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Sulfonated polyether (ether) ketone, or sulfonated PEEK (sPEEK) membranes are one possible candidate for proton-transfer membranes in hydrogen fuel cells. Reaction with hydroxy radicals is expected to be a significant source of degradation of these membranes during fuel cell operation. In this work, the reactivity of the sPEEK polymer molecule with OH radicals is studied by M062X hybrid density functional calculations of the energetics of several reaction paths in a water environment as modeled by polarized continuum model (PCM) calculations. Reactants, products, encounter minima and transition states are optimized for a reaction pathway in which OH addition is followed by acid-catalyzed water elimination which cationizes the polymer, degradation is expected to follow this reaction as the unstable cation then undergoes bond-breaking or other reactions. Two pathways for this acid-catalyzed cationization, one in which a water molecule plays the role of an additional co-catalyst, are reported. Further calculations explore reaction pathways in which addition of OH to the polymer is followed by bond breaking reactions which would break the polymer chain or the bond between the polymer and sulfonyl groups. Examination of the free energy barriers to all these reactions, relative to reactants, suggest that these direct bond-breaking reactions may compete somewhat with acid-catalyzed water elimination following OH addition.

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BA.2/BA.2.12.1 and BA.4/BA.5 subvariants have mutations associated with increased capacity to evade immunity when compared with prior variants. We evaluated mRNA monovalent booster dose effectiveness among persons ≥5 years old during BA.2/BA.2.12.1 and BA.4/BA.5 predominance. Methods A test-negative, case-control analysis included data from 12 148 pharmacy SARS-CoV-2 testing sites nationwide for persons aged ≥5 years with ≥1 coronavirus disease-2019 (COVID-19)-like symptoms and a SARS-CoV-2 nucleic acid amplification test from April 2 to August 31, 2022. Relative vaccine effectiveness (rVE) was estimated comparing 3 doses of COVID-19 mRNA monovalent vaccine to 2 doses; for tests among persons ≥50 years, rVE estimates also compared 4 doses to 3 doses (≥4 months since third dose). Results A total of 760 986 test-positive cases and 817 876 test-negative controls were included. Among individuals ≥12 years, rVE of 3 versus 2 doses ranged by age group from 45% to 74% at 1-month post vaccination and waned to 0% by 5–7 months post vaccination during the BA.4/BA.5 period. Adults aged ≥50 years (fourth dose eligible) who received 4 doses were less likely to have symptomatic SARS-CoV-2 infection compared with those with 3 doses; this rVE remained >0% through at least 3 months since last dose. For those aged ≥65 years, rVE of 4 versus 3 doses 1-month post vaccination was higher during BA.2/BA.2.12.1 (rVE = 49%; 95% confidence interval [CI], 43%–53%) than BA.4/BA.5 (rVE = 40%; 95% CI, 36%–44%). In 50- to 64-year-olds, rVE estimates were similar. Conclusions Monovalent mRNA booster doses provided additional protection against symptomatic SARS-CoV-2 infection during BA.2/BA.2.12.1 and BA.4/BA.5 subvariant circulation, but protection waned over time.

On September 1, 2022, bivalent COVID-19 mRNA vaccines, composed of components from the SARS-CoV-2 ancestral and Omicron BA.4/BA.5 strains, were recommended by the Advisory Committee on Immunization Practices (ACIP) to address reduced effectiveness of COVID-19 monovalent vaccines during SARS-CoV-2 Omicron variant predominance (1). Initial recommendations included persons aged ≥12 years (Pfizer-BioNTech) and ≥18 years (Moderna) who had completed at least a primary series of any Food and Drug Administration-authorized or -approved monovalent vaccine ≥2 months earlier (1). On October 12, 2022, the recommendation was expanded to include children aged 5-11 years. At the time of recommendation, immunogenicity data were available from clinical trials of bivalent vaccines composed of ancestral and Omicron BA.1 strains; however, no clinical efficacy data were available. In this study, effectiveness of the bivalent (Omicron BA.4/BA.5-containing) booster formulation against symptomatic SARS-CoV-2 infection was examined using data from the Increasing Community Access to Testing (ICATT) national SARS-CoV-2 testing program.* During September 14-November 11, 2022, a total of 360,626 nucleic acid amplification tests (NAATs) performed at 9,995 retail pharmacies for adults aged ≥18 years, who reported symptoms consistent with COVID-19 at the time of testing and no immunocompromising conditions, were included in the analysis. Relative vaccine effectiveness (rVE) of a bivalent booster dose compared with that of ≥2 monovalent vaccine doses among persons for whom 2-3 months and ≥8 months had elapsed since last monovalent dose was 30% and 56% among persons aged 18-49 years, 31% and 48% among persons aged 50-64 years, and 28% and 43% among persons aged ≥65 years, respectively. Bivalent mRNA booster doses provide additional protection against symptomatic SARS-CoV-2 in immunocompetent persons who previously received monovalent vaccine only, with relative benefits increasing with time since receipt of the most recent monovalent vaccine dose. Staying up to date with COVID-19 vaccination, including getting a bivalent booster dose when eligible, is critical to maximizing protection against COVID-19 (1).

The Centers for Medicare and Medicaid Services Severe Sepsis and Septic Shock Management Bundle (SEP-1) assesses antibiotic administration, lactate measurement, and blood culture collection within 3 h of severe sepsis onset. The impact of the SEP-1 3-hour bundle among patients with severe sepsis is not extensively described. This investigation aimed to describe the impact of 3-hour bundle compliance on 28-day in-hospital mortality in patients with severe sepsis.This was a retrospective, propensity adjusted, nested case-control study assessing the impact of compliance with a 3-hour sepsis bundle among patients with severe sepsis.This study was conducted at a large, academic, tertiary care medical center in Detroit, Michigan from July 1, 2017 to December 31, 2019.Cases were defined as those suffering 28-day in-hospital mortality. Controls were defined as those surviving at or discharged by 28 days. Patients were separated based on 3-hour bundle compliance or noncompliance. Nested and overall cohorts were assessed. Severe sepsis time zero was manually validated. Patients with shock, requiring vasopressors within 8 h of time zero, or those not meeting SEP-1 inclusion criteria were excluded.The primary outcome was the propensity adjusted odds of 28-day in-hospital mortality among 3-hour bundle compliant versus noncompliant patients. Secondary outcomes included mortality for individual bundle element compliance, progression to septic shock, and predictors of mortality according to logistic regression.A total of 325 compliant and 325 noncompliant patients were included. The median Sequential Organ Failure Assessment (SOFA) score was three in each group. There was no difference in propensity adjusted odds of mortality among those compliant versus noncompliant with the 3-hour bundle (odds-ratio [OR] 1.039; 95% CI: 0.721-1.497; p = 0.838) or with individual bundle elements. SOFA score and female sex were predictors of mortality.Three-hour bundle compliance did not impact 28-day in-hospital mortality in patients with severe sepsis. Further research is needed to understand the impact of 3-hour bundle compliance on mortality in severe sepsis.

Purpose The purpose of this report is to describe the activities of critical care and ambulatory care pharmacists in a multidisciplinary transitions-of-care (TOC) service for critically ill patients with pulmonary arterial hypertension (PAH) receiving PAH medications. Summary Initiation of medications for treatment of PAH involves complex medication access steps. In the ambulatory care setting, multidisciplinary teams often have a process for completing these steps to ensure access to PAH medications. Patients with PAH are frequently admitted to an intensive care unit (ICU), and their home PAH medications are continued and/or new medications are initiated in the ICU setting. Inpatient multidisciplinary teams are often unfamiliar with the medication access steps unique to PAH medications. The coordination and completion of medication access steps in the inpatient setting is critical to ensure access to medications at discharge and prevent delays in care. A PAH-specific TOC bundle for patients prescribed a PAH medication who are admitted to the ICU was developed by a multidisciplinary team at an academic teaching hospital. The service involves a critical care pharmacist completing a PAH medication history, assessing for PAH medication access barriers, and referring patients to an ambulatory care pharmacist for postdischarge telephone follow-up. In collaboration with the PAH multidisciplinary team, a standardized workflow to be initiated by the critical care pharmacist was developed to streamline completion of PAH medication access steps. Within 3 days of hospital discharge, the ambulatory care pharmacist calls referred patients to ensure access to PAH medications, provide disease state and medication education, and request that the patient schedule a follow-up office visit to take place within 14 days of discharge. Conclusion Collaboration by a PAH multidisciplinary team, critical care pharmacist, and ambulatory care pharmacist can improve TOC related to PAH medication access for patients with PAH. The PAH TOC bundle serves as a model that may be transferable to other health centers.

Background: Heparin exposure and device-related thrombocytopenia complicate the diagnosis of heparin-induced thrombocytopenia (HIT) in patients receiving mechanical circulatory support (MCS). To improve anticoagulation management for patients with newly implanted MCS devices, incidence of confirmed HIT needs to be further characterized. Objectives: The purpose of this study is to describe the incidence of HIT and clinical utility of the 4Ts score in patients with newly implanted MCS devices. Methods: This is a retrospective analysis of MCS patients receiving unfractionated heparin from 2014 to 2017. The primary end point was incidence of laboratory-confirmed HIT. Strong positive, likely positive, low probability, and negative HIT categories were established based on heparin-induced platelet antibody (HIPA) and serotonin release assay (SRA). Secondary end points include characterization of platelet trends, argatroban use, incidence of HIT among each of the MCS devices, and utility of 4Ts score. Results: A total of 342 patient encounters met inclusion criteria, of which 68 HIPA tests and 25 SRAs were ordered. The incidence of HIT was 0.88% (3/342) and 4.4% (3/68) in patients with suspected HIT. Of the 68 HIPA tests, 3 (4.4%) were considered strong positive and 3 of the 25 SRAs were positive. Median 4Ts score was 4 [2.5-4] and optical density 0.19 [0.11-0.54]. The positive predictive value for the 4Ts score was 0.15 (CI = 0.03-0.46) and negative predictive value, 0.93 (CI = 0.82-0.98). Conclusion and Relevance: HIT occurs infrequently with newly implanted MCS devices. The 4Ts score appears to have a high negative predictive value for ruling out HIT.

Pulmonary arterial hypertension has evolved from a fatal disease with few treatment options to a chronic condition with improved survival. This improvement is possible through development of effective therapies as well as the expansion of risk stratification scores to assist clinical decision making. Despite improved disease control, quality of life, and overall prognosis, many challenges remain. The treatment itself is burdensome, with significant impact on quality of life. Many patients with pulmonary arterial hypertension still present with advanced, often end-stage disease. Increased use of mechanical circulatory support and catheter-based interventions have expanded use of extracorporeal life support and right ventricle assist devices. For these reasons as well as the long-term relationships pulmonary hypertension physicians have with patients and their families, navigating the course of the illness in a considered, proactive way is essential. Understanding individual goals and revisiting them as they change over time requires comfort with the conversation itself. There are many barriers and challenges to having effective, compassionate conversations in the clinical setting with time constraints being the most often cited. Compressed visits are necessarily focused on the clinical aspects, therapy and medication adherence and tolerance. Clinicians are sometimes wary of diminishing hope in the face of ongoing treatment. Having sufficient experience and comfort with these discussions can be empowering. In this paper, we discuss the challenges involved and propose a framework to assist in incorporating these discussions into clinical care.

Hyperlactatemia and lactic acidosis are two syndromes that are associated with morbidity and mortality. Medication-induced hyperlactatemia and lactic acidosis are diagnoses of exclusion and have the potential to be overlooked. The purposes of this systematic review are to identify published reports of medication-induced lactate level elevations to aid clinicians in diagnosing and comprehending the underlying mechanism of this rare adverse drug effect and to provide management strategies. The PubMed database was searched for case reports, case series, retrospective studies, and prospective studies describing cases of medication-induced lactate level elevation, including lactic acidosis and hyperlactatemia, published between January 1950 and June 2017. A standardized search strategy was used, and the articles identified underwent two rounds of independent evaluation by two reviewers to assess for inclusion. Articles were included if they described at least one patient older than 12 years with hyperlactatemia or lactic acidosis caused by a medication with United States Food and Drug Administration (FDA) approval and if alternative etiologies for an elevated lactate level were ruled out. Metformin and nucleoside/nucleotide reverse transcriptase inhibitors were excluded since the pathophysiology and incidence of lactic acidosis have been well established for these agents. Overall, 1918 articles were identified, and 101 met inclusion criteria. A total of 286 patients experienced medication-induced lactate level elevations, from which 59 unique medications were identified. The most commonly identified agents were epinephrine and albuterol. Medication-induced lactate level elevation was classified as lactic acidosis (64.0%), hyperlactatemia (31.1%), or not specified (4.9%). The doses ingested included FDA-labeled doses (86%), intentional overdoses (10.8%), or prescribed doses exceeding the FDA-labeled dose (3.1%). Medications were continued without a change (40.8%), were permanently discontinued (34.4%), were continued with a dosage reduction (11.6%), or were initially withheld then resumed after lactate level normalized (2.9%); medication management for the remaining 10.0% was not reported. Forty-six patients died (16%). Six deaths were attributed by treating clinicians to be secondary to medication-induced lactic acidosis. Management strategies were heterogeneous, and treatment included supportive care, exogenous bicarbonate therapy, medication specific antidotes, and decontamination strategies. Unexplained lactate level elevations should prompt clinicians to assess for medication-induced lactate level elevations. Pharmacists are members of the health care team that are well positioned to serve as experts in the diagnosis and management of medication-induced lactate level elevations.

Purpose The Delphi method was used to develop best practice recommendations (BPR) for safe use of pulmonary hypertension (PH) pharmacotherapies and to describe the pharmacist's role in provision of care. Methods A core group reviewed PH medication-safety literature and developed initial BPR. Pharmacists practicing at PH-accredited Centers of Comprehensive Care who met defined PH expert criteria were invited to participate on an expert panel. In round 1 of a 4-round Delphi process, expert input was provided on the BPR. Feedback was incorporated into BPR for the next round. Round 2 proceeded in identical fashion to round 1. In round 3, BPR were deliberated in a teleconference and underwent voting at the cessation of the round using a 5-point Likert scale. Median scores of 3.75 resulted in a best practice statement being rejected, reviewed in round 4, or accepted in the final BPR, respectively. In round 4, the remaining BPR were discussed and underwent voting. BPR were assigned a level of evidence and strength of recommendation based on voting results. Results Eleven PH experts agreed to participate and met expert inclusion criteria, along with 2 pharmacists from the core group, bringing the total number of expert panel members to 13. To guide safe use of PH pharmacotherapies, 26 BPR were developed, categorized into 5 practice domains, comprising the PH Care Center accreditation process, inpatient practice, formulary management, diagnostics, and ambulatory care. BPR included provisions for safe use of parenteral prostacyclin agents and healthcare practitioner education. Conclusion The Delphi method was used to develop BPR to guide safe use of PH pharmacotherapies.

Efficacy of 2 doses of the BNT162b2 COVID-19 vaccine (Pfizer-BioNTech) against COVID-19 was high in pediatric trials conducted before the SARS-CoV-2 Omicron variant emerged. Among adults, estimated vaccine effectiveness (VE) of 2 BNT162b2 doses against symptomatic Omicron infection was reduced compared with prior variants, waned rapidly, and increased with a booster.To evaluate the association of symptomatic infection with prior vaccination with BNT162b2 to estimate VE among children and adolescents during Omicron variant predominance.A test-negative, case-control analysis was conducted using data from 6897 pharmacy-based, drive-through SARS-CoV-2 testing sites across the US from a single pharmacy chain in the Increasing Community Access to Testing platform. This analysis included 74 208 tests from children 5 to 11 years of age and 47 744 tests from adolescents 12 to 15 years of age with COVID-19-like illness who underwent SARS-CoV-2 nucleic acid amplification testing from December 26, 2021, to February 21, 2022.Two BNT162b2 doses 2 weeks or more before SARS-CoV-2 testing vs no vaccination for children; 2 or 3 doses 2 weeks or more before testing vs no vaccination for adolescents (who are recommended to receive a booster dose).Symptomatic infection. The adjusted odds ratio (OR) for the association of prior vaccination and symptomatic SARS-CoV-2 infection was used to estimate VE: VE = (1 - OR) × 100%.A total of 30 999 test-positive cases and 43 209 test-negative controls were included from children 5 to 11 years of age, as well as 22 273 test-positive cases and 25 471 test-negative controls from adolescents 12 to 15 years of age. The median age among those with included tests was 10 years (IQR, 7-13); 61 189 (50.2%) were female, 75 758 (70.1%) were White, and 29 034 (25.7%) were Hispanic/Latino. At 2 to 4 weeks after dose 2, among children, the adjusted OR was 0.40 (95% CI, 0.35-0.45; estimated VE, 60.1% [95% CI, 54.7%-64.8%]) and among adolescents, the OR was 0.40 (95% CI, 0.29-0.56; estimated VE, 59.5% [95% CI, 44.3%-70.6%]). During month 2 after dose 2, among children, the OR was 0.71 (95% CI, 0.67-0.76; estimated VE, 28.9% [95% CI, 24.5%-33.1%]) and among adolescents, the OR was 0.83 (95% CI, 0.76-0.92; estimated VE, 16.6% [95% CI, 8.1%-24.3%]). Among adolescents, the booster dose OR 2 to 6.5 weeks after the dose was 0.29 (95% CI, 0.24-0.35; estimated VE, 71.1% [95% CI, 65.5%-75.7%]).Among children and adolescents, estimated VE for 2 doses of BNT162b2 against symptomatic infection was modest and decreased rapidly. Among adolescents, the estimated effectiveness increased after a booster dose.

IMPORTANCE: Monitoring COVID-19 vaccine performance over time since vaccination and against emerging variants informs control measures and vaccine policies. OBJECTIVE: To estimate the associations between symptomatic SARS-CoV-2 infection and receipt of BNT162b2, mRNA-1273, and Ad26.COV2.S by day since vaccination before and during Delta variant predominance (pre-Delta period: March 13-May 29, 2021; Delta period: July 18-October 17, 2021). DESIGN, SETTING, AND PARTICIPANTS: Test-negative, case-control design with data from 6884 US COVID-19 testing sites in the pharmacy-based Increasing Community Access to Testing platform. This study included 1 634 271 laboratory-based SARS-CoV-2 nucleic acid amplification tests (NAATs) from adults 20 years and older and 180 112 NAATs from adolescents 12 to 19 years old with COVID-19–like illness from March 13 to October 17, 2021. EXPOSURES: COVID-19 vaccination (1 Ad26.COV2.S dose or 2 mRNA doses) 14 or more days prior. MAIN OUTCOMES AND MEASURES: Association between symptomatic infection and prior vaccination measured using the odds ratio (OR) from spline-based multivariable logistic regression. RESULTS: The analysis included 390 762 test-positive cases (21.5%) and 1 423 621 test-negative controls (78.5%) (59.9% were 20-44 years old; 9.9% were 12-19 years old; 58.9% were female; 71.8% were White). Among adults 20 years and older, the BNT162b2 mean OR for days 14 to 60 after a second dose (initial OR) was lower during the pre-Delta period (0.10 [95% CI, 0.09-0.11]) than during the Delta period (0.16 [95% CI, 0.16-0.17]) and increased with time since vaccination (per-month change in OR, pre-Delta: 0.04 [95% CI, 0.02-0.05]; Delta: 0.03 [95% CI, 0.02-0.03]). The initial mRNA-1273 OR was 0.05 (95% CI, 0.04-0.05) during the pre-Delta period, 0.10 (95% CI, 0.10-0.11) during the Delta period, and increased with time (per-month change in OR, pre-Delta: 0.02 [95% CI, 0.005-0.03]; Delta: 0.03 [95% CI, 0.03-0.04]). The Ad26.COV2.S initial OR was 0.42 (95% CI, 0.37-0.47) during the pre-Delta period and 0.62 (95% CI, 0.58-0.65) during the Delta period and did not significantly increase with time since vaccination. Among adolescents, the BNT162b2 initial OR during the Delta period was 0.06 (95% CI, 0.05-0.06) among 12- to 15-year-olds, increasing by 0.02 (95% CI, 0.01-0.03) per month, and 0.10 (95% CI, 0.09-0.11) among 16- to 19-year-olds, increasing by 0.04 (95% CI, 0.03-0.06) per month. CONCLUSIONS AND RELEVANCE: Among adults, the OR for the association between symptomatic SARS-CoV-2 infection and COVID-19 vaccination (as an estimate of vaccine effectiveness) was higher during Delta variant predominance, suggesting lower protection. For mRNA vaccination, the steady increase in OR by month since vaccination was consistent with attenuation of estimated effectiveness over time; attenuation related to time was greater than that related to variant.

Assessing COVID-19 vaccine performance against the rapidly spreading SARS-CoV-2 Omicron variant is critical to inform public health guidance.To estimate the association between receipt of 3 doses of Pfizer-BioNTech BNT162b2 or Moderna mRNA-1273 vaccine and symptomatic SARS-CoV-2 infection, stratified by variant (Omicron and Delta).A test-negative case-control analysis among adults 18 years or older with COVID-like illness tested December 10, 2021, through January 1, 2022, by a national pharmacy-based testing program (4666 COVID-19 testing sites across 49 US states).Three doses of mRNA COVID-19 vaccine (third dose ≥14 days before test and ≥6 months after second dose) vs unvaccinated and vs 2 doses 6 months or more before test (ie, eligible for a booster dose).Association between symptomatic SARS-CoV-2 infection (stratified by Omicron or Delta variants defined using S-gene target failure) and vaccination (3 doses vs unvaccinated and 3 doses vs 2 doses). Associations were measured with multivariable multinomial regression. Among cases, a secondary outcome was median cycle threshold values (inversely proportional to the amount of target nucleic acid present) for 3 viral genes, stratified by variant and vaccination status.Overall, 23 391 cases (13 098 Omicron; 10 293 Delta) and 46 764 controls were included (mean age, 40.3 [SD, 15.6] years; 42 050 [60.1%] women). Prior receipt of 3 mRNA vaccine doses was reported for 18.6% (n = 2441) of Omicron cases, 6.6% (n = 679) of Delta cases, and 39.7% (n = 18 587) of controls; prior receipt of 2 mRNA vaccine doses was reported for 55.3% (n = 7245), 44.4% (n = 4570), and 41.6% (n = 19 456), respectively; and being unvaccinated was reported for 26.0% (n = 3412), 49.0% (n = 5044), and 18.6% (n = 8721), respectively. The adjusted odds ratio for 3 doses vs unvaccinated was 0.33 (95% CI, 0.31-0.35) for Omicron and 0.065 (95% CI, 0.059-0.071) for Delta; for 3 vaccine doses vs 2 doses the adjusted odds ratio was 0.34 (95% CI, 0.32-0.36) for Omicron and 0.16 (95% CI, 0.14-0.17) for Delta. Median cycle threshold values were significantly higher in cases with 3 doses vs 2 doses for both Omicron and Delta (Omicron N gene: 19.35 vs 18.52; Omicron ORF1ab gene: 19.25 vs 18.40; Delta N gene: 19.07 vs 17.52; Delta ORF1ab gene: 18.70 vs 17.28; Delta S gene: 23.62 vs 20.24).Among individuals seeking testing for COVID-like illness in the US in December 2021, receipt of 3 doses of mRNA COVID-19 vaccine (compared with unvaccinated and with receipt of 2 doses) was less likely among cases with symptomatic SARS-CoV-2 infection compared with test-negative controls. These findings suggest that receipt of 3 doses of mRNA vaccine, relative to being unvaccinated and to receipt of 2 doses, was associated with protection against both the Omicron and Delta variants, although the higher odds ratios for Omicron suggest less protection for Omicron than for Delta.

Coronavirus disease 2019 (COVID-19) can progress to cytokine storm that is associated with organ dysfunction and death. The purpose of the present study is to determine clinical characteristics associated with 28 day in-hospital survival in patients with coronavirus disease 2019 (COVID-19) that received tocilizumab. This was a retrospective observational cohort study conducted at a five hospital health system in Michigan, United States. Adult patients with confirmed COVID-19 that were admitted to the hospital and received tocilizumab for cytokine storm from March 1, 2020 through April 3, 2020 were included. Patients were grouped into survivors and non-survivors based on 28 day in-hospital mortality. Study day 0 was defined as the day tocilizumab was administered. Factors independently associated with in-hospital survival at 28 days after tocilizumab administration were assessed. Epidemiologic, demographic, laboratory, prognostic scores, treatment, and outcome data were collected and analyzed. Clinical response was collected and defined as a decline of two levels on a six-point ordinal scale of clinical status or discharged alive from the hospital. Of the 81 patients included, the median age was 64 (58–71) years and 56 (69.1%) were male. The 28 day in-hospital mortality was 43.2%. There were 46 (56.8%) patients in the survivors and 35 (43.2%) in the non-survivors group. On study day 0 no differences were noted in demographics, clinical characteristics, severity of illness scores, or treatments received between survivors and non-survivors. C-reactive protein was significantly higher in the non-survivors compared to survivors. Compared to non-survivors, recipients of tocilizumab within 12 days of symptom onset was independently associated with survival (adjusted OR: 0.296, 95% CI: 0.098–0.889). SOFA score ≥8 on day 0 was independently associated with mortality (adjusted OR: 2.842, 95% CI: 1.042–7.753). Clinical response occurred more commonly in survivors than non-survivors (80.4% vs. 5.7%; p, Highlights • Patients receiving tocilizumab within 12 days of COVID-19 symptom onset had an increase in 28 day in-hospital survival. • A higher severity of illness prior to tocilizumab administration was associated with increased mortality. • Secondary infections occurred in 22.2% receiving tocilizumab, but infection was not associated with increased mortality.

Argatroban is a parenteral direct thrombin inhibitor that requires close monitoring to ensure safety and efficacy. Limited data exist to describe its effect in critically ill patients. This was a retrospective, single-center, cohort study that aimed to compare argatroban dosing requirements in those receiving extracorporeal life support (ECLS), continuous renal replacement therapy (CRRT), or neither. Organ dysfunction was assessed using a modified version of the Sequential Organ Failure Assessment (modSOFA) that incorporated the use of extracorporeal support systems. Eighty patients were included in the study (n = 20, 20, 40 in the ECLS, CRRT, and support-free groups, respectively). The majority of patients were Child-Pugh classification B (73%). Median modSOFA scores were higher in the ECLS (16.5) and CRRT (15.5) groups than in the support-free group (7.5) (P .001). There was no difference in the primary outcome of first therapeutic argatroban dose between the three groups (0.5 μg/kg/min for each; IQRs 0.25-0.50, 0.11-0.50, and 0.25-0.50, respectively; P = .455). The ECLS group had the lowest mean (0.39 μg/kg/min), minimum (0.20 μg/kg/min), and final (0.43 μg/kg/min) doses. ECLS patients had more supratherapeutic aPTTs and dose changes overall, supporting the need for more frequent anticoagulation monitoring or dose reductions in this population. Total modSOFA score demonstrated a moderate inverse correlation with first therapeutic dose (dose = 0.54 - (modSOFA score × 0.012); R = -0.342, P = .002). Overall, initial argatroban doses of 0.3-0.5 μg/kg/min appear to achieve therapeutic aPTT values in the studied populations.

Heterobimetallic Mn/Fe proteins represent a new cofactor paradigm in bioinorganic chemistry and pose countless outstanding questions. The assembly of the active site defies common chemical convention by contradicting the Irving-Williams series, while the scope of reactivity remains unexplored. In this work, the assembly and C-H bond activation process in the Mn/Fe R2-like ligand-binding oxidase (R2lox) protein is investigated using a suite of biophysical techniques, including time-resolved optical spectroscopy, global kinetic modeling, X-ray crystallography, electron paramagnetic resonance spectroscopy, protein electrochemistry, and mass spectrometry. Selective metal binding is found to be under thermodynamic control, with the binding sites within the apo-protein exhibiting greater Mn(II) affinity than Fe(II) affinity. The comprehensive analysis of structure and reactivity of wild-type R2lox and targeted primary and secondary sphere mutants indicate that the efficiency of C-H bond activation directly correlates with the Mn/Fe cofactor reduction potentials and is inversely related to divalent metal binding affinity. These findings suggest the R2lox active site is precisely tuned for achieving both selective heterobimetallic binding and high levels of reactivity and offer a mechanism to examine the means by which proteins achieve appropriate metal incorporation.

Microfabricated needle arrays for minimally invasive bioassay and drug delivery have been the subject of a great deal of excitement and research for nearly two decades. In particular, the application of microneedles to accessing and analyzing dermal interstitial fluid, in lieu of venous blood, could greatly facilitate point-of-care diagnosis and health monitoring in austere environments. However, there have been only a few successful demonstrations of in vivo collection of ISF from human skin using a microfabricated needle array. In this paper we present an empirically determined requisite feature of microfabricated hollow silicon needles that enable collection of ISF from human skin during in vivo testing. Success was only achieved by microneedles with this specific geometric feature, or shape. To inform microneedle design and fabrication, a silicon etch simulation program was developed to predict 3D shape evolution. The microfabrication process, a simulation example and in vivo test results are presented.

The heterobimetallic R2lox protein binds both manganese and iron ions in a site-selective fashion and activates oxygen, ultimately performing C-H bond oxidation to generate a tyrosine-valine crosslink near the active site. In this work, we demonstrate that, following assembly, R2lox undergoes photoinduced changes to the active site geometry and metal coordination motif. Through spectroscopic, structural, and mass spectrometric characterization, the photoconverted species is found to consist of a tyrosinate-bound iron center following light-induced decarboxylation of a coordinating glutamate residue and cleavage of the tyrosine-valine cross-link. This process occurs with high quantum efficiencies (Phi = 3%) using violet and near-ultraviolet light, suggesting that the photodecarboxylation is initiated via ligandto-metal charge transfer excitation. Site-directed mutagenesis and structural analysis suggest that the cross-linked tyrosine-162 is the coordinating residue. One primary product is observed following irradiation, indicating potential use of this class of proteins, which contains a putative substrate channel, for controlled photoinduced decarboxylation processes, with relevance for in vivo functionality of R2lox as well as application in environmental remediation.

Background The early administration of corticosteroids (CS) in patients with severe COVID-19 (hospitalized with need for supplemental oxygen) has been the only therapy to improve survival. However, the optimal dosing of CS remains unclear. Beginning March 2020 methylprednisolone (MP) in a dose of 40mg twice daily (high dose CS - HDC) was adopted at our institution. Based on emerging trials, this dose of MP was reduced to 16mg twice daily (moderate dose CS – MDC) in November 2020. The study aims to evaluate the outcome difference in patients receiving HDC versus MDC. Methods This pre-post quasi-experimental study was done at Henry Ford Hospital, an 877-bed tertiary care hospital in Detroit, Michigan. Consecutive patients in the HDC group from September 1, 2020 to November 15, 2020 were compared to the MDC group from November 30, 2020 to January 20, 2021. Only hospitalized patients with severe COVID-19 were included. The primary outcome was 28-day mortality. Secondary outcomes included progression to mechanical ventilation, length of hospital stay, discharge on supplemental oxygen and CS-associated adverse events. Patient demographics were evaluated using descriptive statistics. Bivariate and multivariable logistic regression analysis was planned to test the association between primary outcome and exposure. Results 470 patients were evaluated, 218 and 252 in the HDC and MDC groups respectively. Clinical characteristics and severity of illness on admission were comparable in both groups (Table 1). Among comorbidities - lung disease, cardiovascular disease and hypertension were higher in MDC. Antibiotic and tocilizumab use were lower in MDC. Significantly more patients in MDC group received oral CS. There was no difference in mortality between HDC and MDC through bivariate and multivariate analysis (14.7% and 13.5%, p < 0.712, adjusted OR 0.913 [0.514-1.619]) (Table 2,3). Median length of hospital stay was 5 and 6 days in HDC and MDC respectively (p < 0.001). There was no difference in CS-associated adverse events. Conclusion The survival in severe COVID-19 patients treated with MDC is comparable to HDC. Oral corticosteroids are an equally effective option. Disclosures Rachel Kenney, PharmD, Medtronic, Inc. (Other Financial or Material Support, spouse is an employee and shareholder)

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Dexmedetomidine has revolutionized the field of critical care medicine, providing clinicians a short-acting, well-tolerated sedative. Cardiovascular adverse effects are well described with this agent (1). Less common adverse effects such as fever are increasingly being reported (2). Previous studies demonstrated no appreciable rate of dexmedetomidine-related fever (1, 3). Here we report a case of high-grade fever in the intensive care unit (ICU) after initiation of dexmedetomidine, with resolution after discontinuation. CASE PRESENTATION: A 34-year-old male with a past medical history of alcohol abuse and asthma was admitted to the general ward with Coronavirus disease 2019 (COVID-19) pneumonia. His course was complicated by severe hypoxia and subsequent pulseless electrical activity (PEA) arrest, requiring ICU transfer after achieving return of circulation and undergoing mechanical ventilation. On hospital day 7, after improvement in respiratory status with COVID-19 management including corticosteroids, as well as treatment with ceftriaxone and azithromycin given concern for superimposed bacterial pneumonia, he was transitioned to dexmedetomidine in preparation for a ventilator weaning trial. He developed fevers over the following 12 hours, initially to 39.4 C (102.9 F) prompting empiric sepsis management with intravenous fluids and broad-spectrum antibiotics (see figure-1). Despite this, he continued to have fevers to a maximum core temperature of 41.1 C (106 F). Blood, fungal, and respiratory cultures were unremarkable. With no clear infectious source or alternative explanation for severe hyperthermia, the decision was made to wean off dexmedetomidine given suspicion for drug-induced fever, upon which core temperature returned to 37.8 C (100.1 F). He remained afebrile, and eventually extubated and discharged in stable condition. DISCUSSION: We present a case of severe hyperthermia corresponding to, with a probable association using the Naranjo Adverse Drug Reaction Probability Scale, dexmedetomidine initiation, followed by resolution of fever after discontinuation. Antimicrobial therapy had no observable effect on the fever, and extensive infectious work-up was unremarkable. Completely attributing a febrile episode in the ICU setting to a medication is a difficult task. Furthermore, adequately powering studies to identify rare medication adverse effects in the ICU is a challenge, which may explain the absence of fever as a documented adverse effect of dexmedetomidine (1,2,4). In this case, no alternate diagnoses were evident, thus management was focused on discontinuing the presumed inciting agent. CONCLUSIONS: Recognizing dexmedetomidine as an etiology of severe hyperthermia in the ICU may help mitigate excessive therapies and improve outcomes. Further research is warranted to describe risk factors and proper recognition for when fevers occur with dexmedetomidine. REFERENCE #1: Hospira (2014) Precedex® (dexmedetomidine hydrochloride) [package insert]. Lake Forest, IL: Hospira, Inc. REFERENCE #2: Peterson J, Thomas W, Michaud C, et al. Incidence of Fever Associated With Dexmedetomidine in the Adult Intensive Care Unit. J Pharm Pract. 2021 Apr 5:8971900211004828. REFERENCE #3: Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine for Long-Term Sedation Investigators. JAMA. 2012 Mar 21;307(11):1151-60. DISCLOSURES: No relevant relationships by Raef Fadel, source=Web Response No relevant relationships by Sara Hegab, source=Web Response No relevant relationships by Michael Reaume, source=Web Response No relevant relationships by Zachary Smith, source=Web Response

Impella devices are percutaneously inserted ventricular assist devices which require a continuous purge solution that contains heparin to prevent pump thrombosis and device failure. We describe 2 patients with heparin-induced thrombocytopenia (HIT) supported with an Impella device utilizing an argatroban-based purge solution. Case 1 involved an 83-year-old female with biventricular failure which resulted in right ventricle Impella support. The purge solution was changed to include argatroban due to concern of device clotting in the setting of HIT. Case 2 involved a 55-year-old male with worsening cardiogenic shock which resulted in left ventricle Impella support. Due to decreased purge flow rates and concerns for clotting, argatroban was added to the purge solution. Both patients’ total argatroban regimens were monitored and adjusted by pharmacy, resulting in therapeutic anticoagulation without any major bleeding or thrombotic events. Subsequently, a protocol was designed and implemented. These case reports appear to demonstrate the safe and effective use of argatroban purge solutions for the necessary anticoagulation with an Impella device. Further studies are needed to confirm these results and determine the optimal dosing regimen.

Objective: To describe the incidence of 30 day healthcare encounters following an index hospitalization in an uninsured and insured population. Methods: This was a retrospective cohort study conducted at an urban, tertiary care hospital. Patients admitted between 7/1/2010 - 6/30/2011 that were between the ages of 18-64 were included if they had a financial code for no insurance or commercial insurance provider. The primary outcome assessed between groups was incidence of 30 day healthcare encounter following hospital disharge to either the emergency department or hospital. Results: 5,489 patients were admitted over the study period 2,093 uninsured and 3,396 insured. The number of 30 day healthcare encounters for the uninsured and insured groups were 348 (16.6%) and 566 (16.7%), respectively (p = 0.99). The uninsured population was more likely to be have a 30 day healthcare encounter in the emergency department 237 (11.3%) vs 246 (7.2%), p

BackgroundWhen screening for breast cancer, the radiological interpretation of mammograms is a difficult task, particularly when classifying precancerous growth such as microcalcifications (MCs). Biophysical modeling of benign vs. malignant growth of MCs in simulated mammographic backgrounds may improve characterization of these structures MethodsA mathematical model based on crystal growth rules for calcium oxide (benign) and hydroxyapatite (malignant) was used in conjunction with simulated mammographic backgrounds, which were generated by fractional Brownian motion of varying roughness and quantified by the Hurst exponent to mimic tissue of varying density. Simulated MC clusters were compared by fractal dimension, average circularity of individual MCs, average number of MCs per cluster, and average cluster area. ResultsBenign and malignant clusters were distinguishable by average circularity, average number of MCs per cluster, and average cluster area with p

Chronic thromboembolic pulmonary hypertension (CTEPH) is a subset of pulmonary hypertension caused by acute and recurrent pulmonary emboli. Pulmonary thromboendarterectomy is the treatment of choice, but 10-50% of patients are ineligible for this procedure. We describe the case of a 25-year-old, morbidly obese (228-kg, body mass index 83.5 kg/m(2) ) pregnant woman (G3 P2 ) who presented at 24 weeks' gestation; bilateral pulmonary angiography revealed filling defects and confirmed the diagnosis of CTEPH. The patient was evaluated and deemed to present too high of a risk for pulmonary thromboendarterectomy, so a multidisciplinary team initiated medical therapy. Sildenafil 20 mg orally 3 times/day was started at week 24 of gestation, and inhaled iloprost was added at 26 weeks and titrated to 5 µg inhaled every 2 hrs in order to optimize hemodynamic status prior to a cesarean section delivery scheduled to be performed 6 weeks later. At 32 weeks of gestation, the patient's pulmonary arterial systolic pressure was 77 mm Hg, right atrial pressure was 15 mm Hg, and pulmonary capillary wedge pressure of 16 mm Hg, and a healthy 1741-g male infant was delivered by cesarean section. The patient was transferred back to the medical intensive care unit in stable condition and discharged home 9 days following the procedure. Pharmacotherapeutic strategies for patients with CTEPH who become pregnant are limited to phosphodiesterase type 5 inhibitors and prostacyclin analog therapies due to the teratogenicity of the other drug classes used to treat the disorder (endothelin receptor antagonists and soluble guanylate cyclase stimulators). To our knowledge, this is the first case report of inhaled iloprost use in addition to oral sildenafil to improve patient symptomatology and hemodynamics during the peripartum period of a young pregnant patient with inoperable CTEPH. This drug therapy was used safely, with no noted adverse effects to the newborn or to the patient.

Treprostinil diolamine is the first oral dosage preparation of a prostacyclin analogue for use in treatment naive pulmonary arterial hypertension (PAH). This case series and review of the available literature describes the experience of patients with PAH receiving treprostinil by intravenous (IV), subcutaneous (SQ), or inhalation route who were transitioned to treprostinil diolamine. At our institution, 3 patients were transitioned to treprostinil diolamine who received treprostinil administered by each of the alternative routes: IV, SQ, and inhalation. All patients tolerated the transition without significant worsening of disease end points. In the literature, 5 additional reports representing 48 patients were transitioned to treprostinil diolamine from an alternate route of administration. A majority (92%) of patients were hospitalized during the cross-titration phase and tolerated the transition without changes in disease markers or significant adverse effect. Six (13%) patients required reinitiation of parenteral therapy due to clinical decline. The most common dosing frequency utilized for treprostinil diolamine was 3 times per day. In patients with stable PAH receiving parenteral or inhaled treprostinil, a transition to treprostinil diolamine was a safe approach in a highly select population meeting clinical end points. Additional studies are required to further describe this clinical strategy before accepted in clinical practice.

Purpose Results of a study to apply lean methodology to an inpatient pharmacy workflow to optimize timely administration of Centers for Medicare and Medicaid Services (CMS)–approved antibiotics for patients with severe sepsis or septic shock are presented. Methods This quasi-experimental study was conducted at an 802-bed institution using lean methodology to assess the inpatient pharmacy workflow for dispensing antibiotics to adult patients. The preintervention and postintervention phases occurred from February to September, 2015, and from October 2015 to May 2016, respectively. Patients were included if they were hospitalized with an intensive care department 9 or 10 code for severe sepsis or septic shock, had an order for a CMS-approved antibiotic, and met clinical criteria for severe sepsis or septic shock. Patients were excluded if they received first-dose antibiotics in the emergency department. The primary outcome was time from CMS-approved antibiotic order entry to medication administration. Secondary outcomes included timeliness of individual workflow dispensing parameters, patient outcomes, and compliance with the newly implemented workflow. Results A total of 102 patients were included, 54 in the preintervention and 48 in the postintervention group. Baseline demographics between the groups were similar. There was a significant reduction in the median time from order entry to antibiotic administration by 40 minutes (preintervention phase 120 minutes versus postintervention phase 80 minutes, p = 0.014). Time from order verification to administration was significantly reduced. There was no difference in other secondary outcomes. Conclusion Lean methodology was successfully used to reduce time to antibiotic administration, which led to improved compliance with the newly implemented sepsis CMS core measure.

The Food and Drug Administration Amendments Act was introduced in 2007, requiring manufacturers to develop and implement a risk evaluation and mitigation strategy (REMS) when a drug’s prescribing information alone does not ensure that the benefits of a drug outweigh its potential risk.[1][1]–[3

Right ventricular failure (RVF) is the leading cause of morbidity and mortality for patients with a left ventricular assist device (LVAD). There is limited data to support lowering pulmonary pressure with a phosphodiesterase inhibitor to improve right ventricular function. This study aims to

Mechanical circulatory support (MCS) devices provide hemodynamic support in patients with cardiogenic shock or end-stage heart failure. Heparin exposure and device related thrombocytopenia complicate the diagnosis of heparin-induced thrombocytopenia (HIT) and may lead to unnecessary treatment with

A simple, effective, and universal model is presented for the formation of silicon nanowires during silver metal assisted chemical etching of silicon. The model explains nanowire formation in terms of well-known and well-understood principles of electrochemical exchange current densities at silver metal/solution interfaces, silicon/silver ion reaction kinetics, and diffusion limited aggregatoon (DLA) kinetics. The role of the metal in the formation of nanowires is clearly defined and the model is easily extended to other transition metal systems, including: Pt, Au and Pd.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease of the pulmonary vascular bed that is characterized by elevations in the mean pulmonary artery pressure in the setting of perfusion defects on ventilation–perfusion scan, and subsequently confirmed by pulmonary angiography. CTEPH, or World Health Organization (WHO) group 4 pulmonary hypertension, is a result of unresolved thromboembolic obstruction in the pulmonary arteries. Pulmonary endarterectomy (PEA) is the treatment of choice for CTEPH as it is a potentially curative therapy. However, up to one-third of patients are not candidates for the surgery, either due to distal and inaccessible nature of the lesions or comorbid conditions. Due to remodeling that occurs in nonobstructed pulmonary vessels, a portion of patients who have undergone PEA have residual CTEPH after the procedure, attributable to high shear stress prior to PEA. This phenomenon has led to the understanding of a so-called “two-compartment model” of CTEPH, opening the door to pharmacologic treatment strategies. In 2013, riociguat, a soluble guanylate cyclase stimulator, was approved in the US and Europe for the treatment of inoperable or persistent/recurrent CTEPH. This article reviews the current management of CTEPH with a focus on riociguat.

In this study, we mapped achievement levels from the National Assessment of Educational Progress (NAEP) onto the score scales for selected assessments from the Trends in International Mathematics and Science Study (TIMSS) and the Program for International Student Achievement (PISA). The mapping was conducted on NAEP, TIMSS, and PISA Mathematics assessments in 2003. A focus of the study was on whether the NAEP achievement levels were set too high. The results indicated that students from many other countries had substantially larger percentages of students meeting NAEP mathematics achievement levels. In general, the findings suggest the NAEP standard for Advanced is high, but not too high when considered within an international context. With respect to the NAEP standard of Proficient, none of the top-performing countries approached 100% proficient, which seems to underscore the different conceptualizations of “Proficient” in NAEP and No Child Left Behind.