Mathematical modeling of liver injury and dysfunction after acetaminophen overdose: early discrimination between survival and death.

UNLABELLED: Acetaminophen (APAP) is the leading cause of acute liver injury in the developed world. Timely administration of N-acetylcysteine (N-Ac) prevents the progression of serious liver injury and disease, whereas failure to administer N-Ac within a critical time frame allows disease progression and in the most severe cases may result in liver failure or death. In this situation, liver transplantation may be the only life-saving measure. Thus, the outcome of an APAP overdose depends on the size of the overdose and the time to first administration of N-Ac. We developed a system of differential equations to describe acute liver injury due to APAP overdose. The Model for Acetaminophen-induced Liver Damage (MALD) uses a patient's aspartate aminotransferase (AST), alanine aminotransferase (ALT), and international normalized ratio (INR) measurements on admission to estimate overdose amount, time elapsed since overdose, and outcome. The mathematical model was then tested on 53 patients from the University of Utah. With the addition of serum creatinine, eventual death was predicted with 100% sensitivity, 91% specificity, 67% positive predictive value (PPV), and 100% negative predictive value (NPV) in this retrospective study. Using only initial AST, ALT, and INR measurements, the model accurately predicted subsequent laboratory values for the majority of individual patients. This is the first dynamical rather than statistical approach to determine poor prognosis in patients with life-threatening liver disease due to APAP overdose. CONCLUSION: MALD provides a method to estimate overdose amount, time elapsed since overdose, and outcome from patient laboratory values commonly available on admission in cases of acute liver failure due to APAP overdose and should be validated in multicenter prospective evaluation.

Prospectively Assessed Long-Term Outcomes of Patients with E-Cigarette- or Vaping-associated Lung Injury.

Rationale: E-cigarette- or vaping-associated lung injury (EVALI) was first identified in 2019. The long-term respiratory, cognitive, mood disorder, and vaping behavior outcomes of patients with EVALI remain unknown. Objectives: To determine the long-term respiratory, cognitive, mood disorder, and vaping behavior outcomes of patients with EVALI. Methods: We prospectively enrolled patients with EVALI from two health systems. We assessed outcomes at 1 year after onset of EVALI using validated instruments measuring cognitive function, depression, anxiety, post-traumatic stress, respiratory disability, coronavirus disease (COVID-19) infection, pulmonary function, and vaping behaviors. We used multivariable regression to identify risk factors of post-EVALI vaping behaviors and to identify whether admission to the intensive care unit (ICU) was associated with cognitive, respiratory, or mood symptoms. Results: Seventy-three patients completed 12-month follow-up. Most patients were male (66.7%), young (mean age, 31 ± 11 yr), and White (85%) and did not need admission to the ICU (59%). At 12 months, 39% (25 of 64) had cognitive impairment, whereas 48% (30 of 62) reported respiratory limitations. Mood disorders were common, with 59% (38 of 64) reporting anxiety and/or depression and 62% (39 of 63) having post-traumatic stress. Four (6.4%) of 64 reported a history of COVID-19 infection. Despite the history of EVALI, many people continued to vape. Only 38% (24 of 64) reported quitting all vaping and smoking behaviors. Younger age was associated with reduced vaping behavior after EVALI (odds ratio, 0.93; P = 0.02). ICU admission was not associated with cognitive impairment, dyspnea, or mood symptoms. Conclusions: Patients with EVALI, despite their youth, commonly have significant long-term respiratory disability; cognitive impairment; symptoms of depression, anxiety, post-traumatic stress; and persistent vaping.

SARS-CoV-2 innate effector associations and viral load in early nasopharyngeal infection.

COVID-19 causes severe disease with poor outcomes. We tested the hypothesis that early SARS-CoV-2 viral infection disrupts innate immune responses. These changes may be important for understanding subsequent clinical outcomes. We obtained residual nasopharyngeal swab samples from individuals who requested COVID-19 testing for symptoms at drive-through COVID-19 clinical testing sites operated by the University of Utah. We applied multiplex immunoassays, real-time polymerase chain reaction assays and quantitative proteomics to 20 virus-positive and 20 virus-negative samples. ACE-2 transcripts increased with infection (OR =17.4, 95% CI [CI] =4.78-63.8) and increasing viral N1 protein transcript load (OR =1.16, CI =1.10-1.23). Transcripts for two interferons (IFN) were elevated, IFN-λ1 (OR =71, CI =7.07-713) and IFN-λ2 (OR =40.2, CI =3.86-419), and closely associated with viral N1 transcripts (OR =1.35, CI =1.23-1.49 and OR =1.33 CI =1.20-1.47, respectively). Only transcripts for IP-10 were increased among systemic inflammatory cytokines that we examined (OR =131, CI =1.01-2620). We found widespread discrepancies between transcription and translation. IFN proteins were unchanged or decreased in infected samples (IFN-γ OR =0.90 CI =0.33-0.79, IFN-λ2,3 OR =0.60 CI =0.48-0.74) suggesting viral-induced shut-off of host antiviral protein responses. However, proteins for IP-10 (OR =3.74 CI =2.07-6.77) and several interferon-stimulated genes (ISG) increased with viral load (BST-1 OR =25.1, CI =3.33-188; IFIT1 OR =19.5, CI =4.25-89.2; IFIT3 OR =245, CI =15-4020; MX-1 OR =3.33, CI =1.44-7.70). Older age was associated with substantial modifications of some effects. Ambulatory symptomatic patients had an innate immune response with SARS-CoV-2 infection characterized by elevated IFN, proinflammatory cytokine and ISG transcripts, but there is evidence of a viral-induced host shut-off of antiviral responses. Our findings may characterize the disrupted immune landscape common in patients with early disease.

SARS-CoV-2 Innate Effector Associations and Viral Load in Early Nasopharyngeal Infection.

To examine innate immune responses in early SARS-CoV-2 infection that may change clinical outcomes, we compared nasopharyngeal swab data from 20 virus-positive and 20 virus-negative individuals. Multiple innate immune-related and ACE-2 transcripts increased with infection and were strongly associated with increasing viral load. We found widespread discrepancies between transcription and translation. Interferon proteins were unchanged or decreased in infected samples suggesting virally-induced shut-off of host anti-viral protein responses. However, IP-10 and several interferon-stimulated gene proteins increased with viral load. Older age was associated with modifications of some effects. Our findings may characterize the disrupted immune landscape of early disease.

Validation of a single-stage submaximal treadmill walking test.

The single-stage treadmill walking test of Ebbeling et al. is commonly used to predict maximal oxygen consumption (.VO(2max)) from a submaximal effort between 50% and 70% of the participant's age-predicted maximum heart rate. The purpose of this study was to determine if this submaximal test correctly predicts .VO(2max) at the low (50% of maximum heart rate) and high (70% of maximum heart rate) ends of the specified heart rate range for males and females aged 18 - 55 years. Each of the 34 participants completed one low-intensity and one high-intensity trial. The two trials resulted in significantly different estimates of .VO(2max) (low-intensity trial: mean 40.5 ml . kg(-1) . min(-1), s = 9.3; high-intensity trial: 47.5 ml . kg(-1) . min(-1), s = 8.8; P < 0.01). A subset of 22 participants concluded their second trial with a .VO(2max) test (mean 47.9 ml . kg(-1) . min(-1), s = 8.9). The low-intensity trial underestimated (mean difference = -3.5 ml . kg(-1) . min(-1); 95% CI = -6.4 to -0.6 ml . kg(-1) . min(-1); P = 0.02) and the high-intensity trial overestimated (mean difference = 3.5 ml . kg(-1) . min(-1); 95% CI = 1.1 to 6.0 ml . kg(-1) . min(-1); P = 0.01) the measured .VO(2max). The predictive validity of Ebbeling and colleagues' single-stage submaximal treadmill walking test is diminished when performed at the extremes of the specified heart rate range.