Reconsidering the use of race adjustments in maternal serum screening.

The use of race in maternal serum screening is problematic because race is a social construct rather than a distinct biological classifier. Nevertheless, laboratories offering this testing are encouraged to use race-specific cutoff values for maternal serum screening biomarkers to determine the risk of fetal abnormalities. Large cohort studies examining racial differences in maternal serum screening biomarker concentrations have yielded conflicting results, which we postulate may be explained by genetic and socioeconomic differences between racial cohorts in different studies. We recommend that the use of race in maternal serum screening should be abandoned. Further research is needed to identify socioeconomic and environmental factors that contribute to differences in maternal serum screening biomarker concentrations observed between races. A better understanding of these factors may facilitate accurate race-agnostic risk estimates for aneuploidy and neural tube defects.

Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection.

BACKGROUND: The effect of procalcitonin-guided use of antibiotics on treatment for suspected lower respiratory tract infection is unclear. METHODS: In 14 U.S. hospitals with high adherence to quality measures for the treatment of pneumonia, we provided guidance for clinicians about national clinical practice recommendations for the treatment of lower respiratory tract infections and the interpretation of procalcitonin assays. We then randomly assigned patients who presented to the emergency department with a suspected lower respiratory tract infection and for whom the treating physician was uncertain whether antibiotic therapy was indicated to one of two groups: the procalcitonin group, in which the treating clinicians were provided with real-time initial (and serial, if the patient was hospitalized) procalcitonin assay results and an antibiotic use guideline with graded recommendations based on four tiers of procalcitonin levels, or the usual-care group. We hypothesized that within 30 days after enrollment the total antibiotic-days would be lower - and the percentage of patients with adverse outcomes would not be more than 4.5 percentage points higher - in the procalcitonin group than in the usual-care group. RESULTS: A total of 1656 patients were included in the final analysis cohort (826 randomly assigned to the procalcitonin group and 830 to the usual-care group), of whom 782 (47.2%) were hospitalized and 984 (59.4%) received antibiotics within 30 days. The treating clinician received procalcitonin assay results for 792 of 826 patients (95.9%) in the procalcitonin group (median time from sample collection to assay result, 77 minutes) and for 18 of 830 patients (2.2%) in the usual-care group. In both groups, the procalcitonin-level tier was associated with the decision to prescribe antibiotics in the emergency department. There was no significant difference between the procalcitonin group and the usual-care group in antibiotic-days (mean, 4.2 and 4.3 days, respectively; difference, -0.05 day; 95% confidence interval [CI], -0.6 to 0.5; P=0.87) or the proportion of patients with adverse outcomes (11.7% [96 patients] and 13.1% [109 patients]; difference, -1.5 percentage points; 95% CI, -4.6 to 1.7; P<0.001 for noninferiority) within 30 days. CONCLUSIONS: The provision of procalcitonin assay results, along with instructions on their interpretation, to emergency department and hospital-based clinicians did not result in less use of antibiotics than did usual care among patients with suspected lower respiratory tract infection. (Funded by the National Institute of General Medical Sciences; ProACT ClinicalTrials.gov number, NCT02130986 .).

Review of the Preanalytical Errors That Impact Therapeutic Drug Monitoring.

PURPOSE: Preanalytical errors comprise the majority of testing errors experienced by clinical laboratories and significantly impact the accuracy of therapeutic drug monitoring (TDM). METHODS: Specific preanalytical factors in sample timing, collection, transport, processing, and storage that lead to errors in TDM were reviewed. We performed a literature search using several scientific databases including PubMed, ScienceDirect, Scopus, Web of Science, and ResearchGate for human studies published in the English language from January 1980 to February 2021, reporting on TDM and the preanalytical phase. RESULTS: Blood collection errors (ie, wrong anticoagulant/clot activator used, via an intravenous line, incorrect time after dosing) delay testing, cause inaccurate results, and adversely impact patient care. Blood collected in lithium heparin tubes instead of heparin sodium tubes produce supertoxic lithium concentrations, which can compromise care. Specimens collected in serum separator gel tubes cause falsely decreased concentrations due to passive absorption into the gel when samples are not processed and analyzed quickly. Dried blood spots are popular for TDM as they are minimally invasive, allowing for self-sampling and direct shipping to a clinical laboratory using regular mail. However, blood collection techniques, such as trauma to the collection site, filter paper fragility, and hematocrit (Hct) bias, can adversely affect the accuracy of the results. Volumetric absorptive microsampling is a potential alternative to dried blood spot that offers fast, volume-fixed sampling, low pain tolerance, and is not susceptible to Hct concentrations. CONCLUSIONS: The identification of preanalytical factors that may negatively impact TDM is critical. Developing workflows that can standardize TDM practices, align appropriate timing and blood collection techniques, and specimen processing will eliminate errors.

Association Between Intravenous Fluid Bolus and Biomarker Trajectory During Prehospital Care.

Background: Patients with acute illness who receive intravenous (IV) fluids prior to hospital arrival may have a lower in-hospital mortality. To better understand whether this is a direct treatment effect or epiphenomenon of downstream care, we tested the association between a prehospital fluid bolus and the change in inflammatory cytokines measured at prehospital and emergency department timepoints in a sample of non-trauma, non-cardiac arrest patients at risk for critical illness. Methods: In a prospective cohort study, we screened 4,013 non-trauma, non-cardiac arrest encounters transported by City of Pittsburgh Emergency Medical Services (EMS) to 2 hospitals from August 2013 to February 2014. In 345 patients, we measured prehospital biomarkers (IL-6, IL-10, and TNF) at 2 time points: the time of prehospital IV access placement by EMS and at ED arrival. We determined the relative change for marker X as: ([XED - XEMS]/XEMS). We determined the risk-adjusted association between prehospital IV fluid bolus and relative change for each marker using multivariable linear regression. Results: Among 345 patients, 88 (26%) received a prehospital IV fluid bolus and 257 (74%) did not. Compared to patients who did not receive prehospital fluids, median prehospital IL-6 was greater initially in subjects receiving a prehospital IV fluid bolus (22.3 [IQR 6.4-113] vs. 11.5 [IQR 5.5-47.6]). Prehospital IL-10 and TNF were similar in both groups (IL-10: 3.5 [IQR 2.2-25.6] vs. 3.0 [IQR 1.9-9.0]; TNF: 7.5 [IQR 6.4-10.4] vs. 6.9 [IQR 6.0-8.3]). After adjustment for demographics, illness severity, and prehospital transport time, we observed a relative decrease in IL-6 at hospital arrival in those receiving a prehospital fluid bolus (adjusted ß = -10.0, 95% CI: -19.4, -0.6, p = 0.04), but we did not detect a significant change in IL-10 (p = 0.34) or TNF (p = 0.53). Conclusions: Among non-trauma, non-cardiac arrest patients at risk for critical illness, a prehospital IV fluid bolus was associated with a relative decrease in IL-6, but not IL-10 or TNF.

Monocyte Distribution Width: A Novel Indicator of Sepsis-2 and Sepsis-3 in High-Risk Emergency Department Patients.

OBJECTIVES: Most septic patients are initially encountered in the emergency department where sepsis recognition is often delayed, in part due to the lack of effective biomarkers. This study evaluated the diagnostic accuracy of peripheral blood monocyte distribution width alone and in combination with WBC count for early sepsis detection in the emergency department. DESIGN: An Institutional Review Board approved, blinded, observational, prospective cohort study conducted between April 2017 and January 2018. SETTING: Subjects were enrolled from emergency departments at three U.S. academic centers. PATIENTS: Adult patients, 18-89 years, with complete blood count performed upon presentation to the emergency department, and who remained hospitalized for at least 12 hours. A total of 2,212 patients were screened, of whom 2,158 subjects were enrolled and categorized per Sepsis-2 criteria, such as controls (n = 1,088), systemic inflammatory response syndrome (n = 441), infection (n = 244), and sepsis (n = 385), and Sepsis-3 criteria, such as control (n = 1,529), infection (n = 386), and sepsis (n = 243). INTERVENTIONS: The primary outcome determined whether an monocyte distribution width of greater than 20.0 U, alone or in combination with WBC, improves early sepsis detection by Sepsis-2 criteria. Secondary endpoints determined monocyte distribution width performance for Sepsis-3 detection. MEASUREMENTS AND MAIN RESULTS: Monocyte distribution width greater than 20.0 U distinguished sepsis from all other conditions based on either Sepsis-2 criteria (area under the curve, 0.79; 95% CI, 0.76-0.82) or Sepsis-3 criteria (area under the curve, 0.73; 95% CI, 0.69-0.76). The negative predictive values for monocyte distribution width less than or equal to 20 U for Sepsis-2 and Sepsis-3 were 93% and 94%, respectively. Monocyte distribution width greater than 20.0 U combined with an abnormal WBC further improved Sepsis-2 detection (area under the curve, 0.85; 95% CI, 0.83-0.88) and as reflected by likelihood ratio and added value analyses. Normal WBC and monocyte distribution width inferred a six-fold lower sepsis probability. CONCLUSIONS: An monocyte distribution width value of greater than 20.0 U is effective for sepsis detection, based on either Sepsis-2 criteria or Sepsis-3 criteria, during the initial emergency department encounter. In tandem with WBC, monocyte distribution width is further predicted to enhance medical decision making during early sepsis management in the emergency department.

Design and rationale of the Procalcitonin Antibiotic Consensus Trial (ProACT), a multicenter randomized trial of procalcitonin antibiotic guidance in lower respiratory tract infection.

BACKGROUND: Overuse of antibiotics is a major public health problem, contributing to growing antibiotic resistance. Procalcitonin has been reported to be commonly elevated in bacterial, but not viral infection. Multiple European trials found procalcitonin-guided care reduced antibiotic use in lower respiratory tract infection, with no apparent harm. However, applicability to US practice is limited due to trial design features impractical in the US, between-country differences, and residual safety concerns. METHODS: The Procalcitonin Antibiotic Consensus Trial (ProACT) is a multicenter randomized trial to determine the impact of a procalcitonin antibiotic prescribing guideline, implemented with basic reproducible strategies, in US patients with lower respiratory tract infection. DISCUSSION: We describe the trial methods using the Consolidated Standards of Reporting Trials (CONSORT) framework, and the rationale for key design decisions, including choice of eligibility criteria, choice of control arm, and approach to guideline implementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02130986 . Registered May 1, 2014.

Elaidate, an 18-carbon trans-monoenoic fatty acid, but not physiological fatty acids increases intracellular Zn(2+) in human macrophages.

Artificial trans fatty acids promote atherosclerosis by blocking macrophage clearance of cell debris. Classical fatty-acid response mechanisms include TLR4-NF-κB activation, and Erk1/2 phosphorylation, but these may not indicate long-term mechanisms. Indeed, nuclear NF-κB was increased by 60 min treatment by 30 µM of the 18 carbon trans unsaturated fatty acid elaidic acid (elaidate), the physiological cis-unsaturated fatty acid oleic acid (oleate), and the 18 or 16 carbon saturated fatty acids stearic and palmitic acid (stearate or palmitate). However, except for stearate, effects on related pathways were minimal at 44 h. To determine longer term effects of trans fatty acids, we compared mRNA expression profiles of (trans) elaidate to (cis) oleate, 30 µM, at 44 h in human macrophages. We found that elaidate changed Zn(2+) -homeostasis gene mRNAs markedly. This might be important because Zn(2+) is a major regulator of macrophage activity. Messenger RNAs of seven Zn(2+) -binding metallothioneins decreased 2-4-fold; the zinc importer SLC39A10 increased twofold, in elaidate relative to oleate-treated cells. Results were followed by quantitative PCR comparing cis, trans, and saturated fatty acid effects on Zn(2+) -homeostasis gene mRNAs. This confirmed that elaidate uniquely decreased metallothionein expression and increased SLC39A10 at 44 h. Further, intracellular Zn(2+) was measured using N-(carboxymethyl)-N-[2-[2-[2(carboxymethyl) amino]-5-(2,7,-difluoro-6-hydroxy-3-oxo-3H-xanthen-9-yl)-phenoxy]-ethoxy]-4-methoxyphenyl]glycine, acetoxymethyl ester (FluoZin-3-AM). This showed that, at 44 h, only cells treated with elaidate had increased Zn(2+) . The durable effect of elaidate on Zn(2+) activation is a novel and specific effect of trans fatty acids on peripheral macrophage metabolism.

A rapid host-protein test for differentiating bacterial from viral infection: Apollo diagnostic accuracy study.

Objectives: To determine the diagnostic accuracy of a rapid host-protein test for differentiating bacterial from viral infections in patients who presented to the emergency department (ED) or urgent care center (UCC). Methods: This was a prospective multicenter, blinded study. MeMed BV (MMBV), a test based on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-inducible protein-10 (IP-10), and C-reactive protein (CRP), was measured using a rapid measurement platform. Patients were enrolled from 9 EDs and 3 UCCs in the United States and Israel. Patients >3 months of age presenting with fever and clinical suspicion of acute infection were considered eligible. MMBV results were not provided to the treating clinician. MMBV results (bacterial/viral/equivocal) were compared against a reference standard method for classification of infection etiology determined by expert panel adjudication. Experts were blinded to MMBV results. They were provided with comprehensive patient data, including laboratory, microbiological, radiological and follow-up. Results: Of 563 adults and children enrolled, 476 comprised the study population (314 adults, 162 children). The predominant clinical syndrome was respiratory tract infection (60.5% upper, 11.3% lower). MMBV demonstrated sensitivity of 90.0% (95% confidence interval [CI]: 80.3-99.7), specificity of 92.8% (90.0%-95.5%), and negative predictive value of 98.8% (96.8%-99.6%) for bacterial infections. Only 7.2% of cases yielded equivocal MMBV scores. Area under the curve for MMBV was 0.95 (0.90-0.99). Conclusions: MMBV had a high sensitivity and specificity relative to reference standard for differentiating bacterial from viral infections. Future implementation of MMBV for patients with suspected acute infections could potentially aid with appropriate antibiotic decision-making.

Metallothionein-induced zinc partitioning exacerbates hyperoxic acute lung injury.

Hypozincemia, with hepatic zinc accumulation at the expense of other organs, occurs in infection, inflammation, and aseptic lung injury. Mechanisms underlying zinc partitioning or its impact on extrahepatic organs are unclear. Here we show that the major zinc-binding protein, metallothionein (MT), is critical for zinc transmigration from lung to liver during hyperoxia and preservation of intrapulmonary zinc during hyperoxia is associated with an injury-resistant phenotype in MT-null mice. Particularly, lung-to-liver zinc ratios decreased in wild-type (WT) and increased significantly in MT-null mice breathing 95% oxygen for 72 h. Compared with female adult WT mice, MT-null mice were significantly protected against hyperoxic lung injury indicated by reduced inflammation and interstitial edema, fewer necrotic changes to distal airway epithelium, and sustained lung function at 72 h hyperoxia. Lungs of MT-null mice showed decreased levels of immunoreactive LC3, an autophagy marker, compared with WT mice. Analysis of superoxide dismutase (SOD) activity in the lungs revealed similar levels of manganese-SOD activity between strains under normoxia and hyperoxia. Lung extracellular SOD activity decreased significantly in both strains at 72 h of hyperoxia, although there was no difference between strains. Copper-zinc-SOD activity was ~4× higher under normoxic conditions in MT-null compared with WT mice but was not affected in either group by hyperoxia. Collectively the data suggest that genetic deletion of MT-I/II in mice is associated with compensatory increase in copper-zinc-SOD activity, prevention of hyperoxia-induced zinc transmigration from lung to liver, and hyperoxia-resistant phenotype strongly associated with differences in zinc homeostasis during hyperoxic acute lung injury.

PATHWAYS ASSOCIATED WITH POSITIVE SEPSIS SURVIVAL OUTCOMES IN AFRICAN AMERICAN/BLACK AND NON-HISPANIC WHITE PATIENTS WITH URINARY TRACT INFECTION.

ABSTRACT: Urinary tract infections (UTIs) are a common cause of sepsis worldwide. Annually, more than 60,000 US deaths can be attributed to sepsis secondary to UTIs, and African American/Black adults have higher incidence and case-fatality rates than non-Hispanic White adults. Molecular-level factors that may help partially explain differences in sepsis survival outcomes between African American/Black and Non-Hispanic White adults are not clear. In this study, patient samples (N = 166) from the Protocolized Care for Early Septic Shock cohort were analyzed using discovery-based plasma proteomics. Patients had sepsis secondary to UTIs and were stratified according to self-identified racial background and sepsis survival outcomes. Proteomics results suggest patient heterogeneity across mechanisms driving survival from sepsis secondary to UTIs. Differentially expressed proteins (n = 122, false discovery rate-adjusted P < 0.05) in Non-Hispanic White sepsis survivors were primarily in immune system pathways, while differentially expressed proteins (n = 47, false discovery rate-adjusted P < 0.05) in African American/Black patients were mostly in metabolic pathways. However, in all patients, regardless of racial background, there were 16 differentially expressed proteins in sepsis survivors involved in translation initiation and shutdown pathways. These pathways are potential targets for prognostic intervention. Overall, this study provides information about molecular factors that may help explain disparities in sepsis survival outcomes among African American/Black and Non-Hispanic White patients with primary UTIs.

Proteomic changes associated with racial background and sepsis survival outcomes.

Intra-abdominal infection is a common cause of sepsis, and intra-abdominal sepsis leads to ∼156 000 U.S. deaths annually. African American/Black adults have higher incidence and mortality rates from sepsis compared to Non-Hispanic White adults. A limited number of studies have traced survival outcomes to molecular changes; however, these studies primarily only included Non-Hispanic White adults. Our goal is to better understand molecular changes that may contribute to differences in sepsis survival in African American/Black and Non-Hispanic White adults with primary intra-abdominal infection. We employed discovery-based plasma proteomics of patient samples from the Protocolized Care for Early Septic Shock (ProCESS) cohort (N = 107). We identified 49 proteins involved in the acute phase response and complement system whose expression levels are associated with both survival outcome and racial background. Additionally, 82 proteins differentially-expressed in survivors were specific to African American/Black or Non-Hispanic White patients, suggesting molecular-level heterogeneity in sepsis patients in key inflammatory pathways. A smaller, robust set of 19 proteins were in common in African American/Black and Non-Hispanic White survivors and may represent potential universal molecular changes in sepsis. Overall, this study identifies molecular factors that may contribute to differences in survival outcomes in African American/Black patients that are not fully explained by socioeconomic or other non-biological factors.

The comparative effectiveness of COVID-19 monoclonal antibodies: A learning health system randomized clinical trial.

BACKGROUND: Monoclonal antibodies (mAb) that neutralize SARS-CoV-2 decrease hospitalization and death compared to placebo in patients with mild to moderate COVID-19; however, comparative effectiveness is unknown. We report the comparative effectiveness of bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab. METHODS: A learning health system platform trial in a U.S. health system enrolled patients meeting mAb Emergency Use Authorization criteria. An electronic health record-embedded application linked local mAb inventory to patient encounters and provided random mAb allocation. Primary outcome was hospital-free days to day 28. Primary analysis was a Bayesian model adjusting for treatment location, age, sex, and time. Inferiority was defined as 99% posterior probability of an odds ratio < 1. Equivalence was defined as 95% posterior probability the odds ratio is within a given bound. FINDINGS: Between March 10 and June 25, 2021, 1935 patients received treatment. Median hospital-free days were 28 (IQR 28, 28) for each mAb. Mortality was 0.8% (1/128), 0.8% (7/885), and 0.7% (6/922) for bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively. Relative to casirivimab-imdevimab (n = 922), median adjusted odds ratios were 0.58 (95% credible interval [CI] 0.30-1.16) and 0.94 (95% CI 0.72-1.24) for bamlanivimab (n = 128) and bamlanivimab-etesevimab (n = 885), respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab. INTERPRETATION: Among patients with mild to moderate COVID-19, bamlanivimab-etesevimab or casirivimab-imdevimab treatment resulted in 86% probability of equivalence. No treatment met prespecified criteria for statistical equivalence. Median hospital-free days to day 28 were 28 (IQR 28, 28) for each mAb. FUNDING AND REGISTRATION: This work received no external funding. The U.S. government provided the reported mAb. This trial is registered at ClinicalTrials.gov, NCT04790786.

Effectiveness of Casirivimab-Imdevimab and Sotrovimab During a SARS-CoV-2 Delta Variant Surge: A Cohort Study and Randomized Comparative Effectiveness Trial.

Importance: The effectiveness of monoclonal antibodies (mAbs), casirivimab-imdevimab and sotrovimab, is unknown in patients with mild to moderate COVID-19 caused by the SARS-CoV-2 Delta variant. Objective: To evaluate the effectiveness of mAb against the Delta variant compared with no mAb treatment and to ascertain the comparative effectiveness of casirivimab-imdevimab and sotrovimab. Design, Setting, and Participants: This study comprised 2 parallel studies: (1) a propensity score-matched cohort study of mAb treatment vs no mAb treatment and (2) a randomized comparative effectiveness trial of casirivimab-imdevimab and sotrovimab. The cohort consisted of patients who received mAb treatment at the University of Pittsburgh Medical Center outpatient infusion centers and emergency departments from July 14 to September 29, 2021. Participants were patients with a positive SARS-CoV-2 test result who were eligible to receive mAbs according to emergency use authorization criteria. Exposure: For the trial, patients were randomized to either intravenous casirivimab-imdevimab or sotrovimab according to a system therapeutic interchange policy. Main Outcomes and Measures: For the cohort study, risk ratio (RR) estimates for the primary outcome of hospitalization or death by 28 days were compared between mAb treatment and no mAb treatment using propensity score-matched models. For the comparative effectiveness trial, the primary outcome was hospital-free days (days alive and free of hospitalization) within 28 days after mAb treatment, where patients who died were assigned -1 day in a bayesian cumulative logistic model adjusted for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio (OR) less than 1. Equivalence was defined as a 95% posterior probability that the OR was within a given bound. Results: A total of 3069 patients (1023 received mAb treatment: mean [SD] age, 53.2 [16.4] years; 569 women [56%]; 2046 had no mAb treatment: mean [SD] age, 52.8 [19.5] years; 1157 women [57%]) were included in the prospective cohort study, and 3558 patients (mean [SD] age, 54 [18] years; 1919 women [54%]) were included in the randomized comparative effectiveness trial. In propensity score-matched models, mAb treatment was associated with reduced risk of hospitalization or death (RR, 0.40; 95% CI, 0.28-0.57) compared with no treatment. Both casirivimab-imdevimab (RR, 0.31; 95% CI, 0.20-0.50) and sotrovimab (RR, 0.60; 95% CI, 0.37-1.00) were associated with reduced hospitalization or death compared with no mAb treatment. In the clinical trial, 2454 patients were randomized to receive casirivimab-imdevimab and 1104 patients were randomized to receive sotrovimab. The median (IQR) hospital-free days were 28 (28-28) for both mAb treatments, the 28-day mortality rate was less than 1% (n = 12) for casirivimab-imdevimab and less than 1% (n = 7) for sotrovimab, and the hospitalization rate by day 28 was 12% (n = 291) for casirivimab-imdevimab and 13% (n = 140) for sotrovimab. Compared with patients who received casirivimab-imdevimab, those who received sotrovimab had a median adjusted OR for hospital-free days of 0.88 (95% credible interval, 0.70-1.11). This OR yielded 86% probability of inferiority for sotrovimab vs casirivimab-imdevimab and 79% probability of equivalence. Conclusions and Relevance: In this propensity score-matched cohort study and randomized comparative effectiveness trial, the effectiveness of casirivimab-imdevimab and sotrovimab against the Delta variant was similar, although the prespecified criteria for statistical inferiority or equivalence were not met. Both mAb treatments were associated with a reduced risk of hospitalization or death in nonhospitalized patients with mild to moderate COVID-19 caused by the Delta variant. Trial Registration: ClinicalTrials.gov Identifier: NCT04790786.