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Abstract Background Prescribing cascades, which occur when a medication is used to treat the side effect of another medication, are important contributors to polypharmacy. There is an absence of studies that evaluate interventions to address them. We describe an application of the Behaviour Change Wheel (BCW) to design theory-informed interventions for addressing prescribing cascades within interprofessional primary care teams. Methods The BCW framework was applied to guide intervention development. This report describes the first seven steps. Three behaviours were developed based on data collected from two qualitative studies exploring why and how cascades occur across practice settings. A target behaviour was selected and the COM-B model was applied to identify relevant factors for interprofessional primary care teams. Relevant intervention types, policy options, and corresponding behaviour change techniques (BCTs) were identified, and intervention examples drafted. Prioritization of behaviours and intervention examples were guided by the APEASE criteria. Results The three behaviours involved supporting: (1) healthcare providers (HCPs) to ask about, investigate and manage cascades, (2) the public to ask about prescribing cascades, and (3) the public to share medication histories and experiences with HCPs. The team selected the HCP behaviour, A-I-D (ask, investigate, deprescribe), for intervention development. Psychological capability and physical opportunity were the most relevant COM-B components. Ten intervention options comprised of BCTs were developed, which are ready for further prioritization by stakeholders. These can be grouped into: provision of educational materials for use by HCPs; provision of consultation or training to support HCPs; and knowledge mobilization strategies. Through the process, the team identified that development of a practice guidance tool, which assists HCPs to investigate and manage prescribing cascades, is needed to support further intervention development. Conclusions The BCW framework guided the design of intervention examples to support primary HCPs practicing in interprofessional teams to address prescribing cascades. When identifying interventions for future consultation, creation of a practice guidance tool was prioritized as it underpins all proposed interventions for addressing prescribing cascades in practice. Further research is needed to determine what primary HCPs would need in this practice guidance tool and how it will be used in practice, to support its development.

Kai Cao,1,2 Xu-Yuan Quan,1 Yan Hou1,3,4 1Department of Biostatistics, School of Public Health, Peking University, Beijing, 100191, People’s Republic of China; 2Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100005, People’s Republic of China; 3Beijing Cancer Hospital, Beijing, 100142, People’s Republic of China; 4Peking University Clinical Research Center, Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, People’s Republic of ChinaCorrespondence: Yan Hou, Email houyan@bjmu.edu.cnAbstract: In recent years, patient-focused drug development (PFDD) has received widespread attention as a new paradigm in clinical trials. The PFDD emphasizes patients are partners in research projects, where patients can participate in research design, implementation, and outcome measurement, rather than just providing data. PFDD has shown great value in the research and development of pharmaceutical products, such as in accelerating the process of patient enrollment and improving the success rate of drug approval. Many countries and regions, including the United States, China, and Europe, have issued relevant regulatory policies and guidelines related to PFDD, covering study design, implementation, and risk–benefit assessment. The core of PFDD implementation is clinical outcome assessment (COA), of which patient-reported outcome (PRO) is most common. As far as the US Food and Drug Administration is concerned, there are numerous COA tools waiting for qualification, but currently all qualified are PROs. This review focuses on PRO and explores the key elements of PRO instruments’ development, application, and inclusion in regulatory decision-making.Keywords: patient-reported outcome, patient-focused, drug, development, clinical trial

Abstract Background Inconsistent study results and contradictory recommendations from health authorities regarding the use of apixaban in patients on hemodialysis have generated considerable uncertainty among clinicians, making investigations of appropriate dosing an unmet need. Methods We analyzed pre-dialysis apixaban drug levels from a tertiary care dialysis unit, comparing 2.5 mg once versus twice daily dosing. We applied mixed-effects models including dialysis modality, adjusted standard Kt/V, ultrafiltration, and dialyzer characteristics. We included an exploratory analysis of bleeding events and compared the drug levels of our dialysis patients to those from non-CKD reference populations taking the standard dose of 5 mg twice daily. Results We analyzed 143 drug levels from 24 patients. Mean (SD) age at first drug level measurement was 64.7 (15.9) years (50 % female), median (IQR) follow-up was 12.5 (5.5 – 21) months. For the apixaban 2.5 mg once and twice daily groups, median (IQR) drug levels were 54.4 (< 40 – 72.1) and 71.3 (48.8 – 104.1) ng/mL respectively (P < 0.001). Levels were below the detection limit in 30 % (with 2.5 mg once daily) and 14 % (with 2.5 mg twice daily) respectively. Only dosing group (twice versus once daily) was independently associated with higher drug levels (P = 0.002). Follow-up did not suggest accumulation. The 95th percentile of drug levels did not exceed those of non-CKD populations taking 5 mg twice daily. Median (IQR) drug levels before a bleeding (8 episodes) were higher than those without a subsequent bleeding: 111.6 (83.1 – 129.3) versus 54.8 (< 40 – 77.1) ng/mL (P < 0.001). Concomitant antiplatelet therapy was used in 86% of those with bleeding events versus 6% without bleeding events (P < 0.001). Conclusions Drug monitoring may be a contributory tool to increase patient safety. Despite non-existing target ranges, drug levels on both edges of the spectrum (e.g. below detectability or beyond the 95th percentiles of reference populations) may improve decision-making in highly individualized risk-benefit analyses.

Human immunodeficiency virus (HIV) is no longer considered a contraindication for kidney transplantation (KT). KT management in HIV patients is a complex process with challenges, such as drug interactions between immunosuppression and antiretroviral (ARV) therapy. In our country, no KT has been performed thus far in this category of patients.

The preventive policy is the best way to envisage the existence of the criminal personality, and since the phenomenon of illicit drug dealing is increasing in Iraqi society; We chose it from this aspect, especially after the issuance of the Narcotic Drugs and Psychotropic Substances Law No. (50) for the year 2017 AD, by examining the legislator’s preventive policy in this law and in the legislations subject to comparison.The criminalization contained in the law is of the type of preventive (precautionary) criminalization, and the criminal behavior in the drug law is such as crimes of danger and not harm. Therefore, objective prevention (the subject of our discussion) aims to prevent harm that affects the health of individuals, the decline of human energy in society and the economy and the spread of crime and others, the law also included many forms of behavior that the legislator incriminated,

Abstract Psoriasis is a complex inflammatory skin disease manifested by altered proliferation and differentiation of keratinocytes with dysfunctional apoptosis. This study aimed to identify regulatory factors and comprehend the underlying mechanisms of inefficient apoptosis to open up promising therapeutic approaches. Incorporating human protein interactions, apoptosis proteins, and physical relationships of psoriasis-apoptosis proteins helped us to generate a psoriasis-apoptosis interaction (SAI) network. Subsequently, topological and functional analyses of the SAI network revealed effective proteins, functional modules, hub motifs, dysregulated pathways and transcriptional gene regulatory factors. Network pharmacology, molecular docking and molecular dynamics simulation methods identified the potential drug-target interactions. RELA, MAPK1, MAPK3, MMP9, IL1B, AKT1 and STAT1 were revealed as effective proteins. The MAPK1-MAPK3-RELA motif was identified as a hub regulator in the crosstalk between 41 pathways. Among all pathways, “lipid and atherosclerosis” was found to be the predominant pathway. Acetylcysteine, arsenic-trioxide, β-elemene, bortezomib and curcumin were identified as potential drugs to inhibit pathway crosstalk. Experimental verifications were performed using the literature search, GSE13355 and GSE14905 microarray datasets. Drug-protein-pathway interactions associated with apoptosis were deciphered. These findings highlight the role of hub motif-mediated pathway-pathway crosstalk associated with apoptosis in the complexity of psoriasis and suggest crosstalk inhibition as an effective therapeutic approach.

Objective: Nursing students attended distance learning due to the pandemic, which made it more difficult for them to learn how to calculate the right dose because drug dose calculation requires constant practice. This study investigated whether Padlet helped nursing students to learn how to calculate the right dose. Method: This study adopted a single-group pretest-posttest experimental research design. This study was conducted in the nursing department of a university in Turkey. The sample consisted of 42 first-year nursing students. Students participating in the research answered the “form for promotional features” and “drug dose calculation knowledge test” sent via Google Forms. Then, the researcher and participants shared and discussed the questions, pictures, and videos they prepared for drug dose calculation on Padlet for three weeks. At the end of three weeks, all participants filled out the knowledge test again. Number, percentage, and Wilcoxon test were used for data analysis. Results: It was determined that the students’ test score average regarding drug dose calculation skills increased at a statistically significant level (p

Abstract Background Substance use disorders are a widely recognized problem among hepatitis C-infected patients; moreover, substance abuse by intravenous injection is a common mode of transmission of the hepatitis C virus worldwide. The frequency of substance use disorders and their relation to hepatitis C infection are still unknown in Iraq. This cross-sectional study, conducted among a sample of hepatitis C- infected patients attending the Gastrointestinal Tract Center in Baghdad Medical City, aimed to examine the prevalence of substance use disorders, the sociodemographic characteristics of the abusers, and the relation between intravenous drug abuse and hepatitis C virus infection. All participants were subjected to an Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) questionnaire and a data form to determine sociodemographic characteristics and hepatitis C virus-related risk factors. Results In a total of 300 hepatitis C virus-infected patients, the prevalence of substance use disorders was 53.6%. Among these patients, 43.6% abused nicotine, 6% abused licit drugs, and 4% abused alcohol. No one reported illicit drug abuse. Intravenous drug abuse was rare, and there was no relationship found between intravenous drug abuse and hepatitis C infection. Cupping (23%) and blood transfusion (20.3%) were both significantly associated with hepatitis C transmission in this study (p > 0.001). Conclusion This study revealed a high prevalence (53.6%) of substance abuse in this sample of hepatitis C-infected patients, with nicotine being the most commonly abused substance. However, there was no relationship between hepatitis C infection and intravenous drug abuse. Common risk factors that might contribute to hepatitis C transmission among this population include cupping and blood transfusion.

Abstract Background Hepatocellular carcinoma (HCC) constitutes an important contributor to fatalities. Coronavirus disease 2019 (COVID-19) frequently presents with complications such as respiratory distress, systemic inflammatory responses, and damage to various organs. Several studies have investigated the relationship between COVID-19 and mortality in patients with liver cancer, but there are few research on the relationship between them. This study is to explore the correlation between the two diseases and drugs treating them. Methods The Gene Expression Omnibus (GEO) database provides gene datasets of COVID-19 patients and HCC patients. Through differential gene analysis and weighted gene co-expression network analysis, we determined 223 genes represented in HCC and COVID-19. We then used functional annotation, protein–protein interaction network construction, predictive model development and verification, prognostic value analysis, and miRNA–gene network construction. Besides, we created a drug–hub–gene network by predicting possible medications that interact with hub genes using the Drug–Gene Interaction Database (DGIdb). Ultimately, we applied immunohistochemistry to ascertain the hub genes expression. Results This study revealed that eight core genes (RRM2, TPX2, DTL, CDT1, TYMS, CDCA5, CDC25C, and HJURP) co-existed in both HCC and COVID-19 and were differentially expressed in both HCC and normal tissues.CDC25C, RRM2, CDCA5, and HJURP had diagnostic value (AUC > 0.8) and prognostic value (adjusted P-value

Jiankang Wu,1– 4 Yan Chen1– 4 1Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, People’s Republic of China; 3Clinical Medical Research Center for Pulmonary and Critical Care Medicine, Changsha, Hunan, People’s Republic of China; 4Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Yan Chen, Email chenyan99727@csu.edu.cnAbstract: Extracellular vesicles (EVs) are nanoscale lipid bilayer vesicles released during cell activation, cellular damage, or apoptosis. They carry nucleic acids, proteins, and lipids facilitating intercellular communication and activate signaling pathways in target cells. In non-small cell lung cancer (NSCLC), EVs may contribute to tumor growth and metastasis by modulating immune responses, facilitating epithelial-mesenchymal transition, and promoting angiogenesis, while potentially contributing to resistance to chemotherapy drugs. EVs in liquid biopsies serve as non-invasive biomarkers for early cancer detection and diagnosis. Due to their small size, inherent molecular transport properties, and excellent biocompatibility, EVs also act as natural drug delivery vehicles in NSCLC therapy. Keywords: extracellular vesicles, non-small cell lung cancer, immunity, metastasis, drug, biomarkers

In order to micro and Nano sizing a drug via supercritical fluid technology, it is necessary to obtain its solubility in various ranges of pressures and temperatures. For this purpose, solubility of Niclosamide piperazine, in supercritical carbon dioxide (SC-CO2) was measured by a new static method, for the first time. The measurements were performed at various circumstances, i.e. temperatures = 308, 318, 328 and 338 K and pressures = 12–27 MPa. The obtained results indicate that pressure significantly influences the solubility of Niclosamide piperazine, with a measured solubility ranging from 0.77 × 10−7 to 13.60 × 10−7 in mole fraction. To study theoretically the solubility of Niclosamide piperazine, the obtained results are modeled using nine semi-empirical equations i.e. Garlapati-Madras, Chrastil, Kumar-Johnston, Sodeifian et al. (models I-II), Bartle et al., Bian et al., Sung-Shim, Mendez-Santiago-Teja and Peng-Robinson EoS with van der Waals mixing rule. Among which the Bian et al., model and Peng-Robinson EoS showed the minimum AARD% of about 4.45 % (corresponding corrected Akaike Information Criterion is −704.09) and 7.54 % (corresponding corrected Akaike Information Criterion is −699.24), respectively. Finally, enthalpies for the binary mixture of Niclosamide piperazine-supercritical carbon dioxide binary system has been determined, for the first time.

Background: Pooled procurement is key to managing drug spending amid rising healthcare costs, but conclusive evidence on its sustained impact is lacking, driven by market competition. Objective: This study aims to evaluate the trends and factors influencing the price changes of drugs awarded for pooled procurement systems utilizing a drug price index analysis. Methods: This retrospective study involved a review of secondary data on public pooled procurement of drugs in Malaysia. Drugs were selected through purposive sampling and focused on eight therapeutic subgroups that showed significant patterns of expenditure and consumption. The observed data are retrieved from centralized contracts that were managed through a tendering process spanning from 2010 to 2021. A price index was computed to assess fluctuations in pharmaceutical pricing and market competition. To assess the influence of potential variables on market competition, quantified through the drug price index, a multiple linear regression analysis was utilized. The variables studied include product age, quantity index, bidding periods, therapeutic subgroups, and market competition elements such as types and number of competing products, dosage form, and types of procurements. The significance level was set at p

This work looks into how well Cu-doped zinc oxide works as a photocatalyst when exposed to visible light to break down sulphanilamide. The synthesized samples were characterized by XRD and then FTIR techniques for structural besides compositional analysis. The approximate value of bandgap found out by NBE values of PL spectra showed a decrease in bandgap with doping. Deconvoluted PL spectra revealed the presence of radiative recombination pathways associated with zinc interstitial and zinc vacancy in addition to band-to-band recombination in all samples. FESEM images showed a nanoflake shape for pure ZnO, while Cu-ZnO had a pseudo-spherical shape. SQUID-VSM was adopted to understand the magnetic nature of freshly prepared, heated, and unheated aged samples. Ferromagnetic behavior was observed with saturation magnetization of 5.56 × 10−4, 2.88 × 10−4, and 2.78 × 10−4 emu/g for freshly prepared, heated, and unheated aged samples, respectively. A 2 % Cu-doped sample exhibited the highest efficiency of 92.3 % towards the degradation of sulphanilamide. Since we got better efficiency for 2 % Cu-ZnO, we should further decrease the doping percentage and check whether we will get even higher efficiency in the future. The photocatalytic degradation efficiency of ternary ZnO compounds, codoped ZnO, should be evaluated, yet another future scope.

Chronic pain, which is described as pain lasting for greater than 3 months, accounts for a large percentage of economic debt in the United States, with approximately 20% of Americans experiencing a form of chronic pain. Despite the current pharmacologic recommendations for pain treatment, there are differences in how medications are prescribed to patients. Gender and sex are common variables when discussing biases in both pain perception and treatment. Pain perception can differ amongst the sexes based on a myriad of reasons such as differences in gonadal hormones or chronic pain syndromes. The purpose of this narrative literature review is to report physiologic and pharmacokinetic differences between the sexes and highlight the possible biases in pain treatment amongst men and women. By bringing awareness to differences in pain perception and treatment experienced by men and women, clinically, we can increase the efficacy of pain management amongst the sexes.

The research targeting the prevention of complications through natural constituents, instigated by the cancer has recently drawn much more attention over the globe. The research in this direction also revealed that the use of natural constituents would considered a promising strategy for diminishing the aforementioned disease and its consequences. Because of the easy availability and safe nature, the recent years, natural resources as strong anticancer agents. In this regard, here we introduced the possibility of using the methanolic extract of Physalis angulata root as a strong candidate and implemented the applicability of LC-MS to unveil the presence of various phytocompounds. The anticancer potential exhibited by Physalis angulata root followed by its ability to induce toxicity against the microbial population enhanced the interest in unveiling the phytochemical compounds including Absintholide, Curcumin dimer 1, Mytilin A, Ginsenoside F1, Encecalin , Ganoderic acid TQ, Alnustone, Rhamnetin 3-sophoroside, Gibberellin A14 aldehyde, Thiolutin, Euglobal III and Epomusenin B. The presence of various macro and micronutrients suggested that Physalis angulata is a prominent resource for future research targeting pharmacological research, especially anticancer research.

BackgroundThis study provides an overview of the clinical applications of drugs and their metabolites analysis in biological fluids and identifies commonly used analytical techniques for bioanalysis.MethodsOriginal open-access articles published between 31 October 2005 and 31 October 2020 in Google Scholar, MEDLINE, PubMed, and Embase were reviewed, and pertinent findings of the individual studies were pooled and presented using tables. This review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA).ResultsFifteen studies met the eligibility criteria and were included in the review. These studies show that qualitative identification and quantitative determination of drugs and their metabolites in biological fluids are important for therapeutic drug monitoring (TDM), pharmacokinetic and pharmacodynamic studies, drug abuse control, and forensic and toxicological analyses. Spectroscopic, electrochemical, and hyphenated and nonhyphenated chromatographic techniques are used to analyse drugs and their metabolites in biological fluids. However, hyphenated techniques are the preferred analytical methods because of their sensitivity, selectivity, accuracy, reproducibility, efficiency, and rapid analysis.Conclusion/RecommendationsBioanalysis is important for pharmacokinetic and pharmacodynamic studies, therapeutic drug monitoring, forensic and toxicological analyses, and drug abuse control using different bioanalytical techniques. However, hyphenated techniques are the most commonly used bioanalytical techniques. Bioanalysis of drugs and their metabolites needs to be improved to provide good medical and pharmaceutical care to patients, to confirm forensic and toxicological cases, and to control drug abuse.

BackgroundPulmonary hypertension (PH) can lead to right ventricular hypertrophy, significantly increasing mortality rates. This study aims to clarify PH-specific metabolites and their impact on genomic and post-translational modifications (PTMs) in cancer, evaluating DHA and EPA’s therapeutic potential to mitigate oxidative stress and inflammation.MethodsData from 289,365 individuals were analyzed using Mendelian randomization to examine 1,400 metabolites’ causal roles in PH. Anti-inflammatory and antioxidative effects of DHA and EPA were tested in RAW 264.7 macrophages and cancer cell lines (A549, HCT116, HepG2, LNCaP). Genomic features like CNVs, DNA methylation, tumor mutation burden (TMB), and PTMs were analyzed. DHA and EPA’s effects on ROS production and cancer cell proliferation were assessed.ResultsWe identified 57 metabolites associated with PH risk and examined key tumor-related pathways through promoter methylation analysis. DHA and EPA significantly reduced ROS levels and inflammatory markers in macrophages, inhibited the proliferation of various cancer cell lines, and decreased nuclear translocation of SUMOylated proteins during oxidative stress and inflammatory responses. These findings suggest a potential anticancer role through the modulation of stress-related nuclear signaling, as well as a regulatory function on cellular PTMs.ConclusionThis study elucidates metabolic and PTM changes in PH and cancer, indicating DHA and EPA’s role in reducing oxidative stress and inflammation. These findings support targeting these pathways for early biomarkers and therapies, potentially improving disease management and patient outcomes.

Objective: Glucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained under contexts that allow the defence of lean mass. Methods: We investigate the metabolic effects of the long-acting glucagon receptor agonist, G108, when administered to obese mice at low-doses, and with dietary protein supplementation. Results: Dietary protein supplementation can only fully defend lean mass at a low dose of G108 that is sub-anorectic and does not reduce fat mass. However, in this context, G108 is still highly effective at improving glucose tolerance and reducing liver fat in obese mice. Mechanistically, liver RNA-Seq analysis reveals that dietary protein supplementation defends anabolic processes in low-dose G108-treated mice, and its effects on treatment-relevant glucose and lipid pathways are preserved. Conclusion: Glucagon-mediated energy expenditure and weight loss may be mechanistically coupled to hypoaminocidemia and lean mass loss. However, our data suggest that glucagon can treat MAFLD at doses which allow full defence of lean mass given sufficient dietary protein intake. Therefore, proportionate glucagon therapy may be safe and effective in targeting hepatocytes and improving in glycaemia and liver fat.

Background: β-Lactams remain the most reported drug allergy globally, with the volume and diversity of related drug allergy research continuing to accumulate. Recognizing evolving research trends can help inform future directions and encourage synergistic collaborations. Objective: We conducted a comprehensive bibliometric analysis of all publications relevant to β-lactam allergy, with a focus on longitudinal publication rates, international collaborations, and key word/trend analysis. Methods: Meta-data from all original articles, letters, and reviews relevant to β-lactam allergy on the Web of Science Core Collection up until December 31, 2023, were analyzed. Results: From 1966 to 2023, there were 4451 records (3536 articles, 631 reviews, and 284 letters) from 78 countries. There was an exponential increase in publications, especially during the past decade, with half of all publications on β-lactam allergy published during this time (50.6% [2252 of 4452]). Overall, 18.1% of the publications (805 of 4452) involved international coauthorships, with a significant increase since the previous decade (12.7% vs 23.3% [P < .001]). The most frequent key words in the first published half of articles were skin testing (84 of 1919), IgE (57 of 1919), and anaphylaxis (49 of 1919); in contrast to the key word skin testing (137 of 3351), the key words drug provocation test (121 of 3351), antimicrobial resistance (120 of 3351), and antimicrobial stewardship (118 of 3351) were the most frequent key words in the latter half. Conclusion: There has been a surge in publications, international collaboration, and shifting paradigms in β-lactam allergy research. The field has evolved beyond focusing on in vitro tests or desensitization toward antimicrobial stewardship. However, there still seems to be relatively fewer collaborations with non-Western countries. Further international collaborations to harmonize delabeling strategies against the threat of mislabeled β-lactam allergy should be encouraged.

In this work, an eco-friendly, stable, simple, new super adsorbent adsorption properties based on biopolymer sodium alginate was successfully deliberated by a combination of a simple crosslinking method. We prepared two hydrogel including (SA-g-P(Ac-co-AM) hydrogel and the second hydrogel after loading CNT/ZnO onto hydrogel. These new hydrogel surfaces were prepared from two monomers (acryl acid and acrylamide) to remove Chloramphenicol CHZ drug. The physical characterizations of new super adsorbent hydrogel nanocomposite were evaluated by XRD, FTIR, TGA, EDX and TEM. The practical experiments involved calculation of the best wavelength and study of best condition of adsorption factors such as effect of equilibrium time, weight of hydrogel nanocomposite, temperature solution, pH solution, and adsorbent regeneration experiments (Desorption). The removal percentage of CHZ drug increased from 55.45 to 89.8%, and adsorption capacity was changed from 65.5 to 110 mg g-1 on to hydrogel nanocomposite. The isotherm Freundlich and isotherm Langmuir were too introduced. All data followed the model Freundlich isotherm in the presence of CHZ drug. The change enthalpy (∆H) value was positive indicating the adsorption method endo-thermic presses and spontaneous of change Gibes free energy (∆G) negative value, as well as positive value of change entropy (∆S).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their analgesic, antipyretic, and anti-inflammatory properties. However, they are also associated with a broad spectrum of hypersensitivity reactions, ranging from mild cutaneous manifestations to severe systemic responses. The complex nature of these reactions and their underlying mechanisms pose challenges in diagnosis and management. We review the clinical evidence to six distinct clinical phenotypes of NSAID hypersensitivity, including: NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA), NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous disease (NECD), NSAID-induced urticaria/angioedema (NIUA), food-dependent NSAID-induced hypersensitivity reactions (FDNIH), and selective NSAID-induced delayed reactions (SNIDR). This review aims to provide a comprehensive review of NSAID hypersensitivity reactions based on clinical phenotyping, which can aid in understanding and managing these adverse events.

In silico methods are a set of theoretical computer tools that analyze and correlate a series of physical, chemical and mathematical parameters with the purpose of studying the behavior of drugs and their protein therapeutic targets. These studies relate experimental data and theoretical data of interactions. drug-protein based on molecular descriptors. Among these methods, the most relevant are molecular docking, which relates the molecular dynamics between drug-protein structures, and the structure-activity relationship or QSAR method, which correlates physicochemical, electronic, and steric parameters of drugs with their biological activity. The mathematical results obtained through these methods allow generating a series of predictions of theoretical-experimental relationship.

Introduction Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia, but without appropriate monitoring, it can be associated with potentially fatal outcomes. An International Adult Clozapine Titration Guideline categorizes patients into normal or slow metabolizers. Categorization provides clozapine titration schedules and recommends regular c-reactive protein (CRP) and clozapine concentration monitoring to reduce the risk of adverse drug reactions (ADRs). The impact of the guideline on clozapine ADRs has not been evaluated. Methods A retrospective chart review assessed clozapine titrations, laboratory monitoring, ADRs, and discontinuations for clozapine-naive adult inpatients at a single center from January 1, 2013, to June 1, 2022. Each patient’s cumulative weekly clozapine dosage was compared with their guideline recommended dosage to create a percent accordance. Linear logistic regression evaluated the relationship between titration speed and the presence of an ADR, while descriptive statistics analyzed laboratory monitoring. Results Forty-three patients were included, with the majority being White males with schizophrenia. An inverse relationship existed between the last inpatient week clozapine dose percent accordance and the probability of an ADR. Nonobese patients were less likely than obese patients to experience an ADR (odds ratio = 0.17; 95% CI, 0.03-0.99). CRP and clozapine concentration monitoring was suboptimal. Discussion Based on our small retrospective review of primarily White males, more aggressive clozapine titrations did not increase ADRs. Future studies with more diverse samples are needed and should focus on specific ADRs, which may have increased occurrence with rapid titrations. Obese patients were at higher risk of ADRs, correlating with the guideline-recommended slower titrations for these patients.

Abstract We aimed to assess salivary and seroprevalence of Toxoplasma immunoglobulins in risky populations and evaluate drug docking targeting TgERP. A cross-sectional study was conducted in Alexandria University hospitals’ outpatient clinics. 192 participants were enrolled from September 2022 to November 2023. Anti-Toxoplasma IgG and IgM were determined in serum and saliva by ELISA. An in-Silico study examined TgERP’s protein–protein interactions (PPIs) with pro-inflammatory cytokine receptors, anti-inflammatory cytokine, cell cycle progression regulatory proteins, a proliferation marker, and nuclear envelope integrity-related protein Lamin B1. Our findings revealed that anti-T. gondii IgG were detected in serum (66.1%) and saliva (54.7%), with 2.1% of both samples were positive for IgM. Salivary IgG had 75.59% sensitivity, 86.15% specificity, 91.40% PPV, 64.40% NPP, 79.17% accuracy and fair agreement with serum IgG. On the other hand, the sensitivity, specificity, PPV, NPV, and accuracy in detecting salivary IgM were 75.0%, 99.47%, 75.0%, 99.47%, and 98.96%. AUC 0.859 indicates good discriminatory power. Examined synthetic drugs and natural products can target specific amino acids residues of TgERP that lie at the same binding interface with LB1 and Ki67, subsequently, hindering their interaction. Hence, salivary samples can be a promising diagnostic approach. The studied drugs can counteract the pro-inflammatory action of TgERP.

Abstract Objectives In Canada, substance-related accidental acute toxicity deaths (AATDs) continue to rise at the national and sub-national levels. However, it is unknown if, where, when, and to what degree AATDs cluster in space, time, and space–time across the country. The objectives of this study were to 1) assess for clusters of AATDs that occurred in Canada during 2016 and 2017 at the national and provincial/territorial (P/T) levels, and 2) examine the substance types detected in AATD cases within each cluster. Methods Two years of person-level data on AATDs were abstracted from coroner and medical examiner files using a standardized data collection tool, including the decedent's postal code and municipality information on the places of residence, acute toxicity (AT) event, and death, and the substances detected in the death. Data were combined with Canadian census information to create choropleth maps depicting AATD rates by census division. Spatial scan statistics were used to build Poisson models to identify clusters of high rates (p

Introduction: Nowadays, the management of drug effluents, as emerging pollutants, has attracted great attention due to human health and ecological adverse effects. During the COVID-19 pandemic, two drugs, Fexofenadine and Montelukast, have been used in large quantities for patients with lung involvement. The aim of this study is to investigate the feasibility of removing Fexofenadine and Montelukast and determine the removal kinetics. Material and Methods: In this study, we used Rhodotron accelerator to determine kinetic coefficients for the removal of drugs. Our research focused on studying the kinetics of E-Beam radiation reactions and the generation of significant amounts of free radicals during these processes. We employed first-order and second-order kinetic models under laboratory conditions, taking into account various influencing factors to establish the rate of removal. Results: The results showed that the decomposition of Fexofenadine and Montelukast drugs by high-energy E-Beam bending process is a pseudo-first-order reaction with a coefficient of more than 0.9105 and 0.998, respectively. The results showed that the reaction rate constant depended significantly on the initial concentration of Fexofenadine and Montelukast drugs and their molecular structure. Conclusion: Using a Rhodotron accelerator is important for removing Fexofenadine and Montelukast from the aquatic environment.

Abstract The Amyloid precursor protein (APP) is a transmembrane glycoprotein from which amyloid-β (Aβ) peptides are generated after proteolytic cleavage. Aβ peptides are the main constituent of amyloid plaques in Alzheimer’s Disease (AD). The physiological functions of APP in the human adult brain are very diverse including intracellular signaling, synaptic and neuronal plasticity, and cell adhesion, among others. There is growing evidence that APP becomes dysfunctional in AD and that this dyshomeostasis may impact several APP functions beyond Aβ generation. The vast majority of current anti-amyloid approaches in AD have focused on reducing the synthesis of Aβ or increasing the clearance of brain Aβ aggregates following a paradigm in which Aβ plays a solo in APP dyshomeostasis. A wider view places APP at the center stage in which Aβ is an important, but not the only, factor involved in APP dyshomeostasis. Under this paradigm, APP dysfunction is universal in AD, but with some differences across different subtypes. Little is known about how to approach APP dysfunction therapeutically beyond anti-Aβ strategies. In this review, we will describe the role of APP dyshomeostasis in AD beyond Aβ and the potential therapeutic strategies targeting APP.

The long-term survival rate of patients with hepatocellular carcinoma （HCC） is poor， and drug efficacy is an important factor affecting clinical prognosis. N6-methyladenosine （m6A） modification is the most abundant modification in eukaryotic RNA， which can affect the occurrence and development of HCC and drug efficacy by regulating cancer-related biological functions. However， the role of m6A modification in HCC drug treatment has not been fully elucidated. Therefore， the biological functions of different regulatory members of the m6A modification process （methyltransferase， demethyltransferase and binding protein） in HCC drug treatment were illustrated， proposing that regulatory members of the m6A modification process can be used as biomarkers for HCC prognosis evaluation and have the potential to become therapeutic targets and providing novel insights for HCC precision medicine.

Vitamin C is one of the most well-known and most frequently used substances found in various pharmaceutical preparations. Patients consider it as a safe compound with multidirectional beneficial effects, while chemists have been presenting various possibilities for its determination for many years. The aim of this review is to present the current range of drugs and dietary supplements containing vitamin C available in Poland, divided into appropriate categories, taking into account doses, forms and other ingredients. The second goal is to summarize the main analytical methods for determining the content of ascorbic acid. A review of available preparations showed disproportions between a small group of drugs and a very large group of dietary supplements, which turned out to be significantly diversified in various aspects. In turn, the review of analytical methods clearly indicates the dominant share of spectroscopic ones and the fact that researchers focus primarily on improving basic, commonly known techniques.

The P2X7 receptor, a member of the P2X receptor family, plays a crucial role in various physiological processes, particularly pain perception. Its expression across immune, neuronal, and glial cells facilitates the release of pro-inflammatory molecules, thereby influencing pain development and maintenance, as evidenced by its association with pulpitis in rats. Notably, P2X receptors such as P2X3 and P2X7 are pivotal in dental pain pathways, making them promising targets for novel analgesic interventions. Leveraging graph neural networks (GNNs) presents an innovative approach to model graph data, aiding in the identification of drug targets and prediction of their efficacy, complementing advancements in genomics and proteomics for therapeutic development. In this study, 921 drug-gene interactions involving P2X receptors were accessed through https://www.probes-drugs.org/. These interactions underwent meticulous annotation, preprocessing, and subsequent utilization to train and assess GNNs. Furthermore, leveraging Cytoscape, the CytoHubba plugin, and other bioinformatics tools, gene expression networks were constructed to pinpoint hub genes within these interactions. Through analysis, SLC6A3, SLC6A2, FGF1, GRK2, and PLA2G2A were identified as central hub genes within the context of P2X receptor-mediated drug-gene interactions. Despite achieving a 65 percent accuracy rate, the GNN model demonstrated suboptimal predictive power for gene-drug interactions associated with oral pain. Hence, further refinements and enhancements are imperative to unlock its full potential in elucidating and targeting pathways underlying oral pain mechanisms.

Abstract Background Physiotherapy interventions effectively improved fatigue and physical functioning in non-COVID patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). There is a research gap on the effectiveness of physiotherapy interventions versus drug management on ME/CFS in post-COVID-19 conditions (PCC). Methods We planned a three-arm prospective randomized control trial on 135 PCC cases with ME/CFS who are diagnosed between 20 November 2023 and 20 May 2024 from a population-based cohort. The study aims to determine the effectiveness of physiotherapy interventions as adapted physical activity and therapeutic exercise (APTE) provided in institution-based care versus telemedicine compared with drug management (DM). Participants will be assigned to three groups with the concealed location process and block randomization with an enrollment ratio of 1:1:1. The post-treatment evaluation will be employed after 2 months of interventions, and follow-up will be taken after 6 months post-intervention. The Chalder fatigue scale will measure the primary outcome of fatigue. SF-36 and the disability-adjusted life years (DALYs) will measure the secondary outcome of physical functioning and episodic disability. Discussion This study will address the research gap to determine the appropriate approach of physiotherapy or drug management for ME/CFS in PCC cases. The future direction of the study will contribute to developing evidence-based practice in post-COVID-19 condition rehabilitation. Trial registration The trial is registered prospectively from a primary Clinical Trial Registry side of WHO CTRI/2024/01/061987. Registered on 29 January 2024.

Abstract Drug-induced liver injury (DILI) is a prevalent disorder that can be led on by almost all drug types. The majority of benign DILI cases become better after drug discontinuation. To stop the development of acute or chronic liver failure, it is crucial to identify and get rid of the offending substance as soon as feasible. DILI does not have any identified risk factors, but certain people may be more susceptible due to genetic vulnerability and previous liver disease. Some patients may exhibit indications of systemic hypersensitivity, even though the majority of patients have clinical symptoms that are the same as those of other liver illnesses. Rapid drug withdrawal and supportive care aimed at reducing uncomfortable symptoms comprise the treatment for drug- and herbal-induced liver damage.

In recent years, the frequency of contrast-enhanced radiological studies has increased significantly, and the issues of their selection and rational use do not lose their relevance. These methodological recommendations represent a complete up-to-date guide for using contrast agents (CA) in radiology. Types of currently used CA in computed tomography, magnetic resonance imaging, and ultrasound examinations are described. Safety rules for injection of each CA type are systematized, the principles of dosing and possible side effects are explained. In addition, it is important to highlight the issues of interactions between CA and other drugs that patient might take, in particular, the possible deterioration of renal function when using CA in diabetes mellitus patients taking metformin. It should be noted that these recommendations have undergone significant changes in recent years. Also questionnaire templates for patients prior to the contrast-enhanced study are given in the supplements. The methodological guidelines are based on current publications of international experts on CA use in radiology as well as on the data of two major guidelines: American College of Radiologists (ACR) Guidelines (2023) and European Society of Urogenital Radiology (ESUR) Safety Recommendations (2018, version 10). Thus, the information presented is validated, which provides grounds for its application in real clinical practice. The guidelines will be actualized as new scientific evidence becomes available, but to date they appear to be the most relevant.

Background: Adverse effects following immunizations (AEFIs) can contribute to vaccine hesitancy. Objective: We evaluated clinical outcomes of AEFIs subsequent to administration of the coronavirus disease 2019 (COVID-19) vaccine at 2 pediatric allergy centers. Methods: Data on pediatric patients referred for COVID-19 AEFI concerns between March 2021 and October 2022 were reviewed. The collected data included patient demographics, clinical characteristics, outcomes of prior COVID-19 vaccination, recommendations after consultation, and outcomes of revaccination. Results: The 163 patients were separated into 2 groups based on the absence (n = 89 [54.6%]) or presence (n = 74 [45.4%]) of prior COVID-19–related AEFIs. The most common reason for referral without a prior AEFI was another suspected drug allergy (n = 58 [35.6%]). All patients in this group were recommended for COVID-19 vaccination. Of the 163 patients, 82 (92.1%) proceeded with vaccination, with 77 of them (93.9%) tolerating vaccination. Most of those with a prior COVID-19–related AEFI had a delayed cutaneous reaction (n = 60 [37.0%]); 1 patient (0.6%) had suspected anaphylaxis. In this group, 6 (8.1%) were advised to postpone COVID-19 vaccination until their debilitating skin conditions had improved in response to further treatment, whereas 45 (77.6%) tolerated subsequent vaccination to the same or an alternate COVID-19 vaccine type. The most common AEFI on revaccination was urticaria (in 8 of 11 patients [72.7%]). AEFI on revaccination was significantly associated with a history of spontaneous urticaria or angioedema (relative risk = 3.6 [95% CI = 1.30-9.99]; P = .020) and urticaria following COVID-19 vaccination previously (relative risk = 4.12 [95% CI = 1.22-13.87]; P = .017). Conclusions: Children with a history of urticaria or angioedema related or unrelated to prior COVID-19 vaccination were at higher risk of a COVID-19–related AEFI on revaccination, although most were able to complete the vaccination series under the management of our immunology/allergy service.

Introduction Throughout history and up until the present, there has been a medicine shortage. In the early 1920s, there was a shortage of insulin, which is when drug scarcity first appeared in the records. Drug shortages are now more prevalent globally than they were back then. The goal of this essay is to pinpoint the key components that make up a definition for medication shortages and to pinpoint the circumstances that should be considered when reporting drug shortages in databases. Understanding the factors that led certain organizations to create their own definition of a medicine shortage was crucial for achieving these goals. The pharmaceutical regulatory environment can be connected to several reasons why there are medication shortages, including parallel trading, quality standards, and business choices to halt or reduce manufacturing. The many rules governing medicine shortages have not yet been the subject of a thorough investigation. This protocol’s objective is to analyze the pertinent legislative and regulatory frameworks in the European pharmaceutical system that affect medication shortages. The objectives of the study will be the non–availability of drugs at an outpatient pharmacy and to analyze the reason of non–availability of drugs. Methods An observational study will be adopted in this study. It includes a collection of data from the patient coming to the outpatient pharmacy of AVBRH Sawangi (Meghe) Wardha. Expected result It can lead to delayed treatment for patients seeking alternative medication. It can also lead to increased healthcare costs if patients seek alternative treatments that are more expensive or require additional medical care. The unavailability of drugs can also lead to frustration and anxiety for patients who need medication to manage their health condition. It can also negatively impact the reputation of the hospital.

Cerebroside sulfotransferase (CST) is a key enzyme in sulfatide biosynthesis and regulation of the myelin sheath in the nervous system. To counter sulfatide accumulation with the deficiency of aryl sulfatase A, CST is considered a target protein in substrate reduction therapy in metachromatic leukodystrophy. In this study, 461 phytoconstituents from four herbs of Medhya Rasayana were screened using multi-pronged virtual screening methods including molecular docking, molecular dynamics (MD) simulation, and reverse pharmacophore analysis. The initial screening of the top 15 hits was based on the binding affinity of the compounds toward the CST substrate-binding site using the lowest free energy of a binding score cutoff of ≤ −7.5 kcal/mol, with the number of conformations in the largest cluster more than 75. The absorption, distribution, metabolism, and excretion (ADME) and toxicity-based pharmacokinetic analysis delivered the top four hits: 18alpha-glycyrrhetinic acid, lupeol, alpha carotene, and beta-carotene, with high blood–brain barrier permeability and negligible toxicity. Furthermore, a 100-ns simulation of protein–ligand complexes with a trajectory analysis of structural deviation, compactness, intramolecular interactions, principal component analysis, free energy landscape, and dynamic cross-correlation analysis showed the binding potential and positioning of the four hits in the binding pocket. Thus, an in-depth analysis of protein–ligand interactions from pre- and post-molecular dynamics simulation, along with reverse pharmacophore mapping, suggests that 18alpha-glycyrrhetinic acid is the most potent and specific CST inhibitor, while beta-carotene could be considered the second most potent compound for CST inhibition as it also exhibited overall stability throughout the simulation. Therefore, the computational drug screening approach applied in this study may contribute to the development of oral drugs as a therapeutic option for metachromatic leukodystrophy.

Artesunate (ART) is a classic antimalarial drug with high efficiency, low toxicity and tolerance. It has been shown to be safe and has good anti-tumor effect. Existing clinical studies have shown that the anti-tumor mechanisms of ART mainly include inducing apoptosis and autophagy of tumor cells, affecting tumor microenvironment, regulating immune response, overcoming drug resistance, as well as inhibiting tumor cell proliferation, migration, invasion, and angiogenesis. ART has been proven to fight against lung cancer, hepatocarcinoma, lymphoma, multiple myeloma, leukemia, colorectal cancer, ovarian cancer, cervical cancer, malignant melanoma, oral squamous cell carcinoma, bladder cancer, prostate cancer and other neoplasms. In this review, we highlight the effects of ART on various tumors with an emphasis on its anti-tumor mechanism, which is helpful to propose the potential research directions of ART and expand its clinical application.

IntroductionMachine learning (ML) algorithms and statistical modeling offer a potential solution to offset the challenge of diagnosing early Alzheimer's disease (AD) by leveraging multiple data sources and combining information on neuropsychological, genetic, and biomarker indicators. Among others, statistical models are a promising tool to enhance the clinical detection of early AD. In the present study, early AD was diagnosed by taking into account characteristics related to whether or not a patient was taking specific drugs and a significant protein as a predictor of Amyloid-Beta (Aβ), tau, and ptau [AT(N)] levels among participants.MethodsIn this study, the optimization of predictive models for the diagnosis of AD pathologies was carried out using a set of baseline features. The model performance was improved by incorporating additional variables associated with patient drugs and protein biomarkers into the model. The diagnostic group consisted of five categories (cognitively normal, significant subjective memory concern, early mildly cognitively impaired, late mildly cognitively impaired, and AD), resulting in a multinomial classification challenge. In particular, we examined the relationship between AD diagnosis and the use of various drugs (calcium and vitamin D supplements, blood-thinning drugs, cholesterol-lowering drugs, and cognitive drugs). We propose a hybrid-clinical model that runs multiple ML models in parallel and then takes the majority's votes, enhancing the accuracy. We also assessed the significance of three cerebrospinal fluid biomarkers, Aβ, tau, and ptau in the diagnosis of AD. We proposed that a hybrid-clinical model be used to simulate the MRI-based data, with five diagnostic groups of individuals, with further refinement that includes preclinical characteristics of the disorder. The proposed design builds a Meta-Model for four different sets of criteria. The set criteria are as follows: to diagnose from baseline features, baseline and drug features, baseline and protein features, and baseline, drug and protein features.ResultsWe were able to attain a maximum accuracy of 97.60% for baseline and protein data. We observed that the constructed model functioned effectively when all five drugs were included and when any single drug was used to diagnose the response variable. Interestingly, the constructed Meta-Model worked well when all three protein biomarkers were included, as well as when a single protein biomarker was utilized to diagnose the response variable.DiscussionIt is noteworthy that we aimed to construct a pipeline design that incorporates comprehensive methodologies to detect Alzheimer's over wide-ranging input values and variables in the current study. Thus, the model that we developed could be used by clinicians and medical experts to advance Alzheimer's diagnosis and as a starting point for future research into AD and other neurodegenerative syndromes.

Introduction: The problem of drug shortages is not new, but it has reached unprecedented levels in recent years. In community pharmacies, pharmacists are forced to develop daily strategies to deal with such shortages and ensure patient care. These efforts result in significant constraints and adjustments to pharmacists' daily practices. The aim of this study is to explore the possible relationship between the consequences of drug shortages and the well-being of pharmacists in pharmacies. Material & method: This study adopts an exploratory qualitative approach by interviewing pharmacists working in community pharmacies in Wallonia. The data were collected between March and June 2023 through individual semi-structured interviews using a resolute guide. The interview guide was adapted as the interviews progressed and according to the pharmacists' views. 16 participants were included, including 7 owner pharmacists, 3 non-owners, and 6 non-titular pharmacists. The interviews were transcribed and then analyzed through a thematic approach. Results: An in-depth study of the day-to-day reality of pharmacies that is open to the public highlights the time-consuming nature of drug shortages, with various implications for pharmacists' relationships, finances, and workload. However, these professionals also highlight the recognition of patients when a solution is discovered, with some sources saying that shortages value the pharmacist's ability and enhance the profession. Finally, about the possibility of change in the training of pharmacists is also addressed by some pharmacists. Conclusion: Drug shortages demand changes in pharmaceutical practice and appear to affect the well-being of pharmacists in public settings. However, the impact seems complex and is amplified by the lack of personnel. With shortages continuing to rise in recent years, it would be wise to analyze the longer-term effects of this phenomenon.

Apoptosis is an evolutionarily conserved cell death pathway that plays a crucial role in maintaining tissue homeostasis, orchestrating organismal development, and eliminating damaged cells. Dysregulation of apoptosis can contribute to the pathogenesis of malignant tumors and neurodegenerative diseases. Anticancer drugs typically possess the capacity to induce apoptosis in tumor cells. The Bcl-2 protein family, consisting of 27 members in humans, serves as the key regulator of mitochondrial function. This family can be divided into two functional groups: anti-apoptotic proteins (e.g., Bcl-2, Bcl-xl, Mcl-1) and pro-apoptotic proteins (e.g., Bad, Bax). Mcl-1 exerts its function by binding pro-apoptotic Bcl-2 proteins thereby preventing apoptosis induction. Overexpression of Mcl-1 not only correlates closely with tumorigenesis but also associates significantly with resistance towards targeted therapy and conventional chemotherapy. Effective induction of apoptosis can be achieved through inhibition or interference with Mcl-1. Thus, this mini review discusses existing Mcl-1 inhibitors.

Drug infusion therapy after surgery for urothelial carcinoma is an effective measure to reduce cancer recurrence rate. Hydrogels are drug carriers with good biocompatibility and high drug loading capacity, which can optimize the pharmacokinetics of drugs in the urinary system to improve the therapeutic effect. Compared with the traditional free drug in situ perfusion, the hydrogel drug loading system can still maintain effective drug concentration in the face of continuous urinary flushing due to its good mucosal adhesion effect. The significantly prolonged drug retention time can not only improve the therapeutic effect of drugs, but also reduce the discomfort and risk of urinary tract infections caused by frequent drug infusion, and improve patient compliance. In addition, the combination of hydrogel with nanoparticles and magnetic materials can also improve the mucosal permeability and targeting effect of the hydrogel drug loading system, so as to overcome the mucus layer of urinary epithelium and the physiological barrier of tumor and minimize the impact on normal tissue and cell functions. At present, the research of hydrogels for urothelial cancer treatment involves chemotherapy, immunotherapy, gene therapy, inhibition of metabolism and multi strategy synergistic therapy. This review summarizes the research progress of hydrogels for the treatment of urothelial carcinoma, hoping to provide a reference for the future research of safe, reliable, effective, and advanced hydrogels with little side effects.

Ovarian cancer (OC) is one of the most common malignancies and a leading cause of death among women worldwide. The ubiquitin pathway plays an important role in OC development. Using the single nucleotide polymorphism data obtained using the prevalence and dominance strategies, four ubiquitin marker genes were identified according to their expression levels: BARD1, BRCA2, FANCA, and BRCA1. Based on these four genes, a consensus clustering of OC expression data was performed. The significant differences in the survival analysis, ESTIMATE, and CIBERSORT results among the clusters indicated the pivotal role of these four genes in OC development. Of the ubiquitin-representative genes in each cluster, two ubiquitin genes, TOP2A and MYLIP, were identified in the survival risk model after univariate survival, Least Absolute Shrinkage and Selection Operator regression, and multivariate survival analyses. The reliability and robustness of both the training and validation data were confirmed by comparing the significant survival difference between high- and low-risk patients. We further explored the association between our risk model and clinical outcomes as well as predicted potentially interacting drugs. The co-expression network showed clear interactions among the four marker genes and two model genes and between high- and low-risk differentially expressed genes. Significantly enriched genes were found in pathways associated with ion channels, channel activity, and neuroactive ligand–receptor interactions. Therefore, suggesting the involvement of ubiquitin genes in the survival and development of OC through neurohumoral regulation. Our results will provide valuable reference or supplementary information for studies investigating OC diagnosis and therapies.

Cardiovascular diseases (CVDs) have a complex pathogenesis and pose a major threat to human health. Cardiomyocytes have a low regenerative capacity, and their death is a key factor in the morbidity and mortality of many CVDs. Cardiomyocyte death can be regulated by specific signaling pathways known as programmed cell death (PCD), including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, etc. Abnormalities in PCD can lead to the development of a variety of cardiovascular diseases, and there are also molecular-level interconnections between different PCD pathways under the same cardiovascular disease model. Currently, the link between programmed cell death in cardiomyocytes and cardiovascular disease is not fully understood. This review describes the molecular mechanisms of programmed death and the impact of cardiomyocyte death on cardiovascular disease development. Emphasis is placed on a summary of drugs and potential therapeutic approaches that can be used to treat cardiovascular disease by targeting and blocking programmed cell death in cardiomyocytes.

Retinoic acid receptor β2 (RARβ2) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal regenerative effect. We have developed a first-in-class RARβ agonist drug, C286, that modulates neuron-glial pathways to induce functional recovery in a rodent model of sensory root avulsion. Here, using genome-wide and pathway enrichment analysis of avulsed rats' spinal cords, we show that C286 also influences the extracellular milieu (ECM). Protein expression studies showed that C286 upregulates tenascin-C, integrin-α9, and osteopontin in the injured cord. Similarly, C286 remodulates these ECM molecules, hampers inflammation and prevents tissue loss in a rodent model of spinal cord contusion C286. We further demonstrate C286's efficacy in human iPSC-derived neurons, with treatment resulting in a significant increase in neurite outgrowth. Additionally, we identify a putative efficacy biomarker, S100B, which plasma levels correlated with axonal regeneration in nerve-injured rats. We also found that other clinically available retinoids, that are not RARβ specific agonists, did not lead to functional recovery in avulsed rats, demonstrating the requirement for RARβ specific pathways in regeneration. In a Phase 1 trial, the single ascending dose (SAD) cohorts showed increases in expression of RARβ2 in white blood cells correlative to increased doses and at the highest dose administered, the pharmacokinetics were similar to the rat proof of concept (POC) studies. Collectively, our data suggests that C286 signalling in neurite/axonal outgrowth is conserved between species and across nerve injuries. This warrants further clinical testing of C286 to ascertain POC in a broad spectrum of neurodegenerative conditions.