Peptidyl arginine deiminases (PAD) are proteins that modify arginine residues to citrulline. In humans there are five isoforms PAD1-4 and PAD6. PAD4 is involved in several human diseases such as ...Alzheimer, breast cancer, rheumatoid arthritis and therefore has been recognized as a potential pharmacological target.
In this work, 3175 molecules retrieved from ZINC12 Food and Drug Administration (FDA) catalog database were assayed through a structure-based virtual screening to identify potential PAD4 binders. Three were confirmed through enzyme inhibition studies. Flow cytometry analysis were used to check for drug cytotoxic effects on blood cells from three healthy donors.
Molecular docking in a wild-type PAD4 structure showed the top 20 FDA molecules with the best binding energies. Those molecules were distributed in clusters of mixed binding energies but with similar chemical structures. These patterns along with the FDA information were used to aid in the rational selection of methotrexate, testosterone and leucovorin compounds for in vitro evaluations. Time course fluorescent enzyme kinetics confirmed that methotrexate (0.01–1 mmol) and testosterone enanthate (49.9–12.5 mmol) inhibit PAD4 at similar levels to the known inhibitor BB-Cl-amidine (8.8 mmol), except leucovorin. The chosen concentrations lack cytotoxic effects on blood cells.
These findings encourage repositioning campaigns in the quest of PAD4 inhibitors.
Medical imaging-based triage is a critical tool for emergency medicine in both civilian and military settings. Ultrasound imaging can be used to rapidly identify free fluid in abdominal and thoracic ...cavities which could necessitate immediate surgical intervention. However, proper ultrasound image capture requires a skilled ultrasonography technician who is likely unavailable at the point of injury where resources are limited. Instead, robotics and computer vision technology can simplify image acquisition. As a first step towards this larger goal, here, we focus on the development of prototypes for ultrasound probe securement using a robotics platform. The ability of four probe adapter technologies to precisely capture images at anatomical locations, repeatedly, and with different ultrasound transducer types were evaluated across more than five scoring criteria. Testing demonstrated two of the adapters outperformed the traditional robot gripper and manual image capture, with a compact, rotating design compatible with wireless imaging technology being most suitable for use at the point of injury. Next steps will integrate the robotic platform with computer vision and deep learning image interpretation models to automate image capture and diagnosis. This will lower the skill threshold needed for medical imaging-based triage, enabling this procedure to be available at or near the point of injury.
Point-of-care ultrasound imaging is a critical tool for patient triage during trauma for diagnosing injuries and prioritizing limited medical evacuation resources. Specifically, an eFAST exam ...evaluates if there are free fluids in the chest or abdomen but this is only possible if ultrasound scans can be accurately interpreted, a challenge in the pre-hospital setting. In this effort, we evaluated the use of artificial intelligent eFAST image interpretation models. Widely used deep learning model architectures were evaluated as well as Bayesian models optimized for six different diagnostic models: pneumothorax (i) B- or (ii) M-mode, hemothorax (iii) B- or (iv) M-mode, (v) pelvic or bladder abdominal hemorrhage and (vi) right upper quadrant abdominal hemorrhage. Models were trained using images captured in 27 swine. Using a leave-one-subject-out training approach, the MobileNetV2 and DarkNet53 models surpassed 85% accuracy for each M-mode scan site. The different B-mode models performed worse with accuracies between 68% and 74% except for the pelvic hemorrhage model, which only reached 62% accuracy for all model architectures. These results highlight which eFAST scan sites can be easily automated with image interpretation models, while other scan sites, such as the bladder hemorrhage model, will require more robust model development or data augmentation to improve performance. With these additional improvements, the skill threshold for ultrasound-based triage can be reduced, thus expanding its utility in the pre-hospital setting.
Sustainability indices are a way of quantifying the progress that a certain region has achieved in terms of sustainability that can be transmitted to society and decision makers. The watershed ...approach has become relevant for managing water resources and ensuring their sustainability. This study combined the above two approaches by applying an adapted watershed sustainability index (WSI) to evaluate the sustainable development of the Santiago–Guadalajara River basin (SGRB), which passes through Guadalajara, the second-most populous city in Mexico. The river is the most polluted waterway in the country. The WSI of each sub-basin places the SGRB at a sustainability level between low in the upper and lower basin region and intermediate in the central basin region. Regions with a low sustainability level are characterized by environmental degradation due to changes in land use, while in the region with intermediate sustainability, the factor that most affect the evaluation is water availability. An overall sustainability score of WSI = 0.36 was obtained for the study area, which is lower than that of any other basins evaluated in the same manner around the world. These results send a clear message to decision makers of the three government levels, in charge of the environmental sustainability of the basin, of the need to take action to facilitate its recovery.
Tuning the electronic structure of metal–organic frameworks is the key to extending their functionality to the photocatalytic conversion of absorbed gases. Herein we discuss how the band edge ...positions in zeolitic imidazolate frameworks (ZIFs) can be tuned by mixing different imidazole‐based linkers within the same structure. We present the band alignment for a number of known and hypothetical Zn‐based ZIFs with respect to the vacuum level. Structures with a single type of linker exhibit relatively wide band gaps; however, by mixing linkers of a low‐lying conduction edge with linkers of a high‐lying valence edge, we can predict materials with ideal band positions for visible‐light water splitting and CO2 reduction photocatalysis. By introducing copper in the tetrahedral position of the mixed‐linker ZIFs, it would be possible to increase both photo‐absorption and the electron–hole recombination times.
The sum of its parts: A computational study shows that using mixed linkers within zeolitic imidazolate frameworks provides a route for tuning their electronic gaps and band edge positions. It is theoretically possible in this way to match the electronic structure requirements for photocatalytic reactions including water splitting and CO2 reduction.
Viral sepsis has been proposed as an accurate term to describe all multisystemic dysregulations and clinical findings in severe and critically ill COVID-19 patients. The adoption of this term may ...help the implementation of more accurate strategies of early diagnosis, prognosis, and in-hospital treatment. We accurately quantified 110 metabolites using targeted metabolomics, and 13 cytokines/chemokines in plasma samples of 121 COVID-19 patients with different levels of severity, and 37 non-COVID-19 individuals. Analyses revealed an integrated host-dependent dysregulation of inflammatory cytokines, neutrophil activation chemokines, glycolysis, mitochondrial metabolism, amino acid metabolism, polyamine synthesis, and lipid metabolism typical of sepsis processes distinctive of a mild disease. Dysregulated metabolites and cytokines/chemokines showed differential correlation patterns in mild and critically ill patients, indicating a crosstalk between metabolism and hyperinflammation. Using multivariate analysis, powerful models for diagnosis and prognosis of COVID-19 induced sepsis were generated, as well as for mortality prediction among septic patients. A metabolite panel made of kynurenine/tryptophan ratio, IL-6, LysoPC a C18:2, and phenylalanine discriminated non-COVID-19 from sepsis patients with an area under the curve (AUC (95%CI)) of 0.991 (0.986–0.995), with sensitivity of 0.978 (0.963–0.992) and specificity of 0.920 (0.890–0.949). The panel that included C10:2, IL-6, NLR, and C5 discriminated mild patients from sepsis patients with an AUC (95%CI) of 0.965 (0.952–0.977), with sensitivity of 0.993(0.984–1.000) and specificity of 0.851 (0.815–0.887). The panel with citric acid, LysoPC a C28:1, neutrophil-lymphocyte ratio (NLR) and kynurenine/tryptophan ratio discriminated severe patients from sepsis patients with an AUC (95%CI) of 0.829 (0.800–0.858), with sensitivity of 0.738 (0.695–0.781) and specificity of 0.781 (0.735–0.827). Septic patients who survived were different from those that did not survive with a model consisting of hippuric acid, along with the presence of Type II diabetes, with an AUC (95%CI) of 0.831 (0.788–0.874), with sensitivity of 0.765 (0.697–0.832) and specificity of 0.817 (0.770–0.865).
Introduction
Dealing with intercultural communicative barriers in European countries’ national health services is an increasing and necessary challenge to guarantee migrant women's right to health ...care. This integrative review describes the communication barriers and facilitators that migrant women encounter to access and use sexual and reproductive health (SRH) services in Europe.
Methods
A literature search was performed to identify original studies in PubMed, CINAHL, PsycINFO, Web of Science, and Scopus, using keywords associated with migrant women and SRH services. This was supplemented by scanning the reference lists from relevant studies and similar reviews. Studies exploring the perspective of migrant women about communication barriers and facilitators to the access and use of SRH services were included, whereas those that solely explored health professional's experiences were excluded. Findings were organized into 4 themes: (1) verbal‐linguistic barriers, (2) nonverbal language barriers, (3) cultural barriers, and (4) communication facilitators.
Results
Nineteen studies met the inclusion criteria. Results showed that when women had problems understanding or being understood by health professionals, they experienced feelings of anxiety, fear, insecurity, and discrimination that discouraged them from using SRH services. The most requested facilitators by women were health education, access to professional interpreters and translation of written information, and increasing the practitioners’ cultural competence.
Discussion
Communication barriers undermine migrant women's right to benefit from preventive SRH programs and to make informed decisions concerning their health. It is necessary to establish tailored plans in each health care center to improve intercultural communication that integrate facilitators proposed by women. Future research should provide solid evidence on the effectiveness of each facilitator implemented.
The clinical effectiveness of coronavirus disease 2019 (COVID-19) vaccination in kidney transplant (KT) recipients is lower than in the general population.
From April to October 2021, 481 KT ...recipients with COVID-19, included in the Spanish Society of Nephrology COVID-19 Registry, were analyzed. Data regarding vaccination status and vaccine type were collected, and outcomes of unvaccinated or partially vaccinated patients (n = 130) were compared with fully vaccinated patients (n = 351).
Clinical picture was similar and survival analysis showed no differences between groups: 21.7% of fully vaccinated patients and 20.8% of unvaccinated or partially vaccinated died (P = 0.776). In multivariable analysis, age and pneumonia were independent risk factors for death, whereas vaccination status was not related to mortality. These results remained similar when we excluded patients with partial vaccination, as well as when we analyzed exclusively hospitalized patients. Patients vaccinated with mRNA-1273 (n = 213) showed a significantly lower mortality than those who received the BNT162b2 vaccine (n = 121) (hazard ratio: 0.52; 95% confidence interval, 0.31-0.85; P = 0.010).
COVID-19 severity in KT patients has remained high and has not improved despite receiving 2 doses of the mRNA vaccine. The mRNA-1273 vaccine shows higher clinical effectiveness than BNT162b2 in KT recipients with breakthrough infections. Confirmation of these data will require further research taking into account the new variants and the administration of successive vaccine doses.
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