On the possibility of predicting glycaemia 'on the fly' with constrained IoT devices in type 1 diabetes mellitus patients

Type 1 Diabetes Mellitus (DM1) patients are used to checking their blood glucose levels several times per day through finger sticks and, by subjectively handling this information, to try to predict their future glycaemia in order to choose a proper strategy to keep their glucose levels under control, in terms of insulin dosages and other factors. However, recent Internet of Things (IoT) devices and novel biosensors have allowed the continuous collection of the value of the glucose level by means of Continuous Glucose Monitoring (CGM) so that, with the proper Machine Learning (ML) algorithms, glucose evolution can be modeled, thus permitting a forecast of this variable. On the other hand, glycaemia dynamics require that such a model be user-centric and should be recalculated continuously in order to reflect the exact status of the patient, i.e., an ‘on-the-fly’ approach. In order to avoid, for example, the risk of being disconnected from the Internet, it would be ideal if this task could be performed locally in constrained devices like smartphones, but this would only be feasible if the execution times were fast enough. Therefore, in order to analyze if such a possibility is viable or not, an extensive, passive, CGM study has been carried out with 25 DM1 patients in order to build a solid dataset. Then, some well-known univariate algorithms have been executed in a desktop computer (as a reference) and two constrained devices: a smartphone and a Raspberry Pi, taking into account only past glycaemia data to forecast glucose levels. The results indicate that it is possible to forecast, in a smartphone, a 15-min horizon with a Root Mean Squared Error (RMSE) of 11.65 mg/dL in just 16.15 s, employing a 10-min sampling of the past 6 h of data and the Random Forest algorithm. With the Raspberry Pi, the computational effort increases to 56.49 s assuming the previously mentioned parameters, but this can be improved to 34.89 s if Support Vector Machines are applied, achieving in this case an RMSE of 19.90 mg/dL. Thus, this paper concludes that local on-the-fly forecasting of glycaemia would be affordable with constrained devices.The authors would like to thank to the Endocrinology Department of the Morales Meseguer and Virgen de la Arrixaca hospitals of the city of Murcia (Spain). This work has been sponsored by the Spanish Ministry of Economy and Competitiveness through 387 the PERSEIDES (ref. TIN2017-86885-R) and CHIST-ERA (ref. PCIN-2016-010) projects; by MINECO grant BES-2015-071956 and by the European Comission through the H2020-ENTROPY-649849 EU Projec

Utility of big data in predicting short-term blood glucose levels in type 1 diabetes mellitus through machine learning techniques

Machine learning techniques combined with wearable electronics can deliver accurate short-term blood glucose level prediction models. These models can learn personalized glucose–insulin dynamics based on the sensor data collected by monitoring several aspects of the physiological condition and daily activity of an individual. Until now, the prevalent approach for developing data-driven prediction models was to collect as much data as possible to help physicians and patients optimally adjust therapy. The objective of this work was to investigate the minimum data variety, volume, and velocity required to create accurate person-centric short-term prediction models. We developed a series of these models using different machine learning time series forecasting techniques suitable for execution within a wearable processor. We conducted an extensive passive patient monitoring study in real-world conditions to build an appropriate data set. The study involved a subset of type 1 diabetic subjects wearing a flash glucose monitoring system. We comparatively and quantitatively evaluated the performance of the developed data-driven prediction models and the corresponding machine learning techniques. Our results indicate that very accurate short-term prediction can be achieved by only monitoring interstitial glucose data over a very short time period and using a low sampling frequency. The models developed can predict glucose levels within a 15-min horizon with an average error as low as 15.43 mg/dL using only 24 historic values collected within a period of sex hours, and by increasing the sampling frequency to include 72 values, the average error is reduced to 10.15 mg/dL. Our prediction models are suitable for execution within a wearable device, requiring the minimum hardware requirements while at simultaneously achieving very high prediction accuracy.The authors would like to thank to the Endocrinology Department of the Morales Meseguer and Virgen de la Arrixaca hospitals of the city of Murcia (Spain). This work was sponsored by the Spanish Ministry of Economy and Competitiveness through 387 the PERSEIDES (ref. TIN2017-86885-R) and CHIST-ERA (ref. PCIN-2016-010) projects; by MINECO grant BES-2015-071956, and by the European Comission through the H2020-ENTROPY-649849 EU Project

Baseline and time-updated factors in preclinical development of anionic dendrimers as successful anti-HIV-1 vaginal microbicides

Although a wide variety of topical microbicides provide promising in vitro and in vivo efficacy, most of them failed to prevent sexual transmission of human immunodeficiency virus type 1 (HIV-1) in human clinical trials. In vitro, ex vivo, and in vivo models must be optimized, considering the knowledge acquired from unsuccessful and successful clinical trials to improve the current gaps and the preclinical development protocols. To date, dendrimers are the only nanotool that has advanced to human clinical trials as topical microbicides to prevent HIV-1 transmission. This fact demonstrates the importance and the potential of these molecules as microbicides. Polyanionic dendrimers are highly branched nanocompounds with potent activity against HIV-1 that disturb HIV-1 entry. Herein, the most significant advancements in topical microbicide development, trying to mimic the real-life conditions as closely as possible, are discussed. This review also provides the preclinical assays that anionic dendrimers have passed as microbicides because they can improve current antiviral treatments' efficacy.This work has been (partially) funded by the RD16/0025/0019 projects as part of Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (2013–2016) and cofinanced by Instituto de Salud Carlos III (ISCIII) and Fondo Europeo de Desarrollo Regional (FEDER), RETIC PT17/0015/0042, Fondo de Investigacion Sanitaria (FIS) (grant no. PI16/01863) and EPIICAL project. COST CA17140 Cancer Nanomedicine-“From the Bench to Bedside.” This work has also been supported by the Ministry of Economy and Competitiveness #CGL2013-40564-R and Gordon and Betty Moore Foundation grant no. 5334. This work was also funded by research grants from ISCIII (grant numbers PI20CIII/00004, and RD16CIII/0002/0002) to Salvador Resino. The study was also funded by the Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CB21/13/00044). DS-C is a “Sara Borrell” researcher from ISCIII (grant no. CD20CIII/00001).S

Effects of ITO based back contacts on Cu(In,Ga)Se2 thin films, solar cells, and mini-modules relevant for semi-transparent building integrated photovoltaics

This study presents the results of the development of semi-transparent Cu(In,Ga)Se2 (CIGSe) mini-modules for the application in building integrated photovoltaics (BIPV). Applying in-situ X-ray diffraction in real-time during CIGSe growth we find that the bulk of indium-tin-oxide (ITO), acting as the transparent back contact, is chemically stable in CIGSe processing. CIGSe layers grown on reactively sputtered ITO (Ar/O2 flux ratio = 60:1) or on ITO annealed in ambient air have a pro-portionally higher (220/204) orientation compared to CIGSe layers grown on as fabricated ITO sputtered solely by Ar. However, independent from the fabrication and annealing state of the ITO back contact, after CIGSe deposition at high substrate temperatures >= 600 degrees C accumulation of Ga at the CIGSe/ITO back contact interface combined with reduced solar cell efficiency is observed. This Ga accumulation visible in elemental depth profiles is attributed to the formation of gallium -oxide (GaOx). Applying a very thin (approximate to 10-30 nm) functional molybdenum layer in between CIGSe and the ITO back contact inhibits the formation of GaOx. Based on this Mo/ITO back contact configuration semi-transparent 10 x 10 cm2 mini-modules with 14 cells interconnected in series have been fabricated. Module parameters resulted in a fill factor of 63% and >12% in efficiency. The solar active coverage of the modules amounts to approximate to 70%, and the average visible transmittance (in the range 380-780 nm) of the transparent sections was 27.6% (9.6% for the total area of the device). Optimisation of the Mo/ITO contact allows increasing this transparency to values > 50%. Long-term outdoor testing of a semi-transparent module prototype reveals no degradation in electric output power for 3 months, demonstrating the device stability under changing climatic conditions

Insights into interface and bulk defects in a high efficiency kesterite-based device

This work provides a detailed analysis of a high efficiency Cu2ZnSnSe4 device using a combination of advanced electron microscopy and spectroscopy techniques. In particular, a full picture of the different defects present at the interfaces of the device and in the bulk of the absorber is achieved through the combination of high resolution electron microscopy techniques with Raman, X-ray fluorescence and Auger spectroscopy measurements at the macro, micro and nano scales. The simultaneous investigation of the bulk and the interfaces allows assessing the impact of the defects found in each part of the device on its performance. Despite a good crystalline quality and homogeneous composition in the bulk, this work reports, for the first time, direct evidence of twinning defects in the bulk, of micro and nano-voids at the back interface and of grain-to-grain non-uniformities and dislocation defects at the front interface. These, together with other issues observed such as strong absorber thickness variations and a bilayer structure with small grains at the bottom, are shown to be the main factors limiting the performance of CZTSe devices. These results open the way to the identification of new solutions to further developing the kesterite technology and pushing it towards higher performances. Moreover, this study provides an example of how the advanced characterization of emergent multilayer-based devices can be employed to elucidate their main limitations.Peer ReviewedPostprint (author's final draft

Impact of a TAK-1 inhibitor as a single or as an add-on therapy to riociguat on the metabolic reprograming and pulmonary hypertension in the SUGEN5416/hypoxia rat model.

Background: Despite increasing evidence suggesting that pulmonary arterial hypertension (PAH) is a complex disease involving vasoconstriction, thrombosis, inflammation, metabolic dysregulation and vascular proliferation, all the drugs approved for PAH mainly act as vasodilating agents. Since excessive TGF-β signaling is believed to be a critical factor in pulmonary vascular remodeling, we hypothesized that blocking TGFβ-activated kinase 1 (TAK-1), alone or in combination with a vasodilator therapy (i.e., riociguat) could achieve a greater therapeutic benefit. Methods: PAH was induced in male Wistar rats by a single injection of the VEGF receptor antagonist SU5416 (20 mg/kg) followed by exposure to hypoxia (10%O2) for 21 days. Two weeks after SU5416 administration, vehicle, riociguat (3 mg/kg/day), the TAK-1 inhibitor 5Z-7-oxozeaenol (OXO, 3 mg/kg/day), or both drugs combined were administered for 7 days. Metabolic profiling of right ventricle (RV), lung tissues and PA smooth muscle cells (PASMCs) extracts were performed by magnetic resonance spectroscopy, and the differences between groups analyzed by multivariate statistical methods. Results: In vitro, riociguat induced potent vasodilator effects in isolated pulmonary arteries (PA) with negligible antiproliferative effects and metabolic changes in PASMCs. In contrast, 5Z-7-oxozeaenol effectively inhibited the proliferation of PASMCs characterized by a broad metabolic reprogramming but had no acute vasodilator effects. In vivo, treatment with riociguat partially reduced the increase in pulmonary arterial pressure (PAP), RV hypertrophy (RVH), and pulmonary vascular remodeling, attenuated the dysregulation of inosine, glucose, creatine and phosphocholine (PC) in RV and fully abolished the increase in lung IL-1β expression. By contrast, 5Z-7-oxozeaenol significantly reduced pulmonary vascular remodeling and attenuated the metabolic shifts of glucose and PC in RV but had no effects on PAP or RVH. Importantly, combined therapy had an additive effect on pulmonary vascular remodeling and induced a significant metabolic effect over taurine, amino acids, glycolysis, and TCA cycle metabolism via glycine-serine-threonine metabolism. However, it did not improve the effects induced by riociguat alone on pulmonary pressure or RV remodeling. None of the treatments attenuated pulmonary endothelial dysfunction and hyperresponsiveness to serotonin in isolated PA. Conclusion: Our results suggest that inhibition of TAK-1 induces antiproliferative effects and its addition to short-term vasodilator therapy enhances the beneficial effects on pulmonary vascular remodeling and RV metabolic reprogramming in experimental PAH.This work was supported by the Instituto de Salud Carlos III-ISCIII (Grant numbers: PI15/01100 and PI19/01616 to LM), the Spanish Ministry of Science and Innovation MCIN (Grant numbers: PID 2019-107363RB-I00 to FP-V, PID 2020-117939RBI00 to AC and PID 2021-123238OB-I00, PDC 2021-121696-I00 to JRC and PID2019-106564RJ-I00 to JI-G), the Comunidad de Madrid-CAM (CM S2017/BMD-3727 to AC and LM and B2017/ BMD3875 to JI-G) and, as appropriate, by “ERDF A way of making Europe”, co-funded by the “European Union”. FP-V received funding from Fundación Contra la Hipertensión Pulmonar (Empathy grant) and JR-C from La Caixa Foundation (Health Research Call 2020: HR20-00075). This work was performed under the Maria de Maeztu Units of Excellence Programme–Grant MDM-2017-0720 funded by MCIN/AEI/10.13039/501100011033.S

Comunica-Media: Uso de la grabación de clases, el screencast y la videoconferencia en el aula

A medida que la tecnología mejora y se extiende entre los usuarios es conveniente y necesario que los sistemas educativos se adapten y aprovechen lo que estas nuevas tecnologías pueden ofrecer. Así se puede motivar más a los alumnos y profesores ofreciéndoles contenidos más completos e interactivos. En esta comunicación se presenta el proyecto Comunica-Media del Servicio de Innovación Educativa de la Universidad Politécnica de Madrid (UPM). El objetivo principal de este proyecto es promover y evaluar el uso de la grabación de clases, la videoconferencia y el screencast en seis diferentes escuelas y asignaturas de la UPM

SARS-CoV-2 Seroprevalence Study in Pediatric Patients and Health Care Workers Using Multiplex Antibody Immunoassays

SARS-CoV-2 infection has become a global health problem specially exacerbated with the continuous appearance of new variants. Healthcare workers (HCW) have been one of the most affected sectors. Children have also been affected, and although infection generally presents as a mild disease, some have developed the Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS). We recruited 190 adults (HCW and cohabitants, April to June 2020) and 57 children (April 2020 to September 2021), of whom 12 developed PIMS-TS, in a hospital-based study in Spain. Using an in-house Luminex assay previously validated, antibody levels were measured against different spike and nucleocapsid SARS-CoV-2 proteins, including the receptor-binding domain (RBD) of the Alpha, Beta, Gamma, and Delta variants of concern (VoC). Seropositivity rates obtained from children and adults, respectively, were: 49.1% and 11% for IgG, 45.6% and 5.8% for IgA, and 35.1% and 7.3% for IgM. Higher antibody levels were detected in children who developed PIMS-TS compared to those who did not. Using the COVID-19 IgM/IgA ELISA (Vircell, S.L.) kit, widely implemented in Spanish hospitals, a high number of false positives and lower seroprevalences compared with the Luminex estimates were found, indicating a significantly lower specificity and sensitivity. Comparison of antibody levels against RBD-Wuhan versus RBD-VoCs indicated that the strongest positive correlations for all three isotypes were with RBD-Alpha, while the lowest correlations were with RBD-Delta for IgG, RBD-Gamma for IgM, and RBD-Beta for IgA. This study highlights the differences in antibody levels between groups with different demographic and clinical characteristics, as well as reporting the IgG, IgM, and IgA response to RBD VoC circulating at the study period

Biological significance of monoallelic and biallelic BIRC3 loss in del(11q) chronic lymphocytic leukemia progression

© The Author(s) 2021.BIRC3 is monoallelically deleted in up to 80% of chronic lymphocytic leukemia (CLL) cases harboring del(11q). In addition, truncating mutations in the remaining allele of this gene can lead to BIRC3 biallelic inactivation, which has been shown to be a marker for reduced survival in CLL. Nevertheless, the biological mechanisms by which these lesions could contribute to del(11q) CLL pathogenesis and progression are partially unexplored. We implemented the CRISPR/Cas9-editing system to generate isogenic CLL cell lines harboring del(11q) and/or BIRC3 mutations, modeling monoallelic and biallelic BIRC3 loss. Our results reveal that monoallelic BIRC3 deletion in del(11q) cells promotes non-canonical NF-κB signaling activation via RelB-p52 nuclear translocation, being these effects allelic dose-dependent and therefore further enhanced in del(11q) cells with biallelic BIRC3 loss. Moreover, we demonstrate ex vivo in primary cells that del(11q) cases including BIRC3 within their deleted region show evidence of non-canonical NF-κB activation which correlates with high BCL2 levels and enhanced sensitivity to venetoclax. Furthermore, our results show that BIRC3 mutations in del(11q) cells promote clonal advantage in vitro and accelerate leukemic progression in an in vivo xenograft model. Altogether, this work highlights the biological bases underlying disease progression of del(11q) CLL patients harboring BIRC3 deletion and mutation.This work was supported by grants from the Spanish Fondo de Investigaciones Sanitarias PI15/01471, PI18/01500, Instituto de Salud Carlos III (ISCIII), European Regional Development Fund (ERDF) “Una manera de hacer Europa”, “Consejería de Educación, Junta de Castilla y León” (SA271P18), “Proyectos de Investigación del SACYL”, Spain GRS 2062/A/19, GRS 1847/A/18, GRS1653/A17,“Fundación Memoria Don Samuel Solórzano Barruso” (FS/23-2018), by grants (RD12/0036/0069) from Red Temática de Investigación Cooperativa en Cáncer (RTICC), Universidad de Salamanca (Programa XIII), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC CB16/12/00233) and SYNtherapy “Synthetic Lethality for Personalized Therapy-based Stratification In Acute Leukemia” (ERAPERMED2018-275); ISCIII (AC18/00093), co-funded by ERDF/ESF, “Investing in your future”. M.Q.Á. and A.E.R.V. are supported with a research grant by FEHH (“Fundación Española de Hematología y Hemoterapia”); M.H.S. holds a Sara Borrell postdoctoral contract (CD19/00222) from the Instituto de Salud Carlos III (ISCIII). C.P.C. was supported by an “Ayuda predoctoral en Oncología” (AECC) and is a recipient of a PFIS grant (FI19/00191) from Instituto de Salud Carlos III; PFIS grant and Sara Borrell postdoctoral contrat are co-founded by Fondo Social Europeo (FSE) “El Fondo Social Europeo invierte en tu futuro”; J.L.O. and R.B.S. are supported by a grant from the University of Salamanca (“Contrato postdoctoral programa II”)

Biological significance of monoallelic and biallelic BIRC3 loss in del(11q) chronic lymphocytic leukemia progression

Article number: 127[EN]BIRC3 is monoallelically deleted in up to 80% of chronic lymphocytic leukemia (CLL) cases harboring del(11q). In addition, truncating mutations in the remaining allele of this gene can lead to BIRC3 biallelic inactivation, which has been shown to be a marker for reduced survival in CLL. Nevertheless, the biological mechanisms by which these lesions could contribute to del(11q) CLL pathogenesis and progression are partially unexplored. We implemented the CRISPR/Cas9-editing system to generate isogenic CLL cell lines harboring del(11q) and/or BIRC3 mutations, modeling monoallelic and biallelic BIRC3 loss. Our results reveal that monoallelic BIRC3 deletion in del(11q) cells promotes non-canonical NF-κB signaling activation via RelB-p52 nuclear translocation, being these effects allelic dose-dependent and therefore further enhanced in del(11q) cells with biallelic BIRC3 loss. Moreover, we demonstrate ex vivo in primary cells that del(11q) cases including BIRC3 within their deleted region show evidence of non-canonical NF-κB activation which correlates with high BCL2 levels and enhanced sensitivity to venetoclax. Furthermore, our results show that BIRC3 mutations in del(11q) cells promote clonal advantage in vitro and accelerate leukemic progression in an in vivo xenograft model. Altogether, this work highlights the biological bases underlying disease progression of del(11q) CLL patients harboring BIRC3 deletion and mutation