Levels Of Drug Resistance Research Articles

Drug-resistance characteristics, genetic diversity, and transmission dynamics of multidrug-resistant or rifampicin-resistant Mycobacterium tuberculosis from 2019 to 2021 in Sichuan, China

BackgroundMultidrug- or rifampicin-resistant tuberculosis (TB; MDR/RR-TB) is a significant public health threat. However, the mechanisms involved in its transmission in Sichuan, China are unclear. To provide a scientific basis for MDR/RR-TB control and prevention, we investigated the drug-resistance characteristics, genetic diversity, and transmission dynamics and analyzed the demographic and clinical characteristics of patients to identify risk factors for the acquisition of MDR/RR-TB in Sichuan, Western China.MethodsWhole-genome sequencing was performed using a sample comprised of all MDR/RR-TB strains isolated from patients with pulmonary TB (≥ 15 years) at the 22 surveillance sites in Sichuan province between January 2019 and December 2021, to analyze genotypic drug resistance and genetic diversity. Moreover, we performed statistical analyses of the epidemiological characteristics and risk factors associated with the transmission dynamics of MDR/RR-TB.ResultsThe final analysis included 278 MDR/RR TB strains. Lineage 2.2, the major sub-lineage, accounted for 82.01% (228/278) of isolates, followed by lineage 4.5 (9.72%, 27/278), lineage 4.4 (6.83%, 19/278), and lineage 4.2 (1.44%, 4/278). The drug resistance rates, ranging from high to low, were as follows: isoniazid (229 [82.37%]), streptomycin (177 [63.67%]), ethambutol (144 [51.80%]), pyrazinamide (PZA, 119 [42.81%]), fluoroquinolones (FQs, 93 [33.45%]). Further, the clofazimine, bedaquiline, and delamanid resistance rates were 2.88, 2.88, and 1.04%, respectively. The gene composition cluster rate was 32.37% (90/278). In addition, 83.81% (233/278) of MDR/RR-TB cases were determined to be likely caused by transmission. Finally, patients infected with lineage two strains and strains with the KatG S315T amino acid substitution presented a higher risk of MDR/RR-TB transmission.ConclusionTransmission plays a significant role in the MDR/RR-TB burden in Sichuan province, and lineage 2 strains and strains harboring KatG S315T have a high probability of transmission. Further, high levels of FQ and PZA drug resistance suggest an urgent need for drug susceptibility testing prior to designing therapeutic regimens. New anti-TB drugs need to be used standardly and TB strains should be regularly monitored for resistance to these drugs.

Nitric Oxide-Releasing Topical Treatments for Cutaneous Melanoma.

Melanoma is an aggressive skin cancer notorious for high levels of drug resistance. Additionally, current treatments such as immunotherapies are often associated with numerous adverse side effects. The use of nitric oxide (NO) may represent an attractive treatment for melanoma due to NO's various anticancer properties, unlikeliness to foster resistance, and limited toxicity toward healthy tissues. The anticancer effects of chemical NO donors have been explored previously but with limited understanding of the needed characteristics for exerting optimal antimelanoma activity. Herein, the in vitro therapeutic efficacy of three macromolecular NO donor systems (i.e., cyclodextrin, mesoporous silica nanoparticles, and hyaluronic acid) with tunable NO-release kinetics was explored by evaluating skin permeation along with toxicity against melanoma and healthy skin cells. Cytotoxicity against melanoma cells was dependent on NO payload and not donor identity or NO-release kinetics. In contrast, cytotoxicity against healthy cells was primarily influenced by the macromolecular NO donor, with cyclodextrin- and hyaluronic acid-based NO donors having the highest therapeutic indices. In vitro skin permeation was influenced by both the size and charge of the NO donor, with smaller, more neutral donors resulting in greater permeation. A Pluronic F127 organogel was optimized for the delivery of a cyclodextrin-based NO donor. Delivery of the NO donor in this manner resulted in increased in vitro skin permeation and reduced tumor growth in an in vivo model.

Patterns of Transmitted Drug Resistance Mutations and HIV-1 Subtype Dynamics in ART-Naïve Individuals in Veneto, Italy, from 2017 to 2024.

This study investigates the prevalence and patterns of transmitted drug resistance mutations (TDRMs) and HIV-1 subtypes among antiretroviral therapy (ART) naïve individuals in Veneto, Italy, from 2017 to 2024. This research aims to understand the dynamic landscape of TDRMs and HIV-1 genetic diversity to inform treatment strategies effectively. We included all adult ART-naïve people with HIV (PWH) from seven infectious disease units in Veneto, Italy. We collected the genotypic resistance testing conducted to predict drug susceptibility and subtype distribution using the Stanford HIVdb algorithm. We included 762 PWH, showing a slight but statistically significant decline in the B subtype among Italian PWH (p = 0.045) and an increase in non-B subtypes among foreigners, though it was not statistically significant (p = 0.333). The most frequent mutations were in Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs), especially in non-B subtypes, with a notable rise from 10.7% in 2017-2019 to 15.5% in 2020-2024. Notably, TDRMs were consistently detected, highlighting an ongoing challenge despite the stable prevalence observed over the years. In addition, the data revealed a concerning rise in mutations against newer drug classes, such as integrase inhibitors. Conclusively, the study underscores the necessity of continuous surveillance of HIV subtypes and resistance patterns to adapt ART regimens optimally. Despite the stable levels of drug resistance, the emergence of resistance against newer drugs necessitates ongoing vigilance and possible adjustment in treatment protocols to enhance clinical outcomes and manage HIV drug resistance effectively.

Inter-Species Competition of Mono- or Dual Species Biofilms- of MDR-Staphylococcus aureus and Pseudomonas aeruginosa Promotes the Killing Efficacy of Phage or Phage Cocktail

Pseudomonas aeruginosa and Staphylococcus aureus are opportunistic bacteria frequently linked to burn wound infections. These bacteria can grow as biofilms, which increases their level of drug resistance to current antibiotics. The purpose of the present study is to analyze the effect of biofilm formation, phage and phage cocktail action on single species and dual species biofilms I, e the coexistence of Gram positive (S. aureus) and Gram negative (P. aeruginosa). To this scenario, we employed multi-drug resistant bacteria (P. aeruginosa and S. aureus at 109 CFU/µL) biofilm as single and in combination of both Gram-positive and Gram-negative bacterial biofilms of 24 h grown with respective phage (109 PFU/µL) and phage cocktail (109 PFU/µL) at 4 h of incubation under static conditions. The bacteriolytic activity of phages vB_SAnS_SADP1 and vB_PAnP_PADP4 on 24-h-old biofilms of P. aeruginosa (0.761 ± 0.031) and S. aureus (0.856 ± 0.055), both alone and in combination (0.67 ± 0.02), was the focus of this investigation. The structural organization of biofilms in single- or dual-species combinations under in vitro conditions was validated by scanning and confocal laser scanning microscopy investigations. After 24 h of incubation, single-species biofilms are denser and more resilient whereas dual species biofilms are more loosely associated. Loose association of dual-species biofilm under scanning electron microscopic images at the same conditions, indicated the interspecies -competition of the Gram-positive and Gram-negative bacteria and dual-species biofilms (0.67 ± 0.02) have weak associations and are readily impacted by phage and a phage cocktail (0.16 ± 0.02). Dual-species biofilms were more readily impacted in in vitro settings.

Pneumatic extrusion bioprinting-based high throughput fabrication of a melanoma 3D cell culture model for anti-cancer drug screening

The high incidence of malignant melanoma highlights the need forin vitromodels that accurately represent the tumour microenvironment, enabling developments in melanoma therapy and drug screening. Despite several advancements in 3D cell culture models, appropriate melanoma models for evaluating drug efficacy are still in high demand. The 3D pneumatic extrusion-based bioprinting technology offers numerous benefits, including the ability to achieve high-throughput capabilities. However, there is a lack of research that combines pneumatic extrusion-based bioprinting with analytical assays to enable efficient drug screening in 3D melanoma models. To address this gap, this study developed a simple and highly reproducible approach to fabricate a 3D A375 melanoma cell culture model using the pneumatic extrusion-based bioprinting technology. To optimise this method, the bioprinting parameters for producing 3D cell cultures in a 96-well plate were adjusted to improve reproducibility while maintaining the desired droplet size and a cell viability of 92.13 ± 6.02%. The cross-linking method was optimised by evaluating cell viability and proliferation of the 3D bioprinted cells in three different concentrations of calcium chloride. The lower concentration of 50 mM resulted in higher cell viability and increased cell proliferation after 9 d of incubation. The A375 cells exhibited a steadier proliferation rate in the 3D bioprinted cell cultures, and tended to aggregate into spheroids, whereas the 2D cell cultures generally formed monolayered cell sheets. In addition, we evaluated the drug responses of four different anti-cancer drugs on the A375 cells in both the 2D and 3D cell cultures. The 3D cell cultures exhibited higher levels of drug resistance in all four tested anti-cancer drugs. This method presents a simple and cost-effective method of producing and analysing 3D cell culture models that do not add additional complexity to current assays and shows considerable potential for advancing 3D cell culture models' drug efficacy evaluations.

A study on factors influencing delayed sputum conversion in newly diagnosed pulmonary tuberculosis based on bacteriology and genomics

Conversion of sputum from positive to negative is one of the indicators to evaluate the efficacy of anti-tuberculosis treatment (ATT). We investigate the factors associated with delayed sputum conversion after 2 or 5 months of ATT from the perspectives of bacteriology and genomics. A retrospective study of sputum conversion in sputum positive 1782 pulmonary tuberculosis (PTB) was conducted from 2021 to 2022 in Beijing, China. We also designed a case-matched study including 24 pairs of delayed-sputum-conversion patients (DSCPs) and timely-sputum-conversion patients (TSCPs), and collect clinical isolates from DSCPs before and after ATT and initial isolates of TSCPs who successfully achieved sputum conversion to negative after 2 months of ATT. A total of 75 strains were conducted drug sensitivity testing (DST) of 13 anti-TB drugs and whole-genome sequencing (WGS) to analyze the risk factors of delayed conversion and the dynamics changes of drug resistance and genomics of Mycobacterium tuberculosis (MTB) during ATT. We found TSCPs have better treatment outcomes and whose initial isolates show lower levels of drug resistance. Clinical isolates of DSCPs showed dynamically changing of resistance phenotypes and intra-host heterogeneity. Single nucleotide polymorphism (SNP) profiles showed large differences between groups. The study provided insight into the bacteriological and genomic variation of delayed sputum conversion. It would be helpful for early indication of sputum conversion and guidance on ATT.

Antibody-drug conjugates combined with immunotherapy: a potential game changer in the treatment of upper tract urothelial carcinoma

Currently, treatment strategies for upper tract urothelial carcinoma (UTUC) are changing rapidly. However, there are many limitations in the implementation of new surgical methods and systemic treatment options, which cannot reverse the current status quo of UTUC treatment. In recent years, antibody-drug conjugates have shown great potential in the field of cancer treatment, which can activate the immune system and enhance the effect of immunotherapy while accurately killing targeted tumor cells. The results of multiple clinical trials, including the EV-302 study, have confirmed that combination therapy can improve the survival rate of patients with advanced urothelial cancer, and may replace chemotherapy as the first-line treatment for advanced urothelial cancer. However, there are still a series of challenges in the application of combination therapy in UTUC, such as low level of evidence, adverse reactions, and drug resistance. In the future, it is necessary to focus on clinical trials of UTUC combination therapy, further optimize antibody drug conjugates and immunotherapy drugs to adapt to the disease characteristics of UTUC, and further study the molecular biology characteristics of UTUC to meet this series of challenges.

Proteomics Analysis of Interactions between Drug-Resistant and Drug-Sensitive Cancer Cells: Comparative Studies of Monoculture and Coculture Cell Systems.

Cell-cell interactions, which allow cells to communicate with each other through molecules in their microenvironment, are critical for the growth, health, and functions of cells. Previous studies show that drug-resistant cells can interact with drug-sensitive cells to elevate their drug resistance level, which is partially responsible for cancer recurrence. Studying protein targets and pathways involved in cell-cell communication provides essential information for fundamental cell biology studies and therapeutics of human diseases. In the current studies, we performed direct coculture and indirect coculture of drug-resistant and drug-sensitive cell lines, aiming to investigate intracellular proteins responsible for cell communication. Comparative studies were carried out using monoculture cells. Shotgun bottom-up proteomics results indicate that the P53 signaling pathway has a strong association with drug resistance mechanisms, and multiple TP53-related proteins were upregulated in both direct and indirect coculture systems. In addition, cell-cell communication pathways, including the phagosome and the HIF-signaling pathway, contribute to both direct and indirect coculture systems. Consequently, AK3 and H3-3A proteins were identified as potential targets for cell-cell interactions that are relevant to drug resistance mechanisms. We propose that the P53 signaling pathway, in which mitochondrial proteins play an important role, is responsible for inducing drug resistance through communication between drug-resistant and drug-sensitive cancer cells.

Human umbilical cord mesenchymal stem cells promoted tumor cell growth associated with increased interleukin-18 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is experiencing a concerning rise in both incidence and mortality rates. Current therapeutic strategies are limited in their effectiveness, largely due to the complex causes of the disease and significant levels of drug resistance. Given the latest developments in human umbilical cord mesenchymal stem cells (hUC-MSCs) research, there is a debate over the continued use of stem cell transplantation for treating tumors. Consequently, this study seeks to explore the role of hUC-MSCs in the management of HCC. HUC-MSCs increased the number (10.75 ± 1.50) in the DEN/TCPOBOP-induced mice hepatoma model, compared with DMSO group (7.25 ± 1.71). Moreover, the liver index in hUC-MSCs group (0.21 ± 0.06) was greater than that in DMSO group (0.09 ± 0.01). Immunohistochemical (IHC) analysis revealed that while hUC-MSCs did not alter Foxp3 expression, they significantly stimulated Ki67 expression, indicative of increased tumor cellular proliferation. Additionally, immunofluorescence (IF) studies showed that hUC-MSCs increased CD8+ T cell counts without affecting macrophage numbers. Notably, granzyme B expression remained nearly undetectable. We observed that serum IL-18 levels were higher in the hUC-MSCs group (109.66 ± 0.38 pg/ml) compared to the DMSO group (91.14 ± 4.37 pg/ml). Conversely, IL-1β levels decreased in the hUC-MSCs group (63.00 ± 0.53 pg/ml) relative to the DMSO group (97.38 ± 9.08 pg/ml). According to this study, hUC-MSCs promoted the growth of liver tumors. Therefore, we proposed that hUC-MSCs are not suitable for treating HCC, as they exhibit clinically prohibited abnormalities.

Bisphosphonates synergistically enhance the antifungal activity of azoles in dermatophytes and other pathogenic molds.

Fungal infections of the skin, hair, and nails, generally grouped together as "tineas" are the most prevalent infectious diseases globally. These infections, caused by fungal species known as dermatophytes, are generally superficial, but can in some cases become aggressive. They are also notoriously difficult to resolve, with few effective treatments and rising levels of drug resistance. Here, we report a potential new treatment that combines azole antifungals with bisphosphonates. Bisphosphonates are approved for the treatment of low bone density diseases, and in fungi they inhibit the biosynthesis of the cell membrane, which is also the target of azoles. Combinations were synergistic across the dermatophyte species and prevented the development of resistance. We extended the study to molds that cause invasive disease, finding synergy in some problematic species. We suggest bisphosphonates could be repurposed as synergents for tinea treatment, and that this combination could be fast-tracked for use in clinical therapy.

Particle uptake in cancer cells can predict malignancy and drug resistance using machine learning.

Tumor heterogeneity is a primary factor that contributes to treatment failure. Predictive tools, capable of classifying cancer cells based on their functions, may substantially enhance therapy and extend patient life span. The connection between cell biomechanics and cancer cell functions is used here to classify cells through mechanical measurements, via particle uptake. Machine learning (ML) was used to classify cells based on single-cell patterns of uptake of particles with diverse sizes. Three pairs of human cancer cell subpopulations, varied in their level of drug resistance or malignancy, were studied. Cells were allowed to interact with fluorescently labeled polystyrene particles ranging in size from 0.04 to 3.36 μm and analyzed for their uptake patterns using flow cytometry. ML algorithms accurately classified cancer cell subtypes with accuracy rates exceeding 95%. The uptake data were especially advantageous for morphologically similar cell subpopulations. Moreover, the uptake data were found to serve as a form of "normalization" that could reduce variation in repeated experiments.

Measuring protective efficacy and quantifying the impact of drug resistance: A novel malaria chemoprevention trial design and methodology.

Recently revised WHO guidelines on malaria chemoprevention have opened the door to more tailored implementation. Countries face choices on whether to replace old drugs, target additional age groups, and adapt delivery schedules according to local drug resistance levels and malaria transmission patterns. Regular routine assessment of protective efficacy of chemoprevention is key. Here, we apply a novel modelling approach to aid the design and analysis of chemoprevention trials and generate measures of protection that can be applied across a range of transmission settings. We developed a model of genotype-specific drug protection, which accounts for underlying risk of infection and circulating genotypes. Using a Bayesian framework, we fitted the model to multiple simulated scenarios to explore variations in study design, setting, and participant characteristics. We find that a placebo or control group with no drug protection is valuable but not always feasible. An alternative approach is a single-arm trial with an extended follow-up (>42 days), which allows measurement of the underlying infection risk after drug protection wanes, as long as transmission is relatively constant. We show that the currently recommended 28-day follow-up in a single-arm trial results in low precision of estimated 30-day chemoprevention efficacy and low power in determining genotype differences of 12 days in the duration of protection (power = 1.4%). Extending follow-up to 42 days increased precision and power (71.5%) in settings with constant transmission over this time period. However, in settings of unstable transmission, protective efficacy in a single-arm trial was overestimated by 24.3% if recruitment occurred during increasing transmission and underestimated by 15.8% when recruitment occurred during declining transmission. Protective efficacy was estimated with greater precision in high transmission settings, and power to detect differences by resistance genotype was lower in scenarios where the resistant genotype was either rare or too common. These findings have important implications for the current guidelines on chemoprevention efficacy studies and will be valuable for informing where these studies should be optimally placed. The results underscore the need for a comparator group in seasonal settings and provide evidence that the extension of follow-up in single-arm trials improves the accuracy of measures of protective efficacy in settings with more stable transmission. Extension of follow-up may pose logistical challenges to trial feasibility and associated costs. However, these studies may not need to be repeated multiple times, as the estimates of drug protection against different genotypes can be applied to different settings by adjusting for transmission intensity and frequency of resistance.

Assessment of bacterial profile, antimicrobial susceptibility status, and associated factors of isolates among hospitalized patients at Dessie Comprehensive Specialized Hospital, Northeast Ethiopia

BackgroundAntimicrobial resistant bacteria among hospitalized patients are becoming a major public health threat worldwide, mainly in developing countries. Infections by these multidrug resistant pathogens cause high rate of mortality, prolong hospital stays, and affect individual and country economies in greater amounts. Thus, this study aimed to assess the bacterial profile, antimicrobial susceptibility status, and associated factors of isolates from hospitalized patients at the Dessie Comprehensive Specialized Hospital.MethodologyThis hospital-based cross-sectional study was conducted between February and April 2021. Consecutive sampling was used to select the study participants. All bacterial isolates were identified using standard bacteriological techniques. Antibiotic susceptibility testing was performed using disk diffusion technique. The data was analyzed using SPSS version 25. Descriptive statistics and logistic regression were used. A P-value of less than 0.05 was considered statistically significant.ResultsOf 384 clinical samples (blood, urine, stool, wound, vaginal discharge, and ear discharge) processed 180 (46.9%) were culture positive. Overall, Escherichia coli was the predominant isolate (41; 22.8%), followed by Staphylococcus aureus (36; 20%). Most of the isolates were from blood (70; 38.9%). The level of overall drug resistance of the gram-negative bacteria isolates for ampicillin, tetracycline, and cotrimoxazole was (104; 88.1%), (79; 75.9%), and (78; 75.0%), respectively. The overall multidrug rate of isolates was 143 (79.4%). Variables such as history of invasive procedures, chronic underlying diseases, history of hospitalization, and habit of eating raw animal products were statistically significant for the acquisition of bacterial infection.Conclusions and recommendationE. Coli and S. aureus were the most common isolates. Most of the isolates were resistant to commonly prescribed antibiotics. And also, consumption of raw animal products, chronic underlying disease, previous hospitalization, history of invasive procedures, and educational status were associated with the acquisition of bacterial infections. Therefore, routine antimicrobial susceptibility testing, proper patient management, wise use of antibiotics in clinical settings and health education are recommended.

In-silico exploration and structure-based design of Praziquantel derivatives as potential inhibitors of schistosoma mansoni Glutathione S-transferase (SmGST)

Schistosomiasis is a chronic parasitic disease with significant public health challenges due to the limited number of treatment options and increasing levels of drug resistance against the only available drug, Praziquantel (PZQ). Consequently, there has been ongoing research in discovering new and more effective drugs for treating schistosomiasis. In this regards, structure-based drug design was employed to generate novel derivatives of PZQ with enhanced binding affinities. Molecular-docking simulations of twenty-four derivatives was performed, with the goal of identifying a prominent lead for further design. Among the screened derivatives, compound 23 showed the most favorable binding energies (Moldock score of -101.846 kcal mol−1) making it the preferred lead candidate. Five novel `compounds were designed, each demonstrating enhanced binding energies (ranging from -108.645 to -112.237 kcal mol−1) compared to the standard drug with a Moldock score of -90.663 kcal mol−1. Notably, 23d demonstrated the highest binding energies among the designed entities (-112.237 kcal mol−1). The identified compounds displayed potent inhibition of Schistosoma mansoni Glutathione S-transferase (SmGST) and met the drug-likeness criteria of the Lipinski, Ghose, Verber, and Egan. Additionally, a blood-brain barrier (BBB) value > -1 and a central nervous system (CNS) value > -3, signifying their capability to efficiently traverse the BBB and access the CNS. Furthermore, they were found to be non-AMES toxic, ensuring their safety in this regard. Molecular dynamic simulations and density function theory confirmed the ligands' chemical reactivity and ligand-complex stability under biological conditions. This makes them promising candidates for the development of drugs for treating Schistosomiasis.

Exposure of Mycobacterium tuberculosis to human alveolar lining fluid shows temporal and strain-specific adaptation to the lung environment

Upon infection, Mycobacterium tuberculosis (M.tb) reaches the alveolar space and comes in close contact with the lung mucosa or human alveolar lining fluid (ALF) for an uncertain period of time prior to its encounter with alveolar cells. We showed that homeostatic ALF hydrolytic enzymes modify the M.tb cell envelope, driving M.tb-host cell interactions. Still, the contribution of ALF during M.tb infection is poorly understood. Here, we exposed 4 M.tb strains with different levels of virulence, transmissibility, and drug resistance (DR) to physiological concentrations of human ALF for 15-min and 12-h, and performed RNA sequencing. Gene expression analysis showed a temporal and strain-specific adaptation to human ALF. Differential expression (DE) of ALF-exposed vs. unexposed M.tb revealed a total of 397 DE genes associated with lipid metabolism, cell envelope and processes, intermediary metabolism and respiration, and regulatory proteins, among others. Most DE genes were detected at 12-h post-ALF exposure, with DR-M.tb strain W-7642 having the highest number of DE genes. Interestingly, genes from the KstR2 regulon, which controls the degradation of cholesterol C and D rings, were significantly upregulated in all strains post-ALF exposure. These results indicate that M.tb-ALF contact drives initial bacterial metabolic and physiologic changes, which may have implications in the early events of M.tb infection.

Structure-Based In Silico Approaches Reveal IRESSA as a Multitargeted Breast Cancer Regulatory, Signalling, and Receptor Protein Inhibitor.

Breast cancer begins in the breast cells, mainly impacting women. It starts in the cells that line the milk ducts or lobules responsible for producing milk and can spread to nearby tissues and other body parts. In 2020, around 2.3 million women across the globe received a diagnosis, with an estimated 685,000 deaths. Additionally, 7.8 million women were living with breast cancer, making it the fifth leading cause of cancer-related deaths among women. The mutational changes, overexpression of drug efflux pumps, activation of alternative signalling pathways, tumour microenvironment, and cancer stem cells are causing higher levels of drug resistance, and one of the major solutions is to identify multitargeted drugs. In our research, we conducted a comprehensive screening using HTVS, SP, and XP, followed by an MM/GBSA computation of human-approved drugs targeting HER2/neu, BRCA1, PIK3CA, and ESR1. Our analysis pinpointed IRESSA (Gefitinib-DB00317) as a multitargeted inhibitor for these proteins, revealing docking scores ranging from -4.527 to -8.809 Kcal/mol and MM/GBSA scores between -49.09 and -61.74 Kcal/mol. We selected interacting residues as fingerprints, pinpointing 8LEU, 6VAL, 6LYS, 6ASN, 5ILE, and 5GLU as the most prevalent in interactions. Subsequently, we analysed the ADMET properties and compared them with the standard values of QikProp. We extended our study for DFT computations with Jaguar and plotted the electrostatic potential, HOMO and LUMO regions, and electron density, followed by a molecular dynamics simulation for 100 ns in water, showing an utterly stable performance, making it a suitable drug candidate. IRESSA is FDA-approved for lung cancer, which shares some pathways with breast cancers, clearing the hurdles of multitargeted drugs against breast and lung cancer. This has the potential to be groundbreaking; however, more studies are needed to concreate IRESSA's role.

Diagnosis of Human Cytomegalovirus Drug Resistance Mutations in Solid Organ Transplant Recipients-A Review.

Human cytomegalovirus (HCMV) infection may be asymptomatic in healthy individuals but can cause severe complications in immunocompromised patients, including transplant recipients. Breakthrough and drug-resistant HCMV infections in such patients are major concerns. Clinicians are first challenged to accurately diagnose HCMV infection and then to identify the most effective antiviral drug and determine when to initiate therapy, alter drug dosage, or switch medication. This review critically examines HCMV diagnostics approaches, particularly for immunocompromised patients, and the development of genotypic techniques to rapidly diagnose drug resistance mutations. The current standard method to identify prevalent and well-known resistance mutations involves polymerase chain reaction amplification of UL97, UL54, and UL56 gene regions, followed by Sanger sequencing. This method can confirm clinical suspicion of drug resistance as well as determine the level of drug resistance and range of cross-resistance with other drugs. Despite the effectiveness of this approach, there remains an urgent need for more rapid and point-of-care HCMV diagnosis, allowing for timely lifesaving intervention.

Prediction of anticancer drug resistance using a 3D microfluidic bladder cancer model combined with convolutional neural network-based image analysis.

Bladder cancer is the most common urological malignancy worldwide, and its high recurrence rate leads to poor survival outcomes. The effect of anticancer drug treatment varies significantly depending on individual patients and the extent of drug resistance. In this study, we developed a validation system based on an organ-on-a-chip integrated with artificial intelligence technologies to predict resistance to anticancer drugs in bladder cancer. As a proof-of-concept, we utilized the gemcitabine-resistant bladder cancer cell line T24 with four distinct levels of drug resistance (parental, early, intermediate, and late). These cells were co-cultured with endothelial cells in a 3D microfluidic chip. A dataset comprising 2,674 cell images from the chips was analyzed using a convolutional neural network (CNN) to distinguish the extent of drug resistance among the four cell groups. The CNN achieved 95.2% accuracy upon employing data augmentation and a step decay learning rate with an initial value of 0.001. The average diagnostic sensitivity and specificity were 90.5% and 96.8%, respectively, and all area under the curve (AUC) values were over 0.988. Our proposed method demonstrated excellent performance in accurately identifying the extent of drug resistance, which can assist in the prediction of drug responses and in determining the appropriate treatment for bladder cancer patients.

Characterization and risk assessment of novel SXT/R391 integrative and conjugative elements with multidrug resistance in Proteus mirabilis isolated from China, 2018-2020.

Proteus mirabilis can transfer transposons, insertion sequences, and gene cassettes to the chromosomes of other hosts through SXT/R391 integrative and conjugative elements (ICEs), significantly increasing the possibility of antibiotic resistance gene (ARG) evolution and expanding the risk of ARGs transmission among bacteria. A total of 103 strains of P. mirabilis were isolated from 25 farms in China from 2018 to 2020. The positive detection rate of SXT/R391 ICEs was 25.2% (26/103). All SXT/R391 ICEs positive P. mirabilis exhibited a high level of overall drug resistance. Conjugation experiments showed that all 26 SXT/R391 ICEs could efficiently transfer to Escherichia coli EC600 with a frequency of 2.0 × 10-7 to 6.0 × 10-5. The acquired ARGs, genetic structures, homology relationships, and conservation sequences of 26 (19 different subtypes) SXT/R391 ICEs were investigated by high-throughput sequencing, whole-genome typing, and phylogenetic tree construction. ICEPmiChnHBRJC2 carries erm (42), which have never been found within an SXT/R391 ICE in P. mirabilis, and ICEPmiChnSC1111 carries 19 ARGs, including clinically important cfr, blaCTX-M-65, and aac(6')-Ib-cr, making it the ICE with the most ARGs reported to date. Through genetic stability, growth curve, and competition experiments, it was found that the transconjugant of ICEPmiChnSCNNC12 did not have a significant fitness cost on the recipient bacterium EC600 and may have a higher risk of transmission and dissemination. Although the transconjugant of ICEPmiChnSCSZC20 had a relatively obvious fitness cost on EC600, long-term resistance selection pressure may improve bacterial fitness through compensatory adaptation, providing scientific evidence for risk assessment of horizontal transfer and dissemination of SXT/R391 ICEs in P. mirabilis.IMPORTANCEThe spread of antibiotic resistance genes (ARGs) is a major public health concern. The study investigated the prevalence and genetic diversity of integrative and conjugative elements (ICEs) in Proteus mirabilis, which can transfer ARGs to other hosts. The study found that all of the P. mirabilis strains carrying ICEs exhibited a high level of drug resistance and a higher risk of transmission and dissemination of ARGs. The analysis of novel multidrug-resistant ICEs highlighted the potential for the evolution and spread of novel resistance mechanisms. These findings emphasize the importance of monitoring the spread of ICEs carrying ARGs and the urgent need for effective strategies to combat antibiotic resistance. Understanding the genetic diversity and potential for transmission of ARGs among bacteria is crucial for developing targeted interventions to mitigate the threat of antibiotic resistance.

Urinary Tract Infection Related to Indwelling Catheterization and Associated Factors Among ≥ 50-year-old Females at A Tertiary Care Hospital, Odisha, India

This study determines the association factors of demographic variables with urinary tract infections (UTIs) among females ≥ 50 years or older. Routine microbiological analysis of the urine samples was done to find the dominant microorganisms in these older females and their level of drug resistance. One hundred elderly females with indwelling catheterization were admitted to two different hospitals. The semi-structured questionnaire tool has been used to collect socio-demographic variables and investigate UTIs. A structured 2-point rating scale was used to determine the factors associated with UTIs. A rating scale was employed, assigning a score of 1 for "yes" and 2 for "no". Urine samples were collected from the participants and diagnosed with routine microbiological tests. UTIs related to indwelling catheterization were 20% between the ages of 50–59 years, and 92% were Married older females. There was an association of factors with marital status, P= 4.033782, df=1, andᵡ²=0.0446, to be statistically significant. Investigation with demographic variables and duration of indwelling catheterization was not statistically significant. Multidrugresistant Escherichia coli and four different species of Candida were the dominant microorganisms isolated. The identification of UTIs and associated factors with catheterisation will help in controlling the UTIs related to indwelling catheterization and associated factors among older females≥ 50 years of age and endeavours by nursing staff for the good supervisory arrangement for nursing staff and students during indwelling catheterization of the patient. Further, the microbiological analysis results can help develop a suitable antibiotic usage policy for reducing antibiotic resistance.