Novel Intracellular Sbv Reducing Activity Correlates with Antimony Susceptibility in Leishmania donovani

The standard treatment of human visceral leishmaniasis involves the use of pentavalent antimony (Sbv). Its mechanism of action is unknown because of the limited information available about intracellular antimony metabolism and about the genes that regulate these processes. Herein, flow injection-inductively coupled plasma mass spectrometry (ICP-MS), flow injection hydride generation ICP-MS, and ion chromatography ICP-MS were used to measure antimony accumulation and intracellular metabolism in the human protozoan parasite Leishmania donovani. Amastigotes (the intracellular form) and promastigotes (the extracellular form) accumulate Sbv and Sb III via separate transport systems. Stage-specific intracellular Sbv reducing activity was apparent in amastigotes, which reduced the negligibly toxic Sbv to highly toxic SbIII. This amastigote-specific reducing activity was deficient in the Pentostam-resistant mutant L. donovani Ld1S.20. These data indicate that parasite susceptibility to Sbv correlates with its level of Sbv reducing activity. Also, in promastigotes of both wild-type L. donovani and the Pentostam-resistant mutant L. donovani Ld1S.20, Sbv inhibited the toxicity of SbIII but not of AsIII. Both Sbv and SbIII were toxic to wild-type amastigotes. However, as observed in promastigotes, in mutant amastigotes Sbv inhibits Sb III but not AsIII activity. Anion exchange chromatography showed that intracellular antimony metabolism occurred in both promastigotes and amastigotes. These data demonstrate that the interaction between the two antimony oxidation states occurs intracellularly, within the parasite. The results also indicate that Sbv anti-leishmanial activity is dependent on its reduction to SbIII. The mechanism of this novel intracellular Sbv reduction has yet to be identified, and it may or may not be enzymatic. This is the first description of intracellular Sb v reducing activity in Leishmania as well as in any prokaryotic or eukaryotic cell

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 \u3e3 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

Development of Autoantibodies Following BNT162b2 mRNA COVID-19 Vaccination and Their Association with Disease Flares in Adult Patients with Autoimmune Inflammatory Rheumatic Diseases (AIIRD) and the General Population: Results of 1-Year Prospective Follow-Up Study

Development of autoantibodies following BNT162b2 mRNA COVID-19 vaccination and their association with disease flares in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) and the general population: results of 1-year prospective follow-up study. We conducted a prospective study aimed at investigating the incidence of appearance of autoantibodies (antinuclear, antiphospholipid, and rheumatoid factor) in the sera of 463 adult patients with AIIRD compared to 55 controls from the general population prior to, and following the second and third vaccine doses, and at 1-year of follow-up. Pre- and post-vaccination disease activity indices and the association of autoantibodies with rheumatic disease flares and new onset AIIRD were examined. Autoantibody development of any type in AIIRD patients vs. the controls was 4.0% (vs. 6.7%, p = 0.423) following two vaccine doses and 7.6% (vs. 0%, p = 0.152) after three doses. There was no significant difference in sex, age, or disease-type among individuals with and without autoantibody development, regardless of the immunosuppressant use. More patients developed autoantibodies following the third than the second vaccine dose (p = 0.004). Disease flares occurred in 5.8% and 7.2% of AIIRD patients following second and third vaccine doses, respectively, with autoantibody production increasing the risk of flares following the second (p = 0.002) and third (p = 0.004) vaccine doses. BNT162b2 vaccination resulted in the development of autoantibodies in a minority of AIIRD patients and controls. Autoantibody development was associated with disease flares in patients, but no new-onset autoimmunity was observed

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

Abstract 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