Reversion of Ebolavirus Disease from a Single Intramuscular Injection of a pan-Ebolavirus Immunotherapeutic

Intravenous administration (IV) of antiviral monoclonal antibodies (mAbs) is challenging due to limited resources for performing infusions during an ongoing epidemic. An ebolavirus therapeutic administered via intramuscular (IM) injection would reduce these burdens and allow rapid treatment of exposed individuals during an outbreak. Here, we demonstrate how MBP134, a two mAb pan-ebolavirus cocktail, reverses the course of Sudan ebolavirus (SUDV/Gulu) disease with a single IV or IM dose in non-human primates (NHPs) as far as five days post-exposure. Furthermore, we investigated the utility of adding half-life extension mutations to the MBP134 mAbs, ultimately creating a half-life extended cocktail designated MBP431. MBP431 demonstrated an extended serum half-life in vivo and offered complete or significant protection with a single IM dose delivered as a post-exposure prophylactic (PEP) or therapeutic in NHPs challenged with EBOV. These results support the use of MBP431 as a rapidly deployable IM medical countermeasure against every known ebolavirus.

Preliminary Evidence of the Efficacy of Nitric Acid Treatment in Onychomycosis

Onychomycosis is the main cause of toenail disorders and is produced by a fungal infection. It is becoming more prevalent because of new lifestyles and immunosuppression statuses. The therapeutic approach to onychomycosis is under considerable study because of the lengthy treatments that require strong patient commitment, the limited efficacy of treatments, the inclusion of active substances that can be hepatotoxic and cause pharmacological interactions, and/or the questionable efficacy of treatments due to a lack of clinical trials. This study responds to the demand for rapid treatment with minimal pharmacological interactions. Methods: The efficacy of nitric acid 60% treatment in patients with onychomycosis was monitored and studied. The antifungal efficacy of nitric acid was measured by microbiological culture before and after treatment and the clinical evolution of nail dystrophy was quantitatively measured by monitoring with the Onychomycosis Severity Index (OSI). Results: The results show that, with the protocol used, nitric acid 60% painlessly cured 40% (microbiologic cure) of the cases treated, and in all cases, clinical improvement was observed (p = 0.011). Conclusions: The treatment with nitric acid 60% is as efficient as conventional treatments, requires less patient compliance of the treatment and produces no pharmacological interactions, providing alternative treatment in the case of hepatotoxicity.

METASTART: A Systematic Review and Meta-Analysis of the Diagnostic Accuracy of the Simple Triage and Rapid Treatment (START) Algorithm for Disaster Triage

Introduction: The goal of disaster triage at both the prehospital and in-hospital level is to maximize resources and optimize patient outcomes. Of the disaster-specific triage methods developed to guide health care providers, the Simple Triage and Rapid Treatment (START) algorithm has become the most popular system world-wide. Despite its appeal and global application, the accuracy and effectiveness of the START protocol is not well-known. Objectives: The purpose of this meta-analysis was two-fold: (1) to estimate overall accuracy, under-triage, and over-triage of the START method when used by providers across a variety of backgrounds; and (2) to obtain specific accuracy for each of the four START categories: red, yellow, green, and black. Methods: A systematic review and meta-analysis was conducted that searched Medline (OVID), Embase (OVID), Global Health (OVID), CINAHL (EBSCO), Compendex (Engineering Village), SCOPUS, ProQuest Dissertations and Theses Global, Cochrane Library, and PROSPERO. The results were expanded by hand searching of journals, reference lists, and the grey literature. The search was executed in March 2020. The review considered the participants, interventions, context, and outcome (PICO) framework and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Accuracy outcomes are presented as means with 95% confidence intervals (CI) as calculated using the binomial method. Pooled meta-analyses of accuracy outcomes using fixed and random effects models were calculated and the heterogeneity was assessed using the Q statistic. Results: Thirty-two studies were included in the review, most of which utilized a non-randomized study design (84%). Proportion of victims correctly triaged using START ranged from 0.27 to 0.99 with an overall triage accuracy of 0.73 (95% CI, 0.67 to 0.78). Proportion of over-triage was 0.14 (95% CI, 0.11 to 0.17) while the proportion of under-triage was 0.10 (95% CI, 0.072 to 0.14). There was significant heterogeneity of the studies for all outcomes (P < .0001). Conclusion: This meta-analysis suggests that START is not accurate enough to serve as a reliable disaster triage tool. Although the accuracy of START may be similar to other models of disaster triage, development of a more accurate triage method should be urgently pursued.

Metagenomic Next-Generation Sequencing in the Diagnosis of Deep Sternal Wound Infection After Cardiac Transplantation: A Case Report and Literature Review

Purpose: To explore the value of metagenomics next-generation sequencing (mNGS) for deep sternal wound infection (DSWI) diagnosis. Methods: mNGS was used to diagnose DSWI after cardiac transplantation; DSWI was treated with surgical debridement, wound care, and antibiotic therapy guided by mNGS. Results: Coinfection of methicillin-resistant Staphylococcus aureus (MRSA) and cytomegalovirus (CMV) was detected in this patient. The infection was controlled and the wound healed successfully with the specific medicine based on mNGS results for 3 weeks. Conclusion: mNGS is effective to achieve precise, individualized, and rapid treatment for wound infection.

Ketamine—New Possibilities in the Treatment of Depression: A Narrative Review

The SARS-CoV-2 coronavirus epidemic has led to an increase in the number of people with depression. Symptoms related to the mental sphere (mainly depression and anxiety) may be experienced by one third of the worldwide population. This entails the need for the effective and rapid treatment of depressive episodes. An effective drug seems to be s-ketamine, which was accepted in March 2019 by the Food and Drug Administration (FDA) for the treatment of drug-resistant depression. This drug provides a quick antidepressant effect with maximum effectiveness achieved after 24 h. It also appears to reduce the occurrence of suicidal thoughts. However, research into undesirable effects, especially in groups of people susceptible to psychotic episodes or those who use alcohol or psychoactive substances, is necessary.

Disease Kinetics Measured By Circulating Tumor DNA Correlates with Treatment Response after Tafasitamab in Combination with R-CHOP with or without Lenalidomide in First Line Treatment of DLBCL

Background Currently available clinical and biological prognostic factors do not adequately identify first-line DLBCL patients at risk for treatment failure. In DLBCL, circulating tumor DNA (ctDNA) can be utilized as a for molecular disease classification, detect minimal residual disease (MRD) or predict disease progression. We hypothesized that ctDNA detected by the EuroClonality immunoglobulin-based next generation sequencing (IG-NGS) assay correlates with treatment response and outcome. Patients and methods Overall, 451 samples (41 diagnostic fresh frozen paraffin embedded (FFPE) biopsies, 64 peripheral blood mononuclear cells (PBMC) and 346 plasma samples) from patients from a Phase Ib study in de novo DLBCL treated with tafasitamab and R-CHOP or tafasitamab and R-CHOP in combination with Lenalidomide (First-MIND; MOR208C107) were analyzed. DNA from FFPE or diagnostic PBMC was sequenced by using a 2-step PCR approach with the Euroclonality NGS IGH-VJ, IGH-DJ and IGK primer sets (euroclonality.org) (Brüggemann, Leukemia, 2019) with a number of primers adapted for usage in short fragment cfDNA. IG markers were identified at abundance level ≥5% of annotated IG reads and a &gt;1 log higher abundance to the next most frequent clonotype. Disease related clonotypes were traced in plasma during (C2D1 and C4D1 n=34) and at end of treatment (EOT n=32) by a 1-step PCR approach and sequencing of at least 5000 human genome equivalents (hGE) of cell free (cf)DNA. ctDNA levels were determined as the number of specific clonotype molecules per input genome equivalents normalized by a reference standard DNA spiked into each sample as cIT-QC (Knecht, Leukemia, 2019) and reported per plasma volume. Data were analysed by ARResT/Interrogate (Bystry, Bioinformatics, 2017). Patients were reported MRD positive if ≥1 clonal IG rearrangement was detected. Results From 41 patients with available diagnostic FFPE and sufficient DNA quality for marker screening, 34 (89%) had at least 1 detectable clonal marker (IGH-VJ, IGH-DJ or IGK). One clonal IG marker was identified in 20/34 (59%) patients, whereas two or three markers were identified in 9 (27%) and 5 (14%) patients, respectively. Disease specific clonotypes identified in FFPE were recovered in 11/34 PBMC samples (32%) with a median abundance of 0,29% (range 0.006-21.9%) demonstrating a peripheral blood involvement. In 32/33 (97%) pretreatment plasma samples, ctDNA was detected with a median copy number of 172.5/ml plasma. cfDNA and ctDNA levels prior to treatment correlated with IPI and LDH (Fig1). ctDNA dynamics during treatment demonstrated rapid treatment response at C2D1. 23/34 samples were either MRD neg (n=19) or showed a ctDNA reduction ≥ 2 log levels (Fig2). At C4D1 7/34 (20%) samples had low-level detectable MRD and at EOT 29/32 (91%) patients achieved MRD negativity after treatment with tafasitamab and R-CHOP +/- lenalidomide (LOD 2 x 10 -4 for follow-up samples). Early ctDNA dynamics predicted metabolic response when applying a threshold of ctDNA reduction to &lt;1% after the first treatment cycle. 25/28 (89%) patients completing treatment and achieving PET-response could be identified early during treatment by ctDNA assessment. Conclusion Baseline ctDNA levels determined by the EuroClonality IG-NGS assay and absolute cfDNA amounts correlated with pre-treatment risk factors. ctDNA dynamics after the 1 st treatment cycle demonstrated rapid treatment response to tafasitamab + RCHOP +/- lenalidomide and correlated with metabolic response. Assessment of ctDNA dynamics allows early response assessment and might be useful for risk stratification in patients with DLBCL. Figure 1 Figure 1. Disclosures Kuffer: Morphosys AG: Current Employment. Blair: Morphosys AG: Current Employment.