Distinct dermatomyositis populations are detected with different autoantibody assay platforms.

OBJECTIVES: To compare autoantibody-defined dermatomyositis sub-populations using immunoprecipitation-based assays, a commercially available line immunoblot assay and alternate commercial ELISA assays. METHODS: Banked plasma from 261 carefully phenotyped dermatomyositis patients was studied. Immunoprecipitation-based assays were used to detect antibodies against Mi2, TIF1-γ MDA5, NXP2, SAE1 and PM-Scl, while anti-Jo1 antibodies were assayed using ELISA. These data were compared with that obtained using a commercial line immunoblot, and, additionally, for Mi2, TIF1-γ, MDA5, commercially available ELISA kits. Test agreement was measured using Cohen's kappa statistic, and phenotypic differences between differentially identified groups are described. RESULTS: Line immunoblot, immunoprecipitation, and ELISA detected increasingly larger nested pools of anti-TIF1-γ samples, with increasing frequency of concurrent anti-Mi2 reactivity and decreasing incidence of malignancy. Line immunoblot and immunoprecipitation showed fair concordance for identifying anti-NXP2 antibodies (Cohen's kappa=0.71) but very good agreement for identifying antibodies against Mi2, MDA5, and SAE1 (Cohen's κ=0.9, 0.94, 0.88, respectively). Anti-PM-Scl results showed moderate agreement (Cohen's κ=0.48) between immunoblot and immunoprecipitation. CONCLUSIONS: Our results demonstrate that for some specificities, especially anti-TIF1-γ, antibody results obtained using different assay platforms vary, and identify significantly different patient populations. These findings highlight the need for standard adoption of carefully validated platforms to detect dermatomyositis autoantibodies.

A Quantitative Source-to-Outcome Case Study To Demonstrate the Integration of Human Health and Ecological End Points Using the Aggregate Exposure Pathway and Adverse Outcome Pathway Frameworks.

Exposure to environmental contaminants can lead to adverse outcomes in both human and nonhuman receptors. The Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) frameworks can mechanistically inform cumulative risk assessment for human health and ecological end points by linking together environmental transport and transformation, external exposure, toxicokinetics, and toxicodynamics. This work presents a case study of a hypothetical contaminated site to demonstrate a quantitative approach for implementing the AEP framework and linking this framework to AOPs. We construct an AEP transport and transformation model and then quantify external exposure pathways for humans, fishes, and small herbivorous mammals at the hypothetical site. A Monte Carlo approach was used to address parameter variability. Source apportionment was quantified for each species, and published pharmacokinetic models were used to estimate internal target site exposure from external exposures. Published dose-response data for a multispecies AOP network were used to interpret AEP results in the context of species-specific effects. This work demonstrates (1) the construction, analysis, and application of a quantitative AEP model, (2) the utility of AEPs for organizing mechanistic exposure data and highlighting data gaps, and (3) the advantages provided by a source-to-outcome construct for leveraging exposure data and to aid transparency regarding assumptions.

A Case Study Application of the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) Frameworks to Facilitate the Integration of Human Health and Ecological End Points for Cumulative Risk Assessment (CRA).

Cumulative risk assessment (CRA) methods promote the use of a conceptual site model (CSM) to apportion exposures and integrate risk from multiple stressors. While CSMs may encompass multiple species, evaluating end points across taxa can be challenging due to data availability and physiological differences among organisms. Adverse outcome pathways (AOPs) describe biological mechanisms leading to adverse outcomes (AOs) by assembling causal pathways with measurable intermediate steps termed key events (KEs), thereby providing a framework for integrating data across species. In this work, we used a case study focused on the perchlorate anion (ClO4-) to highlight the value of the AOP framework for cross-species data integration. Computational models and dose-response data were used to evaluate the effects of ClO4- in 12 species and revealed a dose-response concordance across KEs and taxa. The aggregate exposure pathway (AEP) tracks stressors from sources to the exposures and serves as a complement to the AOP. We discuss how the combined AEP-AOP construct helps to maximize the use of existing data and advances CRA by (1) organizing toxicity and exposure data, (2) providing a mechanistic framework of KEs for integrating data across human health and ecological end points, (3) facilitating cross-species dose-response evaluation, and (4) highlighting data gaps and technical limitations.

Prevention of colonization and infection by Klebsiella pneumoniae carbapenemase-producing enterobacteriaceae in long-term acute-care hospitals.

BACKGROUND: Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae (hereafter "KPC") are an increasing threat to healthcare institutions. Long-term acute-care hospitals (LTACHs) have especially high prevalence of KPC. METHODS: Using a stepped-wedge design, we tested whether a bundled intervention (screening patients for KPC rectal colonization upon admission and every other week; contact isolation and geographic separation of KPC-positive patients in ward cohorts or single rooms; bathing all patients daily with chlorhexidine gluconate; and healthcare-worker education and adherence monitoring) would reduce colonization and infection due to KPC in 4 LTACHs with high endemic KPC prevalence. The study was conducted between 1 February 2010 and 30 June 2013; 3894 patients were enrolled during the preintervention period (lasting from 16 to 29 months), and 2951 patients were enrolled during the intervention period (lasting from 12 to 19 months). RESULTS: KPC colonization prevalence was stable during preintervention (average, 45.8%; 95% confidence interval [CI], 42.1%-49.5%), declined early during intervention, then reached a plateau (34.3%; 95% CI, 32.4%-36.2%; P<.001 for exponential decline). During intervention, KPC admission prevalence remained high (average, 20.6%, 95% CI, 19.1%-22.3%). The incidence rate of KPC colonization fell during intervention, from 4 to 2 acquisitions per 100 patient-weeks (P=.004 for linear decline). Compared to preintervention, average rates of clinical outcomes declined during intervention: KPC in any clinical culture (3.7 to 2.5/1000 patient-days; P=.001), KPC bacteremia (0.9 to 0.4/1000 patient-days; P=.008), all-cause bacteremia (11.2 to 7.6/1000 patient-days; P=.006) and blood culture contamination (4.9 to 2.3/1000 patient-days; P=.03). CONCLUSIONS: A bundled intervention was associated with clinically important and statistically significant reductions in KPC colonization, KPC infection, all-cause bacteremia, and blood culture contamination in a high-risk LTACH population.

Anti-Peptidylarginine Deiminase 4 Autoantibodies and Disease Duration as Predictors of Treatment Response in Rheumatoid Arthritis.

BACKGROUND: Given that autoantibodies to peptidylarginine deiminase 4 (PAD4) are associated with erosive disease in established rheumatoid arthritis (RA), this study was conducted to compare the clinical and prognostic use of anti-PAD4 antibodies in patients with early and established RA. METHODS: Sera from patients with early (duration <2 years; n = 422) or established (duration ≥2 years; n = 359) RA from two randomized clinical trials of tofacitinib ± methotrexate compared with adalimumab + MTX or MTX alone were evaluated for the presence of anti-PAD4 and anti-PAD3/4 antibodies at baseline and posttreatment time points. Summary statistics were calculated for demographic, clinical, and serological characteristics, and generalized estimating equations were used to model clinical outcomes by disease duration according to anti-PAD4 status. RESULTS: Anti-PAD4 antibodies were present in 22% and 40% of patients with early and established RA, respectively, stable following treatment, and associated with baseline joint damage only in established RA. In early RA, baseline anti-PAD4 antibodies were associated with a greater improvement in disease activity score 28-joint count using C-reactive protein levels after treatment compared with individuals with negative anti-PAD4 (P = 0.049). Tofacitinib ± MTX was more broadly efficacious than MTX alone at improving clinical outcomes in early and established RA, irrespective of anti-PAD4 status (P < 0.05 for all), whereas adalimumab + MTX exhibited differential benefits in achieving disease activity score remission in early RA (P = 0.036) and American College of Rheumatology 20 responses in established RA (P = 0.002). CONCLUSION: Differences in prevalence, clinical associations, and treatment-response outcomes according to anti-PAD4 antibody status in early and established RA suggests the existence of a therapeutic window to prevent the accumulation of irreversible joint damage in early patients with RA with anti-PAD4 antibodies.

The Association Between Social Determinants of Health, Risk Factors, Job Performance, and Health Care Costs in an Employed Population.

OBJECTIVE: The aim of the study is to compare employees of a US school district based on their social determinants of health (SDoH). Methods: Employees ( N = 5006) were categorized into low-, medium-, or high-need SDoH tiers. Of them, n = 2469 also participated in a health risk appraisal in 2019. Subjects' average health care costs, health risk factors, and self-rated job performance were compared by SDoH tier and race. Results: Significant differences were observed among the SDoH comparison groups regarding age, gender, race, and marital status. SDoH was associated with health care costs, number of health risk factors, and self-rated job performance differently for Black and White employees. Conclusions: SDoH are complex and multifaceted. Black employees in the high-need SDoH group had higher average health care costs, lower self-rated job performance, and more average health risk factors than subjects in the lower need tiers.

The importance of long-term acute care hospitals in the regional epidemiology of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae.

BACKGROUND: In the United States, Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae are increasingly detected in clinical infections; however, the colonization burden of these organisms among short-stay and long-term acute care hospitals is unknown. METHODS: Short-stay acute care hospitals with adult intensive care units (ICUs) in the city of Chicago were recruited for 2 cross-sectional single-day point prevalence surveys (survey 1, July 2010-January 2011; survey 2, January-July 2011). In addition, all long-term acute care hospitals (LTACHs) in the Chicago region (Cook County) were recruited for a single-day point prevalence survey during January-May 2011. Swab specimens were collected from rectal, inguinal, or urine sites and tested for Enterobacteriaceae carrying blaKPC. RESULTS: We surveyed 24 of 25 eligible short-stay acute care hospitals and 7 of 7 eligible LTACHs. Among LTACHs, 30.4% (119 of 391) of patients were colonized with KPC-producing Enterobacteriaceae, compared to 3.3% (30 of 910) of short-stay hospital ICU patients (prevalence ratio, 9.2; 95% confidence interval, 6.3-13.5). All surveyed LTACHs had patients harboring KPC (prevalence range, 10%-54%), versus 15 of 24 short-stay hospitals (prevalence range, 0%-29%). Several patient-level covariates present at the time of survey-LTACH facility type, mechanical ventilation, and length of stay-were independent risk factors for KPC-producing Enterobacteriaceae colonization. CONCLUSIONS: We identified high colonization prevalence of KPC-producing Enterobacteriaceae among patients in LTACHs. Patients with chronic medical care needs in long-term care facilities may play an important role in the spread of these extremely drug-resistant pathogens.

Migraine Headache in an Employed Population: Demographics, Health Risks, Pharmaceutical Utilization, and Productivity Loss.

OBJECTIVE: Demographics, health risks, pharmaceutical utilization, and other characteristics of adults with and without migraine who were employed by a school district in the southern United States were compared. METHODS: A total of 4528 employees completed a health risk appraisal. A diagnosis of migraine was reported by 11%. Employees with and without migraine were compared on several measures. RESULTS: Demographic and health risk differences were observed among the comparison groups. One-fifth of migraineurs had a prescription for an opioid, which was associated with very high average annual health care costs ($17,791) compared with migraineurs without opioid ($3907). CONCLUSIONS: Migraine is common in the workforce. Employers may want to educate employees with migraine about evidence-based treatments. Benefit plan design should be consistent with current accepted treatment guidelines for opioid use.

Application of an Accessible Interface for Pharmacokinetic Modeling and In Vitro to In Vivo Extrapolation.

Regulatory toxicology testing has traditionally relied on in vivo methods to inform decision-making. However, scientific, practical, and ethical considerations have led to an increased interest in the use of in vitro and in silico methods to fill data gaps. While in vitro experiments have the advantage of rapid application across large chemical sets, interpretation of data coming from these non-animal methods can be challenging due to the mechanistic nature of many assays. In vitro to in vivo extrapolation (IVIVE) has emerged as a computational tool to help facilitate this task. Specifically, IVIVE uses physiologically based pharmacokinetic (PBPK) models to estimate tissue-level chemical concentrations based on various dosing parameters. This approach is used to estimate the administered dose needed to achieve in vitro bioactivity concentrations within the body. IVIVE results can be useful to inform on metrics such as margin of exposure or to prioritize potential chemicals of concern, but the PBPK models used in this approach have extensive data requirements. Thus, access to input parameters, as well as the technical requirements of applying and interpreting models, has limited the use of IVIVE as a routine part of in vitro testing. As interest in using non-animal methods for regulatory and research contexts continues to grow, our perspective is that access to computational support tools for PBPK modeling and IVIVE will be essential for facilitating broader application and acceptance of these techniques, as well as for encouraging the most scientifically sound interpretation of in vitro results. We highlight recent developments in two open-access computational support tools for PBPK modeling and IVIVE accessible via the Integrated Chemical Environment (https://ice.ntp.niehs.nih.gov/), demonstrate the types of insights these tools can provide, and discuss how these analyses may inform in vitro-based decision making.

Results of a Virtual Migraine Education Program in an Employed Population.

OBJECTIVE: Migraine affects about 15% of the world's population and disproportionately affects adults who are working age. It is associated with higher healthcare costs, absenteeism, and lost productivity. A metropolitan school district in the southern United States offered a virtual migraine education program to their teaching employees. METHODS: Seventy-nine employees completed a migraine questionnaire at both baseline and 3-month follow-up. The program included webinars, educational videos, and other intranet-based resources. RESULTS: Results found that program participants reported a significant improvement in the frequency and severity of migraine as well as a reduction in lost on-the-job productivity. A majority of participants reported making positive changes to reduce triggers and better manage stress. CONCLUSIONS: An employer-offered migraine education program distributed virtually to remote workers has the potential to improve migraine symptoms and treatment as well as productivity.

IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function.

BackgroundSome clinical features of severe COVID-19 represent blood vessel damage induced by activation of host immune responses initiated by the coronavirus SARS-CoV-2. We hypothesized autoantibodies against angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor expressed on vascular endothelium, are generated during COVID-19 and are of mechanistic importance.MethodsIn an opportunity sample of 118 COVID-19 inpatients, autoantibodies recognizing ACE2 were detected by ELISA. Binding properties of anti-ACE2 IgM were analyzed via biolayer interferometry. Effects of anti-ACE2 IgM on complement activation and endothelial function were demonstrated in a tissue-engineered pulmonary microvessel model.ResultsAnti-ACE2 IgM (not IgG) autoantibodies were associated with severe COVID-19 and found in 18/66 (27.2%) patients with severe disease compared with 2/52 (3.8%) of patients with moderate disease (OR 9.38, 95% CI 2.38-42.0; P = 0.0009). Anti-ACE2 IgM autoantibodies were rare (2/50) in non-COVID-19 ventilated patients with acute respiratory distress syndrome. Unexpectedly, ACE2-reactive IgM autoantibodies in COVID-19 did not undergo class-switching to IgG and had apparent KD values of 5.6-21.7 nM, indicating they are T cell independent. Anti-ACE2 IgMs activated complement and initiated complement-binding and functional changes in endothelial cells in microvessels, suggesting they contribute to the angiocentric pathology of COVID-19.ConclusionWe identify anti-ACE2 IgM as a mechanism-based biomarker strongly associated with severe clinical outcomes in SARS-CoV-2 infection, which has therapeutic implications.FUNDINGBill & Melinda Gates Foundation, Gates Philanthropy Partners, Donald B. and Dorothy L. Stabler Foundation, and Jerome L. Greene Foundation; NIH R01 AR073208, R01 AR069569, Institutional Research and Academic Career Development Award (5K12GM123914-03), National Heart, Lung, and Blood Institute R21HL145216, and Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Science Foundation Graduate Research Fellowship (DGE1746891).

Evaluation of Inhalation Exposures and Potential Health Impacts of Ingredient Mixtures Using in vitro to in vivo Extrapolation.

In vitro methods offer opportunities to provide mechanistic insight into bioactivity as well as human-relevant toxicological assessments compared to animal testing. One of the challenges for this task is putting in vitro bioactivity data in an in vivo exposure context, for which in vitro to in vivo extrapolation (IVIVE) translates in vitro bioactivity to clinically relevant exposure metrics using reverse dosimetry. This study applies an IVIVE approach to the toxicity assessment of ingredients and their mixtures in e-cigarette (EC) aerosols as a case study. Reported in vitro cytotoxicity data of EC aerosols, as well as in vitro high-throughput screening (HTS) data for individual ingredients in EC liquids (e-liquids) are used. Open-source physiologically based pharmacokinetic (PBPK) models are used to calculate the plasma concentrations of individual ingredients, followed by reverse dosimetry to estimate the human equivalent administered doses (EADs) needed to obtain these plasma concentrations for the total e-liquids. Three approaches (single actor approach, additive effect approach, and outcome-oriented ingredient integration approach) are used to predict EADs of e-liquids considering differential contributions to the bioactivity from the ingredients (humectant carriers [propylene glycol and glycerol], flavors, benzoic acid, and nicotine). The results identified critical factors for the EAD estimation, including the ingredients of the mixture considered to be bioactive, in vitro assay selection, and the data integration approach for mixtures. Further, we introduced the outcome-oriented ingredient integration approach to consider e-liquid ingredients that may lead to a common toxicity outcome (e.g., cytotoxicity), facilitating a quantitative evaluation of in vitro toxicity data in support of human risk assessment.

Performance of the quick COVID-19 severity index and the Brescia-COVID respiratory severity scale in hospitalized patients with COVID-19 in a community hospital setting.

OBJECTIVE: To evaluate the performance of the Quick COVID-19 Severity Index (qCSI) and the Brescia-COVID Respiratory Severity Scale (BCRSS) in predicting intensive care unit (ICU) admissions and in-hospital mortality in patients with coronavirus disease 2019 (COVID-19) pneumonia. METHODS: This was a retrospective cohort study of 313 consecutive hospitalized adult patients (18 years or older) with confirmed COVID-19. The area under the receiver operating characteristic curve (AUC) was used to assess the discriminatory power of the qCSI score and BCRSS prediction rule compared to the CURB-65 score for predicting mortality and intensive care unit admission. RESULTS: The overall in-hospital fatality rate was 32.3%, and the ICU admission rate was 31.3%. The CURB-65 score had the highest numerical AUC to predict in-hospital mortality (AUC 0.781) compared to the qCSI score (AUC 0.711) and the BCRSS prediction rule (AUC 0.663). For ICU admission, the qCSI score had the highest numerical AUC (AUC 0.761) compared to the BCRSS prediction rule (AUC 0.735) and the CURB-65 score (AUC 0.629). CONCLUSIONS: The CURB-65 and qCSI scoring systems showed a good performance for predicting in-hospital mortality. The qCSI score and the BCRSS prediction rule showed a good performance for predicting ICU admission.

Clinical Characteristics and Risk Factors for Death of Hospitalized Patients With COVID-19 in a Community Hospital: A Retrospective Cohort Study.

OBJECTIVE: To describe the clinical characteristics, outcomes, and risk factors for death of patients with coronavirus disease 2019 (COVID-19) in a community hospital setting. PATIENTS AND METHODS: This single-center retrospective cohort study included 313 adult patients with laboratory-confirmed COVID-19 admitted to a community hospital in Cook County, Illinois, from March 1, 2020, to May 25, 2020. Demographics, medical history, underlying comorbidities, symptoms, signs, laboratory findings, imaging studies, management, and progression to discharge or death data were collected and analyzed. RESULTS: Of 313 patients, the median age was 68 years (interquartile range, 59.0-78.5 years; range, 19-98 years), 182 (58.1%) were male, 119 (38%) were white, and 194 (62%) were admitted from a long-term care facility (LTCF). As of May 25, 2020, there were 212 (67.7%) survivors identified, whereas 101 (32.3%) nonsurvivors were identified. Multivariable Cox regression analysis showed increasing hazards of inpatient death associated with older age (hazard ratio [HR] 1.02; 95% CI, 1.01-1.04), LTCF residence (HR, 3.23; 95% CI, 1.68-6.20), and quick Sequential Organ Failure Assessment scores (HR, 2.59; 95% CI, 1.78-3.76). CONCLUSION: In this single-center retrospective cohort study of 313 adult patients hospitalized with COVID-19 illness in a community hospital in Cook County, Illinois, older patients, LTCF residents, and patients with high quick Sequential Organ Failure Assessment scores were found to have worse clinical outcomes and increased risk of death.

Early Tocilizumab Dosing Is Associated With Improved Survival in Critically Ill Patients Infected With Severe Acute Respiratory Syndrome Coronavirus-2.

To identify the most efficacious timing for tocilizumab administration in critically ill patients infected with severe acute respiratory syndrome coronavirus-2. DESIGN: Observational multicenter cohort study. SETTING: A total of 23 acute care hospitals in four states. PATIENTS: One-hundred eighteen patients admitted between March 13, 2020, and April 16, 2020. Eighty-one patients received tocilizumab, and 37 were untreated and served as a control group. MEASUREMENTS AND MAIN RESULTS: The main outcome was mortality and was analyzed by timing of tocilizumab dosing. Early dosing was defined as a tocilizumab dose administered prior to or within 1 day of intubation. Late dosing was defined as a dose administered greater than 1 day after intubation. A control group that was treated only with standard of care, and without tocilizumab, was used for comparison. Early tocilizumab therapy was associated with a statistically significant decrease in mortality as compared to patients who were untreated (p = 0.003). Dosing tocilizumab late was associated with an increased mortality compared with the untreated group (p = 0.006). CONCLUSIONS: Early tocilizumab administration was associated with decreased mortality in critically ill severe acute respiratory syndrome coronavirus-2 patients, but a potential detriment was suggested by dosing later in a patient's course.

A North American Cohort of Anti-SAE Dermatomyositis: Clinical Phenotype, Testing, and Review of Cases.

OBJECTIVE: Antibodies against the small ubiquitin-like modifier (SUMO) activating enzyme (SAE) are one of the rarer specificities associated with dermatomyositis (DM). The purpose of this study is to describe the clinical characteristics of patients with anti-SAE autoantibodies in a North American cohort and to ascertain cancer prevalence. We also describe the performance characteristics of the line blotting (Euroimmun) method for antibody detection compared with an immunoprecipitation-based assay. METHODS: Sera from 2127 patients suspected of having myositis were assayed for myositis-specific autoantibodies using the Euroimmun platform. Those positive for SAE autoantibodies were assayed by a second method (immunoprecipitation) for confirmation. Only those cases positive by both methods were taken as definite cases of anti-SAE-positive DM. Chart reviews of these patients were completed to obtain information on clinical characteristics, cancer history, and treatment. RESULTS: Forty-three of 2127 sera were anti-SAE autoantibody positive by Euroimmun (≥15 units, +); of these, only 19 were confirmed positive by immunoprecipitation. All 19 cases had skin involvement and varying presentations of muscle, lung, and joint disease. Cancer occurred coincident with DM in two patients, and cancers were detected more than 5 years from symptom onset in three patients. In a population of suspected inflammatory myositis, a higher cutoff on line blot testing (≥36 units, ++) yielded better agreement with immunoprecipitation methods. CONCLUSION: SAE autoantibodies associate with a clinical phenotype of DM, which most commonly presents with a rash first, followed by muscle involvement and varying extramuscular involvement. As coincident cancer was seen in anti-SAE-positive DM, judicious malignancy screening may be warranted.

Tocilizumab as a Therapeutic Agent for Critically Ill Patients Infected with SARS-CoV-2.

Tocilizumab is an IL-6 receptor antagonist with the ability to suppress the cytokine storm in critically ill patients infected with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). We evaluated patients treated with tocilizumab for a SARS-CoV-2 infection who were admitted between March 13, 2020, and April 16, 2020. This was a multicenter study with data collected by chart review both retrospectively and concurrently. Parameters evaluated included age, sex, race, use of mechanical ventilation (MV), usage of steroids and vasopressors, inflammatory markers, and comorbidities. Early dosing was defined as a tocilizumab dose administered prior to or within 1 day of intubation. Late dosing was defined as a dose administered > 1 day after intubation. In the absence of MV, the timing of the dose was related to the patient's date of admission only. We evaluated 145 patients. The average age was 58.1 years, 64% were men, 68.3% had comorbidities, and 60% received steroid therapy. Disposition of patients was 48.3% discharged and 29.3% died, of which 43.9% were African American. MV was required in 55.9%, of which 34.5% died. Avoidance of MV (P = 0.002) and increased survival (P < 0.001) was statistically associated with early dosing. Tocilizumab therapy was effective at decreasing mortality and should be instituted early in the management of critically ill patients with coronavirus disease 2019) COVID-19).

A Real-World Assessment of Clinical Outcomes and Safety of Eravacycline: A Novel Fluorocycline.

BACKGROUND: Eravacycline is a novel fluorocycline approved for treatment of intraabdominal infections, with a broad spectrum of activity against a range of pathogens including multidrug-resistant species, including ESBL- or KPC-producing isolates. It is approved for twice-daily dosing with no need for adjustment in renal dysfunction. In the concomitant administration with CYP 3A4-inducing drugs, eravacycline dosing should be modified. OBJECTIVE: To evaluate the efficacy and safety of eravacycline in a range of infections such as intraabdominal infections, pneumonia and diabetic foot infections in seriously ill patients. METHODS: A retrospective observational cohort study using electronic patient records of 50 consecutive patients administered eravacycline during inpatient acute care admission or as part of outpatient antibiotic therapy (OPAT). RESULTS: Therapy of 1.5 mg/kg q24h was initiated in the hospital in most patients, although some of the less sick were managed in the office or OPAT setting. All patients concluded their management outside of the hospital. Of the 50 patients, 47 (94%) achieved clinical resolution of their infection and 3 (6%) clinical failures occurred. Only three (6%) patients did not have comorbidities, three had a single comorbidity (6%), and the majority (88%) of patients had two or more comorbidities. Most common infections were intraabdominal (36%), pneumonia (18%), diabetic foot (12%), spontaneous bacterial peritonitis (8%) and empyema (8%). Almost half of infections had more than one pathogen isolated, and resistant isolates were frequent. The drug was well tolerated with only two reports of nausea, which did not result in treatment discontinuation, and in 30 days of post-eravacycline therapy only one case of Clostridiodes difficile. CONCLUSIONS: In this real-world setting, eravacycline demonstrated a similar high level of clinical efficacy as seen in clinical trials, 94%, in a variety of infections, including against multidrug-resistant bacteria, and was well tolerated.

IgM autoantibodies recognizing ACE2 are associated with severe COVID-19.

SARS-CoV-2 infection induces severe disease in a subpopulation of patients, but the underlying mechanisms remain unclear. We demonstrate robust IgM autoantibodies that recognize angiotensin converting enzyme-2 (ACE2) in 18/66 (27%) patients with severe COVID-19, which are rare (2/52; 3.8%) in hospitalized patients who are not ventilated. The antibodies do not undergo class-switching to IgG, suggesting a T-independent antibody response. Purified IgM from anti-ACE2 patients activates complement. Pathological analysis of lung obtained at autopsy shows endothelial cell staining for IgM in blood vessels in some patients. We propose that vascular endothelial ACE2 expression focuses the pathogenic effects of these autoantibodies on blood vessels, and contributes to the angiocentric pathology observed in some severe COVID-19 patients. These findings may have predictive and therapeutic implications.