Thromboprophylaxis with low molecular weight heparin in hospitalized patients with COVID-19 is mandatory, unless contraindicated. Given the links between inflammation and thrombosis, the use of ...higher doses of anticoagulants could improve outcomes. We conducted an open-label, multicenter, randomized, controlled trial in adult patients hospitalized with nonsevere COVID-19 pneumonia and elevated D-dimer. Patients were randomized to therapeutic-dose bemiparin (115 IU/kg daily) versus standard prophylaxis (bemiparin 3,500 IU daily), for 10 days. The primary efficacy outcome was a composite of death, intensive care unit admission, need of mechanical ventilation support, development of moderate/severe acute respiratory distress, and venous or arterial thrombosis within 10 days of enrollment. The primary safety outcome was major bleeding (International Society on Thrombosis and Haemostasis criteria). A prespecified interim analysis was performed when 40% of the planned study population was reached. From October 2020 to May 2021, 70 patients were randomized at 5 sites and 65 were included in the primary analysis; 32 patients allocated to therapeutic dose and 33 to standard prophylactic dose. The primary efficacy outcome occurred in 7 patients (22%) in the therapeutic-dose group and 6 patients (18%) in the prophylactic-dose (absolute risk difference 3.6% 95% confidence interval CI, -16% -24%; odds ratio 1.26 95% CI, 0.37-4.26;
= 0.95). Discharge in the first 10 days was possible in 66 and 79% of patients, respectively. No major bleeding event was registered. Therefore, in patients with COVID-19 hospitalized with nonsevere pneumonia but elevated D-dimer, the use of a short course of therapeutic-dose bemiparin does not appear to improve clinical outcomes compared with standard prophylactic doses.
ClinicalTrials.gov NCT04604327.
Ivermectin inhibits the replication of SARS-CoV-2 in vitro at concentrations not readily achievable with currently approved doses. There is limited evidence to support its clinical use in COVID-19 ...patients. We conducted a Pilot, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of a single dose of ivermectin reduce the transmission of SARS-CoV-2 when administered early after disease onset.
Consecutive patients with non-severe COVID-19 and no risk factors for complicated disease attending the emergency room of the Clínica Universidad de Navarra between July 31, 2020 and September 11, 2020 were enrolled. All enrollments occurred within 72 h of onset of fever or cough. Patients were randomized 1:1 to receive ivermectin, 400 mcg/kg, single dose (n = 12) or placebo (n = 12). The primary outcome measure was the proportion of patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swab at day 7 post-treatment. The primary outcome was supported by determination of the viral load and infectivity of each sample. The differences between ivermectin and placebo were calculated using Fisher's exact test and presented as a relative risk ratio. This study is registered at ClinicalTrials.gov: NCT04390022.
All patients recruited completed the trial (median age, 26 IQR 19–36 in the ivermectin and 21–44 in the controls years; 12 50% women; 100% had symptoms at recruitment, 70% reported headache, 62% reported fever, 50% reported general malaise and 25% reported cough). At day 7, there was no difference in the proportion of PCR positive patients (RR 0·92, 95% CI: 0·77–1·09, p = 1·0). The ivermectin group had non-statistically significant lower viral loads at day 4 (p = 0·24 for gene E; p = 0·18 for gene N) and day 7 (p = 0·16 for gene E; p = 0·18 for gene N) post treatment as well as lower IgG titers at day 21 post treatment (p = 0·24). Patients in the ivermectin group recovered earlier from hyposmia/anosmia (76 vs 158 patient-days; p < 0.001).
Among patients with non-severe COVID-19 and no risk factors for severe disease receiving a single 400 mcg/kg dose of ivermectin within 72 h of fever or cough onset there was no difference in the proportion of PCR positives. There was however a marked reduction of self-reported anosmia/hyposmia, a reduction of cough and a tendency to lower viral loads and lower IgG titers which warrants assessment in larger trials.
ISGlobal, Barcelona Institute for Global Health and Clínica Universidad de Navarra.
Rapid microbiological reports to clinicians are related to improved clinical outcomes. We conducted a 3-year quasi-experimental design, specifically a pretest-posttest single group design in a ...university medical center, to evaluate the clinical impact of rapid microbiological identification information using MALDI-TOF MS on optimizing antibiotic prescription. A total of 363 consecutive hospitalized patients with bacterial infections were evaluated comparing a historical control group (CG) (n = 183), in which the microbiological information (bacterial identification and antibiotic susceptibility) was reported jointly to the clinician between 18:00 h and 22:00 h of the same day and a prospective intervention group (IG) (n = 180); the bacterial identification information was informed to the clinician as soon as it was available between 12:00 h and 14:00 h and the antibiotic susceptibility between 18:00 h and 22:00 h). We observed, in favor of IG, a statistically significant decrease in the information time (11.44 h CG vs. 4.48 h IG (
< 0.01)) from the detection of bacterial growth in the culture medium to the communication of identification. Consequently, the therapeutic optimization was improved by introducing new antibiotics in the 10-24 h time window (
= 0.05) and conversion to oral route (
= 0.01). Additionally, we observed a non-statistically significant decrease in inpatient mortality (global,
= 0.15; infection-related,
= 0.21) without impact on hospital length of stay. In conclusion, the rapid communication of microbiological identification to clinicians reduced reporting time and was associated with early optimization of antibiotic prescribing without worsening clinical outcomes.
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Metabolic syndrome is a collection of abnormalities, including at least three of the following insulin resistance, hypertension, dyslipidemia, type 2 diabetes, obesity, inflammation, ...and non-alcoholic fatty liver disease. 3D printed solid dosage forms have emerged as a promising tool enabling the fabrication of personalized medicines and offering solutions that cannot be achieved by industrial mass production. Most attempts found in the literature to manufacture polypills for this syndrome contain just two drugs. However, most fixed-dose combination (FDC) products in clinical practice required the use of three or more drugs. In this work, Fused deposition modelling (FDM) 3D printing technology coupled with hot-melt extrusion (HME) has been successfully applied in the manufacture of polypills containing nifedipine (NFD), as an antihypertensive drug, simvastatin (SMV), as an antihyperlipidemic drug, and gliclazide (GLZ) as an antiglycemic drug. Hanssen solubility parameters (HSPs) were utilized as predictors to guide the formation of amorphous solid dispersion between drug and polymer to ensure miscibility and enhanced oral bioavailability. The HSP varied from 18.3 for NFD, 24.6 for SMV, and 7.0 for GLZ while the total solubility parameter for the excipient mixture was 27.30.5. This allowed the formation of an amorphous solid dispersion in SMV and GLZ 3D printed tablets compared to NFD which was partially crystalline. Popypill showed a dual release profile combining a faster SMV release (< 6h) with a 24 h sustained release for NDF and GLZ. This work demonstrated the transformation of FDC into dynamic dose-personalized polypills.
Identification of relevant epitopes is crucial for the development of subunit peptide vaccines inducing neutralizing and cellular immunity against SARS-CoV-2. Our aim was the characterization of ...epitopes in the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein to generate a peptide vaccine. Epitope mapping using a panel of 10 amino acid overlapped 15-mer peptides covering region 401-515 from RBD did not identify linear epitopes when tested with sera from infected individuals or from RBD-immunized mice. However, immunization of mice with these 15-mer peptides identified four peptides located at region 446-480 that induced antibodies recognizing the peptides and RBD/S1 proteins. Immunization with peptide 446-480 from S protein formulated with Freund's adjuvant or with CpG oligodeoxinucleotide/Alum induced polyepitopic antibody responses in BALB/c and C56BL/6J mice, recognizing RBD (titres of 3 × 10
4
-3 × 10
5
, depending on the adjuvant) and displaying neutralizing capacity (80-95% inhibition capacity; p < 0.05) against SARS-CoV-2. Murine CD4 and CD8T-cell epitopes were identified in region 446-480 and vaccination experiments using HLA transgenic mice suggested the presence of multiple human T-cell epitopes. Antibodies induced by peptide 446-480 showed broad recognition of S proteins and S-derived peptides belonging to SARS-CoV-2 variants of concern. Importantly, vaccination with peptide 446-480 or with a cyclic version of peptide 446-488 containing a disulphide bridge between cysteines 480 and 488, protected humanized K18-hACE2 mice from a lethal dose of SARS-CoV-2 (62.5 and 75% of protection; p < 0.01 and p < 0.001, respectively). This region could be the basis for a peptide vaccine or other vaccine platforms against Covid-19.
•Ebola virus neutralizing response increases long after recovery in convalescent patients.•Neutralizing titers are higher against the current Makona variant of EBOV.•Convalescent plasma from Ebola ...infection should be tested for neutralizing titer.
The current outbreak of Ebola Virus Disease in West Africa is caused by a new variant of Ebola virus (EBOV) named Makona 2014, whose sequence differs 3% from isolates from Central Africa such as Mayinga 1976 EBOV. The specificity and kinetics of the neutralizing antibody response induced by the circulating Makona EBOV has not been thoroughly studied.
We have used a lentiviral EBOV-glycoprotein (GP)-pseudotyped infection assay to measure Makona-GP and Mayinga-GP specific neutralizing activity of plasma from three convalescent Ebola Virus Disease patients from the current EBOV outbreak at 2, 3, 4 and 9 months post-infection. Total anti-EBOV GP IgG was measured by a commercial ELISA assay.
In convalescent Ebola Virus Disease patients, Makona-GP-specific neutralizing titers increased from 2 months (mean IC50 1/59), 3 months (IC50 1/212), 4 months (IC50 1/239) and up to 9 months (IC50 1/268) post-infection. Neutralizing activity of plasma from the three convalescent Ebola Virus Disease patients was more vigorous against the current Makona-GP pseudotyped EBOV variant than against Mayinga-GP pseudotyped EBOV and this difference was observed at each time point tested: Mayinga vs Makona mean IC50 fold=4.92 at 2 months post-infection, 2.89 fold at 3 months post-infection, 2.23 at 4 months post-infection and 2.98 at 9 months post-infection (all differences p<0.01). Total level of IgG against EBOV-GP did not evolve significantly during the follow up.
In convalescent Ebola Virus Disease patients, EBOV-GP specific neutralizing activity increases over time, at least up to 9 months post-infection, which suggests that active affinity maturation of antibodies takes place long after clinical recovery. EBOV-GP specific neutralizing response is significantly higher against Makona EBOV circulating in West Africa than against the variants included in the currently approved vaccines. Correlates of protection for EBOV vaccines have not been completely established and the relevance of a lower neutralizing activity in convalescent plasma from the current outbreak against one of the EBOV-GPs contained in the vaccines in terms of its potential efficacy does not necessarily preclude its efficacy. However, this observation highlights the concern regarding the natural diversity of EBOV and its subsequent challenge for diagnosis, therapy and vaccine design. EBOV-GP neutralizing activity varies considerably over time in convalescent Ebola Virus Disease patients. Titering of convalescent blood products would be desirable to standardize and evaluate their potential therapeutic value.
Management of patients with hemophilia A (HA) requires the knowledge and experience of specialized health care professionals. However, these patients may need to be attended in emergencies, outside ...the referral hospital, where health care professionals do not know about hemophilia and/or new innovative treatments. This study aimed to develop a simple and practical algorithm that could be used in emergency situations by nonspecialized treaters in HA and bleeding with or without factor VIII (FVIII) inhibitors under emicizumab prophylaxis. A group of experts agreed on a simple algorithm, easy to operate, adapted from previous international guidelines, and based on their clinical experience. The proposed algorithm starts with identifying the patient, confirming the diagnosis of HA, prophylaxis with emicizumab, and/or use of other treatments. After stabilizing the patient and stratifying the bleeding risk, the patient is managed according to the presence/absence of FVIII inhibitors. Patients without FVIII inhibitors should receive FVIII concentrate. Dose and follow-up depend on bleeding localization and severity. Patients with FVIII inhibitors should preferably receive recombinant activated factor VII as bypass agent. A basic coagulation assay, FVIII assessment, and FVIII inhibitors detection assays are necessary in an emergency. However, these tests should be interpreted with caution and appropriately chosen, as emicizumab may alter the results. The management of patients with HA is challenging in emergency situations, especially if they are treated with new agents. Nonspecialized in coagulopathies health care professionals have limited understanding of the disease, highlighting the need for an algorithm to assist them in making informed decisions.
Limited data exist on the treatment and outcomes of patients with chronic total occlusions due to in-stent restenosis (CTO-ISR). We sought to evaluate results and clinical outcomes in percutaneous ...interventions over CTO-ISR.
We conducted a registry in 16 centres involving consecutive patients undergoing attempted percutaneous intervention over CTO-ISR. A total of 233 patients were included, 192 (82.4%) with a successful acute result. The success rate was significantly lower in patients with: lesion in the circumflex artery, ostial lesions, J score >3 and no femoral access. The presence of tandem lesions (OR 0.19, 95% CI: 0.06-0.68; p=0.01) was identified as an independent predictor for outcome. After a median follow-up of 20 months, cardiac death in the successful vs. failed groups was 3% and 8.3%, respectively (p=0.09). Independent predictors for mortality were previous CABG (HR 8, 95% CI: 1.3-50; p=0.02) and multivessel disease (HR 2.3, 95% CI: 1.2-4.3; p=0.01). In the successful group, TLR was 15%, re-occlusion 6% and definite/probable stent thrombosis 1.8%.
Percutaneous treatment of CTO due to ISR in contemporary practice shows a high success rate, resulting in good long-term results. The angiographic and procedural predictors identified may contribute to improving procedural outcome through better patient selection.
We have assessed the contribution of apoptosis-inducing factor (AIF) and inhibitor of caspase-activated DNase (ICAD) to the nuclear morphology and DNA degradation pattern in staurosporine-induced ...apoptosis. Expression of D117E ICAD, a mutant that is resistant to caspase cleavage at residue 117, prevented low molecular weight (LMW) DNA fragmentation, stage II nuclear morphology, and detection of terminal deoxynucleotidyl transferase staining. However, high molecular weight (HMW) DNA fragmentation and stage I nuclear morphology remained unaffected. On the other hand, expression of either D224E or wild type ICAD had no effect on DNA fragmentation or nuclear morphology. In addition, both HMW and LMW DNA degradation required functional executor caspases. Interestingly, silencing of endogenous AIF abolished type I nuclear morphology without any effect on HMW or LMW DNA fragmentation. Together, these results demonstrate that AIF is responsible for stage I nuclear morphology and suggest that HMW DNA degradation is a caspase-activated DNase and AIF-independent process.
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