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BackgroundThe Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is the target for many COVID-19 vaccines. Here we report results for phase 1 clinical trial of two COVID-19 vaccine candidates based on recombinant dimeric RBD (d-RBD).MethodsWe performed a randomized, double-blind, phase I clinical trial in the National Centre of Toxicology in Havana. Sixty Cuban volunteers aged 19-59 years were randomized into three groups (20 subjects each): 1) FINLAY-FR-1 (50 mcg d-RBD plus outer membrane vesicles from N. meningitidis); 2) FINLAY-FR-1A-50 mcg d-RBD (three doses); 3) FINLAY-FR-1A-25 mcg d-RDB (three doses). The FINLAY-FR-1 group was randomly divided to receive a third dose of the same vaccine candidate (homologous schedule) or of FINLAY-FR-1A-50 (heterologous schedule). The primary outcomes were safety and reactogenicity. The secondary outcome was vaccine immunogenicity. Humoral response at baseline and following each vaccination was evaluated using live-virus neutralization test, anti-RBD IgG ELISA and in-vitro neutralization test of RBD:hACE2 interaction.ResultsMost adverse events were of mild intensity (63.5%), solicited (58.8%), and local (61.8%); 69.4% with causal association with vaccination. Serious adverse events were not found. The FINLAY-FR-1 group reported more adverse events than the other two groups. After the third dose, anti-RBD seroconversion was 100%, 94.4% and 90% for the FINLAY-FR-1, FINLAY-FR-1A-50 and FINLAY-FR-1A-25 respectively. The in-vitro inhibition of RBD:hACE2 interaction increased after the second dose in all formulations. The geometric mean neutralizing titres after the third dose rose significantly in the group vaccinated with FINLAY-FR-1 with respect to the other formulations and the COVID-19 Convalescent Serum Panel. No differences were found between FINLAY-FR-1 homologous or heterologous schedules.ConclusionsVaccine candidates were safe and immunogenic, and induced live-virus neutralizing antibodies against SARS-CoV-2. The highest values were obtained when outer membrane vesicles were used as adjuvant.Trial registryhttps://rpcec.sld.cu/en/trials/RPCEC00000338-En

Near-infrared diffuse correlation spectroscopy (NIR-DCS) is an emerging technology for simultaneous measurement of skeletal muscle microvascular oxygen delivery and utilization during exercise. The extent to which NIR-DCS can track acute changes in oxygen delivery and utilization has not yet been fully established. To address this knowledge gap, 14 healthy men performed rhythmic handgrip exercise at 30% maximal voluntary contraction, with and without isolated brachial artery compression, designed to acutely reduce convective oxygen delivery to the exercising muscle. Radial artery blood flow (Duplex Ultrasound) and NIR-DCS derived variables [blood flow index (BFI), tissue oxygen saturation ([Formula: see text]), and metabolic rate of oxygen ([Formula: see text])] were simultaneously measured. During exercise, both radial artery blood flow (+51.6 ± 20.3 mL/min) and DCS-derived BFI (+155.0 ± 82.2%) increased significantly ( P < 0.001), whereas [Formula: see text] decreased −7.9 ± 6.2% ( P = 0.002) from rest. Brachial artery compression during exercise caused a significant reduction in both radial artery blood flow (−32.0 ± 19.5 mL/min, P = 0.001) and DCS-derived BFI (−57.3 ± 51.1%, P = 0.01) and a further reduction of [Formula: see text] (−5.6 ± 3.8%, P = 0.001) compared with exercise without compression. [Formula: see text] was not significantly reduced during arterial compression ( P = 0.83) due to compensatory reductions in [Formula: see text], driven by increases in deoxyhemoglobin/myoglobin (+7.1 ± 6.1 μM, P = 0.01; an index of oxygen extraction). Together, these proof-of-concept data help to further validate NIR-DCS as an effective tool to assess the determinants of skeletal muscle oxygen consumption at the level of the microvasculature during exercise.

SOBERANA 02 has been evaluated in phase I and IIa studies comparing homologous versus heterologous schedule (this one, including SOBERANA Plus). Here, we report results of immunogenicity, safety, and reactogenicity of SOBERANA 02 in a two- or three-dose heterologous scheme in adults.Phase IIb was a parallel, multicenter, adaptive, double-blind, randomized, and placebo-controlled trial. Subjects (n = 810) aged 19-80 years were randomized to receive two doses of SARS-CoV-2 RBD conjugated to tetanus toxoid (SOBERANA 02) and a third dose of dimeric RBD (SOBERANA Plus) 28 days apart; two production batches of active ingredients of SOBERANA 02 were evaluated. Primary outcome was the percentage of seroconverted subjects with ≥4-fold the anti-RBD immunoglobulin G (IgG) concentration. Secondary outcomes were safety, reactogenicity, and neutralizing antibodies.Seroconversion rate in vaccinees was 76.3% after two doses and 96.8% after the third dose of SOBERANA Plus (7.3% in the placebo group). Neutralizing IgG antibodies were detected against D614G and variants of concern (VOCs) Alpha, Beta, Delta, and Omicron. Specific, functional antibodies were detected 7-8 months after the third dose. The frequency of serious adverse events (AEs) associated with vaccination was very low (0.1%). Local pain was the most frequent AE.Two doses of SOBERANA 02 were safe and immunogenic in adults. The heterologous combination with SOBERANA Plus increased neutralizing antibodies, detectable 7-8 months after the third dose.https://rpcec.sld.cu/trials/RPCEC00000347 FUNDING: This work was supported by Finlay Vaccine Institute, BioCubaFarma, and the Fondo Nacional de Ciencia y Técnica (FONCI-CITMA-Cuba, contract 2020-20).

The incorporation of normothermic regional perfusion (NRP) to donors after cardiac death (DCD) allows the recovery of liver grafts without the deleterious effects on graft survival the super-rapid technique may cause. The aim of the present report is to determine if the use of NRP in Maastricht type III DCD donors achieves short- and medium-term results comparable to donors after brain death (DBD).This is an observational cohort study including 117 liver transplants executed between November 2016 and April 2021, divided into NRP (n = 39) and DBD (n = 78).Donors were younger in the NRP group (NRP 52 vs DBD 59.4 years; P.005). Liver recipients in each study group were of similar age and severity of liver disease, although the predominant transplant indication in the NRP group was hepatocellular carcinoma. No differences in ischemia times were found. The incidence of early allograft disfunction and primary nonfunction was balanced between NRP and DBD. Eight patients required retransplant, all of them in the DBD group. No differences were found in biliary complications (NRP 12% vs DBD 5%; P = .104). Ischemic cholangiopathy affected a single DBD patient. Graft survival's Kaplan Meier curve shows a better outcome in the NRP group, although the difference did not reach significance (P = .075).The incorporation of perfusion machines, and specifically the NPR in situ, converts suboptimal liver grafts such as DCD into organs comparable to DBDs.

Background Müllerian adenosarcoma is a rare malignancy. These tumors occur mainly in the uterus, but also in extrauterine locations, usually related to endometriosis. Because of their rarity, there is limited data on optimal management strategies. Case presentation We present a 44-year-old woman with a history of endometriosis who consults for chronic pelvic pain. In the imaging tests, a heterogeneous mass is observed that impresses endometriosis, encompassing the uterus and left appendage. Surgery is performed by finding an extrauterine adenosarcoma that affected the uterus, ovary and bladder wall. Conclusion This is a rare case but should be considered in a patient with atypical clinical characteristics or preoperative pathology, so we show the diagnostic and therapeutic strategies carried out for the resolution of the case.

This review is aimed to focus on NSCLC as an emerging and promising model for active immunotherapy and the challenges for its inclusion in the current clinical scenario. Cancer vaccines for NSCLC have been focused as a therapeutic option based on the identification of a tumor hallmark and the active immunization with the related molecules that triggers cellular and/or humoral responses that consequently destroy or delay the rate of malignant progression. This therapeutic intervention in an established disease state has been aimed to impact into prolonging patient´s survival with ethically accepted quality of life. Understanding of relationship between structure and function in cancer vaccines is essential to interpret their opportunities to impact into prolonging survival and increasing quality of life in cancer patients. It is widely accepted that the failure of the cancer vaccines in the NSCLC scenario is related with its introduction in the advanced disease stages and poor performance status of the patients due to the combination of the tumor induced immunosuppression with the immune senescence. Despite first, second and emerging third line of onco-specific treatments the life expectancy for NSCLC patients diagnosed at advanced stages is surrounding the 12 months of median survival and in facts the today real circumstances are extremely demanding for the success inclusion of cancer vaccines as therapeutic choice in the clinical scenario. The kinetics of the active immunizations encompasses a sequential cascade of clinical endpoints: starting by the activation of the immune system, followed by the antitumor response and finalizing with the consequential impact on patients’ overall survival. Today this cascade of clinical endpoints is the backbone for active immunization assessment and moreover the concept of cancer vaccines, applied in the NSCLC setting, is just evolving as a complex therapeutic strategy, in which the opportunities for cancer vaccines start from the selection of the target cancer hallmark, followed by the vaccine formulation and its platforms for immune potentiating, also cover the successful insertion in the standard of care, the chronic administration beyond progression disease, the personalization based on predictors of response and the potential combination with other targeted therapies.