Selection Of Candidates Research Articles

Genome-wide analysis of Brucella melitensis growth in spleen of infected mice allows rational selection of new vaccine candidates.

Live attenuated vaccines (LAVs) whose virulence would be controlled at the tissue level could be a crucial tool to effectively fight intracellular bacterial pathogens, because they would optimize the induction of protective immune memory while avoiding the long-term persistence of vaccine strains in the host. Rational development of these new LAVs implies developing an exhaustive map of the bacterial virulence genes according to the host organs implicated. We report here the use of transposon sequencing to compare the bacterial genes involved in the multiplication of Brucella melitensis, a major causative agent of brucellosis, in the lungs and spleens of C57BL/6 infected mice. We found 257 and 135 genes predicted to be essential for B. melitensis multiplication in the spleen and lung, respectively, with 87 genes common to both organs. We selected genes whose deletion is predicted to produce moderate or severe attenuation in the spleen, the main known reservoir of Brucella, and compared deletion mutants for these genes for their ability to protect mice against challenge with a virulent strain of B. melitensis. The protective efficacy of a deletion mutant for the plsC gene, implicated in phospholipid biosynthesis, is similar to that of the reference Rev.1 vaccine but with a shorter persistence in the spleen. Our results demonstrate that B. melitensis faces different selective pressures depending on the organ and underscore the effectiveness of functional genome mapping for the design of new safer LAV candidates.

A Combined Computational and Experimental Approach to Studying Tropomyosin Kinase Receptor B Binders for Potential Treatment of Neurodegenerative Diseases.

Tropomyosin kinase receptor B (TrkB) has been explored as a therapeutic target for neurological and psychiatric disorders. However, the development of TrkB agonists was hindered by our poor understanding of the TrkB agonist binding location and affinity (both affect the regulation of disorder types). This motivated us to develop a combined computational and experimental approach to study TrkB binders. First, we developed a docking method to simulate the binding affinity of TrkB and binders identified by our magnetic drug screening platform from Gotu kola extracts. The Fred Docking scores from the docking computation showed strong agreement with the experimental results. Subsequently, using this screening platform, we identified a list of compounds from the NIH clinical collection library and applied the same docking studies. From the Fred Docking scores, we selected two compounds for TrkB activation tests. Interestingly, the ability of the compounds to increase dendritic arborization in hippocampal neurons matched well with the computational results. Finally, we performed a detailed binding analysis of the top candidates and compared them with the best-characterized TrkB agonist, 7,8-dyhydroxyflavon. The screening platform directly identifies TrkB binders, and the computational approach allows for the quick selection of top candidates with potential biological activities based on the docking scores.

Opening doors to more intra-party democracy? Local politicians’ perspectives on including voters in candidate selection processes in Flanders (Belgium)

Opening doors to more intra-party democracy? Local politicians’ perspectives on including voters in candidate selection processes in Flanders (Belgium)

Predicting tumor invasion depth in gastric cancer: developing and validating multivariate models incorporating preoperative IVIM-DWI parameters and MRI morphological characteristics

IntroductionAccurate assessment of the depth of tumor invasion in gastric cancer (GC) is vital for the selection of suitable patients for neoadjuvant chemotherapy (NAC). Current problem is that preoperative differentiation between T1-2 and T3-4 stage cases in GC is always highly challenging for radiologists.MethodsA total of 129 GC patients were divided into training (91 cases) and validation (38 cases) cohorts. Pathology from surgical specimens categorized patients into T1-2 and T3-4 stages. IVIM-DWI and MRI morphological characteristics were evaluated, and a multimodal nomogram was developed. The MRI morphological model, IVIM-DWI model, and combined model were constructed using logistic regression. Their effectiveness was assessed using receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), and clinical impact curves (CIC).ResultsThe combined nomogram, integrating preoperative IVIM-DWI parameters (D value) and MRI morphological characteristics (maximum tumor thickness, extra-serosal invasion), achieved the highest area under the curve (AUC) values of 0.901 and 0.883 in the training and validation cohorts, respectively. No significant difference was observed between the AUCs of the IVIM-DWI and MRI morphological models in either cohort (training: 0.796 vs. 0.835, p = 0.593; validation: 0.794 vs. 0.766, p = 0.79).ConclusionThe multimodal nomogram, combining IVIM-DWI parameters and MRI morphological characteristics, emerges as a promising tool for assessing tumor invasion depth in GC, potentially guiding the selection of suitable candidates for neoadjuvant chemotherapy (NAC) treatment.

Incidence and risk factors for first and recurrent ICD shock therapy in patients with an implantable cardioverter defibrillator.

Advances in medical treatment and outcomes in implantable cardioverter-defibrillator (ICD) recipients incentivize a need for improved candidate selection and identification of risk factors for ICD therapy. We examined contemporary rates of and risk factors for ICD therapy. Patients with ICD for primary (PP) or secondary prevention (SP), implanted between January 2010 and December 2020, were followed for appropriate and inappropriate incident and recurrent shock. Overall, 2998 patients (mean age 61.8 ± 12.7years, 20% female, 73% ICD carriers, and 47.1% SP) were analyzed with a median follow-up of 4.3 (interquartile range (IQR) 2.1-7.4) years. A total of 426/2998 (14.2%) patients had shock; 364/2998 (12.1%) had appropriate and 82/2998 (2.7%) inappropriate shock, with annualized event rates of 2.34 (2.11-2.59) and 0.49 (0.39-0.61) per 100 person-years, respectively. Of those with shock, 133/364 (36.5%) experienced recurrent appropriate shock and 8/364 (2.2%) received recurrent inappropriate shock, with event rates of 10.57 (8.85-12.53) and 0.46 (0.20-0.92), respectively. In multivariable analyses, female sex was associated with a reduced risk of incident appropriate shock (hazard ratio 0.69 [95% confidence interval 0.52; 0.91]). Of other variables, only revascularization status was associated with recurrent appropriate shock in PP, and CRT-D with recurrent appropriate shock in the overall cohort. One in eight ICD recipients received appropriate shock 2-7years after guideline-directed implantation. More than one-third of patients with a first shock experienced recurrent shock. Few clinical variables showed potential in predicting shocks, illustrating a need for more advanced tools to select candidates for implantation.

Use of Structural Alerts for Reactive Metabolites in the Application SpotRM.

Reactive metabolite (RM) formation is widely accepted as playing a crucial role in causing idiosyncratic adverse drug reactions (IADRs), where the liver is most affected. An important goal of drug design is to avoid selection of drug candidates giving rise to RMs and therefore risk causing problems later on involving IADRs. The simplest, initial approach is to avoid test structures that have substructures known or strongly suspected to be associated with IADRs. However, as is evident from the many case reports of IADRs, in most cases a clear association with any (bio)chemical mechanism is lacking, which makes it hard to establish any structure-toxicity relationship. Separate studies of RM formation, in vitro and in vivo, have led to likely evidence and to establishing many structural alerts (SAs) that can be used for fast selection/deselection of planned test compounds. As a background to a discussion of the concept, 25 kinase inhibitor drugs with known problems of hepatotoxicity were probed against a set of SAs contained in the application SpotRM. A clear majority of the probed drugs show liabilities as evident by being flagged by more than one of the fairly established types of SAs. At the same time, no clear SAs were found in three drugs, which is discussed in the broader context of usefulness and selection tactics of SAs in drug design.

Evolutionary dependency of cancer mutations in gene pairs inferred by nonsynonymous-synonymous mutation ratios

BackgroundDetermining the impact of somatic mutations requires understanding the functional relationship of genes acquiring mutations; however, it is largely unknown how mutations in functionally related genes influence each other.MethodsWe employed non-synonymous-to-synonymous or dNdS ratios to evaluate the evolutionary dependency (ED) of gene pairs, assuming a mutation in one gene of a gene pair can affect the evolutionary fitness of mutations in its partner genes as mutation context. We employed PanCancer- and tumor type-specific mutational profiles to infer the ED of gene pairs and evaluated their biological relevance with respect to gene dependency and drug sensitivity.ResultsWe propose that dNdS ratios of gene pairs and their derived cdNS (context-dependent dNdS) scores as measure of ED distinguishing gene pairs either as synergistic (SYN) or antagonistic (ANT). Mutation contexts can induce substantial changes in the evolutionary fitness of mutations in the paired genes, e.g., IDH1 and IDH2 mutation contexts lead to substantial increase and decrease of dNdS ratios of ATRX indels and IDH1 missense mutations corresponding to SYN and ANT relationship with positive and negative cdNS scores, respectively. The impact of gene silencing or knock-outs on cell viability (genetic dependencies) often depends on ED, suggesting that ED can guide the selection of candidates for synthetic lethality such as TCF7L2-KRAS mutations. Using cell line-based drug sensitivity data, the effects of targeted agents on cell lines are often associated with mutations of genes exhibiting ED with the target genes, informing drug sensitizing or resistant mutations for targeted inhibitors, e.g., PRSS1 and CTCF mutations as resistant mutations to EGFR and BRAF inhibitors for lung adenocarcinomas and melanomas, respectively.ConclusionsWe propose that the ED of gene pairs evaluated by dNdS ratios can advance our understanding of the functional relationship of genes with potential biological and clinical implications.

Palliative use of self-expanding metal stents in initially anticancer treatment-intolerant patients with esophageal cancer

BackgroundThe post-insertion clinical course of esophageal self-expandable metal stents (SEMS) in initially frail patients with esophageal carcinoma (EC) with dysphagia remains unclear. This study aimed to assess dysphagia improvement and evaluate prognosis in initially frail patients with advanced EC following SEMS insertion.MethodsWe retrospectively reviewed EC patients with EC who underwent esophageal SEMS insertion at our institution between January 2014 and March 2023. Inclusion criteria comprised Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 3 or ECOG PS 2 for individuals aged ≥ 75 years and recommendation for best supportive care by a multidisciplinary team.ResultsForty-six patients met the inclusion criteria. Among them, 37 patients (80.4%) were ≥ 75 years old, and 21 patients (45.7%) exhibited ECOG PS 3 or 4. Dysphagia score (DS) ≥ 3 was observed in 27 patients (58.7%). All esophageal SEMS insertions were successfully completed. Post-procedure, there were two fatal cases of aspiration pneumonia and one perforation incident. DS improved to ≤ 1 in 25 patients (54.3%), with multivariate analysis indicating DS 3–4 and Glasgow Prognostic Score (GPS) 1–2 as negative predictive factors. The median overall survival was 4.1 months (95% confidence interval 1.8–6.5).ConclusionsEsophageal SEMS insertion effectively alleviated dysphagia in initially frail EC patients, yet prognosis remained poor, with occurrences of some fatal adverse events. Careful selection of candidates for esophageal SEMS insertions is crucial in this demographic, particularly considering the challenges in improving dysphagia for patients with DS 3–4 and GPS 1–2.

Recommendations for clinical decision-making when offering exoskeletons for community use in individuals with spinal cord injury.

Approved in 2014 by the Food and Drug Administration (FDA) for use with a trained companion, personal powered exoskeletons (PPE) for individuals with spinal cord injury (SCI) provide an opportunity for the appropriate candidate to ambulate in their home and community. As an adjunct to wheeled mobility, PPE use allows those individuals who desire to ambulate the opportunity to experience the potential physiological and psychosocial benefits of assisted walking outside of a rehabilitation setting. There exists, however, a knowledge gap for clinicians regarding appropriate candidate selection for use, as well as who might benefit from ambulating with a PPE. The purpose of this paper is to provide guidance for clinicians working with individuals living with SCI by outlining an expert consensus for a PPE decision-making algorithm, as well as a discussion of potential physiological and psychosocial benefits from PPE use based on early evidence in publication.

Plants and their uses in dermatological recipes of the Receptarium of Burkhard III von Hallwyl from 16th century Switzerland – Data mining a historical text and preliminary in vitro screening

Ethnopharmacological relevanceHistorical texts on materia medica can be an attractive source of ethnopharmacological information. Various research groups have investigated corresponding resources from Europe and the Mediterranean region, pursuing different objectives. Regardless of the method used, the indexing of textual information and its conversion into data sets useful for further investigations represents a significant challenge. Aim of the studyFirst, this study aims to systematically catalogue pharmaco-botanical information in the Receptarium of Burkhard von Hallwyl (RBH) in order to identify candidate plants in a targeted manner. Secondly, the potential of RBH as a resource for pharmacological investigations will be assessed by means of a preliminary in vitro screening. Materials and methodsWe developed a relational database for the systematic recording of parameters composing the medical recipes contained in the historical text. Focusing on dermatological recipes, we explored the mentioned plants and their uses by drawing on specific literature. The botanical identities (candidate species) suggested in the literature for the historical plant names were rated based on their plausibility of being the correct attribution. The historical uses were interpreted by consulting medical-historical and modern clinical literature. For the subsequent in vitro screening, we selected candidate species used in recipes directed at the treatment of inflammatory or infectious skin disorders and wounds. Plants were collected in Switzerland and their hydroethanolic crude extracts tested for possible cytotoxic effects and for their potential to modulate the release of IL-6 and TNF in PS-stimulated whole blood and PBMCs. ResultsThe historical text analysis points up the challenges associated with the assessment of historical plant names. Often two or more plant species are available as candidates for each of the 161 historical plant names counted in the 200 dermatological recipes in RBH. On the other hand, our method enabled to draw conclusions about the diseases underlying the 56 medical applications mentioned in the text. On this basis, 11 candidate species were selected for in vitro screening, four of which were used in RBH in herbal simple recipes and seven in a herbal compound formulation. None of the extracts tested showed a noteworthy effect on cell viability except for the sample of Sanicula europaea L. Extracts were tested at 50 μg/mL in the whole blood assay, where especially Vincetoxicum hirundinaria Medik. or Solanum nigrum L. showed inhibitory or stimulatory activities. In the PBMC assay, the root of Vincetoxicum hirundinaria revealed a distinct inhibitory effect on IL-6 release (IC50 of 3.6 μg/mL). ConclusionsUsing the example of RBH, this study illustrates a possible ethnopharmacological path from unlocking the historical text and its subsequent analysis, through the selection and collection of plant candidates to their in vitro investigation. Fully documenting our approach to the analysis of historical texts, we hope to contribute to the discussion on solutions for the digital indexing of premodern information on the use of plants or other natural products.

Safety and reactogenicity of a controlled human infection model of sand fly-transmitted cutaneous leishmaniasis.

The leishmaniases are globally important parasitic diseases for which no human vaccines are currently available. To facilitate vaccine development, we conducted an open-label observational study to establish a controlled human infection model (CHIM) of sand fly-transmitted cutaneous leishmaniasis (CL) caused by Leishmania major. Between 24 January and 12 August 2022, we exposed 14 participants to L. major-infected Phlebotomus duboscqi. The primary objective was to demonstrate effectiveness of lesion development (take rate) and safety (absence of CL lesion at 12 months). Secondary and exploratory objectives included rate of lesion development, parasite load and analysis of local immune responses by immunohistology and spatial transcriptomics. Lesion development was terminated by therapeutic biopsy (between days 14 and 42 after bite) in ten participants with clinically compatible lesions, one of which was not confirmed by parasite detection. We estimated an overall take rate for CL development of 64% (9/14). Two of ten participants had one and one of ten participants had two lesion recurrences 4-8 months after biopsy that were treated successfully with cryotherapy. No severe or serious adverse events were recorded, but as expected, scarring due to a combination of CL and the biopsy procedure was evident. All participants were lesion free at >12-month follow-up. We provide the first comprehensive map of immune cell distribution and cytokine/chemokine expression in human CL lesions, revealing discrete immune niches. This CHIM offers opportunities for vaccine candidate selection based on human efficacy data and for a greater understanding of immune-mediated pathology. ClinicalTrials.gov identifier: NCT04512742 .

TINDAKAN SOSIAL PENGGUNAAN SIMBOL AGAMA DALAM POSTER KAMPANYE LEGISLATIF TAHUN 2019 DI PROVINSI BANTEN

This study discusses the phenomenon of the use of religious attributes in campaign posters that occurred during the general elections (elections) in 2019, especially in the selection of legislative candidates in Banten Province who were the subject of research, which we know that religious attributes are often used by Muslim communities in Banten in conducting worship or religious activities, but the political elite using religious attributes as a political message in this campaign poster makes a shift in meaning and the motives used. To examine the identification of the problem the researcher used Max Weber's Social Action Theory and Husserl's phenomenological method, interpretative paradigms and qualitative approaches to look for explanations about events and interpret phenomena that occur, in collecting data researchers conducted observations, in-depth interviews, documentation and literature presentations. The results of this study indicate that the motives carried out by legislative candidates in using religious attributes in the campaign poster are because of the disclosure of identity, habits, image formation and culture. For symbolic meaning in daily life and politics used to worship and religious activities, respect religious people and attend formal activities. Keywords: Husserl's Phenomenology, Meaning, Political Communication, Social Action

Interaction between political pr and political agenda-setting from the perspective of the presidential elections in the Republic of Moldova, 2024 (case study)

The interaction between political PR and the political media agenda-setting process can play a crucial role in creating a climate of opinion in an electoral context. The presidential initiative to organize a republican referendum on the subject of Moldova's accession to the European Union has become a widely publicized event in the local media. Our working hypothesis is that this initiative, which is an element of political PR, has a strong impact on public opinion, and through the media it manages to superimpose the agenda of an electoral candidate with the public agenda of citizens. We are thus talking about the interaction of the three types of agenda - political agenda, media agenda, public agenda (citizens' agenda).

Understanding predictions of drug profiles using explainable machine learning models

PurposeThe analysis of absorption, distribution, metabolism, and excretion (ADME) molecular properties is of relevance to drug design, as they directly influence the drug’s effectiveness at its target location. This study concerns their prediction, using explainable Machine Learning (ML) models. The aim of the study is to find which molecular features are relevant to the prediction of the different ADME properties and measure their impact on the predictive model.MethodsThe relative relevance of individual features for ADME activity is gauged by estimating feature importance in ML models’ predictions. Feature importance is calculated using feature permutation and the individual impact of features is measured by SHAP additive explanations.ResultsThe study reveals the relevance of specific molecular descriptors for each ADME property and quantifies their impact on the ADME property prediction.ConclusionThe reported research illustrates how explainable ML models can provide detailed insights about the individual contributions of molecular features to the final prediction of an ADME property, as an effort to support experts in the process of drug candidate selection through a better understanding of the impact of molecular features.

SIMULACRUM PEMANFAATAN ARTIFICIAL INTELLIGANCE PADA KAMPANYE POLITIK PILPRES DAN WAPRES 2024 MELALUI VIDEO TIKTOK

Digital systems and networks (internet), which have increasingly developed recently, have triggered various technological innovations. One of the innovations that has received great attention from citizens of the world - indications are that there are various technological discoveries through applications on cellphones - is the presence of Artificial Intelligence (AI) technology. In formats in the media realm - whether films, videos, photos, music or text - AI technology has been presented and used with its sophistication. Although the use of AI actually becomes a simulacrum in text messages - borrowing the concept of simulacrum from Jean Baudrillard - in a number of cinema films and social media. Specifically on social media, AI technology is being used by a number of political parties and success teams or spin doctors from each pair of presidential and vicepresidential candidates in 2024 in delivering their political campaigns. The content of political campaign messages published on social media regarding the election of presidential and vicepresidential candidates (presidential and vice presidential candidates) - including Facebook, YouTube, effective in the context of delivering communication messages. The range of communication or political campaign messages that are appropriate and effective - via cell phones or mobile phones and laptops - is able to reach and shape personal perceptions through cognitive, affective and conative structures or behavior towards potential voters. Although, this research only examines political campaigns using the concept of simulacrum theory and political communication (campaigns) on short videos tens of seconds long that utilize AI technology and are distributed on social media regarding the election of presidential and vice presidential candidates, especially TikTok - considering this social media has penetration and is the highest usage choice – regarding the election of presidential and vice presidential candidates for the period 2024 – 2029.

Newcomers in politics: A thematic analysis of 2023 Malaysian State Election candidates’ TikTok content

Newcomers in politics: A thematic analysis of 2023 Malaysian State Election candidates’ TikTok content

“Machine Learning Approaches to Enhance Candidate Selection: A Comparative Study in HR Recruitment"

“Machine Learning Approaches to Enhance Candidate Selection: A Comparative Study in HR Recruitment"

Early living donor liver transplantation for alcohol-associated hepatitis: Status in the era of increasing demand, unmet needs, and future considerations.

Hazardous alcohol consumption is the leading cause of liver disease worldwide. Alcohol-associated hepatitis (AH) is an acute and serious presentation of alcohol-associated liver disease (ALD) that is associated with high short-term mortality. Medical management remains limited to corticosteroid therapy and intensive nutrition but improves survival in less than 50% of individuals. Liver transplantation (LT) is increasingly recognized as a treatment option for many patients with AH and may lead to greater survival benefit than medical management alone. The rate of wait-listings and LTs for AH has doubled in recent years, especially in the US. Several studies from the West have reported early LT for AH to be successful, where deceased donor LT is the norm. The challenges of LT in living donor centers, particularly for those with AH, are unique and have previously not been discussed in depth. In this review, we aim to discuss the challenges unique to LDLT with respect to candidate and donor selection, ethical considerations, disparities in LDLT, post-LT alcohol relapse, and measures to prevent them while also addressing the definitions and outcomes of early-living donor liver LT (eLDLT) for AH.

Anti-CD19 CAR-T Cell Therapy in Elderly Patients: Multicentric Real-World Experience from GETH-TC/GELTAMO

Chimeric antigen receptor (CAR)-T cell therapy is approved for the treatment of relapsed/refractory (R/R) large B cell lymphoma (LBCL). However, elderly patients might not be candidates for this therapy due to its toxicity, and criteria for candidate selection are lacking. Our aim was to analyze efficacy and toxicity results of CAR-T cell therapy in the population of patients 70 years and older as compared to those obtained in younger patients in the real-world setting. A multicentric retrospective study was performed including patients with R/R aggressive LBCL who received commercial CAR-T cell therapy with either tisagenlecleucel or axicabtagene ciloleucel within the Spanish Group of Hematopoietic Transplant and Cell Therapy/Spanish Group of Lymphomas and Autologous Transplant (GETH-TC/GELTAMO) centers between 2019 and 2023. As of August 2023, 442 adult patients with aggressive LBCL underwent apheresis for CAR-T cell therapy as third or subsequent line and follow-up data was collected. Of 412 infused patients, 71 (17%) were 70 years or older. Baseline characteristics, product selection, and characteristics at apheresis (including disease status, Ann Arbor stage, revised international prognosis index (R-IPI), bulky disease, lactate dehydrogenase [LDH] and ECOG [Eastern Cooperative Group performance status]) were comparable between groups. Median time from both approval to infusion and apheresis to infusion did not differ. No differences were found between groups in overall and complete response rates at 1 and 3 months. With a median follow-up of 12.2 months (range 1-44), 12-month progression-free survival (PFS) and overall survival (OS) were comparable between groups (35.2% in <70 years vs. 35.9% in ≥70 years (P = .938) and 51.1% and 52.1% (P = .885), respectively). Age ≥70 years did not affect PFS (hazard ratio (HR) 0.98, P = .941) and OS (HR 0.97, P = .890) in the univariate and multivariate analysis. Cytokine release syndrome (CRS) was observed in 82% of patients <70 years old and 84.5% in ≥ 70 years old (P = .408). Grade ≥3 CRS was more frequent in the older group (5% vs. 15%, P = .002). In the multivariate analysis, age ≥70 years was associated with an increased risk of grade ≥3 CRS (OR 3.7, P = .013). No differences were observed in terms of overall neurotoxicity (35% vs. 42%, P = .281) or grade ≥3 (12% vs. 17%, P = .33). The proportion of patients with infections, admission to the intensive care unit within the first month, and non-relapse mortality were similar between both groups. CAR-T cell therapy in patients older than 70 years showed similar efficacy to that observed in younger patients in the real-world setting. However, age ≥70 years was an independent risk factor for grades 3-4 CRS. The need for additional strategies to reduce toxicity in this population should be addressed in future studies.

Implementation of K-Nearest Neighbor Method for Selection of New Employee Candidates (Case Study: CV. Syntax Corporation Indonesia)

Implementation of K-Nearest Neighbor Method for Selection of New Employee Candidates (Case Study: CV. Syntax Corporation Indonesia)