Knowledge4COVID-19: A semantic-based approach for constructing a COVID-19 related knowledge graph from various sources and analyzing treatments' toxicities.

In this paper, we present Knowledge4COVID-19, a framework that aims to showcase the power of integrating disparate sources of knowledge to discover adverse drug effects caused by drug-drug interactions among COVID-19 treatments and pre-existing condition drugs. Initially, we focus on constructing the Knowledge4COVID-19 knowledge graph (KG) from the declarative definition of mapping rules using the RDF Mapping Language. Since valuable information about drug treatments, drug-drug interactions, and side effects is present in textual descriptions in scientific databases (e.g., DrugBank) or in scientific literature (e.g., the CORD-19, the Covid-19 Open Research Dataset), the Knowledge4COVID-19 framework implements Natural Language Processing. The Knowledge4COVID-19 framework extracts relevant entities and predicates that enable the fine-grained description of COVID-19 treatments and the potential adverse events that may occur when these treatments are combined with treatments of common comorbidities, e.g., hypertension, diabetes, or asthma. Moreover, on top of the KG, several techniques for the discovery and prediction of interactions and potential adverse effects of drugs have been developed with the aim of suggesting more accurate treatments for treating the virus. We provide services to traverse the KG and visualize the effects that a group of drugs may have on a treatment outcome. Knowledge4COVID-19 was part of the Pan-European hackathon#EUvsVirus in April 2020 and is publicly available as a resource through a GitHub repository and a DOI.

Genetic and Morphological Identification of Spirometra decipiens in Snakes and Domestic Dog Found in Cuba.

Spirometra (Cestoda: Diphyllobothriidea) affects humans and some species of domestic and wild animals which eventually interact with humans. In this article, we report three new cases of Spirometra decipiens (Diesing, 1850) infection observed in two intermediate hosts and one definitive host, in Cuba. Genetic and morphological identification of S. decipiens in two snakes and a domestic dog were carried out by molecular means and routine histological study using hematoxylin-eosin staining, respectively. Taken together, the anatomical location, the host species infected with the specimens and their morphological and genetic features, all the samples were identified as S. decipiens. In each of the three cases, PCR assays using specific primers amplified bands that corresponded to S. decipiens species. To our knowledge, this paper is the first report of S. decipiens in species of Cuban endemic fauna and in the Caribbean islands. These species constitute a real or potential risk of transmission of Spirometra to humans in Cuba.

Multilocus Genotyping of Pneumocystis jirovecii from Deceased Cuban AIDS Patients Using Formalin-Fixed and Paraffin-Embedded Tissues.

The results of the genotypic characterization of Pneumocystis jirovecii are described in lung tissue samples from 41 Cubans who died of AIDS with pneumocystosis between 1995 and 2008. Histological sections of the lung preserved as formalin-fixed and paraffin-embedded tissue were examined. PCR amplification and nucleotide sequencing of the two mitochondrial genes (large and small) of the pathogen allowed verification of a predominance of genotype 3 (85T/248C) of the large mitochondrial gene and genotype 3 (160A/196T) of the small mitochondrial gene over a period of 14 years (1995-2008). These results suggest that the 85T/248C//160A/196T genotype circulates with the highest frequency (81.3%) among AIDS patients in Cuba. Multilocus analysis indicates a limited circulation of pathogen genotypes on the island with the existence of a clonal genotype with an epidemic structure. Furthermore, it appears that circulating strains of P. jirovecii have not developed mutations related to sulfonamide resistance. Taken together, the data in this study revealed important elements about pneumocystosis in Cuban patients dying of AIDS and the usefulness of formalin-fixed and paraffin-embedded samples to carry out molecular epidemiology studies of P. jirovecii.

Virulence Plasmids of Rhodococcus equi Isolates From Cuban Patients With AIDS.

Rhodococcus equi is an animal pathogen and zoonotic human opportunistic pathogen associated with immunosuppressive conditions. The pathogenicity of R. equi is linked to three animal host-associated virulence plasmids encoding a family of "Virulence Associated Proteins" (VAPs). Here, the PCR-based TRAVAP molecular typing system for the R. equi virulence plasmids was applied to 26 R. equi strains isolated between 2010 and 2016 at the Institute of Tropical Medicine "Pedro Kourí," Cuba, from individuals living with HIV/AIDS. TRAVAP detects 4 gene markers, traA common to the three virulence plasmids, and vapA, vapB, and vapN specific to each of the host-associated plasmid types (equine pVAPA, porcine pVAPB, and ruminant pVAPN). Of the 26 isolates, six were positive to the vapB (porcine-type) marker, 4 (15.4%) to the vapA (equine-type) marker, and 1 (3.8%) to the vapN (ruminant-type) marker. Most of the isolates 14 (53.8%) were negative to all TRAVAP markers, suggesting they lacked a virulence plasmid. To our knowledge, this work is the first to report the molecular characterization of R. equi isolates from Cuba. Our findings provide insight into the zoonotic origin of R. equi infections in people and the potential dispensability of the virulence plasmid in immunosuppressed patients.

Detection of single umbilical artery in the first trimester ultrasound: its value as a marker of fetal malformation.

INTRODUCTION: The value of a single umbilical artery (SUA) in first trimester ultrasound is not well established. The aim of our study was to determinate the relevance of diagnosis of single umbilical artery in first trimester ultrasound as an early marker suggesting the presence of malformations or associated chromosomopathies. MATERIAL AND METHODS: Retrospective study of clinical cases of SUA diagnosed at the University Hospital Puerta de Hierro in Madrid (Spain) during the first trimester ultrasound between September 2008 and September 2012. RESULTS: Prevalence of SUA was 1.1% in single pregnancies and 3.3% in twin pregnancies. Sensitivity, specificity, false positive rate, and false negative rate for the finding in the first trimester were 84.2, 99.8, 0.2, and 15.7%, respectively. 17.6% of cases had associated malformations. With an ultrasound in the 16th week most of the cases with significant fetal malformation were diagnosed. DISCUSSION: SUA is a useful marker in the first trimester for fetal malformation pathology, as it will allow detecting a large number of cases with malformations before 20 weeks of gestation.

Chronic perineal pain: analyses of prognostic factors in pudendal neuralgia.

OBJECTIVES: To establish the prognostic factors and outcomes of patients with pudendal neuralgia (PN). MATERIALS AND METHODS: A total of 51 patients with PN treated at the Puerta de Hierro University Hospital of Madrid between January 2011 and June 2012 were included in this study. Patients were compared in relation to pain intensity and response to the first-line treatment of neuropathic pain. Univariate and multivariable Cox regression analyses were used. RESULTS: The median for patients' age, duration, and intensity of pain evaluated by visual analogue scale were 40.9, 3.6, and 7.6 years, respectively. Among 45 patients, there were 19 good responders to first-line treatment for neuropathic pain and 26 nonresponders. The 19 responders measured their improvement at 47%. Tramadol was used for nonresponding patients, 30.8% of whom expressed a 35% improvement. Analysis of 45 patients with PN demonstrated that the pain intensity was associated with dorsal clitoris nerve damage (15.4% vs. 52.2%; P=0.035; odds ratio 4.5; 95% confidence interval [CI], 1.11-18.1) and with sensory deficit at the S2-S4 dermatome map (57.7% vs. 87%; P=0.05; odds ratio 3.7; 95% CI, 0.80-16.8). The pain located at the dorsal clitoris nerve was a significant prognostic factor for having no response to the first-line treatment of neuropathic pain (28% vs. 53%; P=0.033; odds ratio 4.5; 95% CI, 1.06-19.6). DISCUSSION: A mixed analgesic ladder for chronic pain showed improvement in 73% of the patients with PN. Pain restricted to the dorsal clitoris nerve and small fibers in the S2-S4 dermatome were classified as bad prognostic factors. A longer duration of pain was also correlated with a worse prognosis.

Is there any room for therapeutic vaccination against the HIV-1/AIDS?

Any therapeutic vaccination approach against HIV-1 must induce CTL and Th1 cells. But, therapeutic vaccination is more than that. For extensive application of a therapeutic vaccine several questions need to be solved in advance to achieve a global impact. In this commentary some of them are addressed. We analyze the epidemiology, sociology, economy and immunopathology related to the HIV/AIDS disease. Also, important technical issues and real possibilities to overcome at least some of the major limitation of the antiretroviral treatments in the pursuit of an effective vaccine are considered. From the integration of previous analyses some conclusions are drawn. Because it is just a commentary some arguments are not unveiled into their full extension. At the end, we discuss some issues in relation to the development of the vaccine candidate TERAVAC-HIV-1 as a case study.

Follow-up in women with vaginal agenesis after laparoscopic creation of neovagina.

STUDY OBJECTIVE: To compare 2 different methods to create a neovagina in patients with Rokitansky syndrome and to describe their functional results during the follow-up. DESIGN: Descriptive study on functional outcome in 32 patients with Rokitansky syndrome (Canadian Task Classification Force II-2). SETTING: University tertiary Hospital. DESIGN AND PATIENTS: 18 patients (group 1) underwent our original technique. 14 patients (group 2) were operated on with the modified technique. INTERVENTION: Comparison between 2 different techniques of laparoscopic approach. RESULTS: Both groups had excellent surgical outcomes. The modified technique (group 2) obtained an optimal vaginal depth in fewer days than in the first group (p < .001). Consequently, the hospital stay was shorter in the second group (p < .001). Follow-up was 85 months for group 1 and 17.2 months for group 2. Functional outcome was excellent during the follow-up in both groups. CONCLUSION: Laparoscopic creation of a neovagina is a safe, minimally invasive treatment with good functional and sexual results.

Three-dimensional angioultrasonography for the prediction of malignancy in ovarian masses.

OBJECTIVE: To determine the efficacy of the angiographic indexes of 3D power Doppler angiography (3D-PDA) for the diagnosis of malignancy in complex ovarian masses. METHODS: A prospective, observational study of 72 patients with complex adnexal mass. RESULTS: In the morphological study, 3D ultrasound showed sensitivity, specificity, PPV, NPV, PLHR and NLHR of 84.6%, 81.9%, 85.1%, 81.8%, 4.65 and 0.19. No differences in vascular indexes (VI, FI, VFI) between malignant and benign masses were found: VI 5.38 (CI 95% 3.06-7.7) vs. 6.29 (CI 95% 4.41-8.17) (p = 0.53); FI 29.6 (CI 95% 25.17-34.08) vs. 33.8 (CI 95% 30.03-37.3) (p = 0.15); VFI 1.68 (CI 95% 0.94-2.42) vs. 2.37 (CI 95% 1.49-3.25) (p = 0.24). When analysed according to different stages, VI was higher in patients with more advanced stages of disease; 4.34 (95% CI 2.21-6.47) vs. 7.38 (95% CI 4.7-10.06) (p = 0.11). FI was significantly lower in patients with early stages of disease; FI 29.07 (95% CI 21.49-36.68) vs. 36.46 (95% CI 32.31-40.62) (p = 0.04). For VFI, differences were not significant, although there was a strong trend; VFI 1.47 (95% CI 0.67-2.28) vs. 2.86 (95% CI 1.57-4.16) (p = 0.11). 3D-PDA indexes were significantly higher in patients with positive adenopathies. CONCLUSION: 3D-PDA values increase progressively, but not significantly, with the stage of the disease.

Prospective evaluation of 18-fluoro-2-deoxy-D-glucose positron emission tomography for the discrimination of paraaortic nodal spread in patients with locally advanced cervical carcinoma.

MAIN OBJECTIVE: Patients with locally advanced cervical cancer (LACC) are usually treated with concurrent chemoradiotherapy. Extended-field chemoradiotherapy is indicated in cases of paraaortic nodal spread. Nowadays, 18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is considered to be the most accurate image method of detection of node or distant metastases. The goal of this study was to evaluate the accuracy of FDG-PET for detecting paraaortic lymph node (PALN) spread in patients with LACC. METHODS: Patients with LACC from 2 tertiary university hospitals in Madrid, Spain, were submitted to a laparoscopic infrarenal PALN dissection after FDG-PET evaluation. Based on pathologic results as gold standard, sensitivity, specificity, and positive and negative predictive values of FDG-PET were calculated thereafter for PALN metastasis. RESULTS: A total of 52 patients with LACC fulfilled the inclusion criteria. All of them underwent a laparoscopic infrarenal paraaortic lymphadenectomy. Eighteen patients (34.6%) had pathologically proven PALN metastases. Among them, 4 (12.5%) had negative FDG-PET (false negatives). Furthermore, 2 positive FDG-PET patients were not affected after histologic analysis (11.1% false positives). No complications occurred in our series. Sensitivity, specificity, and positive and negative predictive value of the FDG-PET were 77.7, 94.1, 87.5, and 88.9, respectively, for the detection of PALN metastases. CONCLUSIONS: The sensitivity and specificity of FDG-PET remains limited, so PALN dissection should be part of the pretherapeutic staging in every patient with LACC before definitive concurrent chemoradiotherapy.

Th2-Th1 shift with the multiantigenic formulation TERAVAC-HIV-1 in Balb/c mice.

In chronic HIV infection a progressive Th1 to Th2/Th0 cytokine-profile shift is related to disease progression. One of the possible benefits of a therapeutic vaccination might be to counterbalance this phenomenon to allow viral replication control under a Th1-type immune response. TERAVAC-HIV-1 is a multiantigenic formulation vaccine candidate against HIV-1 which comprises the recombinant protein CR3 that contains T cell epitopes and the surface and nucleocapsid antigens of Hepatitis B Virus (HBV). Previous studies showed that such virus like particles of the HBV provide a Th1 adjuvant effect. The present studies examined the capacity of TERAVAC to elicit a Th1 response in the presence of an ongoing HIV-specific Th2-type response in Balb/c mice. To examine this issue, we injected subcutaneously the animals with CR3 or viral lysate in alum which resulted in a Th2-type response. The CR3-specific Th2-type response was verified by induction of IL-4 and IL-10 secretion in ex vivo stimulated splenocytes without secretion of IFN-γ and IgG2a antibodies in serum. Further subcutaneous and simultaneous subcutaneous-nasal immunizations of the same mice with TERAVAC promoted IFN-γ secretion and production of IgG2a antibodies in accordance with a Th1-type response. This result suggests a therapeutic benefit of this vaccine candidate in the restoration of the Th1-type HIV-specific cellular response in seropositive patients.

Estimation of hydrogen sulfide emission rates at several wastewater treatment plants through experimental concentration measurements and dispersion modeling.

The management and operation of wastewater treatment plants (WWTP) usually involve the release into the atmosphere of malodorous substances with the potential to reduce the quality of life of people living nearby. In this type of facility, anaerobic degradation processes contribute to the generation of hydrogen sulfide (H2S), often at quite high concentrations; thus, the presence of this chemical compound in the atmosphere can be a good indicator of the occurrence and intensity of the olfactory impact in a specific area. The present paper describes the experimental and modelling work being carried out by CEAM-UMH in the surroundings of several wastewater treatment plants located in the Valencia Autonomous Community (Spain). This work has permitted the estimation of H2S emission rates at different WWTPs under different environmental and operating conditions. Our methodological approach for analyzing and describing the most relevant aspects of the olfactory impact consisted of several experimental campaigns involving intensive field measurements using passive samplers in the vicinity of several WWTPs, in combination with numerical simulation results from a diagnostic dispersion model. A meteorological tower at each WWTP provided the input values for the dispersion code, ensuring a good fit of the advective component and therefore more confidence in the modelled concentration field in response to environmental conditions. Then, comparisons between simulated and experimental H2S concentrations yielded estimates of the global emission rate for this substance at several WWTPs at different time periods. The results obtained show a certain degree of temporal and spatial (between-plant) variability (possibly due to both operational and environmental conditions). Nevertheless, and more importantly, the results show a high degree of uniformity in the estimates, which consistently stay within the same order of magnitude.

Characterization of the olfactory impact around a wastewater treatment plant: optimization and validation of a hydrogen sulfide determination procedure based on passive diffusion sampling.

A monitoring program based on an indirect method was conducted to assess the approximation of the olfactory impact in several wastewater treatment plants (in the present work, only one is shown). The method uses H2S passive sampling using Palmes-type diffusion tubes impregnated with silver nitrate and fluorometric analysis employing fluorescein mercuric acetate. The analytical procedure was validated in the exposure chamber. Exposure periods ofat least 4 days are recommended. The quantification limit of the procedure is 0.61 ppb for a 5-day sampling, which allows the H2S immission (ground concentration) level to be measured within its low odor threshold, from 0.5 to 300 ppb. Experimental results suggest an exposure time greater than 4 days, while recovery efficiency of the procedure, 93.0+/-1.8%, seems not to depend on the amount of H2S collected by the samplers within their application range. The repeatability, expressed as relative standard deviation, is lower than 7%, which is within the limits normally accepted for this type of sampler. Statistical comparison showed that this procedure and the reference method provide analogous accuracy. The proposed procedure was applied in two experimental campaigns, one intensive and the other extensive, and concentrations within the H2S low odor threshold were quantified at each sampling point. From these results, it can be concluded that the procedure shows good potential for monitoring the olfactory impact around facilities where H2S emissions are dominant.

The role of lymphadenectomy in node-positive epithelial ovarian cancer.

OBJECTIVE: To evaluate the therapeutic role of pelvic and aortic lymphadenectomy in patients with epithelial ovarian cancer (EOC) and positive nodes (stages IIIC and IV). METHODS: Retrospective chart review. Data from all consecutive patients with EOC and positive retroperitoneal lymph nodes (stage IIIC and IV) in Mayo Clinic from 1996 to 2000 were included. To evaluate the impact of nodal metastases, the extent of lymphadenectomy was compared according to the number of nodes removed and positive nodes resected. Multivariable Cox regression and Kaplan-Meier survival curves were used for analysis. RESULTS: The median number of nodes removed was 31 (pelvic, 21.5, and aortic, 10), and the median number of positive nodes was 5. The 5-year overall survival was 44.8%. On multivariate analysis, only the extent of peritoneal metastases before surgery was a significant factor for survival (P = 0.001 for stage IIIC and P = 0.004 for stage IV). Analysis of 83 patients with advanced peritoneal disease more than 2 cm demonstrated before debulking, removal of more than 40 lymph nodes was a significant prognostic factor for overall survival (hazard ratio, 0.52; P = 0.032; 95% confidence interval, 0.29-0.35). In 29 patients with advanced peritoneal disease and no residual disease after debulking, removal of more than 10 positive was a factor for survival. CONCLUSIONS: There was a survival benefit in patients with EOC with advanced peritoneal disease more than 2 cm before debulking when more than 40 lymph nodes were removed. There was an additional survival benefit in those patients with no residual disease after debulking when more than 10 positive nodes were removed.

Two mucosal-parenteral schedules to coadminister a multiantigenic formulation against HIV-1 in Balb/c mice.

Previous studies showed that simultaneous immunization through the nasal (IN) and subcutaneous (SC) route of a multiantigenic formulation induced a Th1 anti-HIV humoral and cellular immune responses. The formulation was comprised of a recombinant protein of HIV-1 (named CR3; Cellular Response number 3) and the surface and nucleocapsid antigens of hepatitis B virus. This study asks whether four times simultaneous administration through the IN and SC routes (SC+IN) of the multiantigenic formulation induces a similar systemic and mucosal immune responses than two sequential IN priming and two SC boosting (2IN&2SC) inoculations in mice. To answer this question, we tested the same total dose of each antigen per animal in both schedules of inoculation. We found that SC+IN and 2IN&2SC coadministration induced comparable levels of CR3(HIV)-specific IFN-γ-secreting cells and CD8+ cells proliferation in the systemic compartment of animals. Consistent with these findings, a similar Th1 profile considering anti-CR3 IgG1:IGg2a ratio was observed. Additionally, the level of IgG antibodies and the frequency of seroconverting animals in vagina were not different. However, in the case of IgA antibodies the same parameters were significantly higher in the SC+IN group. We also found important level of HBsAg-specific antibodies in serum and vaginal washes.

Hysteroscopic dynamic assessment of the endometrium in patients treated with long-term tamoxifen.

STUDY OBJECTIVE: To describe the evolutive endometrial hysteroscopic patterns in patients undergoing long-term tamoxifen treatment. DESIGN: Prospective analysis. Analysis of variance test with post hoc Bonferroni test and homogeneity test of percentages were used for hypothesis contrast between the groups. DESIGN CLASSIFICATION: Canadian task force II-2. SETTING: Four Spanish tertiary care hospitals. PATIENTS: A total of 278 patients with breast cancer diagnosed between 2002 and 2004, which completed 5-years adjuvant therapy with tamoxifen. INTERVENTIONS: Ultrasonography and hysteroscopic explorations were performed before starting the treatment and then at yearly intervals during the 5 years of adjuvant treatment. MEASUREMENTS AND MAIN RESULTS: Hysteroscopic endometrial changes were significant throughout the years of treatment. Tamoxifen-exposed endometria present five different patterns: atrophic, cystic, hypervascularized, endometrial polyp, and suspicious of malignancy. Endometrial carcinoma appeared in four patients (1.5%) that bled during the follow-up. CONCLUSION: Tamoxifen produces five different endometrial patterns that evolve dynamically throughout the 5 years of treatment.

Synthesis of a new chiral pyrrolidine.

The synthesis of a new chiral pyrrolidine has been performed using 2,3-O-isopropylidene-D-erythronolactol as a suitable starting material.

Enhanced immunogenicity and cross-reactivity of HIV-1 V3-peptide and multiple antigen peptides conjugated to distinct carrier proteins.

To be effective, vaccines against the highly variable HIV-1 must elicit antibodies to a huge number of clinical isolates. For this purpose, new strategies to overcome this variability are needed. We previously reported a useful immunogenic strategy which consists of conjugating multiple antigen peptides (MAPs) to HBsAg. This vaccine candidate reduces the dose of immunogen required and increases the cross-reactivity towards other HIV strains. In the present study, we have expanded on those results by working with other carrier proteins. Thus, JY1-peptide (V3 regions of gp120 of HIV-1, subtype D) and JY1-MAP8 were synthesized and coupled to several carrier proteins such as KLH, HBsAg and P64k (recombinant meningococcal protein). Mice were immunized with various conjugates and their antigenicity, immunogenicity, and the level of cross-reactivity to a panel of five heterologous V3 peptides were compared. Our results show that conjugate JY1-MAP8 were not only more immunogenic than conjugate, they were also more or equally as immunogenic as 4-fold more JY1-MAP8 alone. Furthermore, conjugates to HBsAg and KLH were more immunogenic than those to P64k. Moreover, conjugates to HBsAg, KLH and P64k showed enhanced cross-reactivity to heterologous V3 peptides compared to JY1-peptide and JY1-MAP8. The analysis showed that conjugate-based immunogens are more prompt to elicit immunogenicity and cross-reactivity. These results can find application in the development of HIV vaccine candidates.

Anti-HIV-1 and anti-HBV immune responses in mice after parenteral and nasal co-administration of a multiantigenic formulation.

The cell-mediated immune response to HIV-1 is an essential element of the mechanisms for viral replication control. Currently, most of the vaccine candidates in clinical trials were developed to stimulate HIV-1-specific CD8+ cytotoxic (CTL) and CD4+ T helper (Th) lymphocytes. We have been working on a novel approach to develop a vaccine formulation for HIV-1 using a recombinant multiepitopic protein (named CR3), which comprises CTL and Th epitope-rich regions of HIV-1 from several subtype B isolates, co-inoculated with the hepatitis B virus surface (HBsAg) and core (HBcAg) antigens of the hepatitis B virus (HBV) as adjuvant. According to our studies in mice, the nasal-subcutaneous co-administration of this multiantigenic formulation induces a strong Th1-biased specific response against CR3, CD8+ T cells in mice spleen and IFN-gamma-secreting cells in mesenteric lymph nodes. Cross-reactive p24-specific IFN-gamma-secreting cells in spleen were also detected. Moreover, Nef-specific antibodies were elicited in mice sera which might avoid the toxic effects of this antigen. However, a marginal anti-CR3 antibody response was elicited in vaginal mucosa. Additionally, we observed anti-HBsAg and anti-HBcAg cellular and humoral responses. In this regard, our multiantigenic formulation might provide immunity against HBV as an additional benefic considering the high HIV-1-HBV co-infection rate reported worldwide.