Effect of Real-Time Computer-Aided Polyp Detection System (ENDO-AID) on Adenoma Detection in Endoscopists-in-Training: A Randomized Trial.

BACKGROUND: The effect of computer-aided polyp detection (CADe) on adenoma detection rate (ADR) among endoscopists-in-training remains unknown. METHODS: We performed a single-blind, parallel-group, randomized controlled trial in Hong Kong between April 2021 and July 2022 (NCT04838951). Eligible subjects undergoing screening/surveillance/diagnostic colonoscopies were randomized 1:1 to receive colonoscopies with CADe (ENDO-AID[OIP-1]) or not (control) during withdrawal. Procedures were performed by endoscopists-in-training with <500 procedures and <3 years' experience. Randomization was stratified by patient age, sex, and endoscopist experience (beginner vs intermediate level, <200 vs 200-500 procedures). Image enhancement and distal attachment devices were disallowed. Subjects with incomplete colonoscopies or inadequate bowel preparation were excluded. Treatment allocation was blinded to outcome assessors. The primary outcome was ADR. Secondary outcomes were ADR for different adenoma sizes and locations, mean number of adenomas, and non-neoplastic resection rate. RESULTS: A total of 386 and 380 subjects were randomized to CADe and control groups, respectively. The overall ADR was significantly higher in the CADe group than in the control group (57.5% vs 44.5%; adjusted relative risk, 1.41; 95% CI, 1.17-1.72; P < .001). The ADRs for <5 mm (40.4% vs 25.0%) and 5- to 10-mm adenomas (36.8% vs 29.2%) were higher in the CADe group. The ADRs were higher in the CADe group in both the right colon (42.0% vs 30.8%) and left colon (34.5% vs 27.6%), but there was no significant difference in advanced ADR. The ADRs were higher in the CADe group among beginner (60.0% vs 41.9%) and intermediate-level (56.5% vs 45.5%) endoscopists. Mean number of adenomas (1.48 vs 0.86) and non-neoplastic resection rate (52.1% vs 35.0%) were higher in the CADe group. CONCLUSIONS: Among endoscopists-in-training, the use of CADe during colonoscopies was associated with increased overall ADR. (ClinicalTrials.gov, Number: NCT04838951).

PAttern of drug use in PEdiatrics: An observational study in Italian hOSpitals (the PAPEOS study).

AIMS: To assess the extent of off-label drug use and the occurrence of suspected adverse drug reactions (ADRs) among paediatric patients in Italian hospitals. METHODS: We conducted a 2-year prospective cohort study across 22 Italian hospital wards from September 2020 to September 2022. As part of the surveillance project, we performed a 6-month retrieval of all reported ADRs and evaluated all drug prescriptions for their possible off-label use. Following an educational project on pharmacovigilance addressed to healthcare professionals in participating wards, the same data collection was performed. RESULTS: Among the 892 patients included in the study, 64% were admitted to paediatric wards and 36% to neonatal wards. Fifty per cent of all drugs prescribed were used off-label and mainly concerned the administration of a different dose from the one authorized. In neonatal wards, off-label prescriptions occurred slightly more often, with antibacterials being the most frequently used off-label drugs. A total of 35 reports of suspected ADRs were collected, five before the educational project and 30 afterwards. Based on product licence, 10 of the total 35 reports concerned at least one off-label drug use. CONCLUSIONS: The off-label use of drugs in treating paediatric patients was extensive in Italian hospitals. Regulatory interventions are needed to promote the use of drugs based on the latest available literature and improve ADR reporting on children. Paediatric indications and dosages of the drugs most commonly used in children should be supported by appropriate ad hoc studies.

Impact of serious adverse drug reactions on the quality of life of patients on highly active antiretroviral therapy in Maiduguri, northeast Nigeria: a four-year retrospective study.

ABSTRACTSerious adverse drug reactions (sADRs) have a serious impact on the progress being made in providing antiretroviral therapy. The presence of HIV/AIDS and its complications associated with sADRs, has a negative effect on the quality of life (QoL) of people living with HIV/AIDS (PLWHA). This was a descriptive retrospective cohort study of 400 adult HIV patients in which the QoL of PLWHA with sADRs was compared to patients that did not experience ADR who had been on antiretroviral therapy (ART) was followed up for 48 months using the WHOQOL-HIV BREF to measure QoL. Out of 400 patients, 373 (93.25%) respondents completed the study with an overall mean age was 40.8 years (SD ± 8.64). One hundred and ninety-nine patients (53.4%) reported to have experiencing sADR. The response consistently showed significantly higher mean scores in the QoL of patients who had no ADRs in the psychological, social and environments state of health domains compared to those who had ADRs with mean scores (P = 0.000, 0.037 and 0.028), respectively. This study revealed significantly higher scores in patients who had no ADRs compared to those who had ADRs. Low QoL due to serious ADR may add additional burden to HIV disease and complications, and the related discrimination often faced by PLWHA. This study would help clinicians pay serious attention to identifying and promptly managing ADR.

Mining Real-World Big Data to Characterize Adverse Drug Reaction Quantitatively: Mixed Methods Study.

BACKGROUND: Adverse drug reactions (ADRs), which are the phenotypic manifestations of clinical drug toxicity in humans, are a major concern in precision clinical medicine. A comprehensive evaluation of ADRs is helpful for unbiased supervision of marketed drugs and for discovering new drugs with high success rates. OBJECTIVE: In current practice, drug safety evaluation is often oversimplified to the occurrence or nonoccurrence of ADRs. Given the limitations of current qualitative methods, there is an urgent need for a quantitative evaluation model to improve pharmacovigilance and the accurate assessment of drug safety. METHODS: In this study, we developed a mathematical model, namely the Adverse Drug Reaction Classification System (ADReCS) severity-grading model, for the quantitative characterization of ADR severity, a crucial feature for evaluating the impact of ADRs on human health. The model was constructed by mining millions of real-world historical adverse drug event reports. A new parameter called Severity_score was introduced to measure the severity of ADRs, and upper and lower score boundaries were determined for 5 severity grades. RESULTS: The ADReCS severity-grading model exhibited excellent consistency (99.22%) with the expert-grading system, the Common Terminology Criteria for Adverse Events. Hence, we graded the severity of 6277 standard ADRs for 129,407 drug-ADR pairs. Moreover, we calculated the occurrence rates of 6272 distinct ADRs for 127,763 drug-ADR pairs in large patient populations by mining real-world medication prescriptions. With the quantitative features, we demonstrated example applications in systematically elucidating ADR mechanisms and thereby discovered a list of drugs with improper dosages. CONCLUSIONS: In summary, this study represents the first comprehensive determination of both ADR severity grades and ADR frequencies. This endeavor establishes a strong foundation for future artificial intelligence applications in discovering new drugs with high efficacy and low toxicity. It also heralds a paradigm shift in clinical toxicity research, moving from qualitative description to quantitative evaluation.

Emerging trends in research and development on earth abundant materials for ammonia degradation coupled with H2 generation.

Ammonia, as an essential and economical fuel, is a key intermediate for the production of innumerable nitrogen-based compounds. Such compounds have found vast applications in the agricultural world, biological world (amino acids, proteins, and DNA), and various other chemical transformations. However, unlike other compounds, the decomposition of ammonia is widely recognized as an important step towards a safe and sustainable environment. Ammonia has been popularly recommended as a viable candidate for chemical storage because of its high hydrogen content. Although ruthenium (Ru) is considered an excellent catalyst for ammonia oxidation; however, its high cost and low abundance demand the utilization of cheaper, robust, and earth abundant catalyst. The present review article underlines the various ammonia decomposition methods with emphasis on the use of non-noble metals, such as iron, nickel, cobalt, molybdenum, and several other carbides as well as nitride species. In this review, we have highlighted various advances in ammonia decomposition catalysts. The major challenges that persist in designing such catalysts and the future developments in the production of efficient materials for ammonia decomposition are also discussed.

In this dynamic area, ammonia degradation to hydrogen fuel provides a valuable contribution in the carbon neutral economy. Ammonia has been used extensively in several industries and is considered an ideal candidate for hydrogen generation and storage due to its high hydrogen content. Consequently, the ammonia decomposition to yield green hydrogen has become a hot topic in research. Although numerous studies on ammonia decomposition have been conducted over the last few decades, still very few review articles on the most recent advances in this field of catalysis have been published. Through this review, systematic information on the types of decomposition catalysts including both noble (Ru) and non-noble earth abundant metals such as iron, nickel, cobalt, molybdenum, their carbides and nitrides, catalytic routes, as well as the reactivity and mechanism can be comprehended. The literature on newly discovered catalysts, specifically from the last five years, is well documented and explained in this review article. Furthermore, the effect of catalyst supports, their reaction kinetics and mechanistic insights have also been discussed. The challenges and opportunities associated with the decomposition catalysts are comprehensively explicated in the end.

Ammonia decomposition reaction (ADR) is a viable method for hydrogen storage in the form of chemical bonds.Catalysts composed of noble, non-noble metals, amides, imides, carbides, nitrides, and their combinations have been widely explored towards the ADR.Challenges and opportunities in the ammonia oxidation are pointed out.

Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Evolving from the Post COVID-19 Syndrome.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent, debilitating and still enigmatic disease. There is a broad overlap in the symptomatology of ME/CFS and the Post-COVID-19 Syndrome (PCS). A fraction of the PCS patients develop the full clinical picture of ME/CFS. New observations in microvessels and blood from patients suffering from PCS have appeared and include microclots and malformed pathological blood cells. Capillary blood flow is impaired not only by pathological blood components but also by prothrombotic changes in the vascular wall, endothelial dysfunction, and the expression of adhesion molecules in the capillaries. These disturbances can finally cause a low capillary flow and even capillary stasis. A low cardiac stroke volume due to hypovolemia and the inability of the capacitance vessels to adequately constrict to deliver the necessary cardiac preload generate an unfavorable low precapillary perfusion pressure. Furthermore, a predominance of vasoconstrictor over vasodilator influences exists, in which sympathetic hyperactivity and endothelial dysfunction play a strong role, causing the constriction of resistance vessels and of precapillary sphincters, which leads to a fall in capillary pressure behind the sphincters. The interaction of these two precapillary cardiovascular mechanisms causing a low capillary perfusion pressure is hemodynamically highly unfavorable in the presence of a primary capillary stasis, which is already caused by the pathological blood components and their interaction with the capillary wall, to severely impair organ perfusion. The detrimental coincidence of microcirculatory and precapillary cardiovascular disturbances may constitute the key disturbance of the Post-COVID-19 syndrome and finally lead to ME/CFS in predisposed patients because the interaction causes a particular kind of perfusion disturbance-capillary ischemia/reperfusion-which has a high potential of causing mitochondrial dysfunction by inducing sodium- and calcium-overload in skeletal muscles. The latter, in turn, worsens the vascular situation through the generation of reactive oxygen species to close a vicious cycle from which the patient can hardly escape.

Genotypic Analysis of Transmitted and Acquired HIV Drug Resistance in People Living with HIV/AIDS in Surabaya, Indonesia, from 2018 to 2019.

BACKGROUND: Despite the availability of various effective antiretroviral (ARV) drugs, human immunodeficiency virus (HIV) infection has come with HIV drug resistance (HIVDR), which compromises its effectiveness in reducing HIV-related morbidity, mortality, and transmission. The emergence of transmitted (TDR) and acquired HIVDR (ADR) among antiretroviral therapy (ART)-naïve and experienced individuals have been reported in several Indonesian regions. Therefore, continuous HIVDR surveillance is needed in Indonesia, especially in Surabaya, which is identified as having the highest prevalence of HIV infection in East Java; thus, this study aimed to identify the emergence of TDR and ADR among people living with HIV/acquired immune deficiency syndrome (AIDS) (PLWHA). METHODS: Fifty-eight PLWHA infected with HIV type 1 (HIV-1), comprising 21 and 37 ART-naïve and experienced individuals were enrolled in this study, respectively. Blood samples collected from study participants were subjected to genotypic analysis, mainly towards the pol gene encoding protease (PR gene) and reverse transcriptase (RT gene) of HIV-1. RESULTS: Seventeen PR and 21 RT genes were successfully amplified and sequenced from 29 samples. HIV-1 subtyping revealed CRF01_AE as the most dominant subtype (24/29; 82.76%), followed by subtype B (3/29; 10.34%). Uncommon subtypes, including subtype D and a recombinant containing subtypes B and G genomic fragments, were also identified. TDR for PR inhibitors was not detected; however, TDR and ADR for RT inhibitors were identified in 11.11% and 41.67% of samples, respectively. Two amino acid insertions at position 69 of the RT gene (69ins), a previously never-reported mutation in Indonesia, were identified in this study. CONCLUSION: Both TDR and ADR have emerged among PLWHA residing in Surabaya, East Java, Indonesia. Uncommon drug-resistance mutations and subtypes were identified in this study. These situations might hamper ART efficacy and treatment success. Continuous surveillance of HIVDR is necessary to monitor both TDR and ADR in Indonesia.

Knowledge, Attitudes, and Practices of Adverse Drug Reaction Reporting Among Healthcare Professionals in Sri Lanka- A Cross Sectional Study.

Objectives: The objectives of this study were to describe the knowledge, attitudes and practices of Adverse Drug Reactions (ADR) reporting among healthcare professionals at Teaching Hospital Karapitiya (THK), a tertiary care hospital in Sri Lanka. Methodology: A descriptive cross-sectional study was conducted at THK. The healthcare professionals working in THK who were available during the study period were invited to the study. A self-administered pre-tested questionnaire was administered to the participants. Respondents were evaluated for their knowledge, attitudes and practices related to ADR reporting. The data were analyzed using SPSS statistical software. Results: Of the total 444 respondents, 31% were doctors and 69% were nurses. The majority of respondents, 90% (n = 400) were aware of the term ADR, while 64.8% (n = 288) could correctly define it. Among the respondents, 30.8% (n = 137) knew about the types of ADR and only 15.5% (n = 70) were able to mention a drug that is banned due to ADR correctly. Among the respondents, only 38.7% (n = 172) were aware of a formal process of reporting ADR and, only 35.3% (n = 157) stated that they had seen the ADR reporting form. Further, only 33.7% (n = 150) respondents have recognized ADR during their clinical practice and only a small proportion 18.2% (n = 81) have ever reported an ADR during their practice. Regarding attitudes toward ADR reporting, overall 84.1 (n = 373) had positive attitudes toward ADR reporting, while 13.54% (n = 60) of them stayed neutral and 2.25% (n = 10) had negative attitudes toward ADR reporting. Conclusions: Although the majority were aware of ADR , the knowledge and practices regarding spontaneous reporting of ADR are inadequate. However, most respondents have shown a positive attitude toward ADR reporting. A sincere and sustained effort should be made by concerned bodies to enhance the healthcare professionals' knowledge, attitudes, and practices regarding ADR reporting.

Clinical Pertinence and Determinants of Potential Drug-Drug Interactions in Chronic Kidney Disease Patients: A Cross-sectional Study.

Background: Chronic kidney disease (CKD) is one of the major health issues effecting around 15% of world population, and its further complications has raised the need of polypharmacy for management. But this polypharmacy also upsurges the risk of potential drug-drug interactions (pDDIs) in CKD patients, which may further be responsible for increased morbidity and mortality. Objective: The main objective is therefore to evaluate the distribution, severity, causes, associated drug interactions, and clinical relevance of determination of pDDIs in CKD patients. Methods: Medical files of CKD patients examined at nephrology department, Maharishi Markandeshwar Institute of Medical Sciences and Research (MMIMSR), Mullana, between December 2022 and May 2023 were cross-sectionally assessed for this study. Medscape drug interaction checker was used to study patient profiles for pDDIs, and suggestive measures to minimize those pDDIs were studied using DDInter to ensure better clinical decision-making and patient safety. IBM SPSS (version 24) was utilized for statistical analysis. Results: The data reveal that 74.5% of the 200 medical files being evaluated had 839 pDDIs in total, out of which nearly 78.3% of patients had moderate, 15.6% had minor, and 6.07% had serious interactions. The potential adverse outcomes of pDDIs included an irregular heartbeat, hypokalemia, central nervous system (CNS) adverse effects, hypoglycemia, and a decline in therapeutic efficacy. The prevalence of pDDIs was discovered to be substantially correlated with age ≥60 years, (odds ratio [OR] = 0.65; 95% CI = 0.4-0.9; P = 0.040), length of stay ≥10 days (OR = 4.0; 95% CI = 1.29-6.1; P = 0.016), and number of prescribed drugs ≥10 (OR = 5.5; 95% CI = 2.45-10.69; P = 0.004). Conclusion: Patients with CKD have a high incidence of pDDIs (mainly mild to moderate). Older age, duration of hospital stays, and polypharmacy all raise the risk of pDDIs. Healthcare professionals (physicians and clinical pharmacist) should use drug interaction checker software programs like Medscape and DDInter to acquire knowledge about different pDDIS and their alternative measures so that the associated adverse drug reactions (ADRs) can be controlled and rational drug combination can be prescribed for management of CKD ensuring better patient care.

Lack of Effectiveness of Computer Aided Detection for Colorectal Neoplasia: A Systematic Review and Meta-Analysis of Nonrandomized Studies.

BACKGROUND AND AIMS: Benefits of computer-aided detection (CADe) in detecting colorectal neoplasia were shown in many randomized trials in which endoscopists' behavior was strictly controlled. However, the effect of CADe on endoscopists' performance in less-controlled setting is unclear. This systematic review and meta-analyses were aimed at clarifying benefits and harms of using CADe in real-world colonoscopy. METHODS: We searched MEDLINE, EMBASE, Cochrane, and Google Scholar from inception to August 20, 2023. We included nonrandomized studies that compared the effectiveness between CADe-assisted and standard colonoscopy. Two investigators independently extracted study data and quality. Pairwise meta-analysis was performed utilizing risk ratio for dichotomous variables and mean difference (MD) for continuous variables with a 95% confidence interval (CI). RESULTS: Eight studies were included, comprising 9782 patients (4569 with CADe and 5213 without CADe). Regarding benefits, there was a difference in neither adenoma detection rate (44% vs 38%; risk ratio, 1.11; 95% CI, 0.97 to 1.28) nor mean adenomas per colonoscopy (0.93 vs 0.79; MD, 0.14; 95% CI, -0.04 to 0.32) between CADe-assisted and standard colonoscopy, respectively. Regarding harms, there was no difference in the mean non-neoplastic lesions per colonoscopy (8 studies included for analysis; 0.52 vs 0.47; MD, 0.14; 95% CI, -0.07 to 0.34) and withdrawal time (6 studies included for analysis; 14.3 vs 13.4 minutes; MD, 0.8 minutes; 95% CI, -0.18 to 1.90). There was a substantial heterogeneity, and all outcomes were graded with a very low certainty of evidence. CONCLUSION: CADe in colonoscopies neither improves the detection of colorectal neoplasia nor increases burden of colonoscopy in real-world, nonrandomized studies, questioning the generalizability of the results of randomized trials.

A survey on adverse drug reaction studies: data, tasks and machine learning methods.

MOTIVATION: Adverse drug reaction (ADR) or drug side effect studies play a crucial role in drug discovery. Recently, with the rapid increase of both clinical and non-clinical data, machine learning methods have emerged as prominent tools to support analyzing and predicting ADRs. Nonetheless, there are still remaining challenges in ADR studies. RESULTS: In this paper, we summarized ADR data sources and review ADR studies in three tasks: drug-ADR benchmark data creation, drug-ADR prediction and ADR mechanism analysis. We focused on machine learning methods used in each task and then compare performances of the methods on the drug-ADR prediction task. Finally, we discussed open problems for further ADR studies. AVAILABILITY: Data and code are available at https://github.com/anhnda/ADRPModels.

Identification of a novel role for TL1A/DR3 deficiency in acute respiratory distress syndrome that exacerbates alveolar epithelial disruption.

Alveolar epithelial barrier is a potential therapeutic target for acute respiratory distress syndrome (ARDS). However, an effective intervention against alveolar epithelial barrier has not been developed. Here, based on single-cell RNA and mRNA sequencing results, death receptor 3 (DR3) and its only known ligand tumor necrosis factor ligand-associated molecule 1A (TL1A) were significantly reduced in epithelium from an ARDS mice and cell models. The apparent reduction in the TL1A/DR3 axis in lungs from septic-ARDS patients was correlated with the severity of the disease. The examination of knockout (KO) and alveolar epithelium conditional KO (CKO) mice showed that TL1A deficiency exacerbated alveolar inflammation and permeability in lipopolysaccharide (LPS)-induced ARDS. Mechanistically, TL1A deficiency decreased glycocalyx syndecan-1 and tight junction-associated zonula occludens 3 by increasing cathepsin E level for strengthening cell-to-cell permeability. Additionally, DR3 deletion aggravated barrier dysfunction and pulmonary edema in LPS-induced ARDS through the above mechanisms based on the analyses of DR3 CKO mice and DR3 overexpression cells. Therefore, the TL1A/DR3 axis has a potential value as a key therapeutic signaling for the protection of alveolar epithelial barrier.

The effect of the endoscopic device Endocuff™/Endocuff vision™ on quality standards in colonoscopy: A systematic review and meta-analysis of randomized trials.

AIM: The adenoma detection rate (ADR) is an important quality measure, with a high ADR reflecting high-quality colonoscopy. This systematic review and meta-analysis aimed to assess the effects of Endocuff™/Endocuff Vision™-assisted colonoscopy (EAC) versus standard colonoscopy (SC) on ADR and other clinical, patient and resource-use outcomes. METHOD: MEDLINE, EMBASE, Web of Science, Scopus and the Cochrane Central Register of Controlled Trials were searched for full papers reporting randomized studies comparing EAC with SC. The primary outcome was ADR. Secondary outcomes comprised key polyp/adenoma detection, procedure-related, patient-related and health economic measures. Random effects meta-analyses provided pooled estimates of outcomes [risk ratio (RR) or mean difference (MD), with 95% confidence intervals (CI)]. RESULTS: Twelve parallel-group randomized controlled trials (RCTs) and three crossover RCTs with data on 9140 patients were included. EAC significantly increased the ADR (RR 1.18, 95% CI 1.09-1.29), mean adenomas per procedure (MAP) (MD 0.19, 95% CI 0.06-0.33), polyp detection rate (PDR) (RR 1.20, 95% CI 1.10-1.30) and mean polyps per procedure (MPP) (MD 0.39, 95% CI 0.14-0.63) versus SC. EAC significantly increased segmental PDR versus SC in the sigmoid (RR 2.02, 95% CI 1.64-2.49), transverse (RR 1.63, 95% CI 1.09-2.42), ascending (RR 1.74, 95% CI 1.26-2.41) and caecal segments (RR 1.91, 95% CI 1.29-2.82). Procedure-related variables did not differ between arms. There were insufficient data for meta-analysis of health economic or patient-centred outcomes. CONCLUSIONS: EAC increased ADR, MAP, PDR and MPP versus SC without detrimental effects on procedure measures. Cost-effectiveness and patient experience data are lacking and would be valuable to inform practice recommendations.

Sensitivity and specificity in signal detection with the reporting odds ratio and the information component.

PURPOSE: As measures of association between an adverse drug reaction (ADR) and exposure to a drug the reporting odds ratio (ROR) and the information component (IC) can be used. We sought to test the reliability of signal detection with these. METHODS: We simulated ADR counts as binomially distributed random numbers for different expected ADR frequencies and theoretical reporting odds ratios (RORs). We then calculated the empirical IC and the empirical ROR and their confidence intervals. The rate of signals that was detected despite a theoretical ROR of 1 represented the false positive rate, and represented the sensitivity if the ROR was >1. RESULTS: For expected case counts below 1 the false positive rate oscillates from 0.01 to 0.1 even though 0.025 were intended. Even beyond expected case counts of 5 oscillations can cover a range of 0.018 to 0.035. The first n oscillations with the largest amplitude are eliminated if a minimum case count of n is required. To detect an ROR of 2 with a sensitivity of 0.8, a minimum of 12 expected ADRs are required. In contrast, 2 expected ADRs suffice to detect an ROR of 4. CONCLUSION: Summaries of measures for disproportionality should include the expected number of cases in the group of interest if a signal was detected. If no signal was detected the sensitivity for the detection of a representative ROR or the minimum ROR that could be detected with probability 0.8 should be reported.

Discovery of benzochromene derivatives first example with dual cytotoxic activity against the resistant cancer cell MCF-7/ADR and inhibitory effect of the P-glycoprotein expression levels.

A series of 1H-benzo[f]chromene moieties (4a-z) were synthesised under Ultrasonic irradiation and confirmed with spectral analyses. Derivative 4i solely possessed an X-ray single crystal. The anti-proliferative efficacy of the desired molecules has been explored against three cancer cells: MCF-7, HCT-116, and HepG-2 with the cytotoxically active derivatives screened against MCF-7/ADR and normal cells HFL-1 and WI-38. Furthermore, compounds 4b-d, 4k, 4n, 4q, and 4w, which possessed good potency against MCF-7/ADR, were tested as permeability glycoprotein (P-glycoprotein [P-gp]) expression inhibitors. The attained data confirmed that 4b-d, 4q, and 4w exhibited strong expression inhibition against the P-gp alongside its cytotoxic effect on MCF-7/ADR. The western blot results and Rho123 accumulation assays showed that compounds 4b-d, 4q, and 4w effectively inhibited the P-gp expression and efflux function. Meanwhile, 4b-d, 4q, and 4w induced apoptosis and accumulation of the treated MCF-7/ADR cells in the G1 phase and 4k and 4n in the S phase of the cell cycle.

Student engagement in health professions education: A commentary on AMEE Guide No. 152.

It is critical to emphasize the significance of student engagement in health professions as part of our judgment of the program's success. A recent AMEE Guide No. 152 on student engagement has provided a comprehensive understanding of a range of aspects, including the application of this topic. This article discusses specific issues that can add to the value of the Guide. When defining student engagement, it is crucial to establish aspects of 'active; engagement' and 'passive, non-engagement' student reaction to learning. The Job demands-resources (JD-R) and academic demands-resources (AD-R) model fits with the determinants of student engagement. Determinant elements of students' engagement have been incorporated into a model and methods used in measuring student engagement. The model has been applied to problem-based learning and virtual (online learning) program.

Polygenic risk score for ACE-inhibitor-associated cough based on the discovery of new genetic loci.

AIMS: To search for sequence variants associated with ACEi discontinuation and to test their association with ACEi-associated adverse drug reactions (ADRs). METHODS AND RESULTS: A genome-wide association study (GWAS) on ACEi discontinuation was conducted, including 33 959 ACEi-discontinuers and 44 041 controls. Cases were defined as persons who switched from an ACEi treatment to an angiotensin receptor blocker. Controls were defined as persons who continued ACEi treatment for at least 1 year. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed for ACEi discontinuation risk by mixed model regression analysis. Summary statistics from the individual cohorts were meta-analyzed with a fixed-effects model. To test for association with specific ACEi-associated ADRs, any genome-wide significant (P < 5 × 10-8) ACEi discontinuation variants was tested for association with ACEi-associated cough and angioedema. A polygenetic risk score (PRS) based on ACEi discontinuation GWAS data was constructed and tested for association with ACEi-associated cough and angioedema in two population-based samples. In total, seven genetic genome-wide loci were identified, of which six were previously unreported. The strongest association with ACEi discontinuation was at 20q13.3 (NTSR1; OR: 1.21; 95% CI: 1.17-1.24; P = 2.1 × 10-34). Five of seven lead variants were associated with ACEi-associated cough, whereas none were associated with ACEi-associated angioedema. The ACEi discontinuation PRS was associated with ACEi-associated cough in a dose-response manner but not with ACEi-associated angioedema. ACEi discontinuation was genetically correlated with important causes for cough, including gastro-esophageal reflux disease, allergic rhinitis, hay fever, and asthma, which indicates partly shared genetic underpinning between these traits. CONCLUSION: This study showed the advantage of using prescription patterns to discover genetic links with ADRs. In total, seven genetic loci that associated with ACEi discontinuation were identified. There was evidence of a strong association between our ADR phenotype and ACEi-associated cough. Taken together, these findings increase insight into the pathophysiological processes that underlie ACEi-associated ADRs.

Mobility Classification of LoRaWAN Nodes Using Machine Learning at Network Level.

LoRaWAN networks rely heavily on the adaptive data rate algorithm to achieve good link reliability and to support the required density of end devices. However, to be effective the adaptive data rate algorithm needs to be tuned according to the level of mobility of each end device. For that purpose, different adaptive data rate algorithms have been developed for the different levels of mobility of end devices, e.g., for static or mobile end devices. In this paper, we describe and evaluate a new and effective method for determining the level of mobility of end devices based on machine learning techniques and specifically on the support vector machine supervised learning method. The proposed method does not rely on the location capability of LoRaWAN networks; instead, it relies only on data always available at the LoRaWAN network server. Moreover, the performance of this method in a real LoRaWAN network is assessed; the results give clear evidence of the effectiveness and reliability of the proposed machine learning approach.

Deep Learning Neural Network Performance on NDT Digital X-ray Radiography Images: Analyzing the Impact of Image Quality Parameters-An Experimental Study.

In response to the growing inspection demand exerted by process automation in component manufacturing, non-destructive testing (NDT) continues to explore automated approaches that utilize deep-learning algorithms for defect identification, including within digital X-ray radiography images. This necessitates a thorough understanding of the implication of image quality parameters on the performance of these deep-learning models. This study investigated the influence of two image-quality parameters, namely signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), on the performance of a U-net deep-learning semantic segmentation model. Input images were acquired with varying combinations of exposure factors, such as kilovoltage, milli-ampere, and exposure time, which altered the resultant radiographic image quality. The data were sorted into five different datasets according to their measured SNR and CNR values. The deep-learning model was trained five distinct times, utilizing a unique dataset for each training session. Training the model with high CNR values yielded an intersection-over-union (IoU) metric of 0.9594 on test data of the same category but dropped to 0.5875 when tested on lower CNR test data. The result of this study emphasizes the importance of achieving a balance in training dataset according to the investigated quality parameters in order to enhance the performance of deep-learning segmentation models for NDT digital X-ray radiography applications.

The truncated TNL receptor TN2-mediated immune responses require ADR1 function.

The loss of function of exocyst subunit EXO70B1 leads to autoimmunity, which is dependent on TIR-NBS2 (TN2), a truncated intracellular nucleotide-binding and leucine-rich repeat receptor (NLR). However, how TN2 triggers plant immunity and whether typical NLRs are required in TN2-activated resistance remain unclear. Through the CRISPR/Cas9 gene editing system and knockout analysis, we found that the spontaneous cell death and enhanced resistance in exo70B1-3 were independent of the full-length NLR SOC3 and its closest homolog SOC3-LIKE 1 (SOC3-L1). Additionally, knocking out SOC3-L1 or TN2 did not suppress the chilling sensitivity conferred by chilling sensitive 1-2 (chs1-2). The ACTIVATED DISEASE RESISTANCE 1 (ADR1) family and the N REQUIREMENT GENE 1 (NRG1) family have evolved as helper NLRs for many typical NLRs. Through CRISPR/Cas9 gene editing methods, we discovered that the autoimmunity of exo70B1-3 fully relied on ADR1s, but not NRG1s, and ADR1s contributed to the upregulation of TN2 transcript levels in exo70B1-3. Furthermore, overexpression of TN2 also led to ADR1-dependent autoimmune responses. Taken together, our genetic analysis highlights that the truncated TNL protein TN2-triggered immune responses require ADR1s as helper NLRs to activate downstream signaling, revealing the importance and complexity of ADR1s in plant immunity regulation.