Safety and Efficacy of an Oncolytic Adenovirus as an Immunotherapy for Canine Cancer Patients

The use of oncolytic virus is an innovative approach that has shown promising results as a treatment in oncology. Epithelial-derived tumors are the most frequent neoplasms in dogs, but gold standard therapies can be highly invasive procedures. Due to the accessible localization of these tumors, the intratumoral administration is feasible. Therefore, we propose to determine the safety and efficacy of intratumoral administration of oncolytic adenovirus ICOCAV15, in canine patients with epithelial-derived tumors. Eight dogs with carcinoma/adenocarcinoma were intratumorally treated with ICOCAV15. No clinically relevant changes were observed in the blood count, biochemistry and coagulation test analyzed during follow-up. The survival time of the 6/8 dogs exceeded the median survival time with chemotherapy, showing a partial response rate of 25% and 75% of stable disease. ICOCAV15 was detected in the target lesion by qPCR and immunohistochemistry. Also, some of the non-treated metastasis showed an infiltration of ICOCAV15 by immunohistochemistry. The immune populations were evaluated, and an increase of CD8+, MAC387+, CD3+ and CD20+ cells was reported in some of the patients after the inoculation. These results show that intratumoral ICOCAV15 is safe and well tolerated by dogs. Also, they suggest ICOCAV15 could be a new tool in veterinary oncology for accessible carcinomas/adenocarcinomas. The use of oncolytic viruses is an innovative approach to lyse tumor cells and induce antitumor immune responses. Eight dogs diagnosed with carcinoma/adenocarcinoma were intratumorally treated with ICOCAV15, an oncolytic canine adenovirus (CAV). To evaluate the treatment's safety, a blood count, biochemistry, and coagulation test were performed before treatment and during follow-up. Immune populations were analyzed by flow cytometry. Anti-adenovirus antibodies were also determined. The immune infiltration, vascularization, and viral presence in the tumor were determined by CD3, CD4, CD20, CD31 and CAV by immunohistochemistry. All the dogs maintained a good quality of life during follow-up, and some had increased median survival time when compared with dogs treated with chemotherapy. No treatment-related adverse effects were detected. The Response Evaluation Criteria In Solid Tumors criteria were also assessed: two patients showed a partial response and the rest showed stable disease at various times during the study. ICOCAV15 was detected inside the tumor during follow-up, and antiviral antibodies were detected in all patients. Furthermore, the tumor-infiltrating immune cells increased after viral administration. Therefore, we suggest that intratumorally administered ICOCAV15 could represent as a new tool for the treatment of canine carcinoma because it is safe, well-tolerated by dogs, and shows promising results

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Use of very low tidal volumes during high-frequency ventilation reduces ventilator lung injury

The use of volume guarantee (VG) on high-frequency oscillatory ventilation (HFOV) allows to use fixed very low high-frequency tidal volume (VThf), maintaining adequate CO2 removal while potentially reducing the risk of ventilator-induced lung injury. Objective: To demonstrate that the use of very low VThf can be protective compared with standard VThf on HFOV combined with VG in a neonatal animal model. Study design: Experimental study in 2-day-old piglets with induced respiratory distress syndrome ventilated with two different HFOV strategies combined with VG (10 Hz with high VThf versus 20 Hz with very low VThf at similar PaCO2). After 12 h of mechanical ventilation, the pulmonary histologic pattern was analyzed. Results: We found in the 10 Hz group with the higher VThf compared with the 20 Hz and very low VThf group more evident and more severe histological lesions with inflammatory infiltrate within the alveolar wall and alveolar space, as well as large areas of parenchyma consolidation and areas of alveolar hemorrhage in the more severe cases. Conclusion: The use of very low VThf compared with higher VThf at similar CO2 removal reduces lung injury in a neonatal animal model of lung injury after prolonged mechanical ventilation with HFOV combined with VG.Instituto de Salud Carlos IIIDepto. de Salud Pública y Materno - InfantilFac. de MedicinaTRUEpu

Humoral responses to SARS-CoV-2 by healthy and sick dogs during the COVID-19 pandemic in Spain.

COVID-19 is a zoonotic disease caused by SARS-CoV-2. Infections of animals with SARS-CoV-2 have recently been reported, and an increase of severe lung pathologies in domestic dogs has also been detected by veterinarians in Spain. Therefore, further descriptions of the pathological processes in those animals that show symptoms similar to those described in humans affected by COVID-19 would be highly valuable. The potential for companion animals to contribute to the continued transmission and community spread of this known human-to-human disease is an urgent issue to be considered. Forty animals with pulmonary pathologies were studied by chest X-ray, ultrasound analysis, and computed tomography. Nasopharyngeal and rectal swabs were analyzed to detect canine pathogens, including SARS-CoV-2. An additional twenty healthy dogs living in SARS-CoV-2-positive households were included. Immunoglobulin detection by several immunoassays was performed. Our findings show that sick dogs presented severe alveolar or interstitial patterns with pulmonary opacity, parenchymal abnormalities, and bilateral lesions. The forty sick dogs were negative for SARS-CoV-2 but Mycoplasma spp. was detected in 26 of 33 dogs. Five healthy and one pathological dog presented IgG against SARS-CoV-2. Here we report that despite detecting dogs with α-SARS-CoV-2 IgG, we never obtained a positive RT-qPCR for SARS-SoV-2, not even in dogs with severe pulmonary disease; suggesting that even in the case of canine infection, transmission would be unlikely. Moreover, dogs living in COVID-19-positive households could have been more highly exposed to infection with SARS-CoV-2.Study funded by Fundación Universidad Alfonso X el Sabio (1.011.115 grant to A.J.P-B.; 1.011.101 to A.B-F.) and Comunidad de Madrid (COV20/01398 grant to A.J.P-B. and A.B-F.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

Humoral responses to SARS-CoV-2 by healthy and sick dogs during the COVID-19 pandemic in Spain

COVID-19 is a zoonotic disease caused by SARS-CoV-2. Infections of animals with SARS-CoV-2 have recently been reported, and an increase of severe lung pathologies in domestic dogs has also been detected by veterinarians in Spain. Therefore, further descriptions of the pathological processes in those animals that show symptoms similar to those described in humans affected by COVID-19 would be highly valuable. The potential for companion animals to contribute to the continued transmission and community spread of this known human-to-human disease is an urgent issue to be considered. Forty animals with pulmonary pathologies were studied by chest X-ray, ultrasound analysis, and computed tomography. Nasopharyngeal and rectal swabs were analyzed to detect canine pathogens, including SARS-CoV-2. An additional twenty healthy dogs living in SARS-CoV-2-positive households were included. Immunoglobulin detection by several immunoassays was performed. Our findings show that sick dogs presented severe alveolar or interstitial patterns with pulmonary opacity, parenchymal abnormalities, and bilateral lesions. The forty sick dogs were negative for SARS-CoV-2 but Mycoplasma spp. was detected in 26 of 33 dogs. Five healthy and one pathological dog presented IgG against SARS-CoV-2. Here we report that despite detecting dogs with α-SARS-CoV-2 IgG, we never obtained a positive RT-qPCR for SARS-SoV-2, not even in dogs with severe pulmonary disease; suggesting that even in the case of canine infection, transmission would be unlikely. Moreover, dogs living in COVID-19-positive households could have been more highly exposed to infection with SARS-CoV-2.Fundación Universidad Alfonso X el SabioComunidad de MadridDepto. de Medicina y Cirugía AnimalFac. de VeterinariaTRUEpu

How well are we performing the initial assessment of HIV-positive patients? Results from a multicentre cohort in Spain

Objectives The aim of this study was to evaluate adherence to the recommendations of the Spanish guidelines for the initial assessment of patients with HIV infection in the multicentre Cohort of the Spanish HIV/AIDS Network (CoRIS) during the years 2004-2017. Methods We calculated the percentage of patients who had each of 11 clinical and analytical recommended examinations performed in their initial evaluation. We evaluated the factors associated with not performing each examination with multivariable logistic regression models. Results We included 13 612 patients in the study. In the initial assessment, CD4 count and viral load were determined in more than 98.0% of the patients. Serologies for hepatitis A, B and C and syphilis were determined in 55.8%, 66.4%, 89.8% and 81.7% of the patients, respectively. Total cholesterol and creatinine were determined in 78.7% and 78.9% of the patients, respectively. The lowest proportions of examinations were observed for blood pressure, smoking status and latent tuberculosis screening, which were performed in 43.2%, 50.6% and 53.9% of the patients, respectively. Injecting drug users and heterosexual patients (compared to men who have sex with men) and patients with a lower educational level had a higher risk of having an incomplete initial assessment for a substantial number of examinations. Latent tuberculosis screening was less likely in patients with CD4 counts The initial assessment of HIV-infected patients is suboptimal for the evaluation of cardiovascular risk, smoking status, screening of syphilis and viral hepatitis, and diagnosis of latent tuberculosis: adherence to the guidelines was low for these examinations