Search

Papillary thyroid cancer (PTC) is one of the most treatable forms of cancer, with many cases being fully curable. However, resistance to anticancer drugs often leads to metastasis or recurrence, contributing to the failure of cancer therapy and, ultimately, patient mortality. The mechanisms underlying molecular differences in patients with metastatic or recurrent PTC, particularly those resistant to anticancer drugs through epigenetic reprogramming, remain poorly understood. Consequently, refractory PTC presents a critical challenge, and effective therapeutic strategies are urgently needed. Therefore, this study aimed to identify small-molecule inhibitors to enhance treatment efficacy in lenvatinib-resistant PTC. We observed an increase in sarco/endoplasmic reticulum calcium ATPase (SERCA) levels in patient-derived lenvatinib-resistant PTC cells compared with lenvatinib-sensitive ones, highlighting its potential as a therapeutic target. We subsequently identified two SERCA inhibitors [candidates 40 (isoflurane) and 42 (ethacrynic acid)] through in silico screening. These candidates demonstrated significant tumor shrinkage in a xenograft tumor model and reduced cell viability in patient-derived lenvatinib-resistant PTC cells when used in combination with lenvatinib. Our findings have potential clinical value for the development of new combination therapies to effectively target highly malignant, anticancer drug-resistant cancers. [ABSTRACT FROM AUTHOR]

African animal trypanosomosis (AAT) affects the livestock industry, impacting protein intake and herders' livelihoods. Despite the presence of vector flies, livestock owners often rely solely on chemotherapy, with diminazene aceturate being a common choice, particularly among non-elite herders. Cattle herds were sampled during an outbreak and re-sampled 8 weeks post-treatment with diminazene aceturate (Nonazin®) in Ogun and Osun states, Nigeria. Initial sampling was conducted in October 2019 and January 2020 for farms A and B, respectively. A total of 316 cattle, comprising 20 males and 296 females, were sampled through convenient sampling of the entire herd. Nzi traps were deployed to capture Trypanosoma-transmitting vectors. Haematological parameters, microscopic, and molecular assessments were conducted. The total transmitting vectors captured averaged 3.74 fly/trap/day, with Stomoxys niger being the most captured biting fly. Post-treatment prevalence rates were 21.5% and 2.5% with PCR and thin blood smear, respectively, with Trypanosoma congolense and T. vivax being the species detected by both diagnostic methods. The average parasitaemia before treatment was recorded at 1.95 × 104 ± 1.3 × 104, signifying a high parasitic infection, while post-treatment parasitaemia was 1.5 × 102 ± 1.4 × 102. The PCV, Hb, and RBC counts decreased, causing macrocytic normocytic anaemia before treatment, while post-treatment values suggested lower haemoglobin and MCH values with less-characteristic anaemia. Post-treatment trypanosome prevalence suggests the existence of Trypanosoma-resistant strains, potentially widespread in southwest Nigeria. The situation may be exacerbated by the abundance of biting flies during the dry season, leading to a high T. vivax prevalence. [ABSTRACT FROM AUTHOR]

Copyright of Medicina (Buenos Aires) is the property of Medicina (Buenos Aires) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The antibacterial, antibiofilm, and cytotoxicity activity of cell-free supernatants (CFSs) from probiotics, including Lactobacillus plantarum, Bifidobacterium bifidum , and Saccharomyces cerevisiae against multi-drug resistant Escherichia coli evaluated in current research. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the CFSs were determined by analyzing inhibition zone formation using agar disk diffusion for antibacterial activity, microtiter plate for biofilm analysis, and auto-aggregation were done. CFSs substances were analyzed by GC-MS. The MTT assay on HEK293 cells investigated CFS's influence on cell viability. CFSs were examined for biofilm-related virulence genes, including aggR and fimH using real-time polymerase chain reaction (real-time PCR). All CFSs had bacteriostatic and bactericidal effects. The B. bifidum exhibited the highest antibiofilm activity compared to the others. Bifidobacterium bifidum, L. plantarum , and S. cerevisiae produce 19, 16, and 11 mm inhibition zones against E. coli , respectively. GC-MS indicated that Hydroxyacetone, 3-Hydroxybutyric acid, and Oxime-methoxy-phenyl-dominated CFSs from L. plantarum, B. bifidum , and S. cerevisiae CFSs, respectively. The MTT test demonstrated a cell viability rate of over 90%. Statistically, adding all CFSs lowered the relative expression of both aggR and fimH virulence genes. [ABSTRACT FROM AUTHOR]

As malignant central nervous system tumors, glioma have strong aggressiveness and drug resistance, which reduces the survival of patients. This study explores the molecular mechanisms that influence the progression and drug resistance of glioma cells, promoting the progress of glioma research. In this study, miR-92b-3p and CXCL5 expression were determined using real-time quantitative polymerase chain reaction in glioma tissues and cells. Pearson correlation analysis was performed for both. Luciferase activity reports were utilized to confirm the targeted association between miR-92b-3p and CXCL5. The effects of miR-92b-3p and CXCL5 on the proliferation and metastasis of glioma cells were investigated by Transwell and CCK-8 assay. Finally, the Temozolomide (TMZ) drug-resistant cell lines were constructed, and apoptosis experiments were conducted to explore the drug-resistant mechanism of glioma cells. It was found that miR-92b-3p was down-regulated in glioma tissues and cells, while CXCL5 expression was up-regulated, with a negative correlation between the two and a targeting of miR-92b-3p to CXCL5. Up-regulation of miR-92b-3p inhibited the invasive activity of glioma cells, while overexpression of CXCL5 reversed this phenomenon. There was a negative correlation between miR-92b-3p expression and the IC50 value of TMZ in glioma. Up or downregulation of miR-92b-3p promoted and inhibited TMZ-induced apoptosis in glioma cells, respectively, whereas regulation of CXCL5 expression reversed this phenomenon. miR-92b-3p can exert anticancer effect by targeting CXCL5. Upregulating miR-92b-3p can inhibit the activity of glioma cells, and promote the apoptosis of glioma cells induced by TMZ. [ABSTRACT FROM AUTHOR]

With the increasing of Candida albicans infections year by year, and the widespread use of azole drugs, especially fluconazole has led to the emergence of drug resistance. Therefore, new antifungal agents are urgent needed. In this work, we synthesized a series of tryptanthrin derivatives, and all compounds were evaluated for antifungal activities against Candida albicans in vitro. The results indicated that most compounds combined with fluconazole showed good antifungal activity against drug-resistant Candida albicans. Especially, compound 5b combined with fluconazole had an excellent synergistic effect, with MIC50 value of 0.94 μg/mL, and the FICI value of 0.005. Further mechanism study demonstrated that compound 5b significantly inhibited the hyphal growth and biofilm formation of Candida albicans. Compound 5b combined with fluconazole could be considered as a novel antifungal agent. [ABSTRACT FROM AUTHOR]

Abstract Background To explore the value of computed tomography based radiomics in the differential diagnosis of drug-sensitive and drug-resistant pulmonary tuberculosis. Methods The clinical and computed tomography image data of 177 patients who were diagnosed with pulmonary tuberculosis through sputum culture and completed drug-susceptibility testing from April 2018 to December 2020 at the Second Hospital of Nanjing were retrospectively analyzed. Patients with drug-resistant pulmonary tuberculosis (n = 78) and drug-sensitive pulmonary tuberculosis (n = 99) were randomly divided into a training set (n = 124) and a validation set (n = 53) at a ratio of 7:3. Regions of interest were drawn to delineate the lesions and radiomics features were extracted from non-contrast computed tomography images. A radiomics signature based on the valuable radiomics features was constructed and a radiomics score was calculated. Demographic data, clinical symptoms, laboratory results and computed tomography imaging characteristics were evaluated to establish a clinical model. Combined with the Rad-score and clinical factors, a radiomics-clinical model nomogram was constructed. Results Thirteen features were used to construct the radiomics signature. The radiomics signature showed good discrimination in the training set (area under the curve (AUC), 0.891; 95% confidence interval (CI), 0.832–0.951) and the validation set (AUC, 0.803; 95% CI, 0.674–0.932). In the clinical model, the AUC of the training set was 0.780(95% CI, 0.700-0.859), while the AUC of the validation set was 0.692 (95% CI, 0.546–0.839). The radiomics-clinical model showed good calibration and discrimination in the training set (AUC, 0.932;95% CI, 0.888–0.977) and the validation set (AUC, 0.841; 95% CI, 0.719–0.962). Conclusions Simple radiomics signature is of great value in differentiating drug-sensitive and drug-resistant pulmonary tuberculosis patients. The radiomics-clinical model nomogram showed good predictive, which may help clinicians formulate precise treatments.

Introduction: Diabetes mellitus (DM) comorbidity in drug-resistant (DR) pulmonary tuberculosis (TB) patients can be associated with the treatment outcome. In DR-TB patients with DM, the immune system is impaired, which will decrease the success of treatment. Sputum conversion time is an indicator used to predict the treatment outcome. However, there is still no further study related to the association between DM comorbidity and the sputum conversion time in DR-TB patients, especially in Jember. This study aimed to determine the association between DM and sputum conversion time in DR-TB patients at Dr. Soebandi Regional General Hospital, Jember. Methods: This was an analytic observational study with a cross-sectional design. A total of 122 samples of DR-TB patients were taken using the purposive sampling method in 2018-2023 at Dr. Soebandi Regional General Hospital, Jember. The data were analyzed using the Chi-square and logistic regression statistical test. Results: Chi-square analysis showed that DM (p = 0.015; OR = 2.604; 95% CI 1.195-5.674) and age (p = 0.021; OR = 0.377; 95% CI 0.162-0.878) were associated with sputum conversion time. Logistic regression showed that DM was the most associated variable with the sputum conversion time (p = 0.016; OR = 2.604; 95% CI 1.195-5.674) compared to gender, age, TB resistance type, and anti-TB regimen. Conclusion: DM is associated with prolonged sputum conversion time in DR-TB patients at Dr. Soebandi Regional General Hospital, Jember. DM was also the most associated variable with the sputum conversion time compared to gender, age, TB resistance type, and anti-TB regimen.

Since 2022, Europe has had 4 cases of extensively drug-resistant Neisseria gonorrhoeae, sequence type 16406, that is resistant to ceftriaxone and highly resistant to azithromycin. We report 2 new cases from France in 2023 involving strains genetically related to the 4 cases from Europe as well as isolates from Cambodia.

Antimicrobial peptides (AMP) have emerged as promising candidates for addressing the clinical challenges posed by the rapid evolution of antibiotic-resistant microorganisms. Brevinins, a representative frog-derived AMP family, exhibited broad-spectrum antimicrobial activities, attacking great attentions in previous studies. However, their strong haemolytic activity and cytotoxicity, greatly limit their further development. In this work, we identified and characterised a novel brevinin-1 peptide, brevinin-1pl, from the skin secretions of the northern leopard frog, Rana pipiens. Like many brevinins, brevinin-1pl also displayed strong haemolytic activity, resulting in a lower therapeutic index. We employed several bioinformatics tools to analyse the structure and potential membrane interactions of brevinin-1pl, leading to a series of modifications. Among these analogues, des-Ala16-[Lys4]brevinin-1pl exhibited great enhanced therapeutic efficacy in both in vitro and in vivo tests, particularly against some antibiotics-resistant Escherichia coli strains. Mechanistic studies suggest that des-Ala16-[Lys4]brevinin-1pl may exert bactericidal effects through multiple mechanisms, including membrane disruption and DNA binding. Consequently, des-Ala16-[Lys4]brevinin-1pl holds promise as a candidate for the treatment of drug-resistant Escherichia coli infections.

Abstract Objective In Europe, cenobamate has been approved for use as an adjunctive therapy in adult patients with epilepsy (PWE) with focal‐onset seizures (FOS) who have not responded satisfactorily to treatment with at least two antiseizure medications (ASMs). Pivotal trials and real‐world observational studies have demonstrated a high efficacy of cenobamate, even in very difficult‐to‐treat epilepsies. Our aim was to investigate the efficacy of add‐on cenobamate in adult PWE who were prospectively monitored. We compared these results with those previously obtained for add‐on lacosamide, perampanel, and brivaracetam therapy. Methods Patients were enrolled from the CENKORK study, which is a prospective, non‐interventional, open‐label, monocenter cohort study of adult PWE experiencing FOS. The titration of cenobamate was performed according to the guidelines outlined in the summary of product characteristics. The primary outcome measure was the retention rate at 6 months and 1 year. In addition, we assessed seizure‐free rates, the proportion of patients achieving at least a 50% seizure reduction, adverse events, and the reasons for treatment discontinuation. These outcome measures were compared with historical controls treated with adjunctive lacosamide, perampanel, or brivaracetam at our center. Results Between June 2021 and 2022, 172 PWE with ongoing FOS were included. 22 cases were lost to follow‐up, leaving 150 cases for the 1‐year assessment. The retention rates at 6 months and 1 year were 88.7% and 80%, respectively. Seizure freedom was achieved in 14% of patients at both the 6‐month and 1‐year marks, while the ≥50% responder rates were 50% and 61%, respectively. The 6‐month retention rate was significantly higher in cenobamate than in other ASMs (p

Background: Tuberculosis (TB), a global infectious threat, has seen a concerning rise in aminoglycoside-resistant Mycobacterium tuberculosis (M.tb) strains. The potential role of capsule proteins remains largely unexplored. This layer acts as the primary barrier for tubercle bacilli, attempting to infiltrate host cells and subsequent disease development. Methods: The study aims to bridge this gap by investigating the differentially expressed capsule proteins in aminoglycoside-resistant M.tb clinical isolates compared with drug-sensitive isolates employing two-dimensional gel electrophoresis, mass spectrometry, and bioinformatic approaches. Results: We identified eight proteins that exhibited significant upregulation in aminoglycoside-resistant isolates. Protein Rv3029c and Rv2110c were associated with intermediary metabolism and respiration; Rv2462c with cell wall and cell processes; Rv3804c with lipid metabolism; Rv2416c and Rv2623 with virulence and detoxification/adaptation; Rv0020c with regulatory functions; and Rv0639 with information pathways. Notably, the Group-based Prediction System for Prokaryotic Ubiquitin-like Protein (GPS-PUP) algorithm identified potential pupylation sites within all proteins except Rv3804c. Interactome analysis using the STRING 12.0 database revealed potential interactive partners for these proteins, suggesting their involvement in aminoglycoside resistance. Molecular docking studies revealed suitable binding between amikacin and kanamycin drugs with Rv2462c, Rv3804c, and Rv2623 proteins. Conclusion: As a result, our findings illustrate the multifaceted nature of aminoglycoside resistance in M.tb and the importance of understanding how capsule proteins play a role in counteracting drug efficacy. Identifying the role of these proteins in drug resistance is crucial for developing more effective treatments and diagnostics for TB.

Cancer stem cells, a small population of cells with self-renewal and multidirectional differentiation potential in tumor tissues, can initiate primary tumors and mediate treatment resistance, tumor recurrence, and metastasis, but the mechanism of how they affect colorectal cancer at the cellular level is unknown. Therefore, in this study, we explored the effect of cancer stem cells and their exosomes on the malignant phenotype of colorectal cancer. First, CD166+CD44+cancer stem cells (CSCs) were isolated from colorectal cancer tumor tissues, and then cancer stem cell-derived exosomes (CSCexo) and colorectal cancer SW480 cell-derived exosomes (Sexo) were extracted by ultracentrifugation. Then, exosomes were subjected to NTA particle size analysis, electron microscopic observation and identification by Western blotting. Subsequently, the successfully isolated CSC and CSCexo were co-cultured with colorectal cancer SW480 cells. The apoptosis rate of SW480 cells after co-culture was found to decrease from 20% to about 13% by CCK-8, apoptosis assay (P ＜ 0.01) and the invasive ability was significantly increased (P ＜ 0.001) after co-culture with CSC or CSCexo. In addition, in vivo animal experiments revealed that the tumor growth rate of the S-exo treatment group was slower than that of the CSCexo treatment group, and that CSCexo inhibited the drug efficacy of 5-FU against colorectal cancer tumors. PET/CT imaging, immunohistochemical analysis, and Western blotting experiments showed that CSCexo enhanced the uptake of the glucose analog 18F-FDG and the expression of the glycolytic enzymes HK2, PFKFB2, PKM2, and LDHA in colorectal cancer. In addition, interfering with the expression of glycolytic enzymes with siRNAs blocked the drug resistance induced by CSCexo. In summary, this study demonstrates that colorectal cancer stem cells deliver exosomes that affect tumor glucose metabolism pathways and promote chemotherapy resistance and invasive ability, revealing the mechanism of formation and dynamic changes in the malignant tumor microenvironment. [ABSTRACT FROM AUTHOR]

• The seizure type characterized by generalized myoclonic seizure, closely followed by tonic seizure, is designated as MT seizure. • MT seizures predominantly occurred during the sleep period, with male patients constituting a majority of the participants. • The prognosis of Generalized Epilepsy with MT seizure was found to be more favorable compared to other types of epilepsy. To test the hypothesis that myoclonic seizures can evolve to tonic seizures, we documented the electroclinical features of this under-recognized seizure type. We observed a distinct seizure pattern starting with myoclonus without returning to an interictal state, which subsequently evolved into generalized tonic seizures. The detailed symptomatic and electroencephalographic characteristics of this seizure were extracted, and the clinical manifestations, drug curative responses in patients with this seizure were reviewed and analyzed. The onset of all seizures was characterized by a preceding period of myoclonus and bursts of generalized spike or poly-spike slow wave discharges with high amplitude. This was closely followed by the occurrence of tonic seizures, which were distinguished by bursts of generalized fast activity at 10 Hz or higher frequency. This under-recognized seizure type has been designated as myoclonic-to-tonic (MT) seizure. The number of patients identified with MT seizures in this study was 34. The prevalence rate of MT seizures was found to be higher in males. While MT seizures typically included a tonic component, it should be noted that some patients experiencing this seizure type never presented with isolated tonic seizures. Generalized Epilepsy not further defined (GE) accounted for approximately one-third of the diagnosed cases, followed by Lennox-Gastaut syndrome and Epilepsy with Myoclonic-Atonic seizures. In comparison to other types of epilepsy, GE with MT seizures demonstrated a more favorable prognosis. The classification of myoclonic-to-tonic seizure represents a novel approach in comprehending the ictogenesis of generalized seizures and can provide valuable assistance to clinicians in epilepsy diagnosis. [ABSTRACT FROM AUTHOR]

Objective: In Europe, cenobamate has been approved for use as an adjunctive therapy in adult patients with epilepsy (PWE) with focal‐onset seizures (FOS) who have not responded satisfactorily to treatment with at least two antiseizure medications (ASMs). Pivotal trials and real‐world observational studies have demonstrated a high efficacy of cenobamate, even in very difficult‐to‐treat epilepsies. Our aim was to investigate the efficacy of add‐on cenobamate in adult PWE who were prospectively monitored. We compared these results with those previously obtained for add‐on lacosamide, perampanel, and brivaracetam therapy. Methods: Patients were enrolled from the CENKORK study, which is a prospective, non‐interventional, open‐label, monocenter cohort study of adult PWE experiencing FOS. The titration of cenobamate was performed according to the guidelines outlined in the summary of product characteristics. The primary outcome measure was the retention rate at 6 months and 1 year. In addition, we assessed seizure‐free rates, the proportion of patients achieving at least a 50% seizure reduction, adverse events, and the reasons for treatment discontinuation. These outcome measures were compared with historical controls treated with adjunctive lacosamide, perampanel, or brivaracetam at our center. Results: Between June 2021 and 2022, 172 PWE with ongoing FOS were included. 22 cases were lost to follow‐up, leaving 150 cases for the 1‐year assessment. The retention rates at 6 months and 1 year were 88.7% and 80%, respectively. Seizure freedom was achieved in 14% of patients at both the 6‐month and 1‐year marks, while the ≥50% responder rates were 50% and 61%, respectively. The 6‐month retention rate was significantly higher in cenobamate than in other ASMs (p < 0.001 for each comparator). Adverse events were significantly more common with perampanel (p < 0.001). Significance: Add‐on cenobamate proved to be particularly efficacious compared to our experience with other recently introduced ASMs. Plain Language Summary: This observational study was carried out in 172 adult patients with difficult‐to‐treat epilepsy who were treated with adjunctive cenobamate. After 1 year, the data of 150 patients could be analyzed. Seizure freedom, in the preceding 3 months, was achieved in 14%. The rate of PWE continuing cenobamate was 80%. In our hands, cenobamate showed promising efficacy and tolerability even when compared to other recently introduced antiseizure medications. [ABSTRACT FROM AUTHOR]

Although antibiotics are most frequently prescribed for respiratory tract infections, effective interventions for their proper use by physicians have not been fully established. We assessed the impact of educational films on the rates of antibiotic prescriptions for respiratory tract infections using fictitious scenarios. In this nationwide web-based survey prospective study, a total of 1100 physicians were included. The physicians were required to view educational short films and determine the need for prescribing antibiotics in 10 fictitious scenarios involving adults diagnosed with different acute respiratory tract infectious diseases. The antibiotic prescription rates for each scenario were compared before and after viewing the educational short film. The rates of antibiotic prescription significantly decreased after viewing the educational film, especially in cases with a narrowly defined common cold (from 51% to 15%), mild pharyngolaryngitis (from 71% to 25%), and acute bronchitis without chronic respiratory underlying diseases (from 63% to 23%). Alternatively, a slight decrease in rates was observed in cases with moderate or severe rhinosinusitis (from 94% to 79%), moderate or severe acute pharyngitis (from 88% to 69%), and acute bronchitis with chronic lung disease (from 70% to 58%), for which antibiotics are recommended. Educational short films may encourage the proper use of antibiotics for respiratory tract infections; however, the possibility of undertreatment in patients requiring antibiotics must be considered. [ABSTRACT FROM AUTHOR]

Background: Drug resistance is a major obstacle in the treatment of anaplastic thyroid carcinoma (ATC) with the combination of docetaxel (DTX) and doxorubicin (DOX). Excessive intracellular drug efflux is considered a key factor contributing to drug resistance. Therefore, developing drug-loaded microspheres to enhance cellular uptake and inhibit efflux of docetaxel and doxorubicin may be an effective strategy to overcome chemoresistance. Methods: Alginate-Doxorubicin@carboxymethyl chitosan-Docetaxel (A-DOX@C-DTX) microspheres were prepared using an electrostatic spraying-assisted microfluidic device. The microspheres were characterized, and the in vitro drug release profiles and extracellular efflux rates were determined. The effects of A-DOX@C-DTX microspheres on drug-resistant ATC cells were evaluated in vitro. In vivo, a subcutaneous tumor model was established in mice to investigate the effects of A-DOX@C-DTX microspheres on tumor growth, as well as the accumulation and release of the materials at the tumor site. Results: We successfully prepared aliginate/carboxymethyl chitosan (ALG/CMC) microspheres with a core-shell structure. These microspheres exhibited controllable size, good monodispersity, excellent biocompatibility, high encapsulation efficiency for doxorubicin and docetaxel, and high drug loading capacity. Moreover, the microspheres promoted cellular uptake of doxorubicin and docetaxel while inhibiting their efflux. A-DOX@C-DTX microspheres showed significant inhibition of viability, proliferation, migration, and invasion of drug-resistant ATC cells in vitro. In vivo, A-DOX@C-DTX microspheres suppressed tumor growth, induced tumor tissue necrosis, and promoted tumor cell apoptosis. In addition, the microspheres facilitated the enrichment of active substances in the tumor and their sustained release. Conclusion: A-DOX@C-DTX microspheres exhibited superior antitumor effects compared to free drug treatment both in vitro and in vivo, particularly against drug-resistant ATC cells. This improved therapeutic efficacy may be attributed to the enhanced drug uptake and reduced drug efflux in drug-resistant ATC cells facilitated by ALG/CMC microspheres. [ABSTRACT FROM AUTHOR]

The drug-resistant temporal lobe epilepsy (TLE) has recently been associated with single nucleotide variants (SNVs) in microRNA(miR)-146a (MIR-146A) (rs2910164) and Sodium Voltage-Gated Channel Alpha Subunit 1 (SCN1A) (rs2298771 and rs3812718) genes. Moreover, no studies have shown an association between these SNVs and susceptibility to drug-resistant and drug-responsive TLE in Brazil. Thus, deoxyribonucleic acid (DNA) samples from 120 patients with TLE (55 drug-responsive and 65 drug-resistant) were evaluated by real-time polymerase chain reaction (RT-PCR). A total of 1171 healthy blood donor individuals from the Online Archive of Brazilian Mutations (ABraOM, from Portuguese Arquivo Brasileiro On-line de Mutações), a repository containing genomic variants of the Brazilian population, were added as a control population for the studied SNVs. MIR-146A and SCN1A relative expression was performed by quantitative RT-PCR (qRT-PCR). The statistical analysis protocol was performed using an alpha error of 0.05. TLE patient samples and ABraOM control samples were in Hardy–Weinberg equilibrium for all studied SNVs. For rs2910164, the frequencies of the homozygous genotype (CC) (15.00% vs. 9.65%) and C allele (37.80% vs. 29.97%) were superior in patients with TLE compared to controls with a higher risk for TLE disease [odds ratio (OR) = 1.89 (95% confidence interval (95%CI) = 1.06–3.37); OR = 1.38 (95%CI = 1.04–1.82), respectively]. Drug-responsive patients also presented higher frequencies of the CC genotype [21.81% vs. 9.65%; OR = 2.58 (95%CI = 1.25–5.30)] and C allele [39.09% vs. 29.97%; OR = 1.50 (95%CI = 1.01–2.22)] compared to controls. For rs2298771, the frequency of the heterozygous genotype (AG) (51.67% vs. 40.40%) was superior in patients with TLE compared to controls with a higher risk for TLE disease [OR = 2.42 (95%CI = 1.08–5.41)]. Drug-resistant patients presented a higher AG frequency [56.92% vs. 40.40%; OR = 3.36 (95%CI = 1.04–17.30)] compared to the control group. For rs3812718, the prevalence of genotypes and alleles were similar in both studied groups. The MIR-146A relative expression level was lower in drug-resistant compared to drug-responsive patients for GC (1.6 vs. 0.1, p-value = 0.049) and CC (1.8 vs. 0.6, p-value = 0.039). Also, the SCN1A relative expression levels in samples from TLE patients were significantly higher in AG [2.09 vs. 1.10, p-value = 0.038] and GG (3.19 vs. 1.10, p-value < 0.001) compared to the AA genotype. In conclusion, the rs2910164-CC and rs2298771-AG genotypes are exerting significant risk influence, respectively, on responsive disease and resistant disease, probably due to an upregulated nuclear factor kappa B (NF-kB) and SCN1A loss of function. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) continues to be a global health problem due to its high morbidity and death rates. Standardized regimens have been used in traditional TB treatment methods, frequently leading to less-than-ideal results and the establishment of drug-resistant strains. The development of personalized medicine provides a potentially effective remedy to individual patients' by adjusting therapeutic approaches to particular genotypic and phenotypic traits. Detecting TB strains, drug resistance indicators, and host genetic variants that affect treatment results is made possible by genomic and molecular diagnostic approaches. These developments offer helpful information for predicting therapy outcomes and choosing the best treatment plan for each individual.Integrating phenotypic data, such as clinical characteristics, immunological state, and comorbidities, improves diagnostic and treatment decision-making accuracy. The use of targeted drug therapies, such as innovative anti-TB medicines and repurposed medications, which have the potential to overcome drug resistance and boost treatment effectiveness, can be guided by personalized therapy. Personalized interventions based on genetic and phenotypic factors can improve patient outcomes by identifying those at risk of treatment failure or disease progression. This article discusses the importance of personalized therapy for TB patients. It specifically highlights the benefits of using “omics” data to enhance therapeutic results and decrease the risk of drug resistance.

Drug-resistant bacteria constitute a big barrier against current pharmacotherapy. Efforts are urgent to discover antibacterial drugs with novel chemical and biological features. Our work aimed at the synthesis, evaluation of antibacterial effects, and toxicity of licochalcone C (LCC), a naturally occurring chalcone. The synthetic route included six steps, affording a 10% overall yield. LCC showed effects against Gram-positive bacteria (MIC = 6.2–50.0 µg/mL), Mycobacterium species (MIC = 36.2–125 µg/mL), and Helicobacter pylori (MIC = 25 µg/mL). LCC inhibited the biofilm formation of MSSA and MRSA, demonstrating MBIC50 values of 6.25 μg/mL for both strains. The investigations by fluorescence microscopy, using PI and SYTO9 as fluorophores, indicated that LCC was able to disrupt the S. aureus membrane, similarly to nisin. Systemic toxicity assays using Galleria mellonella larvae showed that LCC was not lethal at 100 µg/mL after 80 h treatment. These data suggest new uses for LCC as a compound with potential applications in antibacterial drug discovery and medical device coating. [ABSTRACT FROM AUTHOR]

There were reports of cardiac dysfunction that led to sudden unexpected death in epilepsy (SUDEP) in patients with epilepsy. Early detection of cardiac dysfunction can lead to early management to prevent sudden cardiac death in these patients. The objective of our study is to assess cardiac functions in children with drug-resistant epilepsy (DRE) compared with the normal population by using a standard echocardiogram (SE), tissue Doppler imaging (TDI) and myocardial strain evaluations (MSE). Method: Twenty-seven children who have been diagnosed with DRE based on the International League against Epilepsy (ILAE) were included in the study, along with 27 children whose ages match those of the normal control group. Results: Seventeen children, median age 12  years old, were using more than four anti-seizure medications. Structural brain lesions were the most common cause of epilepsy, 55.6% (15). Generalized tonic–clonic seizures were the most common seizure type, 55.6% (15). Children with DRE had a lower early mitral valve E wave inflow velocity compared with the control group (p  <  0.05). They also had lowered early diastolic velocities (e′) and myocardial performance index (MPI) when compared with the control group (p  <  0.05). There was a statistically significant difference in left ventricular myocardial strain in children with DRE, with an average of −21.1 (IQR −23.5 and −19.4) and control, −25.5 (IQR −27.3 and −24.2). Significance: Children with DRE have an impairment of left ventricular diastolic function and myocardial strain, which could indicate decreased myocardial deformation and contraction compared with controls. These cardiological assessments can be used to evaluate children with DRE for early diagnosis and management of their cardiac dysfunction [ABSTRACT FROM AUTHOR]

Introduction: Implantable medical devices continue to be vulnerable to bacterial infections. The unrelenting formation of antibiotic resistant bacterial strains not only exacerbates these infections but also renders the current treatment strategies impotent. The need is greater than ever for innovative and effective approaches to counteract drug-resistant bacteria. This study examines the innate antibacterial properties of TiO2 nanotube arrays (TNAs) and their ability to locally deliver antibiotics to inactivate gram-positive and gram-negative bacteria, in vitro. Methods: Using a two-step electrochemical anodization process, TNAs with a diameter of ~100 nm and a length of ~5 µm were grown on titanium substrates. Results and Discussion: After 24 h of incubation, as-fabricated TNAs showed 100% clearance of Escherichia coli, and 97% clearance of Staphylococcus aureus growth. The antibiotic-loaded TNAs demonstrated sustained slow-release of cefotaxime and imipenem measured over 14 days. In vitro bacterial studies revealed the capability of cefotaxime- and imipenem-loaded TNAs in completely inhibiting the growth with 100% clearance of Klebsiella pneumoniae after 24 and 48 h of incubation. Bacterial inhibition assay revealed a significantly enlarged inhibition zone difference of 18mm around the imipenem-loaded TNAs against K. pneumoniae compared to the as-fabricated TNAs which was maintained for 7 days with ~10 μgmL-1 of antibiotic released from the TNAs which was found to be lower than the dose required to completely eradicate multidrug resistant bacteria when used in conjunction with the antibacterial TNAs. The results of our study highlight the potential of TNAs as a versatile platform for addressing treatment strategies related to bacterial infections and antibiotic resistance in implantable medical devices. [ABSTRACT FROM AUTHOR]

Quinoline and its derivatives are a family with unique medicinal properties, including antibacterial effects. It was assumed that the four quinoline derivatives 1, 2, 3 and 4 had significant activity against pathogenic bacteria. These compounds were synthesized and characterized by TLC, IR, 1H NMR, and 13C NMR analyses. The biological activity of compounds was determined as inhibition zone (IZ) in mm. For compound 1 IZ was 19 ± 0.22 against Klebsiella pneumoniae, IZ was 18 ± 0.22 against Bacillus subtilis, and IZ was 17 ± 0.22 against Staphylococcus aureus. 2 displayed IZ of 18 ± 0.22 against both Klebsiella pneumoniae and Bacillus subtilis. 3 showed IZ of 17 ± 0.22 against Staphylococcus aureus. 4 displayed IZ of 21 ± 0.22, thus showing a higher inhibitory activity against Escherichia coli, than ciprofloxacin. These results demonstrate the potential of the synthesized compounds to work as antibacterial drugs against these strains by inhibiting or deactivating the target proteins. [ABSTRACT FROM AUTHOR]

The public health care system is currently facing a major problem with malaria. Globally, malarial deaths have decreased by an estimated 40% in the past two decades because of the clinically effective drugs (artemisinin-based combination therapies) against Plasmodium falciparum. In recent years, P falciparum develop resistance against all antimalarial drugs and then becomes developed multidrug resistance that a major challenge. Even though drug discovery programs have made substantial progress in the past decade, the potential for new drugs/combinations to improve the effectiveness of current malaria control strategies. Beyond, we have compiled a comprehensive review of clinically approved anti-malarial drugs with resistance mechanisms and a novel drug-resistance reversal approach in one place to meet this demand. The review aimed to provide detailed information on drug resistance, its regulatory molecular mechanisms responsible for resistance, and the novel available treatment of malaria. In this review, the article will help in developing effective interventions, potential approaches, and strategies to handle antimalarial resistance. This will prevent life-threatening infections. [ABSTRACT FROM AUTHOR]

Epilepsy is a common neurological disorder affecting over 70 million people worldwide. Although many patients achieve seizure control with anti‐epileptic drugs (AEDs), 30%–40% develop drug‐resistant epilepsy (DRE), where seizures persist despite adequate trials of AEDs. DRE is associated with reduced quality of life, increased mortality and morbidity, and greater socioeconomic challenges. The continued intractability of DRE has fueled exponential growth in research that aims to understand and treat this serious condition. However, synthesizing this vast and continuously expanding DRE literature to derive insights poses considerable difficulties for investigators and clinicians. Conventional review methods are often prolonged, hampering the timely application of findings. More‐efficient approaches to analyze the voluminous research are needed. In this study, we utilize a natural language processing (NLP)–based topic modeling approach to examine the DRE publication landscape, uncovering key topics and trends. Documents were retrieved from Scopus, preprocessed, and modeled using BERTopic. This technique employs transformer models like BERT (Bidirectional Encoder Representations from Transformers) for contextual understanding, thereby enabling accurate topic categorization. Analysis revealed 18 distinct topics spanning various DRE research areas. The 10 most common topics, including "AEDs," "Neuromodulation Therapy," and "Genomics," were examined further. "Cannabidiol," "Functional Brain Mapping," and "Autoimmune Encephalitis" emerged as the hottest topics of the current decade, and were examined further. This NLP methodology provided valuable insights into the evolving DRE research landscape, revealing shifting priorities and declining interests. Moreover, we demonstrate an efficient approach to synthesizing and visualizing patterns within extensive literature that could be applied to other research fields. [ABSTRACT FROM AUTHOR]

Biofilm-associated infections caused by drug-resistant and persistent bacteria remain a significant clinical challenge. Here we report that farnesol, commercially available as a cosmetic and flavoring agent, shows significant anti-biofilm properties when dissolved in ethanol using a proprietary formulation emulsion technique. Farnesol in the new formulation inhibits biofilm formation and disrupts established biofilms for Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa, including their polymicrobial biofilms, and, moreover, kills S. aureus persister cells that have developed tolerance to antibiotics. No resistance to farnesol was observed for S. aureus after twenty continuous passages. Farnesol combats biofilms by direct killing, while also facilitating biofilm detachment. Furthermore, farnesol was safe and effective for preventing and treating biofilm-associated infections of both types of bacteria in an ex vivo burned human skin model. These data suggest that farnesol in the new formulation is an effective broad-spectrum anti-biofilm agent with promising clinical potential. Due to its established safety, low-cost, versatility, and excellent efficacy—including ability to reduce persistent and resistant microbial populations—farnesol in the proprietary formulation represents a compelling transformative, translational, and commercial platform for addressing many unsolved clinical challenges. [ABSTRACT FROM AUTHOR]

Aim: Drug‐resistant epilepsy (DRE) is a neurological disorder characterized by uncontrolled seizures. It affects between 10%–40% of the patients with epilepsy worldwide. Drug‐resistant patients have been reported to have a different microbiota composition compared to drug‐sensitive patients and healthy controls. Importantly, fecal microbiota transplantations (FMTs), probiotic and dietary interventions have been shown to be able to reduce seizure frequency and improve the quality of life in drug‐resistant patients. The classic ketogenic diet (KD) and its modifications may reduce seizures in DRE in some patients, whereas in others they do not. The mechanisms mediating the dietary effects remain elusive, although it is known that gut microbes play an important role in transmitting dietary effects to the host. Indeed, specific commensal microbes differ even between responders and non‐responders to KD treatment. Methods: In this narrative mini‐review, we summarize what is known about the gut microbiota changes and ketogenic diets with special focus on patients with DRE. Results and Conclusions: By highlighting unanswered questions and by suggesting future research directions, we map the route towards future improvement of successful DRE therapy. [ABSTRACT FROM AUTHOR]

Bedaquiline resistance is increasingly observed in the treatment of rifampicin-resistant tuberculosis (TB), yet standardized regimens for managing bedaquiline-resistant TB are lacking. Studies indicate a high proportion of bedaquiline-resistant cases have previously been treated for TB, and often involve strains resistant to quinolones. Regular monitoring of the culture status in patients receiving bedaquiline resistance treatment is advised. Methods such as experimental evolution, protein modeling, genome sequencing, and phenotypic analysis have been instrumental in identifying the mechanisms of bedaquiline resistance. Specifically, variants in the Rv0678 transcriptional repressor of the MmpS5-MmpL5 efflux system are linked to this type of resistance. Bayesian probability estimates show promise in determining the genotypic–phenotypic association for bedaquiline resistance, suggesting potential utility in clinical practice. Future research should explore the practical application of Bayesian probabilities in managing bedaquiline resistance. Sequencing-based technologies are anticipated to play a vital role in the early detection and management of drug-resistant TB strains.

Abstract Objective There is growing evidence that ketogenic dietary therapy (KDT) can be safely and efficiently used in young children, but little evidence exists on its use in newborns. Developmental and epileptic encephalopathies starting in the neonatal period or early infancy usually present a poor prognosis. The aim of this study was to evaluate effectiveness, safety, and survival of infants younger than 3 months of age with drug‐resistant epilepsy in whom KDT was used. Methods A retrospective study was conducted to evaluate neonates and infants younger than 3 months who started KDT for drug‐resistant developmental and epileptic encephalopathies at three referral centers. Data were collected on demographic features, time of epilepsy onset, epilepsy syndrome, seizure type, seizure frequency at diet onset, etiology, details regarding diet initiation, type of ketogenic formula, breastfeeding, route of administration, blood ketones, growth, length of NICU stay, and survival. Results Nineteen infants younger than 12 weeks of life who received KDT with a minimum follow‐up of 1 month were included; 13 had early‐infantile developmental and epileptic encephalopathy, four epilepsy of infancy with migrating focal seizures, and two focal epilepsy. A >50% response was observed in 73.7% at 1 month on the diet; 37% achieved a > 75% seizure reduction, and 10.5% became seizure free. At 3 months, a >50% decrease in seizure frequency was observed in 72.2%; 15.8% had a >75% reduction; 21% became seizure free. Overall survival was 76% at 1 year on diet. Incidence of acute and late adverse effects was low and most adverse effects were asymptomatic and manageable. Significance Our experience suggests that KDT is safe and effective in newborns and very young infants; however, further studies on the management of the diet in this vulnerable age group are necessary.

Ruojing Bai, Jun Guo Department of Geriatric Medicine, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of ChinaCorrespondence: Jun Guo, Department of Geriatric Medicine, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of China, Email junguo_med@tsinghua.edu.cnAbstract: Klebsiella pneumoniae (K. pneumoniae), a significant contributor to the global challenge of antibiotic resistance, is not only a ubiquitous component of the human microbiome but also a potent pathogen capable of causing a spectrum of diseases. This review provides a thorough analysis of the intricate interactions between K. pneumoniae and the human immune system, elucidating its substantial impact on metabolic processes. We explore the mechanisms employed by K. pneumoniae to evade and manipulate immune responses, including molecular mimicry, immune modulation, and biofilm formation. The review further investigates the bacterium’s influence on metabolic pathways, particularly glycolysis, highlighting how these interactions exacerbate disease severity. The emergence of multidrug-resistant and extremely drug-resistant strains within the Enterobacteriaceae family has heightened the public health crisis, underscoring the urgency for comprehensive research. We investigate the roles of the host’s complement system, autophagy, cell death mechanisms, and various cytokines in combating K. pneumoniae infections, shedding light on areas that warrant further academic investigation. Additionally, the review discusses the challenges posed by K1- and K2-capsule polysaccharides in vaccine development due to their complex molecular structures and adhesive properties. Acknowledging the limited availability of effective antimicrobials, this review advocates for exploring alternative approaches such as immunotherapeutics, vaccinations, and phage therapy. We consolidate current knowledge on K. pneumoniae, covering classical and non-classical subtypes, antimicrobial resistance-mediated genes, virulence factors, and epidemiological trends in isolation and antibiotic resistance rates. This comprehensive review not only advances our understanding of K. pneumoniae but also underscores the imperative for ongoing research and collaborative efforts to develop new prevention and treatment strategies against this formidable pathogen.Keywords: Klebsiella pneumoniae, complement system, pathogenic mechanism, drug-resistant, treatment strategy

Background: Helicobacter pylori infection is one of the major risk factors for gastroduodenal disease, and invasive or non-invasive tests are available to detect it. Aims and Objectives: The study aims to identify H. pylori phenotypically and genotypically to identify drug-resistant H. pylori in suspected cases of peptic acid disorders at a tertiary care center. Materials and Methods: This 6-month prospective and observational study was performed at Saveetha Medical College and Hospitals. Patients’ gastric biopsy samples were obtained from 105 individuals with gastroduodenal disorders who had upper gastrointestinal endoscopies at the Hospital. A fiber optic endoscope and biopsy forceps were used for the endoscopy. Biopsy samples were collected from the antrum and placed in Eppendorf tubes for fast urease, culture, gram stain, polymerase chain reaction (PCR), and histological analysis. Results: A total of 78 (74%) males and 27 (26%) females were among the 105 patients. Endoscopic findings imply gastritis, gastric ulcer, and duodenal ulcer in 74 patients (70.48%). Rapid urease test (RUT), gram stain, and histology revealed positive results in 20 cases. RUT showed that 30.47% of patients tested positive. Gram stain detected 25.1% of H. pylori infections, and 12 cases were histopathologically positive. By PCR, 21.62% of gastritis patients were positive for H. pylori infection. RUT and PCR give comparable results for detecting H. pylori infection, with a strong association between H. pylori infection and peptic ulcer disease. Conclusion: A combination of RUT and PCR is an effective diagnostic approach for H. pylori infection, allowing doctors to select the most appropriate medications for specific patients.

Background: Antibiotics are inappropriately prescribed for respiratory tract infections for various reasons. The differences of the effects of education based on these reasons has not been fully elucidated. This study assessed the impact of an educational film on antibiotic prescription patterns according to physicians’ prescribing justifications. Methods: This was a secondary analysis of a nationwide web-based survey involving 1100 physicians. The physicians were required to view a short educational film and determine the need for prescribing antibiotics in simulated scenarios of different acute respiratory tract infectious diseases. The associations between the reasons for antibiotic prescription to patients not requiring antibiotics before viewing the educational film and the positive effects of the intervention were analyzed. Results: The educational intervention positively affected prescribing trends among physicians who prescribed antibiotics for “fever” in mild acute rhinosinusitis (prescription rates from 100% to 25.9%), “pus in the laryngopharynx” in mild acute pharyngitis (prescription rates from 100% to 29.6%), and “purulent sputum” in acute bronchitis without chronic lung disease (prescription rates from 100% to 29.9%) before viewing the film. In contrast, no benefits were observed when the justification was “patient’s desire for antibiotics” in mild acute pharyngitis (prescription rates from 100% to 48.5%) and acute bronchitis without chronic lung disease (prescription rates from 100% to 44.0%) or “parents’ desire for antibiotics” in narrowly defined common cold in children (prescription rates from 100% to 45.7%). Conclusions: although educational interventions might reduce inappropriate antibiotic prescription by providing accurate knowledge about respiratory tract infections, they appear ineffective for physicians who prescribe antibiotics based on patients’ or parents’ desires for antibiotic treatment.

Objective: There is growing evidence that ketogenic dietary therapy (KDT) can be safely and efficiently used in young children, but little evidence exists on its use in newborns. Developmental and epileptic encephalopathies starting in the neonatal period or early infancy usually present a poor prognosis. The aim of this study was to evaluate effectiveness, safety, and survival of infants younger than 3 months of age with drug‐resistant epilepsy in whom KDT was used. Methods: A retrospective study was conducted to evaluate neonates and infants younger than 3 months who started KDT for drug‐resistant developmental and epileptic encephalopathies at three referral centers. Data were collected on demographic features, time of epilepsy onset, epilepsy syndrome, seizure type, seizure frequency at diet onset, etiology, details regarding diet initiation, type of ketogenic formula, breastfeeding, route of administration, blood ketones, growth, length of NICU stay, and survival. Results: Nineteen infants younger than 12 weeks of life who received KDT with a minimum follow‐up of 1 month were included; 13 had early‐infantile developmental and epileptic encephalopathy, four epilepsy of infancy with migrating focal seizures, and two focal epilepsy. A >50% response was observed in 73.7% at 1 month on the diet; 37% achieved a > 75% seizure reduction, and 10.5% became seizure free. At 3 months, a >50% decrease in seizure frequency was observed in 72.2%; 15.8% had a >75% reduction; 21% became seizure free. Overall survival was 76% at 1 year on diet. Incidence of acute and late adverse effects was low and most adverse effects were asymptomatic and manageable. Significance: Our experience suggests that KDT is safe and effective in newborns and very young infants; however, further studies on the management of the diet in this vulnerable age group are necessary. [ABSTRACT FROM AUTHOR]

Pharmaceutical effluents primarily enter aquatic environments through the discharge of treated and untreated wastewater from various sources, including hospitals, pharmaceutical manufacturing facilities, and households. Microbes sourced from pharmaceutical effluents such as Pseudomonas spp. pose a significant public health concern because of their high levels of resistance to multiple drugs and extreme multidrug resistance. Therefore, the present study was conducted for the isolation, identification, and molecular characterization of selected isolates from pharmaceutical effluents and also determined their antibiotic sensitivity patterns. From June 2016 to March 2017, a study was conducted on four well-known pharmaceutical companies specializing in antibiotic production in Dhaka and Gazipur. Four wastewater samples were collected from various origins and then brought to the Bacteriology laboratory for microbiological examination. Twelve pure isolates were obtained and characterized through cultural and biochemical tests while molecular identification of Pseudomonas spp. was performed using the 16S rRNA gene sequence. Twelve commercially available antibiotics were used for antibiotic sensitivity tests using Kirby-Bauer disk diffusion methods. We isolated the most predominant isolates, Pseudomonas aeruginosa (41.67%), followed by Bacillus spp. (33.33%) and Staphylococcus spp. (25%) respectively. Among 12 antibiotics, ciprofloxacin is 100% sensitive against P. aeruginosa, while the remaining 11 antibiotics are 100% resistant. Bacillus spp. showed 100% resistance to all antibiotics while 50% sensitive to vancomycin and 100% to chloramphenicol, respectively. Staphylococcus spp. was 100% resistant to all antibiotics. Our research suggested that P. aeruginosa is the reservoir of antibiotic resistance genes and spreads disease to humans from the environment. The findings of this study, i.e., the isolation, identification, and characterization of antibiotic-resistant bacteria from pharmaceutical effluent have highlighted, comprehended, and mitigated the dissemination of antibiotic resistance and opportunistic bacteria. [ABSTRACT FROM AUTHOR]

Direct-acting antiviral agents (DAAs) have shown higher cure rates for treating hepatitis C virus (HCV) by directly interfering with different steps of the HCV life cycle. To optimize drug combinations and accurately quantify the antiviral effect of DAAs treatments, mathematical models should include the intracellular virus replication processes. In this study, we develop a two-strain multiscale age-structured model that includes intracellular viral RNA replication and extracellular viral infection. We prove the existence, positivity, and boundedness of the solution, and derive the conditions for the existence and stability of the three steady states (non-infection steady state, boundary steady state, and coexistence steady state). Under certain biologically reasonable assumptions, we obtain the approximate solutions of the viral load decline of the two virus strains (sensitive and drug-resistant virus strains) during treatment, and the long-term approximation is shown to be in good agreement with the solution of the original model. We also carry out numerical simulations using the long-term approximate solution, providing insights into the influence of antiviral effects on the viral load change of the two virus strains during treatment with DAAs. • A multiscale mixed-ODE-PDE model is developed to study HCV infection. • The model includes intracellular RNA replication and extracellular viral infection. • We studied the existence and stability of the three steady states. • The approximate analytical solution is convenient for data comparison. [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori infection is one of the major risk factors for gastroduodenal disease, and invasive or non-invasive tests are available to detect it. Aims and Objectives: The study aims to identify H. pylori phenotypically and genotypically to identify drug-resistant H. pylori in suspected cases of peptic acid disorders at a tertiary care center. Materials and Methods: This 6-month prospective and observational study was performed at Saveetha Medical College and Hospitals. Patients' gastric biopsy samples were obtained from 105 individuals with gastroduodenal disorders who had upper gastrointestinal endoscopies at the Hospital. A fiber optic endoscope and biopsy forceps were used for the endoscopy. Biopsy samples were collected from the antrum and placed in Eppendorf tubes for fast urease, culture, gram stain, polymerase chain reaction (PCR), and histological analysis. Results: A total of 78 (74%) males and 27 (26%) females were among the 105 patients. Endoscopic findings imply gastritis, gastric ulcer, and duodenal ulcer in 74 patients (70.48%). Rapid urease test (RUT), gram stain, and histology revealed positive results in 20 cases. RUT showed that 30.47% of patients tested positive. Gram stain detected 25.1% of H. pylori infections, and 12 cases were histopathologically positive. By PCR, 21.62% of gastritis patients were positive for H. pylori infection. RUT and PCR give comparable results for detecting H. pylori infection, with a strong association between H. pylori infection and peptic ulcer disease. Conclusion: A combination of RUT and PCR is an effective diagnostic approach for H. pylori infection, allowing doctors to select the most appropriate medications for specific patients. [ABSTRACT FROM AUTHOR]

Salmonella including drug-resistant strains are major foodborne pathogens causing serious illness and pose a great threat to the prevention and control for food safety. Phages can naturally defect the bacterium, is considered as a new and promising biological antimicrobial agent in the post-antibiotic era. A poultry facility in Wuhan, China provided wastewater samples from which a collection of 29 phages were isolated and purified. A broad host spectrum phage ISTP3, which capable of infecting all tested Salmonella, including drug-resistant Salmonella enterica, were examined. Additionally, the effectiveness of this phage ISTP3 in reducing drug-resistant S. enterica was assessed in diverse food samples. Transmission electron microscopy (TEM) and whole genome sequencing demonstrated that ISTP3 was found to belong to family Ackermannviridae. The one-step growth experiment and assays of stability demonstrated that ISTP3 exhibited short periods of inactivity before replicating, produced a significant number of viral progeny during infection, and remained high stable under varying pH and temperature conditions. We evaluated the efficacy of phage ISTP3 against drug-resistant Salmonella on chicken breast and lettuce samples at different temperatures. When applying phage ISTP3 in food matrices, the drug resistant Salmonella count significantly reduced at 4°C and 25°C at an MOI of 100 or 1,000 within a timescale of 12  h. Overall, the results, such as broad host ranges, strictly lytic lifestyles, absence of lysogenic related genes, toxin genes, or virulence genes in the genome, demonstrate that the application of phage ISTP3 as a biocontrol agent has promising potential for preventing and controlling drug-resistant S. typhimurium in the context of food safety, processing, and production. [ABSTRACT FROM AUTHOR]

Introduction: Implantable medical devices continue to be vulnerable to bacterial infections. The unrelenting formation of antibiotic resistant bacterial strains not only exacerbates these infections but also renders the current treatment strategies impotent. The need is greater than ever for innovative and effective approaches to counteract drug-resistant bacteria. This study examines the innate antibacterial properties of TiO2 nanotube arrays (TNAs) and their ability to locally deliver antibiotics to inactivate gram-positive and gram-negative bacteria, in vitro.Methods: Using a two-step electrochemical anodization process, TNAs with a diameter of ∼100 nm and a length of ∼5 µm were grown on titanium substrates.Results and Discussion: After 24 h of incubation, as-fabricated TNAs showed 100% clearance of Escherichia coli, and 97% clearance of Staphylococcus aureus growth. The antibiotic-loaded TNAs demonstrated sustained slow-release of cefotaxime and imipenem measured over 14 days. In vitro bacterial studies revealed the capability of cefotaxime- and imipenem-loaded TNAs in completely inhibiting the growth with 100% clearance of Klebsiella pneumoniae after 24 and 48 h of incubation. Bacterial inhibition assay revealed a significantly enlarged inhibition zone difference of 18 mm around the imipenem-loaded TNAs against K. pneumoniae compared to the as-fabricated TNAs which was maintained for 7 days with ∼10 μgmL−1 of antibiotic released from the TNAs which was found to be lower than the dose required to completely eradicate multidrug resistant bacteria when used in conjunction with the antibacterial TNAs. The results of our study highlight the potential of TNAs as a versatile platform for addressing treatment strategies related to bacterial infections and antibiotic resistance in implantable medical devices.

Jiao Sun,1,&ast; Lichao Fan,2,&ast; Yanping Zhao,3,&ast; Haoyu Wu,2 Ran Li,2 Yao Tian,2 Moxin Cheng,2 Xin Ma,1 Yingying Ma,1 Xinru Yang,1 Adong Shen,4 Yanhong Yu,1 Yu Chen2 1Tuberculosis Laboratory, Shenyang Tenth People’s Hospital/Shenyang Chest Hospital, Shenyang, People’s Republic of China; 2Department of Tuberculosis, Shenyang Tenth People’s Hospital/Shenyang Chest Hospital, Shenyang, People’s Republic of China; 3School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 4National Clinical Research Center for Respiratory Disease, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanhong Yu; Yu Chen, Email 438735174@qq.com; yuchensyxk@163.comObjective: Drug-resistant tuberculosis (DR-TB) in children seriously threatens TB control. Information on the epidemiology and characteristics of DR-TB in children in China is limited. We studied data in Shenyang Tenth People’s Hospital to understand the DR-TB epidemiology in children in Shenyang.Design or Methods: We retrospectively analyzed drug resistance testing data of pediatric TB patients between 2017 and 2021, and included 2976 clinically-diagnosed pediatric TB patients. We described the epidemiology of DR-TB and analyzed the trends of DR-TB incidence. The Kappa value was calculated to assess the agreement between MGIT 960 DST and Xpert MTB/RIF for detecting rifampicin resistance. Multivariate logistic regression was used to identify the risk factors for DR-TB in pediatric patients.Results: Of the 2976 TB patients, 1076 were confirmed by MGIT 960 culture and/or Xpert MTB/RIF. Among the 806 patients identified by MGIT 960 culture, 232 cases (28.78%) were DR-TB. Resistance to the six drugs was in the following order: streptomycin (21.09%), isoniazid (9.35%), rifampin (15.01%), levofloxacin (6.20%), ethambutol (4.22%), and amikacin (3.23%). Alarmingly, 12.90% were MDR-TB (104/806), including 28 (3.47%) pre-XDR-TB. Of the 1076 pediatric TB patients, 295 (27.4%) developed DR-TB to any one drug (including 69 rifampicin-resistant cases identified by Xpert MTB/RIF only). No difference was found in the incidence of pediatric DR-TB between 2017 and 2021. Among 376 patients who were positive for both methods, using the MGIT 960 DST results as the gold standard, Xpert MTB/RIF’s sensitivity for detecting rifampicin resistance was 91.38% and its specificity was 94.65%.Conclusion: Between 2017 and 2021, the DR-TB incidence in children remained unchanged in Shenyang. RR-TB, MDR-TB, and even Pre-XDR-TB require attention in children with drug-resistant TB. Xpert MTB/RIF helped to detect more rifampicin-resistant pediatric patients; thus Xpert MTB/RIF should be widely used as an important complementary tool to detect rifampicin-resistant TB in children.Keywords: tuberculosis, drug-resistant, children, rifampicin, Xpert MTB/RIF, drug susceptibility testing

Abstract Background Tuberculosis (TB) has a high morbidity and mortality rate, and its prevention and treatment focus is on impoverished areas. The Liangshan Yi Autonomous Prefecture is a typical impoverished area in western China with insufficient medical resources and high HIV positivity. However, there have been few reports of TB and drug resistance in this area. Methods We collected the demographic and clinical data of inpatients with sputum smear positive TB between 2015 and 2021 in an infectious disease hospital in the Liangshan Yi Autonomous Prefecture. Descriptive analyses were used for the epidemiological data. The chi-square test was used to compare categorical variables between the drug-resistant and drug-susceptible groups, and binary logistic regression was used to analyse meaningful variables. Results We included 2263 patients, 79.9% of whom were Yi patients. The proportions of HIV (14.4%) and smoking (37.3%) were higher than previously reported. The incidence of extrapulmonary TB (28.5%) was high, and the infection site was different from that reported previously. When drug resistance gene detection was introduced, the proportion of drug-resistant patients became 10.9%. Patients aged 15–44 years (OR 1.817; 95% CI 1.162–2.840; P

Abstract Background Drug-resistant Tuberculosis (DR-TB) is a global health burden with high morbidity and mortality in developing countries including Egypt. The susceptibility to infection with DR-TB strains may be genetically determined. Several interleukin gene polymorphisms were investigated as risk factors for tuberculosis infection but focusing on their association with DR-TB was limited. Therefore, the objective of this study is to assess the association of IL 17 − 197 G > A (rs2275913) single nucleotide polymorphism (SNP) with susceptibility to DR-TB strains in comparison to drug-sensitive tuberculosis (DS-TB) strains in Egyptian patients with pulmonary TB. This cross-sectional study was conducted on 80 patients with DR-TB strains and 80 with DS-TB strains as a control group. Both age and sex were comparable among the study’s groups. IL-17 − 197 G > A (rs2275913) SNP was genotyped by real-time PCR, and IL-17 serum concentration was measured by enzyme-linked immunosorbent assay (ELISA). Results The GA and AA genotype frequencies of IL 17 − 197 G > A (rs2275913) SNP were significantly higher in patients with DR-TB strains than those with DS-TB strains (p A (rs2275913) resulted in higher serum levels of IL-17 and Egyptian patients with such polymorphism are three times at risk of infection with DR-TB strains than patients with wild type.

Bedaquiline resistance is increasingly observed in the treatment of rifampicin-resistant tuberculosis (TB), yet standardized regimens for managing bedaquiline-resistant TB are lacking. Studies indicate a high proportion of bedaquiline-resistant cases have previously been treated for TB, and often involve strains resistant to quinolones. Regular monitoring of the culture status in patients receiving bedaquiline resistance treatment is advised. Methods such as experimental evolution, protein modeling, genome sequencing, and phenotypic analysis have been instrumental in identifying the mechanisms of bedaquiline resistance. Specifically, variants in the Rv0678 transcriptional repressor of the MmpS5-MmpL5 efflux system are linked to this type of resistance. Bayesian probability estimates show promise in determining the genotypic-phenotypic association for bedaquiline resistance, suggesting potential utility in clinical practice. Future research should explore the practical application of Bayesian probabilities in managing bedaquiline resistance. Sequencing-based technologies are anticipated to play a vital role in the early detection and management of drug-resistant TB strains. [ABSTRACT FROM AUTHOR]

Although antibiotics are most frequently prescribed for respiratory tract infections, effective interventions for their proper use by physicians have not been fully established. We assessed the impact of educational films on the rates of antibiotic prescriptions for respiratory tract infections using fictitious scenarios. In this nationwide web-based survey prospective study, a total of 1100 physicians were included. The physicians were required to view educational short films and determine the need for prescribing antibiotics in 10 fictitious scenarios involving adults diagnosed with different acute respiratory tract infectious diseases. The antibiotic prescription rates for each scenario were compared before and after viewing the educational short film. The rates of antibiotic prescription significantly decreased after viewing the educational film, especially in cases with a narrowly defined common cold (from 51% to 15%), mild pharyngolaryngitis (from 71% to 25%), and acute bronchitis without chronic respiratory underlying diseases (from 63% to 23%). Alternatively, a slight decrease in rates was observed in cases with moderate or severe rhinosinusitis (from 94% to 79%), moderate or severe acute pharyngitis (from 88% to 69%), and acute bronchitis with chronic lung disease (from 70% to 58%), for which antibiotics are recommended. Educational short films may encourage the proper use of antibiotics for respiratory tract infections; however, the possibility of undertreatment in patients requiring antibiotics must be considered.