A Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Prediction Model From Standard Laboratory Tests.

BACKGROUND: With the limited availability of testing for the presence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and concerns surrounding the accuracy of existing methods, other means of identifying patients are urgently needed. Previous studies showing a correlation between certain laboratory tests and diagnosis suggest an alternative method based on an ensemble of tests. METHODS: We have trained a machine learning model to analyze the correlation between SARS-CoV-2 test results and 20 routine laboratory tests collected within a 2-day period around the SARS-CoV-2 test date. We used the model to compare SARS-CoV-2 positive and negative patients. RESULTS: In a cohort of 75 991 veteran inpatients and outpatients who tested for SARS-CoV-2 in the months of March through July 2020, 7335 of whom were positive by reverse transcription polymerase chain reaction (RT-PCR) or antigen testing, and who had at least 15 of 20 lab results within the window period, our model predicted the results of the SARS-CoV-2 test with a specificity of 86.8%, a sensitivity of 82.4%, and an overall accuracy of 86.4% (with a 95% confidence interval of [86.0%, 86.9%]). CONCLUSIONS: Although molecular-based and antibody tests remain the reference standard method for confirming a SARS-CoV-2 diagnosis, their clinical sensitivity is not well known. The model described herein may provide a complementary method of determining SARS-CoV-2 infection status, based on a fully independent set of indicators, that can help confirm results from other tests as well as identify positive cases missed by molecular testing.

Modulation of drug-linker design to enhance in vivo potency of homogeneous antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a promising class of anticancer agents which have undergone substantial development over the past decade and are now achieving clinical success. The development of novel site-specific conjugation technologies enables the systematic study of architectural features within the antibody conjugated drug linker that may affect overall therapeutic indices. Here we describe the results of a systematic study investigating the impact of drug-linker design on the in vivo properties of a series of homogeneous ADCs with a conserved site of conjugation, a monodisperse drug loading, a lysosomal release functionality and monomethyl auristatin E as a cytotoxic payload. The ADCs, which differed only in the relative position of certain drug-linker elements within the reagent, were first evaluated in vitro using anti-proliferation assays and in vivo using mouse pharmacokinetics (PK). Regardless of the position of a discrete polymer unit, the ADCs showed comparable in vitro potencies, but the in vivo PK properties varied widely. The best performing drug-linker design was further used to prepare ADCs with different drug loadings of 4, 6 and 8 drugs per antibody and compared to Adcetris® in a Karpas-299 mouse xenograft model. The most efficacious ADC showed complete tumor regression and 10/10 tumor free survivors at a single 0.5mg/kg dose. This study revealed drug-linker design as a critical parameter in ADC development, with the potential to enhance ADC in vivo potency for producing more efficacious ADCs.

Atom-transfer cyclization with CuSO4/KBH4: a formal "activators generated by electron transfer" process also applicable to atom-transfer polymerization.

The 4-exo and 5-exo-trig atom-transfer cyclizations of 1, 8a-e, 9, 12, and 13 can be mediated with as little as 0.05 mol % of Cu(TPMA)SO(4)·5H(2)O in the presence of 2.5 mol % of borohydride salts in 10 min at room temperature in air. This formal "activators generated by electron transfer" (AGET) procedure utilizes a cheap and oxidatively stable copper source (CuSO(4)·5H(2)O) and can be carried out in environmentally benign solvents (EtOH). It is possible to alter the product distribution in the 5-endo radical-polar crossover reactions of 10a,b and 11 by tailoring the amount of borohydride. Cyclization onto alkynes 14 and 15 is also possible in only 20 min. Controlled radical polymerization of styrene, with increased rates over conventional atom-transfer radical polymerization (ATRP), can be carried out in a controlled fashion (Mn, PDI) using either CuBr or CuSO(4)·5H(2)O and Bu(4)NBH(4).

Early lactate clearance is associated with biomarkers of inflammation, coagulation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock.

BACKGROUND: Lactate clearance, a surrogate for the magnitude and duration of global tissue hypoxia, is used diagnostically, therapeutically and prognostically. This study examined the association of early lactate clearance with selected inflammatory, coagulation, apoptosis response biomarkers and organ dysfunction scores in severe sepsis and septic shock. METHODS: Measurements of serum arterial lactate, biomarkers (interleukin-1 receptor antagonist, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-alpha, intercellular adhesion molecule-1, high mobility group box-1, D-Dimer and caspase-3), and organ dysfunction scores (Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II, Multiple Organ Dysfunction Score, and Sequential Organ Failure Assessment) were obtained in conjunction with a prospective, randomized study examining early goal-directed therapy in severe sepsis and septic shock patients presenting to the emergency department (ED). Lactate clearance was defined as the percent change in lactate levels after six hours from a baseline measurement in the ED. RESULTS: Two-hundred and twenty patients, age 65.0 +/- 17.1 years, were examined, with an overall lactate clearance of 35.5 +/- 43.1% and in-hospital mortality rate of 35.0%. Patients were divided into four quartiles of lactate clearance, -24.3 +/- 42.3, 30.1 +/- 7.5, 53.4 +/- 6.6, and 75.1 +/- 7.1%, respectively (p < 0.01). The mean levels of all biomarkers and organ dysfunction scores over 72 hours were significantly lower with higher lactate clearance quartiles (p < 0.01). There was a significant decreased in-hospital, 28-day, and 60-day mortality in the higher lactate clearance quartiles (p < 0.01). CONCLUSIONS: Early lactate clearance as a surrogate for the resolution of global tissue hypoxia is significantly associated with decreased levels of biomarkers, improvement in organ dysfunction and outcome in severe sepsis and septic shock.

Renal biopsy in lupus patients with low levels of proteinuria.

OBJECTIVE: Early and accurate detection of kidney involvement in systemic lupus erythematosus (SLE) improves outcomes. Renal biopsy is required for definitive diagnosis of lupus nephritis (LN). In the absence of acute renal failure (ARF), moderate levels of proteinuria (> 1000 mg/24 h) have been recommended by some to justify biopsy. We investigated whether patients with lower levels of proteinuria without ARF have significant renal disease and should be routinely biopsied. METHODS: We retrospectively evaluated 21 SLE patients with 24-h urine protein < 1000 mg who underwent kidney biopsies. Indications for biopsy included new-onset proteinuria, increasing proteinuria, or hematuria (> 5 red blood cells per high power field). No patient had ARF. RESULTS: Sixteen of 21 (77%) biopsies were diagnostic of LN: 3 class II, 10 class III (5 superimposed class V), 2 class IV (one superimposed class V), and one with class V. One patient had thrombotic microangiopathy. The remaining 4 (23%) patients had non-lupus renal disease. Thirteen patients with class III or greater LN required alterations in therapeutic regimen because of biopsy findings. Of 7 patients without hematuria at the time of biopsy, 4 (57%) had class III, IV, or V LN. One patient without hematuria and < 500 mg/24 h proteinuria had class III LN. CONCLUSION: We found significant renal involvement (Class III, IV, or V LN) in SLE patients with < 1000 mg proteinuria with or without hematuria. Our findings suggest that biopsy be strongly considered in this patient population.

Primary cardiac angiosarcoma: case report and review of the literature.

We report of a young man who was referred for evaluation of the right atrial mass. He had presented outside the hospital with shortness of breath. A transthoracic echocardiogram (TTE) done there showed a bright echodensity in the right atrium with moderate pericardial effusion. He was treated for presumed viral pericarditis. Pericardiocentesis showed a bloody effusion. Four weeks after this initial presentation, a repeat TTE was done to evaluate for recurrent pericardial effusion due to shortness of breath. The right atrial mass had increased in size and no effusion was noted. He was referred to us for further evaluation. The tumor was successfully resected during surgery, and the pathological examination revealed primary cardiac angiosarcoma. The case highlights the misdiagnosis in initial clinical presentation, current diagnostic modalities, and treatment options for cardiac angiosarcoma.

Mycophenolic acid concentrations in long-term heart transplant patients: relationship with calcineurin antagonists and acute rejection.

BACKGROUND: When used in conjunction with steroids and cyclosporin, mycophenolate mofetil (MMF) has been shown to significantly reduce mortality and incidence of rejection in the first year after heart transplantation. It also appears that in this early post-transplantation period, the monitoring of immunosuppressive therapies may be warranted. The current study was undertaken to determine if such monitoring is still useful more than 1 yr after heart transplantation. METHODS: Twenty-six patients who had survived the first year after orthotopic heart transplantation and had been on MMF therapy for more than 3 months were prospectively followed. At the time of their routine endomyocardial biopsy blood samples were taken to monitor immunosuppressive therapy. Most patients had two samples taken, on average 109 d apart. RESULTS: There were 22 episodes of asymptomatic rejection documented on a total of 48 biopsies. Of these, only two were of ISHLT (International Society for Heart and Lung Transplantation) grade 3A the remainder being of ISHLT grades 1 or 2. There was no relation between immunosuppressive regimen (tacrolimus and MMF or cyclosporin and MMF) and rejection. There was no relation between monitored immunosuppressive levels and rejection. Patients with the combination of MMF and tacrolimus had significantly higher plasma mycophenolic acid levels despite significantly lower daily MMF dose. CONCLUSION: There does not appear to be a benefit in continued monitoring of plasma mycophenolic acid levels beyond the first year of heart transplantation. There were significant differences in plasma mycophenolic acid levels depending on the type of calcineurin inhibitor concomitantly used.

Transesophageal Echocardiographic Imaging of the Left Atrium Behind the Ascending Aorta Mimicking Aortic Dissection Validation by Contrast Echocardiography.

We describe the presence of a localized echo-free space behind the ascending aorta, which could mimic an aortic dissection. This space was confirmed to be the left atrium by intraoperative contrast echocardiography.

Identification of the Aortic Arch Branches Using Transesophageal Echocardiography.

In this report we describe the technique used for identification of the individual aortic arch vessels using transesophageal echocardiography.