Brain Tissue-Derived Extracellular Vesicle Mediated Therapy in the Neonatal Ischemic Brain

Hypoxic-Ischemic Encephalopathy (HIE) in the brain is the leading cause of morbidity and mortality in neonates and can lead to irreparable tissue damage and cognition. Thus, investigating key mediators of the HI response to identify points of therapeutic intervention has significant clinical potential. Brain repair after HI requires highly coordinated injury responses mediated by cell-derived extracellular vesicles (EVs). Studies show that stem cell-derived EVs attenuate the injury response in ischemic models by releasing neuroprotective, neurogenic, and anti-inflammatory factors. In contrast to 2D cell cultures, we successfully isolated and characterized EVs from whole brain rat tissue (BEV) to study the therapeutic potential of endogenous EVs. We showed that BEVs decrease cytotoxicity in an ex vivo oxygen glucose deprivation (OGD) brain slice model of HI in a dose- and time-dependent manner. The minimum therapeutic dosage was determined to be 25 μg BEVs with a therapeutic application time window of 4–24 h post-injury. At this therapeutic dosage, BEV treatment increased anti-inflammatory cytokine expression. The morphology of microglia was also observed to shift from an amoeboid, inflammatory phenotype to a restorative, anti-inflammatory phenotype between 24–48 h of BEV exposure after OGD injury, indicating a shift in phenotype following BEV treatment. These results demonstrate the use of OWH brain slices to facilitate understanding of BEV activity and therapeutic potential in complex brain pathologies for treating neurological injury in neonates.

A Ratiometric Theranostic System for Visualization of ONOO– Species and Reduction of Drug-Induced Hepatotoxicity

Peroxynitrite (ONOO–) is a potent reactive nitrogen species that plays a critical mediator in liver injury elicited by drugs such as acetaminophen (APAP). At a therapeutic dosage, most APAP is...

Socio-medical Studies of Individuals Self-treating With Helminths Provide Insight Into Clinical Trial Design for Assessing Helminth Therapy

The virtually complete loss of intestinal worms, known as helminths, from Western society has resulted in elimination of a range of helminth-induced morbidities. Unfortunately, that loss has also led to inflammation-associated deficiencies in immune function, ultimately contributing to widespread pandemics of allergies, autoimmunity, and neuropsychiatric disorders. Several socio-medical studies have examined the effects of intentional reworming, or self-treatment with helminths, on a variety of inflammation-related disorders. In this study, the latest results from ongoing socio-medical studies are described. The results point toward two important factors that appear to be overlooked in some if not most clinical trials. Specifically, (a) the method of preparation of the helminth can have a profound effect on its therapeutic efficacy, and (b) variation between individuals in the effective therapeutic dosage apparently covers a 10-fold range, regardless of the helminth used. These results highlight current limits in our understanding of the biology of both hosts and helminths, and suggest that information from self-treatment may be critical for clinical evaluation of the benefits and limits of helminth therapy.

Potential of Grape Extract in Comparison with Therapeutic Dosage of Antibiotics in Weaning Piglets: Effects on Performance, Digestibility and Microbial Metabolites of the Ileum and Colon

Enteric diseases in piglets, such as post-weaning diarrhea (PWD), often require antibiotic treatment of the entire litter. Grape polyphenols may help overcome PWD and thereby reduce the need for antibiotics. The potential of a grape extract (GE; continuous in-feed supplementation) on performance of weaning piglets, compared with both negative (NC; corn-based diet) and positive control (PC; NC + in-feed antibiotic (amoxicillin) in a therapeutic dosage for day 1–day 5 post weaning) was assessed. Apparent total tract digestibility (ATTD) and microbial metabolites were also evaluated on two sampling points (day 27/28 and day 55/56). We assigned 180 weaning piglets (6.9 ± 0.1 kg body weight (BW)) to 6 male and 6 female pens per treatment with 5 piglets each. Animals from PC showed higher BW on day 13 compared with NC and GE, and a tendency for higher BW on day 56 (p = 0.080) compared to NC. Furthermore, PC increased the average daily feed intake in the starter phase (day 1–day 13), and the average daily gain in the early grower phase (day 14–day 24). Overall, GE improved the ATTD at the same level as PC (ash, acid-hydrolyzed ether extract), or at a higher level than PC (dry matter, organic matter, gross energy, crude protein, P). There were no effects on microbial metabolites apart from minor trends for lactic acid and ammonia. Dietary inclusion of GE may have beneficial effects compared to therapeutic antibiotics, as frequently used at weaning.

Percutaneous dilatational tracheotomy in high-risk ICU patients

Background Percutaneous dilatational tracheotomy (PDT) has become an established procedure in intensive care units (ICU). However, the safety of this method has been under debate given the growing number of critically ill patients with high bleeding risk receiving anticoagulation, dual antiplatelet therapy (DAPT) or even a combination of both, i.e. triple therapy. Therefore, the purpose of this study, including such a high proportion of patients on antithrombotic therapy, was to investigate whether PDT in high-risk ICU patients is associated with elevated procedural complications and to analyse the risk factors for bleeding occurring during and after PDT. Methods PDT interventions conducted in ICUs at 12 European sites between January 2016 and October 2019 were retrospectively analysed for procedural complications. For subgroup analyses, patient stratification into clinically relevant risk groups based on anticoagulation and antiplatelet treatment regimens was performed and the predictors of bleeding occurrence were analysed. Results In total, 671 patients receiving PDT were included and stratified into four clinically relevant antithrombotic treatment groups: (1) intravenous unfractionated heparin (iUFH, prophylactic dosage) (n = 101); (2) iUFH (therapeutic dosage) (n = 131); (3) antiplatelet therapy (aspirin and/or P2Y12 receptor inhibitor) with iUFH (prophylactic or therapeutic dosage) except for triple therapy (n = 290) and (4) triple therapy (DAPT with iUFH in therapeutic dosage) (n = 149). Within the whole cohort, 74 (11%) bleedings were reported to be procedure-related. Bleeding occurrence during and after PDT was independently associated with low platelet count (OR 0.73, 95% CI [0.56, 0.92], p = 0.009), chronic kidney disease (OR 1.75, 95% CI [1.01, 3.03], p = 0.047) and previous stroke (OR 2.13, 95% CI [1.1, 3.97], p = 0.02). Conclusion In this international, multicenter study bronchoscopy-guided PDT was a safe and low-complication airway management option, even in a cohort of high risk for bleeding on cardiovascular ICUs. Low platelet count, chronic kidney disease and previous stroke were identified as independent risk factors of bleeding during and after PDT but not triple therapy.

Prophylactic heparin and risk of orotracheal intubation or death in patients with mild or moderate COVID-19 pneumonia

Prophylactic low molecular weight heparin (pLMWH) is currently recommended in COVID-19 to reduce the risk of coagulopathy. The aim of this study was to evaluate whether the antinflammatory effects of pLMWH could translate in lower rate of clinical progression in patients with COVID-19 pneumonia. Patients admitted to a COVID-hospital in Rome with SARS-CoV-2 infection and mild/moderate pneumonia were retrospectively evaluated. The primary endpoint was the time from hospital admission to orotracheal intubation/death (OTI/death). A total of 449 patients were included: 39% female, median age 63 (IQR, 50–77) years. The estimated probability of OTI/death for patients receiving pLMWH was: 9.5% (95% CI 3.2–26.4) by day 20 in those not receiving pLMWH vs. 10.4% (6.7–15.9) in those exposed to pLMWH; p-value = 0.144. This risk associated with the use of pLMWH appeared to vary by PaO2/FiO2 ratio: aHR 1.40 (95% CI 0.51–3.79) for patients with an admission PaO2/FiO2 ≤ 300 mmHg and 0.27 (0.03–2.18) for those with PaO2/FiO2 > 300 mmHg; p-value at interaction test 0.16. pLMWH does not seem to reduce the risk of OTI/death mild/moderate COVID-19 pneumonia, especially when respiratory function had already significantly deteriorated. Data from clinical trials comparing the effect of prophylactic vs. therapeutic dosage of LMWH at various stages of COVID-19 disease are needed.

Therapeutic effect of CT-P59 against SARS-CoV-2 South African variant

The global circulation of newly emerging variants of SARS-CoV-2 is a new threat to public health due to their increased transmissibility and immune evasion. Moreover, currently available vaccines and therapeutic antibodies were shown to be less effective against new variants, in particular, the South African (SA) variant, termed 501Y.V2 or B.1.351. To assess the efficacy of the CT-P59 monoclonal antibody against the SA variant, we sought to perform as in vitro binding and neutralization assays, and in vivo animal studies. CT-P59 neutralized B.1.1.7 variant to a similar extent as to wild type virus. CT-P59 showed reduced binding affinity against a RBD (receptor binding domain) triple mutant containing mutations defining B.1.351 (K417N/E484K/N501Y) also showed reduced potency against the SA variant in live virus and pseudovirus neutralization assay systems. However, in vivo ferret challenge studies demonstrated that a therapeutic dosage of CT-P59 was able to decrease B.1.351 viral load in the upper and lower respiratory tracts, comparable to that observed for the wild type virus. Overall, although CT-P59 showed reduced in vitro neutralizing activity against the SA variant, sufficient antiviral effect in B.1.351-infected animals was confirmed with a clinical dosage of CT-P59, suggesting that CT-P59 has therapeutic potential for COVID-19 patients infected with SA variant.HighlightsCT-P59 significantly inhibit B.1.1.7 variant to a similar extent as to wild type virusCT-P59 showed reduced potency against the B.1.351 variant in in vitro studiesTherapeutic dosage of CT-P59 showed in vivo neutralizing potency against B.1.351 in ferret challenge study.

Double-edged sword effect of anticoagulant in COVID-19 infection

Coagulation predominant-type coagulopathy such as microthrombosis and macrothrombosis is a well-known recognised complication found in COVID-19 infected critically ill patients. In the context of high incidence of thrombotic events in patients with COVID-19, supplementation with anticoagulant therapy has been routinely recommended and shown to reduce mortality. However, the recommended type, dose, duration and timing of anticoagulant has not been determined yet. Spontaneous retroperitoneal haematoma secondary to anticoagulant therapy is one of the well-known but self-limiting conditions. We report a 51-year-old COVID-19 positive woman, who was taking intermediate-intensity heparin therapy for venous thromboembolism prophylaxis and died from complication of retroperitoneal bleeding. Further studies are needed to verify the risk–benefit ratio of anticoagulant therapy in patients with COVID-19. Although anticoagulant deems appropriate to use in patients with COVID-19, clinicians should be cautious about major bleeding complication such as retroperitoneal haemorrhage even when full therapeutic dosage is not used.