Extracting Temporal Relationships in EHR: Application to COVID-19 Patients.

Association rules are one of the most used data mining techniques. The first proposals have considered relations over time in different ways, resulting in the so-called Temporal Association Rules (TAR). Although there are some proposals to extract association rules in OLAP systems, to the best of our knowledge, there is no method proposed to extract temporal association rules over multidimensional models in these kinds of systems. In this paper we study the adaptation of TAR to multidimensional structures, identifying the dimension that establishes the number of transactions and how to find time relative correlations between the other dimensions. A new method called COGtARE is presented as an extension of a previous approach proposed to reduce the complexity of the resulting set of association rules. The method is tested in application to COVID-19 patients data.

Bioactivity-guided fractionation of Phyllanthus orbicularis and identification of the principal anti HSV-2 compounds.

The antiherpes virus properties of Phyllanthus orbicularis Kunth, a Cuban-endemic medicinal plant, have been reported previously but data on its phytochemical profile and identification of antiviral metabolites as well as their mechanisms of action are still lacking. In this work, a bioactivity-guided phytochemical analysis was performed in order to isolate anti HSV-2 compounds. P. orbicularis contained mainly phenolic acids derivatives and flavonoids. The antiviral effects were attributed to (-)-epicatechin-3-O-gallate (EC(50) = 11.7 µg/mL), procyanidins B1 and B2 (EC(50) = 32.8 µg/mL and 24.2 µg/mL, respectively) as well as oligomeric and polymeric procyanidins and their gallate derivatives. The antiviral mechanisms of the active P. orbicularis extracts and fractions were also investigated and the inhibition of several HSV-2 early replication events and DNA synthesis were observed. This is the first study of extensive fractionation and phytochemical characterization of phenolic compounds from this species.

Polygenic Innate Immunity Score to Predict the Risk of Cytomegalovirus Infection in CMV D+/R- Transplant Recipients. A Prospective Multicenter Cohort Study.

Several genetic polymorphisms of the innate immune system have been described to increase the risk of cytomegalovirus (CMV) infection in transplant patients. The aim of this study was to assess the impact of a polygenic score to predict CMV infection and disease in high risk CMV transplant recipients (heart, liver, kidney or pancreas). On hundred and sixteen CMV-seronegative recipients of grafts from CMV-seropositive donors undergoing heart, liver, and kidney or pancreas transplantation from 7 centres were prospectively included for this purpose during a 2-year period. All recipients received 100-day prophylaxis with valganciclovir. CMV infection occurred in 61 patients (53%) at 163 median days from transplant, 33 asymptomatic replication (28%) and 28 CMV disease (24%). Eleven patients (9%) had recurrent CMV infection. Clinically and/or functionally relevant single nucleotide polymorphisms (SNPs) from TLR2, TLR3, TLR4, TLR7, TLR9, AIM2, MBL2, IL28, IFI16, MYD88, IRAK2 and IRAK4 were assessed by real time polymerase chain reaction (RT-PCR) or sequence-based typing (PCR-SBT). A polygenic score including the TLR4 (rs4986790/rs4986791), TLR9 (rs3775291), TLR3 (rs3775296), AIM2 (rs855873), TLR7 (rs179008), MBL (OO/OA/XAO), IFNL3/IL28B (rs12979860) and IFI16 (rs6940) SNPs was built based on the risk of CMV infection and disease. The CMV score predicted the risk of CMV disease with an AUC of the model of 0.68, with sensitivity and specificity of 64.3 and 71.6%, respectively. Even though further studies are needed to validate this score, its use would represent an effective model to develop more robust scores predicting the risk of CMV disease in donor/recipient mismatch (D+/R-) transplant recipients.

Experimental and genetic evidence for the impact of CD5 and CD6 expression and variation in inflammatory bowel disease.

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) resulting from the interaction of multiple environmental, genetic and immunological factors. CD5 and CD6 are paralogs encoding lymphocyte co-receptors involved in fine-tuning intracellular signals delivered upon antigen-specific recognition, microbial pattern recognition and cell adhesion. While CD5 and CD6 expression and variation is known to influence some immune-mediated inflammatory disorders, their role in IBD remains unclear. To this end, Cd5- and Cd6-deficient mice were subjected to dextran sulfate sodium (DSS)-induced colitis, the most widely used experimental animal model of IBD. The two mouse lines showed opposite results regarding body weight loss and disease activity index (DAI) changes following DSS-induced colitis, thus supporting Cd5 and Cd6 expression involvement in the pathophysiology of this experimental IBD model. Furthermore, DNA samples from IBD patients of the ENEIDA registry were used to test association of CD5 (rs2241002 and rs2229177) and CD6 (rs17824933, rs11230563, and rs12360861) single nucleotide polymorphisms with susceptibility and clinical parameters of CD (n=1352) and UC (n=1013). Generalized linear regression analyses showed association of CD5 variation with CD ileal location (rs2241002CC) and requirement of biological therapies (rs2241002C-rs2229177T haplotype), and with poor UC prognosis (rs2241002T-rs2229177T haplotype). Regarding CD6, association was observed with CD ileal location (rs17824933G) and poor prognosis (rs12360861G), and with left-sided or extensive UC, and absence of ankylosing spondylitis in IBD (rs17824933G). The present experimental and genetic evidence support a role for CD5 and CD6 expression and variation in IBD's clinical manifestations and therapeutic requirements, providing insight into its pathophysiology and broadening the relevance of both immunomodulatory receptors in immune-mediated disorders.

Digital Phenotypes for Personalized Medicine.

In this paper we propose a new definition of digital phenotype to enrich the formulation with information stored in the Electronic Health Records (EHR) plus data obtained using wearables. On this basis, we describe how to use this formalism to represent the health state of a patient in a given moment (retrospective, present, or future) and how can it be applied for personalized medicine to find out the mutations that should be introduced at present to reach a better health status in the future.

Federated Mining of Interesting Association Rules Over EHRs.

Federated learning has a great potential to create solutions working over different sources without data transfer. However current federated methods are not explainable nor auditable. In this paper we propose a Federated data mining method to discover association rules. More accurately, we define what we consider as interesting itemsets and propose an algorithm to obtain them. This approach facilitates the interoperability and reusability, and it is based on the accessibility to data. These properties are quite aligned with the FAIR principles.

Providing an Integrated Access to EHR Using Electronic Health Records Aggregators.

The integration of health data systems is an open problem. Most of the active initiatives are based on the use of standards, each one proposed for a concrete use, without integrating other needs or standards allowing on homogenous use. We propose an alternative to get an unified view of health related data, valid for several uses, that can integrate heterogeneous sources. The proposal set the framework to integrate the developments made so far to automatically learn the extraction and conversion of the data. All the sources are integrated under a single access point. We present the main concepts of EHRagg as a middleware between systems that can incorporate several sources giving an unified access following the FAIR principles.

Electronic Health Records Aggregators (EHRagg ).

BACKGROUND: Integration of health data systems is an open problem. Most of the active initiatives are based on the use of standards. However, achieving a widely and generalized compliment of such standards still seems a costly task that will take a long time to be completed. Even more, most of the standards are proposed for a specific use, without integrating other needs. OBJECTIVES: We propose an alternative to get a unified view of health-related data, valid for several uses, that unites heterogeneous data sources. METHODS: Our proposal integrates developments made so far to automatically learn how to extract and convert data from different health-related systems. It enables the creation of a single multipurpose point of access. RESULTS: We present the EhRagg notion and its related concepts. EHRagg is defined as a middleware that, following the FAIR principles, integrates health data sources offering a unified view over them.

Donor mannose-binding lectin gene polymorphisms influence the outcome of liver transplantation.

Mannose-binding lectin (MBL) is a C-type lectin produced mainly by the liver that binds to a wide range of pathogens. Polymorphisms at the promoter and exon 1 of the MBL2 gene are responsible for low serum levels of MBL and have been associated with an increased risk of infections. We prospectively analyzed 95 liver transplant recipients. Well-known functionally relevant polymorphisms of the MBL2 gene of the liver donor were examined by gene sequencing. Infectious events were collected prospectively. No differences in the incidence of infections were found according to the donor MBL2 genotypes. Survival was lower in patients receiving a liver graft from a donor with an exon 1 MBL2 variant genotype, and they had higher infection-related mortality (50% versus 14%, P = 0.040). No differences were found according to other polymorphisms involving the promoter and 5'-untranslated region. When we analyzed bacterial infection episodes, we found that patients receiving a liver from a donor with an exon 1 variant genotype had a higher incidence of septic shock (46% versus 11%, P = 0.004). Independent variables associated with graft or patient survival were as follows: receiving a graft from a donor with an exon 1 MBL2 variant genotype [adjusted hazard ratio (aHR), 9.64; 95% confidence interval (CI), 2.59-36.0], the Model for End-Stage Liver Disease score (aHR, 1.14; 95% CI, 1.05-1.23), and bacterial infections (aHR, 11.1; 95% CI, 2.73-44.9). Liver transplantation from a donor with a variant MBL2 exon 1 genotype was associated with a worse prognosis, mainly because of infections of higher severity.

The influence of innate immunity gene receptors polymorphisms in renal transplant infections.

BACKGROUND: Genetically defined deficiencies in key components of the innate immune system have been associated with a greater risk of infection. The aim of this study was to assess the influence of genetic variability of innate immune receptors (mannose-binding lectin [MBL], mannose-associated serine-protease-2 [MASP-2], and Toll-like receptors [TLR4]) in the risk of infections after a kidney transplantation. METHODS: All patients undergoing a kidney or kidney-pancreas transplantation during a 3-year period were included. Functionally relevant mutations in MBL2, MASP2, and TLR4 genes were determined by DNA sequencing. The incidence of major bacterial infections, asymptomatic cytomegalovirus (CMV) infection, and CMV disease were compared among groups. RESULTS: There were no differences regarding major transplant characteristics among groups. Older age, requirements for posttransplant hemodialysis, and pretransplant diabetes, but not gene polymorphisms, were associated with a greater number of bacterial infections. In univariate analysis, low-MBL genotypes were associated with CMV disease in pretransplant CMV seropositive patients (P=0.015), whereas the TLR4 mutation was associated with higher risk of CMV primary infection (P=0.024). TLR4 mutation was an independent factor associated with CMV disease (odds ratio 5.84, 95% confidence interval 1.35-25.20, P=0.018). CONCLUSION: Polymorphisms of innate immunity receptors, especially TLR4 mutation, were associated with higher risk of CMV disease, while susceptibility to other infectious disorders was not observed.

Mannan-binding lectin pathway deficiencies and invasive fungal infections following allogeneic stem cell transplantation.

OBJECTIVE: The Mannan-binding lectin (MBL) pathway involves recognition of fungal surfaces by MBL and cleavage of C2 and C4 by MBL-associated serine protease (namely, MASP-2). Recent data show that MBL pathway deficiency might result not only from polymorphisms of the MBL2 gene but also of MASP2. The aim of the study was to assess whether polymorphisms of these genes are associated with invasive fungal infections (IFIs) following allogeneic stem cell transplantation (allo-SCT). METHODS: The promoter and the exon 1 of MBL2 and the exon 3 of MASP2 were sequenced in 106 donor-recipient pairs from HLA-identical sibling allo-SCTs performed in a single institution. RESULTS: Ten percent of the donors and 11% of the recipients carried the MBL-low (O/O, LXA/O) genotypes; 7% of the donors and 3% of the recipients were heterozygous for the MASP2 Asp105Gly variant. Factors associated with a higher probability of IFIs were donor's MBL-low genotype (38% vs 12%, p = 0.01), recipient's MASP2 variant (67% vs 14%, p = 0.01), and acute graft-versus-host disease (GVHD) grades II to IV (27% vs 11%, p = 0.04); in the multivariate analysis MBL-low genotype (relative risk [RR] 7.3, p = 0.003), MASP2 variant (RR 6.4, p = 0.002), and acute GVHD II to IV (RR 3.8, p = 0.02) retained independent prognostic value. CONCLUSION: These results show for the first time that polymorphisms responsible for not only MBL but also MASP-2 deficiency are independent predictive factors for IFI after allo-SCT.

Preparation and Optimization of Fluorescent Thin Films of Rosamine-SiO2/TiO2 Composites for NO2 Sensing.

The incorporation of a prototypical rosamine fluorescent dye from organic solutions into transparent and microstructured columnar TiO2 and SiO2 (MO2) thin films, prepared by evaporation at glancing angles (GAPVD), was evaluated. The aggregation of the adsorbed molecules, the infiltration efficiency and the adsorption kinetics were studied by means of UV-Vis absorption and fluorescence spectroscopies. Specifically, the infiltration equilibrium as well as the kinetic of adsorption of the emitting dye has been described by a Langmuir type adsorption isotherm and a pseudosecond order kinetic model, respectively. The anchoring mechanism of the rosamine to the MO2 matrix has been revealed by specular reflectance Fourier transform infrared spectroscopy and infiltration from aqueous solutions at different pH values. Finally, the sensing performance towards NO2 gas of optimized films has been assessed by following the changes of its fluorescence intensity revealing that the so-selected device exhibited improved sensing response compared to similar hybrid films reported in the literature.

Liquid chromatographic method for quantifying polyphenols in ciders by direct injection.

An analytical method for the quantitative determination of the principal phenolic compounds (benzoic acids, hydroxycinnamic acids, 3-phenylpropionic acids, flavanols, procyanidins, dihydrochalcones, quercetin glycosides) in ciders, which successfully employs a RP-HPLC and photodiode-array detection system without prior treatment of the sample, is described. Parameters usually examined in the method validation were evaluated. Good linearity was obtained with correlation coefficients exceeding 0.999 and the detection limits ranged from 0.07 mg/L (p-hydroxybenzoic acid) to 2 mg/L (hydrocaffeic acid). Recoveries ranging between 90 and 104% and the reproducibility of the method was always < 8% (RSD). The method was applied to a set of commercial samples and the results obtained may be helpful to establish a phenolic profile in Asturian cider.

Highly diastereoselective formation of C2-symmetric bis-thioglycoside Pd(II) complexes: the role of the exo anomeric effect.

Treatment of several C(2) symmetric bis-thioglycosides with Pd(CH(3)CN)(2)Cl(2) always leads to a single diastereomeric Pd(II) complex as a consequence of the exo-anomeric effect.

Recombination Study of Combined Halides (Cl, Br, I) Perovskite Solar Cells.

We report on the preparation of a series of solution-processed perovskite solar cells based on methylammonium (MA) lead halide derivatives, MAPbX3, which show tunable optical properties depending on the nature and ratio of the halides employed (X = Cl, Br, and I). Devices have been prepared with different cell architecture, thin film, and mesoporous scaffold (TiO2 and Al2O3). We have analyzed different sample sets focusing on the characterization of the charge recombination by means of impedance spectroscopy (IS). On the one hand, our study discloses that the insertion of both Cl and Br in the perovskite lattice reduces the charge recombination rates in the light absorber film, thus determining the open circuit voltage (Voc) of the device. The samples prepared on a mesoporous Al2O3 electrode present lower charge recombination rates than those devices prepared on mesoporous TiO2. Furthermore, the addition of Br in the perovskite structure was demonstrated to improve slightly the lifetime of the devices; in fact, the efficiencies of all devices tested remained at least at the 80% of the initial value 1 month after their preparation. These results highlight the crucial role of the charge-recombination processes on the performance of the perovskite solar cells and pave the way for further progress on this field.

Improving hospital decision making with interpretable associations over datacubes.

In this paper we propose a new Classification based on Association Rules (CAR) algorithm that improves the interpretability of the results, works over real data from the electronic health records (EHRs), and allows the study of the patient as a whole. It enables tasks such as the discovery of relationships between diseases, or offering several alternative and reasoned diagnoses for the cases of patients with several diseases that analysed separately could lead to mistaken diagnosis. We aim to achieve several goals: to discover hidden relationships; to improve the interpretability and reduce the complexity of the result; to obtain more reliable diagnosis (getting alternative reasoned diagnoses and higher robustness to noisy rules), and to improve the quality of the classifier avoiding the usual over-fitting problem. To this purpose, we define and exploit hierarchies defined over datacubes dimensions, and change the way the association rules are obtained, and their evaluation at the classification process. To prove the utility of our proposal we have used it in an example of cancer discrimination.

Apple pomace, a by-product from the asturian cider industry, inhibits herpes simplex virus types 1 and 2 in vitro replication: study of its mechanisms of action.

The anti-herpes simplex virus type 1 and anti-herpes simplex virus type 2 effects of apple pomace, a by-product from the cider-processing industry, were investigated. The mechanisms of antiviral action were assessed using a battery of experiments targeting sequential steps in the viral replication cycle. The anti-herpetic mechanisms of apple pomaces included the inhibition of virus attachment to the cell surface and the arrest of virus entry and uncoating. Quercitrin and procyanidin B2 were found to play a crucial role in the antiviral activity.

Contextualized access to electronical health records in cardiology.

In this paper, we propose a new approach for accessing the electronical health records (EHR), and we apply it to the cardiology medical specialty. Though the use of EHR improves the storage and access to the information in it regarding the previous health records in papers, it entails the risk of having the same problems of huge size and of becoming inoperative and really difficult to handle, especially if the user is looking for a specific data item. Our proposal is based on the contextualization of the access, providing the user with the most important information for the assistance act in which he/she is involved. To do this, we define the set of possible contexts and consider different aspects of the pertinence of the documents to each context. We do it by using fuzzy logic and pay special attention to the efficiency, due to the huge size of the involved databases. Our proposal does not limit the access to the EHR, but establishes a prioritization based on the access needs, which provides the system with an additional advantage, easily enabling the use of new terminals and devices like tablet PCs and PDAs, which have great limitations in the interfaces.

Genotypes coding for low serum levels of mannose-binding lectin are underrepresented among individuals suffering from noninfectious systemic inflammatory response syndrome.

Gene polymorphisms, giving rise to low serum levels of mannose-binding lectin (MBL) or MBL-associated protease 2 (MASP2), have been associated with an increased risk of infections. The objective of this study was to assess the outcome of intensive care unit (ICU) patients with systemic inflammatory response syndrome (SIRS) regarding the existence of functionally relevant MBL2 and MASP2 gene polymorphisms. The study included 243 ICU patients with SIRS admitted to our hospital, as well as 104 healthy control subjects. MBL2 and MASP2 single nucleotide polymorphisms were genotyped using a sequence-based typing technique. No differences were observed regarding the frequencies of low-MBL genotypes (O/O and XA/O) and MASP2 polymorphisms between patients with SIRS and healthy controls. Interestingly, ICU patients with a noninfectious SIRS had a lower frequency for low-MBL genotypes and a higher frequency for high-MBL genotypes (A/A and A/XA) than either ICU patients with an infectious SIRS or healthy controls. The existence of low- or /high-MBL genotypes or a MASP2 polymorphism had no impact on the mortality rates of the included patients. The presence of high-MBL-producing genotypes in patients with a noninfectious insult is a risk factor for SIRS and ICU admission.

In vitro anti-herpetic activity of an aqueous extract from the plant Phyllanthus orbicularis.

The Herpesviridae includes at least eight viral species pathogenic for humans, responsible for a wide variety of clinical symptoms. The lack of an effective vaccine and the moderate to high toxicity of the available synthetic anti-herpes compounds emphasises the need for new inhibitors. Several Phyllanthus genus (Euphorbiaceae) members have been widely used in traditional medicine and their biological properties have been intensely studied. In this study we investigated the in vitro antiviral activity of the Cuban-endemic plant Phyllanthus orbicularis H.B.K. against Herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) reference strains and clinical isolates with different sensitivities to acyclovir. The inhibitory activity on Human cytomegalovirus (HCMV) replication was also investigated. The selectivity indexes (SI) found for Ph. orbicularis aqueous extract ranged from 8.7 to 37.6. Studies on the antiviral mechanisms involved revealed that the drug acted at early stages of herpesvirus replication, possibly by producing a virucidal effect, although further inhibition of intracellular replication events could not be ruled out.