Mapping functional regions of essential bacterial proteins with dominant-negative protein fragments.

Massively parallel measurements of dominant-negative inhibition by protein fragments have been used to map protein interaction sites and discover peptide inhibitors. However, the underlying principles governing fragment-based inhibition have thus far remained unclear. Here, we adapted a high-throughput inhibitory fragment assay for use in Escherichia coli, applying it to a set of 10 essential proteins. This approach yielded single amino acid resolution maps of inhibitory activity, with peaks localized to functionally important interaction sites, including oligomerization interfaces and folding contacts. Leveraging these data, we performed a systematic analysis to uncover principles of fragment-based inhibition. We determined a robust negative correlation between susceptibility to inhibition and cellular protein concentration, demonstrating that inhibitory fragments likely act primarily by titrating native protein interactions. We also characterized a series of trade-offs related to fragment length, showing that shorter peptides allow higher-resolution mapping but suffer from lower inhibitory activity. We employed an unsupervised statistical analysis to show that the inhibitory activities of protein fragments are largely driven not by generic properties such as charge, hydrophobicity, and secondary structure, but by the more specific characteristics of their bespoke macromolecular interactions. Overall, this work demonstrates fundamental characteristics of inhibitory protein fragment function and provides a foundation for understanding and controlling protein interactions in vivo.

Epilepsy Care in Latin America and the Caribbean: Overcoming Challenges and Embracing Opportunities.

The burden of epilepsy in the Latin America and the Caribbean (LAC) region causes a profound regional impact on the health care system and significantly contributes to the global epilepsy burden. As in many other resource-limited settings worldwide, health care professionals and patients with epilepsy in LAC countries face profound challenges due to a combination of factors, including high disease prevalence, stigmatization of epilepsy, disparities in access to care, limited resources, substantial treatment gaps, insufficient training opportunities for health care providers, and a diverse patient population with varying needs. This article presents an overview of the epidemiology of epilepsy and discusses the principal obstacles to epilepsy care and key contributors to the epilepsy diagnosis and treatment gap in the LAC region. We conclude by highlighting various initiatives across different LAC countries to improve epilepsy care in marginalized communities, listing strategies to mitigate treatment gaps and facilitate better health care access for patients with epilepsy by enhancing the epilepsy workforce.

EMOKINE: A software package and computational framework for scaling up the creation of highly controlled emotional full-body movement datasets.

EMOKINE is a software package and dataset creation suite for emotional full-body movement research in experimental psychology, affective neuroscience, and computer vision. A computational framework, comprehensive instructions, a pilot dataset, observer ratings, and kinematic feature extraction code are provided to facilitate future dataset creations at scale. In addition, the EMOKINE framework outlines how complex sequences of movements may advance emotion research. Traditionally, often emotional-'action'-based stimuli are used in such research, like hand-waving or walking motions. Here instead, a pilot dataset is provided with short dance choreographies, repeated several times by a dancer who expressed different emotional intentions at each repetition: anger, contentment, fear, joy, neutrality, and sadness. The dataset was simultaneously filmed professionally, and recorded using XSENS® motion capture technology (17 sensors, 240 frames/second). Thirty-two statistics from 12 kinematic features were extracted offline, for the first time in one single dataset: speed, acceleration, angular speed, angular acceleration, limb contraction, distance to center of mass, quantity of motion, dimensionless jerk (integral), head angle (with regards to vertical axis and to back), and space (convex hull 2D and 3D). Average, median absolute deviation (MAD), and maximum value were computed as applicable. The EMOKINE software is appliable to other motion-capture systems and is openly available on the Zenodo Repository. Releases on GitHub include: (i) the code to extract the 32 statistics, (ii) a rigging plugin for Python for MVNX file-conversion to Blender format (MVNX=output file XSENS® system), and (iii) a Python-script-powered custom software to assist with blurring faces; latter two under GPLv3 licenses.

The Use of Corticosteroids or Tocilizumab in COVID-19 Based on Inflammatory Markers.

BACKGROUND: The inflammatory cascade is the main cause of death in COVID-19 patients. Corticosteroids (CS) and tocilizumab (TCZ) are available to treat this escalation but which patients to administer it remains undefined. OBJECTIVE: We aimed to evaluate the efficacy of immunosuppressive/anti-inflammatory therapy in COVID-19, based on the degree of inflammation. DESIGN: A retrospective cohort study with data on patients collected and followed up from March 1st, 2020, to May 1st, 2021, from the nationwide Spanish SEMI-COVID-19 Registry. Patients under treatment with CS vs. those under CS plus TCZ were compared. Effectiveness was explored in 3 risk categories (low, intermediate, high) based on lymphocyte count, C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, and D-dimer values. PATIENTS: A total of 21,962 patients were included in the Registry by May 2021. Of these, 5940 met the inclusion criteria for the present study (5332 were treated with CS and 608 with CS plus TCZ). MAIN MEASURES: The primary outcome of the study was in-hospital mortality. Secondary outcomes were the composite variable of in-hospital mortality, requirement for high-flow nasal cannula (HFNC), non-invasive mechanical ventilation (NIMV), invasive mechanical ventilation (IMV), or intensive care unit (ICU) admission. KEY RESULTS: A total of 5940 met the inclusion criteria for the present study (5332 were treated with CS and 608 with CS plus TCZ). No significant differences were observed in either the low/intermediate-risk category (1.5% vs. 7.4%, p=0.175) or the high-risk category (23.1% vs. 20%, p=0.223) after propensity score matching. A statistically significant lower mortality was observed in the very high-risk category (31.9% vs. 23.9%, p=0.049). CONCLUSIONS: The prescription of CS alone or in combination with TCZ should be based on the degrees of inflammation and reserve the CS plus TCZ combination for patients at high and especially very high risk.

Interobserver reliability of Masei index validation by a multicenter collaborative group of rheumatologists.

MASEI is the main validated ultrasound score for the evaluation of enthesis. The lack of studies facing the agreement to achieve for the interpretation of the MAdrid Sonographic Enthesis Index (MASEI) among researchers from different centers in multicenter studies is of concern. The aim of this multicenter was to evaluate the interobserver reliability of MASEI. An experienced ultrasonographer-rheumatologist performed ultrasound scans of the areas included in MASEI index in three patients with Ankylosing Spondylitis and Psoriatic Arthritis. Videos were captured. The videos were then evaluated by 24 rheumatologists of the ultrasound working group of the Catalan Society of Rheumatology (EcoCAT). A face-to-face training meeting was held. Ten days after the workshop, the study participants evaluated the videos. A reliability assessment was performed. The ICC for the MASEI scores after the workshop was of 0.97 (95% CI 89-99). Reliability did not vary statistically with examiner experience. Globally, no problems of reliability by structures were seen, and all the ICCs were above 0.90 and improved slightly after the educational program. However, the correlation observed between examiners at plantar aponeursis and triceps tendon was weak. The small variability observed in the results of the index validation in our study, suggests that the MASEI index is reproducible by different observers when those are well trained and show awesome results of the enthesis when examined by ultrasound.

Exploitation of dihydroorotate dehydrogenase (DHODH) and p53 activation as therapeutic targets: A case study in polypharmacology.

The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.

Omega-3 Polyunsaturated Fatty Acids Decrease Aortic Valve Disease Through the Resolvin E1 and ChemR23 Axis.

BACKGROUND: Aortic valve stenosis (AVS), which is the most common valvular heart disease, causes a progressive narrowing of the aortic valve as a consequence of thickening and calcification of the aortic valve leaflets. The beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in cardiovascular prevention have recently been demonstrated in a large randomized, controlled trial. In addition, n-3 PUFAs serve as the substrate for the synthesis of specialized proresolving mediators, which are known by their potent beneficial anti-inflammatory, proresolving, and tissue-modifying properties in cardiovascular disease. However, the effects of n-3 PUFA and specialized proresolving mediators on AVS have not yet been determined. The aim of this study was to identify the role of n-3 PUFA-derived specialized proresolving mediators in relation to the development of AVS. METHODS: Lipidomic and transcriptomic analyses were performed in human tricuspid aortic valves. Apoe-/- mice and wire injury in C57BL/6J mice were used as models for mechanistic studies. RESULTS: We found that n-3 PUFA incorporation into human stenotic aortic valves was higher in noncalcified regions compared with calcified regions. Liquid chromatography tandem mass spectrometry-based lipid mediator lipidomics identified that the n-3 PUFA-derived specialized proresolving mediator resolvin E1 was dysregulated in calcified regions and acted as a calcification inhibitor. Apoe-/- mice expressing the Caenorhabditis elegans Fat-1 transgene (Fat-1tg×Apoe-/-), which enables the endogenous synthesis of n-3 PUFA and increased valvular n-3 PUFA content, exhibited reduced valve calcification, lower aortic valve leaflet area, increased M2 macrophage polarization, and improved echocardiographic parameters. Finally, abrogation of the resolvin E1 receptor ChemR23 enhanced disease progression, and the beneficial effects of Fat-1tg were abolished in the absence of ChemR23. CONCLUSIONS: n-3 PUFA-derived resolvin E1 and its receptor ChemR23 emerge as a key axis in the inhibition of AVS progression and may represent a novel potential therapeutic opportunity to be evaluated in patients with AVS.

Senescent accelerated prone 8 (SAMP8) mice as a model of age dependent neuroinflammation.

BACKGROUND: Aging and age-related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain's immune response, plays an important role in aged associated degeneration of central nervous system (CNS). There is a need for well characterized animal models that will allow the scientific community to understand and modulate this process. METHODS: We have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their senescence resistant control mice (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and determined the appearance of Iba1+ clustered cells with aging. To analyze specific constant brain areas, we have performed stereology measurements of Iba1+ cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus plus meningeal membranes (m/Ch), and analyzed their response to systemic lipopolysaccharide (LPS)-driven inflammation. RESULTS: Aged 10 months old SAMP8 mice present many of the hallmarks of aging-dependent neuroinflammation when compared with their SAMR1 control, i.e., increase of protein aggregates, presence of Iba1+ clusters, but not an increase in the number of Iba1+ cells. We have further observed an increase of main inflammatory mediator IL-1ß, and an augment of border MHCII+Iba1+ cells. Isolated CD45+ bMyC from brain parenchyma (BP) and choroid plexus plus meningeal membranes (m/Ch) have been analyzed, showing that there is not a significant increase of CD45+ cells from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL-1ß) transcription is enhanced in CD45+BP cells. Furthermore, LPS-driven systemic inflammation produces inflammatory cytokines mainly in border bMyC, sensed to a lesser extent by the BP bMyC, showing that IL-1ß expression is further augmented in aged SAMP8 compared to control SAMR1. CONCLUSION: Our data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of pro-inflammatory cytokines such as IL-1ß, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.

Predictors of short- and long-term outcomes of patients undergoing transcatheter mitral valve edge-to-edge repair.

OBJECTIVES: Transcatheter mitral valve repair (TMVR) by edge-to-edge therapy is an established treatment for severe mitral valve regurgitation (MR). BACKGROUND: Symptomatic and prognostic benefit in functional MR has been shown recently; nevertheless, data on long-term outcomes are sparse. METHODS AND RESULTS: We analyzed survival of patients treated with isolated edge-to-edge repair from June 2010 to March 2018 (primarily combined edge-to-edge repair with other mitral valve interventions was excluded) in a retrospective monocentric study. Overall, 627 consecutive patients (47.0% females, 78.6 years in mean) were included. Leading etiology was functional MR (57.4%). Follow-up regarding survival was available in 97.0%. While 97.6% were discharged alive, 75.7% were alive after a 1-year, 54.5% after 3-year, 37.6% after 5-year and 21.7% after 7-year follow-up. Higher logistic Euroscores and comorbidities such as COPD and renal insufficiency were associated with higher in-hospital and 1-year mortality. Importantly, in-hospital survival increased over the years. CONCLUSIONS: With the present study we established high survival rates at discharge and after 1 year of patients treated with TMVR. This goes along with high implantation numbers, increased interventional experience and a better in-hospital survival over the years. Long-term mortality in turn was substantially influenced by comorbidities.

"Unlucky punch": unexpected annular rupture during TAVR and successful treatment.

Although rare, annular rupture in TAVR is a feared and often unpredictable complication with relevant impact on in-hospital prognosis. Severe annular calcification is a common risk factor for annular rupture. We report on a case of annular rupture during TAVR with a balloon-expanded prosthesis in the absence of any annular calcification in the planning CT scan and illustrate the proposed pathomechanism as well as its successful immediate surgical management.

Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients: Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation.

RATIONALE: Human cardiac mesenchymal cells (CMSCs) are a therapeutically relevant primary cell population. Diabetes mellitus compromises CMSC function as consequence of metabolic alterations and incorporation of stable epigenetic changes. OBJECTIVE: To investigate the role of α-ketoglutarate (αKG) in the epimetabolic control of DNA demethylation in CMSCs. METHODS AND RESULTS: Quantitative global analysis, methylated and hydroxymethylated DNA sequencing, and gene-specific GC methylation detection revealed an accumulation of 5-methylcytosine, 5-hydroxymethylcytosine, and 5-formylcytosine in the genomic DNA of human CMSCs isolated from diabetic donors. Whole heart genomic DNA analysis revealed iterative oxidative cytosine modification accumulation in mice exposed to high-fat diet (HFD), injected with streptozotocin, or both in combination (streptozotocin/HFD). In this context, untargeted and targeted metabolomics indicated an intracellular reduction of αKG synthesis in diabetic CMSCs and in the whole heart of HFD mice. This observation was paralleled by a compromised TDG (thymine DNA glycosylase) and TET1 (ten-eleven translocation protein 1) association and function with TET1 relocating out of the nucleus. Molecular dynamics and mutational analyses showed that αKG binds TDG on Arg275 providing an enzymatic allosteric activation. As a consequence, the enzyme significantly increased its capacity to remove G/T nucleotide mismatches or 5-formylcytosine. Accordingly, an exogenous source of αKG restored the DNA demethylation cycle by promoting TDG function, TET1 nuclear localization, and TET/TDG association. TDG inactivation by CRISPR/Cas9 knockout or TET/TDG siRNA knockdown induced 5-formylcytosine accumulation, thus partially mimicking the diabetic epigenetic landscape in cells of nondiabetic origin. The novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of αKG dehydrogenase, increased the αKG level in diabetic CMSCs and in the heart of HFD and streptozotocin mice eliciting, in HFD, DNA demethylation, glucose uptake, and insulin response. CONCLUSIONS: Restoring the epimetabolic control of DNA demethylation cycle promises beneficial effects on cells compromised by environmental metabolic changes.

Should kidney allografts from old donors be allocated only to old recipients?

In several deceased donor kidney allocation systems, organs from elderly donors are allocated primarily to elderly recipients. The Eurotransplant Senior Program (ESP) was implemented in 1999, and since then, especially in Europe, the use of organs from elderly donors has steadily increased. The proportion of ≥60-year-old donors reported to the Collaborative Transplant Study (CTS) by European centers has doubled, from 21% in 2000-2001 to 42% in 2016-2017. Therefore, in the era of organ shortage it is a matter of debate whether kidney organs from elderly donors should only be allocated to elderly recipients or whether <65-year-old recipients can also benefit from these generally as "marginal" categorized organs. To discuss this issue, a European Consensus Meeting was organized by the CTS on April 12, 2018, in Heidelberg, in which 36 experts participated. Based on available evidence, it was unanimously concluded that kidney organs from 65- to 74-year-old donors can also be allocated to 55- to 64-year-old recipients, especially if these organs are from donors with no history of hypertension, no increased creatinine, no cerebrovascular death, and no other reasons for defining a marginal donor, such as diabetes or cancer.

Feasibility of a MPR-based 3DTEE guidance protocol for transcatheter direct mitral valve annuloplasty.

OBJECTIVES: Several interventional approaches have been established for the treatment of severe mitral regurgitation (MR) in patients at elevated risk for surgery. Direct annuloplasty is a relatively novel option in transcatheter mitral valve repair dedicated to reverse pathology in specific subsets of MR. With regard to echocardiographic guidance, this procedure presents with higher efforts in comparison with edge-to-edge therapy to enable safe and exact positioning of the device's anchors; evidence on optimal peri-interventional imaging is sparse. We tested a specific 3D-echo-guidance protocol implementing single-beat multiplanar reconstruction (MPR) and evaluated its feasibility. METHODS: Overall, 16 patients consecutively treated with transcatheter direct annuloplasty for severe MR (87.5% functional/6.3% degenerative/6.3% mixed pathology) were entered in this monocentric analysis. Of these, two patients received a combined procedure including edge-to-edge repair. For all implantations, a 3D-echo-guidance protocol inheriting MPR was employed. RESULTS: Periprocedural device time decreased continuously (overall mean 140 ± 55.1 minutes, 213 ± 38 minutes in the first 4 vs 108 ± 33 minutes in the last 4 procedures, P = .018) using the MPR-based echo protocol, going along with reduced fluoroscopy times and doses. Technical success rate was high (93.8%) without any serious cardiac-related adverse events. MR could be relevantly improved. CONCLUSION: Echocardiographic guidance of transcatheter direct annuloplasty using a real time MPR-based protocol is feasible and safe. Optimized imaging might enable reduced implantation times and potentially increases safety.

Dataset Construction from Naturalistic Driving in Roundabouts.

A proper driver characterization in complex environments using computational techniques depends on the richness and variety of data obtained from naturalistic driving. The present article proposes the construction of a dataset from naturalistic driving specific to maneuvers in roundabouts and makes it open and available to the scientific community for performing their own studies. The dataset is a combination of data gathered from on-board instrumentation and data obtained from the post-processing of maps as well as recorded videos. The approach proposed in this paper consists of handling roundabouts as a stretch of road that includes 100 m before the entrance, the internal part, and 100 m after the exit. This stretch of road is then spatially sampled in small sections to which data are associated.

ERV1/ChemR23 Signaling Protects Against Atherosclerosis by Modifying Oxidized Low-Density Lipoprotein Uptake and Phagocytosis in Macrophages.

BACKGROUND: In addition to enhanced proinflammatory signaling, impaired resolution of vascular inflammation plays a key role in atherosclerosis. Proresolving lipid mediators formed through the 12/15 lipoxygenase pathways exert protective effects against murine atherosclerosis. n-3 Polyunsaturated fatty acids, including eicosapentaenoic acid (EPA), serve as the substrate for the formation of lipid mediators, which transduce potent anti-inflammatory and proresolving actions through their cognate G-protein-coupled receptors. The aim of this study was to identify signaling pathways associated with EPA supplementation and lipid mediator formation that mediate atherosclerotic disease progression. METHODS: Lipidomic plasma analysis were performed after EPA supplementation in Apoe-/- mice. Erv1/Chemr23-/- xApoe-/- mice were generated for the evaluation of atherosclerosis, phagocytosis, and oxidized low-density lipoprotein uptake. Histological and mRNA analyses were done on human atherosclerotic lesions. RESULTS: Here, we show that EPA supplementation significantly attenuated atherosclerotic lesion growth induced by Western diet in Apoe-/- mice and was associated with local cardiovascular n-3 enrichment and altered lipoprotein metabolism. Our systematic plasma lipidomic analysis identified the resolvin E1 precursor 18-monohydroxy EPA as a central molecule formed during EPA supplementation. Targeted deletion of the resolvin E1 receptor Erv1/Chemr23 in 2 independent hyperlipidemic murine models was associated with proatherogenic signaling in macrophages, increased oxidized low-density lipoprotein uptake, reduced phagocytosis, and increased atherosclerotic plaque size and necrotic core formation. We also demonstrate that in macrophages the resolvin E1-mediated effects in oxidized low-density lipoprotein uptake and phagocytosis were dependent on Erv1/Chemr23. When analyzing human atherosclerotic specimens, we identified ERV1/ChemR23 expression in a population of macrophages located in the proximity of the necrotic core and demonstrated augmented ERV1/ChemR23 mRNA levels in plaques derived from statin users. CONCLUSIONS: This study identifies 18-monohydroxy EPA as a major plasma marker after EPA supplementation and demonstrates that the ERV1/ChemR23 receptor for its downstream mediator resolvin E1 transduces protective effects in atherosclerosis. ERV1/ChemR23 signaling may represent a previously unrecognized therapeutic pathway to reduce atherosclerotic cardiovascular disease.

Can the simultaneous laparoscopic approach improve the learning of vaginal surgery with meshes in the anatomical model?

AIMS: To evaluate the usefulness of simultaneous laparoscopic assistance to improve understanding of the nonvisible surgical steps in Thiel-embalmed cadaver models for training in vaginal surgery using vaginal mesh kits and to evaluate opinions of this surgical learning procedure in comparison with other learning models. METHODS: Recording of anterior compartment prolapse repair with vaginal mesh kits using an external camera simultaneously with laparoscopic vision during the execution of the procedure at the dissection room. To measure the usefulness of this procedure, we designed an anonymous online survey that was made available to program participants via a computer application (a link to video 1 and the survey is available at encuesta@um.es). RESULTS: After watching the video, 97.2% of participants agreed that laparoscopic vision combined with the vaginal approach was useful in learning this surgical technique, and 95.8% agreed they had learned details of the surgical anatomy of the pelvis. All participants agreed that it should be mandatory to train in these techniques with cadavers before practice with live patients. In addition, 84.7% responded that the cadaveric model was superior to animal and other types of models. CONCLUSION: Laparoscopic inspection of the procedure performed with the vaginal approach allowed a better understanding of the surgical technique by making "visible" the anatomical structures that were commonly only palpated. Use of the cadaverous model was considered most efficient for training in this surgical technique.

Detection of high-risk pregnancies in low-resource settings: a case study in Guatemala.

BACKGROUND: Maternal and neonatal mortality is still very high at a global level, even though its reduction is a goal established among the Sustainable Development Goals by the United Nations. In order to improve prenatal care to address this challenge, this article proposes a strategy to detect and refer high risk pregnancies in rural setting through a portable ultrasound system combined with blood and urine strip tests. METHODS: The Healthy Pregnancy project was conceived as a single, explanatory and positivist case study, with a sample of ten thousand pregnant women attended by itinerant nurses of the Departments of Alta Verapaz and San Marcos. These nurses were trained and equipped with 31 portable ultrasound, and blood and urine tests to detect common obstetric pathology. Moreover, two obstetricians were responsible for remotely supervising the quality of prenatal care. Target communities were selected by the Health Directorates of the public health system from those that had the highest maternal mortality in previous years. RESULTS: The project attended to 10,108 women in 2 years and 3 months. 55 twin gestations (0.54%) were diagnosed. Non-cephalic presentation was found in 14.87% of the pregnant women attended from week 32 onwards. 20 patients were referred for non-evolutive gestation. An 11.08% prevalence of anemia was detected. Urine infections were diagnosed in 16.43% of the cases. Proteinuria was detected in 2.6% of patients, but only 17 of them presented high blood pressure and were therefore referred with a suspected pre-eclampsia. DISCUSSION: The results obtained indicate that an intervention of these characteristics makes it possible to improve the quality of care of rural pregnant women in low and middle-income countries. CONCLUSION: The results show that with suitable equipment, training, and supervision, the nursing staff in charge of care in rural areas can identify and refer most of the obstetric risks in time, which may contribute to the reduction of maternal mortality. TRIAL REGISTRATION: This research was not registered because it is a case study in which the assignment of the medical intervention was not at the discretion of the investigators.

Machine Learning Techniques for Undertaking Roundabouts in Autonomous Driving.

This article presents a machine learning-based technique to build a predictive model and generate rules of action to allow autonomous vehicles to perform roundabout maneuvers. The approach consists of building a predictive model of vehicle speeds and steering angles based on collected data related to driver-vehicle interactions and other aggregated data intrinsic to the traffic environment, such as roundabout geometry and the number of lanes obtained from Open-Street-Maps and offline video processing. The study systematically generates rules of action regarding the vehicle speed and steering angle required for autonomous vehicles to achieve complete roundabout maneuvers. Supervised learning algorithms like the support vector machine, linear regression, and deep learning are used to form the predictive models.

A Flexible 12-Lead/Holter Device with Compression Capabilities for Low-Bandwidth Mobile-ECG Telemedicine Applications.

In recent years, a number of proposals for electrocardiogram (ECG) monitoring based on mobile systems have been delivered. We propose here an STM32F-microcontroller-based ECG mobile system providing both long-term (several weeks) Holter monitoring and 12-lead ECG recording, according to the clinical standard requirements for these kinds of recordings, which in addition can yield further digital compression at stages close to the acquisition. The system can be especially useful in rural areas of developing countries, where the lack of specialized medical personnel justifies the introduction of telecardiology services, and the limitations of coverage and bandwidth of cellular networks require the use of efficient signal compression systems. The prototype was implemented using a small architecture, with a 16-bits-per-sample resolution. We also used a low-noise instrumentation amplifier TI ADS1198, which has a multiplexer and an analog-to-digital converter (16 bits and 8 channels) connected to the STM32F processor, the architecture of which incorporates a digital signal processing unit and a floating-point unit. On the one hand, the system portability allows the user to take the prototype in her/his pocket and to perform an ECG examination, either in 12-lead controlled conditions or in Holter monitoring, according to the required clinical scenario. An app in the smartphone is responsible for giving the users a friendly interface to set up the system. On the other hand, electronic health recording of the patients are registered in a web application, which in turn allows them to connect to the Internet from their cellphones, and the ECG signals are then sent though a web server for subsequent and ubiquitous analysis by doctors at any convenient terminal device. In order to determine the quality of the received signals, system testing was performed in the three following scenarios: (1) The prototype was connected to the patient and the signals were subsequently stored; (2) the prototype was connected to the patient and the data were subsequently transferred to the cellphone; (3) the prototype was connected to the patient, and the data were transferred to the cellphone and to the web via the Internet. An additional benchmarking test with expert clinicians showed the clinical quality provided by the system. The proposed ECG system is the first step and paves the way toward mobile cardiac monitors in terms of compatibility with the electrocardiographic practice, including the long-term monitoring, the usability with 12 leads, and the possibility of incorporating signal compression at the early stages of the ECG acquisition.

The MEK1 inhibitors UO126 and PD98059 block PDGF-AB induced phosphorylation of threonine 292 in porcine smooth muscle cells.

PDGF-AB and FGF-2 (GFs) induce smooth muscle cell (SMC) proliferation which is indispensible for arteriogenesis. While there is common agreement that GFs stimulate SMC proliferation through phosphorylation (P-) of MEK1/2 at Ser218/222, we previously demonstrated that the MEK inhibitors PD98059 and UO126 did not inhibit P-Ser218/222 as originally proposed but caused strong hyperphosphorylation. Here, we demonstrate that GFs increased phosphorylation of MEK1 at Thr292 while UO126 and PD98059 blocked this phosphorylation. This was again surprising since phosphorylation of Thr292 is regarded as a negative feedback loop. Our findings suggest that inhibition of Thr292 phosphorylation in combination with hyperphosphorylation of Ser218/222 serves as an "off" switch of SMC proliferation and potentially of arteriogenesis.