Dose Of Drug Research Articles

Model-Informed Reinforcement Learning for Enabling Precision Dosing Via Adaptive Dosing.

Precision dosing, the tailoring of drug doses to optimize therapeutic benefits andminimize risks in each patient, is essential for drugs with a narrow therapeutic window and severe adverse effects. Adaptive dosing strategies extend the precision dosing concept to time-varying treatments which require sequential dose adjustments based on evolving patient conditions. Reinforcement learning (RL) naturally fits this paradigm: it perfectly mimics the sequential decision-making process where clinicians adapt dose administration based on patient response and evolution monitoring. This paper aims to investigate the potentiality of coupling RL with population PK/PD models to develop precision dosing algorithms, reviewing the most relevant works in the field. Case studies in which PK/PD models were integrated within RL algorithms as simulation engine to predict consequences of any dosing action have been considered and discussed. They mainly concern propofol-induced anesthesia, anticoagulant therapy with warfarin and a variety of anticancer treatments differing for administered agents and/or monitored biomarkers. The resulted picture highlights a certain heterogeneity in terms of precision dosing approaches, applied methodologies, and degree of adherence to the clinical domain. In addition, a tutorial on how a precision dosing problem should be formulated in terms of the key elements composing the RL framework (i.e., system state, agent actions and reward function), and on how PK/PD models could enhance RL approaches is proposed for readers interested in delving in this field. Overall, the integration of PK/PD models into a RL-framework holds great promise for precision dosing, but further investigations and advancements are still needed to address current limitations and extend the applicability of this methodology to drugs requiring adaptive dosing strategies.

Synthesis, Characterization, Phytochemistry, and Therapeutic Potential of Azadirachta indica Conjugated Silver Nanoparticles: A Comprehensive Study on Antidiabetic and Antioxidant Properties.

Nanotechnology has become a major topic of study, particularly in the medical and health domains. Because nanomedicine has a higher recovery rate than other conventional drugs, it has attracted more attention. Green synthesis is the most efficient and sustainable method of creating nanoparticles. The current work used ultraviolet-visible spectroscopy, Fourier-transform infrared spectroscopy, scanning electron microscopy, energy dispersive X-ray, and X-ray diffraction to thoroughly characterize the synthesized silver nanoparticles (AgNPs) from Azadirachta indica leaf extract. Characterization confirmed the synthesis of the AgNPs along with the possible linkage of the phytochemicals with the silver as well as the quantitative analysis and nature of NPs. The antioxidant activity of AgNPs and neem extract was measured by the 2,2-diphenyl-1-picrylhydrazyl assay using various concentrations (20, 40, 60, 80, and 100µg/ml). Additionally, using diabetic mice that had been given alloxan, the in vivo antidiabetic potential of biosynthesized AgNPs was assessed. Eight groups of mice were used to assess the antidiabetic activity: one control group and seven experimental groups (untreated, extract-treated, AgNPs at low and high doses, standard drug, low dose of AgNPs + drug, and high dose of AgNPs + drug). At days 0, 7, 14, 21, and 28, blood glucose levels and body weight were measured. After 28days, the mice were dissected, and the liver, kidney, and pancreas were examined histologically. The results depicted that the AgNPs showed higher (significant) radical scavenging activity (IC50 = 35.2µg/ml) than extract (IC50 = 93.0µg/ml) and ascorbic acid (IC50 = 64.6µg/ml). The outcomes demonstrated that biosynthesized AgNPs had a great deal of promise as an antidiabetic agent and exhibited remarkable effects in diabetic mice given AgNPs, extract, and drug. Remarkable improvement in the body weight and blood glucose level of mice treated with high doses of AgNPs and drug was observed. The body weight and blood glucose level of diabetic mice treated with a high dose of AgNPs + standard drug showed significant improvement, going from 28.7 ± 0.2 to 35.6 ± 0.3g and 248 ± 0.3 to 109 ± 0.1mg/dl, respectively. Significant regeneration was also observed in the histomorphology of the kidney, liver's central vein, and islets of Langerhans after treatment with biosynthesized AgNPs. Diabetic mice given a high dose of AgNPs and drug displayed architecture of the kidney, liver, and pancreas that was nearly identical to that of the control group. According to the current research, biosynthesized AgNPs have strong antioxidant and antidiabetic potential and may eventually provide a less expensive option for the treatment of diabetes.

Inflammation-mediated drug interactions of olokizumab and cytochrome P450 activities in patients with rheumatoid arthritis.

In patients with rheumatoid arthritis (RA), interleukin (IL)-6 affects the activity of cytochrome P450 (CYP) enzymes. Treatment with anti-IL-6 therapy can reverse the IL-6-mediated downregulation of CYP enzymes, resulting in changes in plasma levels of CYP substrates. The primary objective of this study was to evaluate the impact of the IL-6 inhibitor olokizumab on the pharmacokinetics of CYP probe substrates in subjects with active RA. Seventeen patients with active RA were orally administered a phenotyping cocktail of midazolam (CYP3A4 substrate), omeprazole (CYP2C19 substrate), warfarin (CYP2C9 substrate) and caffeine (CYP1A2 substrate) alone and 2weeks after a single subcutaneous injection of 128 mg olokizumab. The pharmacokinetic parameters of each substrate were calculated using noncompartmental analysis. Sixteen of 17 enrolled patients received the complete doses of the cocktail drugs and olokizumab and were eligible for the pharmacokinetic evaluations. After single-dose administration of olokizumab, the exposure of midazolam and omeprazole decreased by 30-33% and 26-32%, respectively, compared to when the substrates were administered along via cocktail. In the presence of olokizumab, caffeine exposure increased by 19-23% compared to caffeine administration alone. There were no significant changes in S-warfarin exposure. In patients with active RA, olokizumab potentially reverses the IL-6-mediated suppression of CYP3A4 and CYP2C19. According to FDA guidance, olokizumab is considered a weak inducer of CYP3A4 and CYP2C19.

Paravertebrally-Injected Multifunctional Hydrogel for Sustained Anti-Inflammation and Pain Relief in Lumbar Disc Herniation.

Pain caused by lumbar disc herniation (LDH) severely compromises patients' quality of life. The combination of steroid and local anesthetics is routinely employed in clinics to alleviate LDH-induced pain. However, the approach only mediates transient efficacy and requires repeated and invasive lumbar epidural injections. Here a paravertebrally-injected multifunctional hydrogel that can efficiently co-load and controlled release glucocorticoid betamethasone and anesthetics ropivacaine for sustained anti-inflammation, reactive oxygen species (ROS)-removal and pain relief in LDH is presented. Betamethasone is conjugated to hyaluronic acid (HA) via ROS-responsive crosslinker to form amphiphilic polymer that self-assemble into particles with ropivacaine loaded into the core. Solution of drug-loaded particles and thermo-sensitive polymer rapidly forms therapeutic hydrogel in situ upon injection next to the herniated disc, thus avoiding invasive epidural injection. In a rat model of LDH, multifunctional hydrogel maintains the local drug concentration 72 times longer than free drugs and more effectively inhibits the expression of pro-inflammatory cytokines and pain-related molecules including cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). Therapeutic hydrogel suppresses the LDH-induced pain in rats for 12 days while the equivalent dose of free drugs is only effective for 3 days. This platform is also applicable to ameliorate pain caused by other spine-related diseases.

Efficacy and safety of alfaxalone compared to propofol in canine refractory status epilepticus: a pilot study

IntroductionRefractory status epilepticus (RSE) is defined as seizure activity that is minimally responsive to first- or second-line antiseizure medications. Constant rate infusion (CRI) intravenous propofol (PPF) is commonly used to treat RSE in dogs and cats. The antiseizure activity of alfaxalone (ALF) in RSE has been demonstrated in various experimental studies. This study compared the clinical efficacy and safety of intramuscular administration followed by CRI infusion of ALF with intravenous administration followed by CRI infusion of PPF to treat canine RSE.Materials and methodsThis was a multicenter, prospective, randomized clinical trial of client-owned dogs referred for status epilepticus that did not respond to first- and second-line drugs. Animals with suspected or confirmed idiopathic or structural epilepsy were included. The dogs were randomly assigned to either the PPF or ALF treatment groups and each group received drug CRI infusions for 6 h. Drug dosages were progressively reduced by 25% every hour from the third hour until suspension after 6 h. Patients were classified as responders or non-responders based on the relapse of epileptic seizures during the 24 h therapy infusion or within 24 h of drug suspension. Univariate statistical analyses were performed.ResultsTwenty dogs were enrolled in the study. Ten (10/20) dogs were randomly allocated to the PPF group and 10 (10/20) to the ALF group. Successful outcomes were obtained in six (6/10) patients in the PPF group and five (5/10) patients in the ALF group. Adverse effects were recorded in six (6/10) and three (3/10) animals in the PPF and ALF groups, respectively. No statistically significant differences in outcomes or the presence of adverse effects were observed between the groups.DiscussionThe results of this preliminary study suggest that ALF can be considered a valid and safe alternative to PPF for the treatment of RSE in dogs, with the additional advantage of intramuscular administration. However, caution should be exercised when using these drugs to provide airway and hemodynamic support.

Real-time analgesic efficacy and factors determining drug requirements of combined spinal-epidural analgesia for labor: a prospective cohort study.

Combined spinal-epidural analgesia (CSEA) is effective but not sufficient for labor pain. This study was conducted to assess the real-time analgesic efficacy, side effects of anesthetic drug dosage, and maternal satisfaction in labor to provide reference for the optimization of labor analgesia. This was a prospective, cohort, single-center study that included 3020 women who received CSEA for labor analgesia. The visual analogue scale (VAS) for labor pain, real-time anesthetic drug dosage, side effects, adverse labor outcomes, factors influencing average drug dosage, and maternal satisfaction with CSEA were assessed. Overall, the VAS labor pain score was lowest at the first hour after the anesthesia was given. After 4h for primiparas and 3h for multiparas, the VAS score was greater than 3 but the anesthetic drug dosage did not reach the maximum allowed dosage at the same time. The average anesthetic drug dosage was positively correlated with fever, urinary retention, uterine atony, prolonged active phase, prolonged second stage, assisted vaginal delivery, and postpartum hemorrhage. The average anesthetic drug dosage was the highest in women ≤ 20years old, those with a body mass index (BMI) ≥ 24.9kg/m2, and those with a primary or secondary education level. Appropriate age guidance and emphasis on education of labor analgesia, weight management during pregnancy, and real-time anesthetic dosage adjustment during labor based on VAS pain score may have positive effects on the satisfaction of labor analgesia. Clinicaltrials.gov (ChiCTR2100051809).

Harnessing Artificial Intelligence to Predict Ovarian Stimulation Outcomes in In Vitro Fertilization: Scoping Review.

In the realm of in vitro fertilization (IVF), artificial intelligence (AI) models serve as invaluable tools for clinicians, offering predictive insights into ovarian stimulation outcomes. Predicting and understanding a patient's response to ovarian stimulation can help in personalizing doses of drugs, preventing adverse outcomes (eg, hyperstimulation), and improving the likelihood of successful fertilization and pregnancy. Given the pivotal role of accurate predictions in IVF procedures, it becomes important to investigate the landscape of AI models that are being used to predict the outcomes of ovarian stimulation. The objective of this review is to comprehensively examine the literature to explore the characteristics of AI models used for predicting ovarian stimulation outcomes in the context of IVF. A total of 6 electronic databases were searched for peer-reviewed literature published before August 2023, using the concepts of IVF and AI, along with their related terms. Records were independently screened by 2 reviewers against the eligibility criteria. The extracted data were then consolidated and presented through narrative synthesis. Upon reviewing 1348 articles, 30 met the predetermined inclusion criteria. The literature primarily focused on the number of oocytes retrieved as the main predicted outcome. Microscopy images stood out as the primary ground truth reference. The reviewed studies also highlighted that the most frequently adopted stimulation protocol was the gonadotropin-releasing hormone (GnRH) antagonist. In terms of using trigger medication, human chorionic gonadotropin (hCG) was the most commonly selected option. Among the machine learning techniques, the favored choice was the support vector machine. As for the validation of AI algorithms, the hold-out cross-validation method was the most prevalent. The area under the curve was highlighted as the primary evaluation metric. The literature exhibited a wide variation in the number of features used for AI algorithm development, ranging from 2 to 28,054 features. Data were mostly sourced from patient demographics, followed by laboratory data, specifically hormonal levels. Notably, the vast majority of studies were restricted to a single infertility clinic and exclusively relied on nonpublic data sets. These insights highlight an urgent need to diversify data sources and explore varied AI techniques for improved prediction accuracy and generalizability of AI models for the prediction of ovarian stimulation outcomes. Future research should prioritize multiclinic collaborations and consider leveraging public data sets, aiming for more precise AI-driven predictions that ultimately boost patient care and IVF success rates.

Smart laser Sintering: Deep Learning-Powered powder bed fusion 3D printing in precision medicine

Medicines remain ineffective for over 50% of patients due to conventional mass production methods with fixed drug dosages. Three-dimensional (3D) printing, specifically selective laser sintering (SLS), offers a potential solution to this challenge, allowing the manufacturing of small, personalized batches of medication. Despite its simplicity and suitability for upscaling to large-scale production, SLS was not designed for pharmaceutical manufacturing and necessitates a time-consuming, trial-and-error adaptation process. In response, this study introduces a deep learning model trained on a variety of features to identify the best feature set to represent drugs and polymeric materials for the prediction of the printability of drug-loaded formulations using SLS. The proposed model demonstrates success by achieving 90% accuracy in predicting printability. Furthermore, explainability analysis unveils materials that facilitate SLS printability, offering invaluable insights for scientists to optimize SLS formulations, which can be expanded to other disciplines. This represents the first study in the field to develop an interpretable, uncertainty-optimized deep learning model for predicting the printability of drug-loaded formulations. This paves the way for accelerating formulation development, propelling us into a future of personalized medicine with unprecedented manufacturing precision.

The Effect of Padlet on Nursing Students’ Drug Dose Calculation Skills

The Effect of Padlet on Nursing Students’ Drug Dose Calculation Skills

Intelligent Systems Based on Cyclodextrins for the Treatment of Breast Cancer.

The incidence of breast cancer has been increasing over the last four decades, although the mortality rate has decreased. Endocrine therapy and chemotherapy are the most used options for cancer treatment but several obstacles are still attributed to these therapies. Smart materials, such as nanocarriers for targeting, delivery and release of active ingredients, sensitive to intrinsic-stimuli (pH-responsive, redox-responsive, enzyme- responsive, and thermo-responsive) and extrinsic-stimuli (ultrasound-responsive, magnetic-responsive, light-responsive) have been studied as a novel strategy in breast cancer therapy. Cyclodextrins (CDs) are used in the design of these stimuli-responsive drug carrier and delivery systems, either through inclusion complexes with hydrophobic molecules or covalent bonds with large structures to generate new materials. The present work aims to gather and integrate recent data from in vitro and in vivo preclinical studies of CD-based stimuli- responsive systems to contribute to the research in treating breast cancer. All drug carriers showed high in vitro release rates in the presence of a stimulus. The stimuli-responsive nanoplatforms presented biocompatibility and satisfactory results of IC50, inhibition of cell viability and antitumor activity against several breast cancer cell lines. Additionally, these systems led to a significant reduction in drug dosages, which encouraged possible clinical studies for better alternatives to traditional antitumor therapies.

De-indexed estimated glomerular filtration rates for the dosing of oral antidiabetic drugs in patients with chronic kidney disease

De-indexed estimated glomerular filtration rates for the dosing of oral antidiabetic drugs in patients with chronic kidney disease

Possibilities of Using Nootropic Drugs to Reduce Neurotoxic Reactions Caused by Anti-tuberculosis Drugs in Experimental Conditions

The objective: to evaluate the neuroprotective activity of cytoflavin and combinations of mexidol with vitamin B6 or Magne B6 by changes in behavioral reactions in rats during in-take of a neurotoxic combination of anti-tuberculosis drugs.Subjects and Methods. Non-linear female rats divided in 4 groups were used in this study. For 14 days, all rats received a combination of Mxf+Lzd+Cs+Pto daily. Additionally, rats of Group 2 were administered cytoflavin before administration of the basic combination; Group 3 – Mexidol + vitamin B6; Group 4 - Mexidol + Magne B6. Doses of anti-tuberculosis drugs, cytoflavin, Mexidol, vitamin B6 and Magne B6 correspond to the recommended doses for humans. The manifestation of neurotoxicity was assessed by changes in behavioral reactions by Open Field Test.Results. Neurotoxicity caused by the combination Mxf+Lzd+Cs+Pto was manifested by a decrease in motor activity, exploratory activity and grooming. With cytoflavin administration, all parameters of behavioral reactions in rats improved. When using Mexidol with vitamin B6, only a slight decrease in grooming versus the baseline level was observed. There was a less qualitative decrease in neurotoxicity manifestations with administration of Mexidol in combination with Magne B6.

Development and validation of stability-indicating method of etrasimod by HPLC/DAD/MS/MS technique with greenness profiling

Etrasimod, a novel selective sphingosine-1-phosphate receptor modulator, was recently approved by the U.S. Food and Drug Administration and the European Medicinal Agency for the treatment of moderately to severely active ulcerative colitis in adults. In this research, the forced degradation study as an integral part of drug product and packaging development, which generates data on degradation mechanisms, is published. The development and validation of the stability-indicating method using a superior high-performance liquid chromatography technique coupled with a diode array detector and tandem mass spectrometer was performed to support the forced degradation study and monitor the formation of degradation products. Etrasimod demonstrated good stability under elevated temperature and basic stress conditions, while acidic hydrolysis, oxidative, and photolytic degradation produced eight degradation products. The knowledge of degradation products will be useful in the long-term stability study for establishing the acceptance criteria of etrasimod as a drug substance and dosage form during quality control and stability assessment. The eco-friendliness of the developed forced degradation procedure was evaluated using various greenness appraisal tools. The green metric tools showed that the forced degradation procedure obeys eco-friendly conditions.

P-002 Acetate attenuates cyclophosphamide-induced testicular toxicity by modulating steroidogenic and apoptotic signaling via an oxidative stress-dependent pathway

Abstract Study question Will acetate therapy attenuate cyclophosphamide-induced testicular toxicity when used concomitantly? Summary answer Acetate attenuated cyclophosphamide-induced testicular toxicity by modulating steroidogenic and apoptotic signaling via an oxidative stress-dependent pathway. What is known already Cyclophosphamide is an anthracycline that is effective in the management of cancers. Nonetheless, a major drawback of this drug is its testicular toxicity. Available evidence in the literature revealed that cyclophosphamide induces testicular toxicity by targeting steroidogenesis and activating oxidative stress, inflammation, and apoptosis. On the other hand, acetate has been reported to exert antioxidant, anti-inflammatory, and anti-apoptotic activities. However, there is no report on the effect of acetate on cyclophosphamide-induced testicular toxicity. Study design, size, duration This is a prospective experimental study using animal model. Twenty-four sexually mature litter-mate male Wistar rats of comparable weight were used for the study. The study lasted 2 weeks. Participants/materials, setting, methods Animals were acclimatized for two weeks, and then randomized into four groups. The control rats received 0.5mL of distilled water p.o for 14 days, acetate-treated rats received 200 mg/kg/day of acetate p.o for 14 days, cyclophosphamide-treated rats received 150 mg/kg of cyclophosphamide i.p on day 8, while acetate + cyclophosphamide-treated rats received treatment as acetate-treated and cyclophosphamide-treated. The doses of drugs used were the Human Equivalent doses for rats and as earlier reported. Main results and the role of chance Acetate attenuated cyclophosphamide-induced alterations in testicular histoarchitecture and the rise in testicular activities of gamma glutamyl transferase and lactate dehydrogenase activities, and lactate levels. In addition, acetate abrogated cyclophosphamide-induced rise in testicular malondialdehyde, TNF-α, IL-1β, NF-kB, and Bax levels, and myeloperoxidase, caspase 9, and caspase 3 activities, which was accompanied by acetate-driven blockade of cyclophosphamide-induced decline in reduced glutathione, Nrf2, and Bcl-2 levels, and glutathione peroxidase, glutathione-S-transferase, superoxide dismutase and catalase activities. Furthermore, acetate alleviated cyclophosphamide-induced suppression of circulatory levels of FSH, LH, and testosterone, testicular concentrations of 3β-HSD, 17β-HSD, and testosterone, and spermatogenesis and lowered sperm quality. Limitations, reasons for caution This was an experimental study using a rat model; hence, the results of this study should be extrapolated to humans with caution. Clinical trials are recommended to validate these findings. Wider implications of the findings The present study revealed the protective effect of acetate treatment on cyclophosphamide-induced testicular toxicity. These findings provide convincing evidence of the attenuating effect of acetate in cyclophosphamide-induced testicular toxicity. Trial registration number N/A

Effectiveness and safety of empegfilgrastim (Extimia®) in patients with solid tumors receiving cytotoxic therapy: final results of the DEFENDOR study

Aim. To evaluate the effectiveness and safety of Extimia® (empegfilgrastim, JSC "BIOCAD") in reducing the frequency, duration of neutropenia, the incidence of febrile neutropenia (FN) and infections caused by FN in patients with solid tumors receiving myelosuppressive therapy. Materials and methods. The paper presents the final results of a multicenter prospective observational post-marketing study of the safety and effectiveness of Extimia® (empegfilgrastim) in patients with solid tumors receiving cytotoxic therapy. For the primary prevention of FN, all patients received empegfilgrastim at 7.5 mg subcutaneously once per course of chemotherapy (CT) 24 hours after the end of CT administration. The primary endpoint included an assessment of the relative dose-intensity (RDI) of the CT courses administered. The endpoints of interest included the assessment of the RDI of CT courses by nosology and CT regimen, the frequency of dose-limiting neutropenia, and the incidence of all adverse events (AEs) in patients who received at least one dose of the study medication, including serious AEs. Results. From February 2021 to December 2022, 3218 patients with various malignancies were included in 41 study centers of the Russian Fede- ration. Of these, 3217 (99.97%) patients received at least one dose of the study drug, and 2663 (82.8%) patients were included in the RDI evaluation population according to the study protocol. The mean age in this group was 56.9 (18–84) years. RDI ≥85% was achieved in 2,415 (90.7%) patients. The mean RDI was 96.2%, with a median of 100%. FN risk factors were present in 1216 (45.7%) patients, with age ≥65 years being the most common risk factor at 761/2663 (28.6%). It should be noted that in patients younger than 65 years, the RDI was 91.5%, and in elderly patients (≥65 years) 88.7%. Dose-limiting neutropenia was reported in 19 (0.7%) patients. There were 74 cases of grade 3–4 AEs (according to CTCAE v.5) in 59 (1.8%) patients. The most common were neutropenia, anemia, and diarrhea in 19 (0.7%), 7 (0.2%), and 6 (0.2%) patients, respectively. Serious AEs were reported in 17 patients (0.5%). Conclusion. Primary prophylaxis of FN with long-acting granulocyte colony-stimulating factor empegfilgrastim effectively maintains RDI in various nosological and therapeutic groups of patients with different CT regimens in real-world clinical practice.

Pyroptosis-related long-noncoding RNA signature predicting survival and immunotherapy efficacy in patients with lung squamous cell carcinoma

Pyroptosis-related long-noncoding RNAs (PRlncRNAs) play an important role in cancer progression. However, their role in lung squamous cell carcinoma (LUSC) is unclear. A risk model was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis based on RNA sequencing data from The Cancer Genome Atlas database. The LUSC cohort was divided into high- and low-risk groups based on the median risk score. For the prognostic value of the model, the Kaplan–Meier analysis, log-rank test, and Cox regression analysis were performed. A nomogram was constructed to predict the prognosis of patients, using a risk score and clinical parameters such as age, sex, clinical stage, and tumor node metastasis classification (TNM) stage. Afterwards, six common algorithms were employed to assess the invasion of immune cells. The Gene Set Enrichment Analysis (GSEA) was conducted to identify differences between patients at high and low risk. Furthermore, the pRRophetic package was employed to forecast the half-maximal inhibitory doses of prevalent chemotherapeutic drugs, while the tumor immune dysfunction and exclusion score was computed to anticipate the response to immunotherapy. The expression levels of the seven PRlncRNAs were examined in both LUSC and normal lung epithelial cell lines using RT-qPCR. Proliferation, migration, and invasion assays were also carried out to investigate the role of MIR193BHG in LUSC cells. Patients in the low-risk group showed prolonged survival in the total cohort or subgroup analysis. The Cox regression analysis showed that the risk model could act as an independent prognostic factor for patients with LUSC. The results of GSEA analysis revealed that the high-risk group showed enrichment of cytokine pathways, Janus tyrosine kinase/signal transducer and activator of the transcription signalling pathway, and Toll-like receptor pathway. Conversely, the low-risk group showed enrichment of several gene repair pathways. Furthermore, the risk score was positively correlated with immune cell infiltration. Moreover, patients in the high-risk category showed reduced responsiveness to conventional chemotherapeutic medications and immunotherapy. The majority of the long noncoding RNAs in the risk model were confirmed to be overexpressed in LUSC cell lines compared to normal lung epithelial cell lines by in vitro tests. Further studies have shown that downregulating the expression of MIR193BHG may inhibit the growth, movement, and infiltration capabilities of LUSC cells, whereas increasing the expression of MIR193BHG could enhance these malignant tendencies. This study found that PRlncRNAs were linked to the prognosis of LUSC patients. The risk model, evaluated across various clinical parameters and treatment modalities, shows potential as a future reference for clinical applications.

Conserved Evolutionary Trajectory Can Be Perturbed to Prevent Resistance Evolution under Norfloxacin Pressure by Forcing Mycobacterium smegmatis on Alternate Evolutionary Paths.

Antibiotic resistance is a pressing health issue, with the emergence of resistance in bacteria outcompeting the discovery of novel drug candidates. While many studies have used Adaptive Laboratory Evolution (ALE) to understand the determinants of resistance, the influence of the drug dosing profile on the evolutionary trajectory remains understudied. In this study, we employed ALE on Mycobacterium smegmatis exposed to various concentrations of Norfloxacin using both cyclic constant and stepwise increasing drug dosages to examine their impact on the resistance mechanisms selected. Mutations in an efflux pump regulator, LfrR, were found in all of the evolved populations irrespective of the drug profile and population bottleneck, indicating a conserved efflux-based resistance mechanism. This mutation appeared early in the evolutionary trajectory, providing low-level resistance when present alone, with a further increase in resistance resulting from successive accumulation of other mutations. Notably, drug target mutations, similar to those observed in clinical isolates, were only seen above a threshold of greater than 4× the minimum inhibitory concentration (MIC). A combination of three mutations in the genes, lfrR, MSMEG_1959, and MSMEG_5045, was conserved across multiple lineages, leading to high-level resistance and preceding the appearance of drug target mutations. Interestingly, in populations evolved from parental strains lacking the lfrA efflux pump, the primary target of the lfrR regulator, no lfrR gene mutations are selected. Furthermore, evolutional trajectories originating from the ΔlfrA strain displayed early arrest in some lineages and the absence of target gene mutations in those that evolved, albeit delayed. Thus, blocking or inhibiting the expression of efflux pumps can arrest or delay the fixation of drug target mutations, potentially limiting the maximum attainable resistance levels.

Contemporary considerations for nephrotoxin stewardship: Estimating kidney function and use of novel biomarkers

AbstractDrug‐associated acute kidney injury (D‐AKI) constitutes approximately 19%–26% of all acute kidney injury (AKI) cases in hospitalized patients. Notably, there is often a deficiency in optimal drug management after D‐AKI diagnosis, with only about half of the patients experiencing discontinuation of nephrotoxins and one‐fifth avoiding further nephrotoxin administration. Nephrotoxin stewardship involves the application of coordinated care management strategies to ensure the safe utilization of nephrotoxins and renally eliminated medications. The purpose of this paper is to review nephrotoxin stewardship strategies and highlight contemporary considerations for estimating kidney function and the use of novel biomarkers as part of the stewardship program. The Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) 2021 serum creatinine formula is now recommended for estimating kidney function for adults in most clinical situations in the United States. It is time to reevaluate how healthcare professionals think of estimating kidney function for drug dosing with the use of the non‐indexed, race‐free, CKDEPI 2021 equation. In addition, widespread use of serum cystatin C (CysC) is anticipated so estimated glomerular filtration rate equations that incorporate serum CysC will need to be further evaluated for drug dosing recommendations and how the use of serum CysC can complement serum creatinine‐based equations. Lastly, novel kidney stress/damage biomarkers should be viewed as a piece of a complex scenario of D‐AKI prediction, diagnosis, and prognosis and should be interpreted along with other diagnostic criteria in relation to the clinical condition of the patient. These contemporary considerations for drug dosing and D‐AKI management are important components of nephrotoxin stewardship.

Effectiveness of exercise training on arterial stiffness and blood pressure among postmenopausal women: a systematic review and meta-analysis

BackgroundThe acute and long-term benefits of exercise training on cardiovascular health have been well established. The systematic review and meta-analysis aimed to systematically assess the effectiveness of exercise training on arterial stiffness and blood pressure among postmenopausal women with elevated blood pressure.MethodsA comprehensive search was conducted on PubMed, Embase, Web of Science, ProQuest, Cochrane Library, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov website from inception to September 30, 2023, to identify the randomized controlled trials (RCTs), which evaluated the effectiveness of exercise training on arterial stiffness and blood pressure in postmenopausal women. Standardized mean differences (SMD), weighted mean differences (WMD), and 95% confidence intervals (95% CIs) were calculated using random/fixed effects models. Quality assessment was performed using the modified Jadad scale and the Cochrane Risk of Bias Tool. Sensitivity analysis and subgroup analysis were conducted based on drug dosage, treatment duration, and age of administration to further explore potential heterogeneity. Funnel plots were performed to assess publication bias and Begg’s regression test was carried out for funnel plot asymmetry.ResultsTwenty-two RCTs involving 1978 participants were included in the quantitative analysis. The mean quality of eligible studies was 4.2 out of 7 based on the modified Jadad scale. The results indicated that exercise training had a significant effect on reducing brachial-ankle pulse wave velocity [MD = − 0.69, 95%CI (− 1.11, − 0.27), P = 0.001], decreasing augmentation index (AIx) [MD = − 6.00, 95%CI (− 6.39, − 5.61), P < 0.00001] and AIx normalized to a heart rate of 75 beats per minute (AIx@75%) [MD = − 7.01, 95%CI − 7.91 to − 6.12, P < 0.00001], lowering systolic blood pressure [MD = − 6.19, 95%CI − 9.24 to − 3.15, P < 0.0001], diastolic blood pressure [MD = − 3.57, 95%CI (− 6.10, − 1.03), P = 0.006) and pulse pressure [MD = − 8.52, 95%CI (− 16.27, − 0.76), P = 0.03]. Subgroup analysis revealed that baseline blood pressure levels had a large impact on the effect of exercise training.ConclusionsThe systematic review and meta-analysis suggested that exercise training may ameliorate arterial stiffness and reduce blood pressure in postmenopausal women with elevated blood pressure. However, the optimal mode of exercise training that improves arterial stiffness and blood pressure in this population requires further investigation.Systematic review registrationPROSPERO CRD42021211268

Cutaneous Adverse Drug Reactions to Antidiabetic Medications and Medical Devices Used in Management of Diabetes Mellitus

Context: Approximately 537 million adults (20 - 79 years) worldwide suffer from diabetes, a number that is estimated to reach 643 million by 2030. With the rising prevalence of diabetes, pharmacological therapy has become a cornerstone for its management. The advent of newer devices and drug categories has led to a multitude of adverse drug reactions, with a significant portion being cutaneous side effects. Given that the majority of patients are on multiple other medications, such as oral hypoglycemic agents, antihypertensives, and drugs for coronary artery disease and dyslipidemia, establishing the specific cause of adverse reactions can be challenging. Since the major step in management depends on avoiding or regulating the dose of the culprit drug, it is crucial for the treating clinician to be aware of the common adverse drug reactions associated with these medications. Objective: The article aims to review the reported cutaneous adverse events of oral hypoglycemic agents, insulin, and newer devices in the management of diabetes mellitus. Evidence Acquisition: A PubMed search was conducted using the keywords 'diabetes,' 'cutaneous side effects,' 'insulin,' 'OHA,' 'sulfonylureas,' 'metformin,' and 'antidiabetic drugs.' Results: New adverse events for each category of drugs are continually being identified and reported. These adverse events range from mild rash/pruritus to severe, life-threatening allergies. Conclusions: The management of any adverse reaction includes identifying and avoiding the causative agent. However, with limited literature on the cutaneous side effects of antidiabetic therapeutics, and many being case reports, it can be difficult for clinicians to diagnose these reactions. Our article provides a concise review of the vast spectrum of cutaneous side effects that these drugs and devices can cause, along with diagnostic tests and management strategies.