetic bronchoconstricting effects within the airways. For years, tiotropium, has been the cornerstone LAMA for chronic obstructive pulmonary disease (COPD) management. Recently, new agents, aclidinium bromide, glycopyrronium bromide, and umeclidinium bromide, have been developed and introduced into clinical practice. Areas covered: This article reviews the clinical efficacy and adverse effects of currently available LAMAs in COPD treatment as well as developing LAMAs in early clinical trials and preclinical studies (V0162, TD-4208, CHF 5407, AZD9164, AZD8683, bencycloquidium). In addition, a new class of molecule that combines muscarinic antagonist and β2-adrenergic properties (MABA) is described and current developmental progress discussed (GSK-961081, THRX-200495). Expert opinion: Future key areas for developing drugs for the management of COPD include prolonged duration of action, optimal delivery systems, synergistic combinations with other drugs, maximization of benefits and minimization of adverse effects. The development of new LAMA and MABA molecules provides exciting progress towards simpler and more effective COPD management.

Introduction: Phosphodiesterase (PDE) inhibitors modulate lung inflammation and cause bronchodilation by increasing intracellular cyclic adenosine 3', 5'-monophosphate in airway smooth muscle and inflammatory cells. Roflumilast is the only approved PDE-4 inhibitor (PDE4I) for use in chronic obstructive pulmonary disease (COPD). Its beneficial clinical effects occur preferentially in patients with chronic bronchitis and frequent COPD exacerbations. Use of roflumilast as adjunctive or alternate therapy to other COPD medications reduces exacerbations and modestly improves lung function., Areas Covered: This article reviews the current role of PDE4I in COPD treatment emphasizing roflumilast's clinical efficacy and adverse effects. This article also reviews developing PDE4Is in early clinical trials and in preclinical studies., Expert Opinion: After decades of research in drug development, PDE4Is are a welcomed addition to the COPD therapeutic armamentarium. In its current clinical role, the salubrious clinical effects of PDE4I in reducing exacerbations and stabilizing the frequent exacerbator phenotype have to be cautiously balanced with numerous adverse effects. Developing drugs may provide similar or better clinical benefits while minimizing adverse effects by changing the mode of drug delivery to inhaled formulations, combining dual PDE isoenzyme inhibitors (PDE1/4I and PDE3/4I) and by forming hybrid molecules with other bronchodilators (muscarinic receptor antagonist/PDE4I and β2-agonist/PDE4I).

Background: Low anti-factor Xa (anti-Xa) concentrations with twice-daily enoxaparin are associated with venous thromboembolism (VTE) in high-risk trauma patients. Concerns have been raised with once-daily dalteparin regarding effectiveness and achievable anti-Xa concentrations. The purpose of this before-and-after study was to evaluate the effectiveness of a VTE prophylaxis protocol using anti-Xa concentrations and associated dalteparin dose adjustment in high-risk trauma patients., Methods: Adult trauma patients receiving VTE chemoprophylaxis and hospitalized for at least 3 days were prospectively followed during two 6-month epochs before (PRE) and after (POST) implementation of anti-Xa monitoring. In both groups, high-risk patients received dalteparin 5,000 U subcutaneously once daily; low-risk patients received subcutaneous unfractionated heparin. High-risk POST patients with anti-Xa less than 0.1 IU/mL 12 hours after initial dalteparin dose received dalteparin every 12 hours. All patients underwent routine VTE ultrasound surveillance of the lower extremities. The primary outcome was incidence of VTE., Results: A total of 785 patients (PRE, n = 428; POST, n = 357) were included. Demographics, injury patterns, Injury Severity Score (ISS), red blood cell transfusions, intensive care unit and hospital stays, and mortality did not differ between groups. Overall, POST patients had lower VTE (7.0% vs. 13%, p = 0.009) including acute VTE (6.4% vs. 12%, p = 0.01) and proximal deep vein thromboembolism (2.2% vs. 5.7%, p = 0.019). Between high-risk patients, VTE occurred in 53 (16.3%) PRE compared with 24 (9.0%) POST patients (p = 0.01); there was no difference in VTE between low-risk patients (PRE, 2.0% vs. POST, 1.1%; p = 0.86). Among 190 high-risk POST patients with anti-Xa, 97 (51%) were less than 0.1 IU/mL. Patients with low anti-Xa had higher rates of VTE (14.0% vs. 5.4%, p = 0.05) and deep vein thromboembolism (14.4% vs. 3.2%, p = 0.01). Younger age (odds ratio, 0.97; 95% confidence interval, 0.95-0.99) and greater weight (odds ratio, 1.02; 95% confidence interval, 1.00-1.03) predicted low anti-Xa on multivariate regression., Conclusion: A VTE prophylaxis protocol using anti-Xa-based dalteparin dosage adjustment in high-risk trauma patients was associated with decreased VTE. Once-daily dalteparin 12-hour anti-Xa concentrations are suboptimal in a majority of patients and associated with VTE., Level of Evidence: Therapeutic study, level IV.

Background: Bronchoalveolar lavage (BAL) is recommended to facilitate the diagnosis of ventilator-associated pneumonia (VAP). It is unclear if bilateral sampling improves the accuracy of BAL., Methods: Consecutive patients with clinical suspicion for VAP were analyzed. All patients underwent bilateral BAL. A threshold of >10(4) colony-forming units (cfu)/mL was diagnostic for VAP (VAP positive). Samples were concordant if the organism(s) and thresholds from both lungs were diagnostically consistent. Organisms 10(4) cfu/mL were considered false-negative samples., Results: Between November 2005 and April 2006, 73 patients were considered clinically suspicious for VAP. Forty-four (60%) patients were VAP positive. Twenty-eight (64%) VAP patients had concordant samples. Overall, there were 15 false-negative samples. Sole use of the unilateral samples to guide treatment would have inappropriately directed antibiotic avoidance and/or discontinuation in 25% of VAP patients. Influence of the chest radiograph was equivocal because of the presence of bilateral infiltrates in 80% of discordant samples., Conclusions: Bilateral BAL improves the accuracy of bronchoscopy in diagnosing VAP. Unilateral BAL may be insensitive in patients with clinically significant contralateral infection.