Search

Yaws, caused by Treponema pallidum ssp. pertenue, remains a significant public health concern in tropical regions of West Africa and the South Pacific, primarily affecting children in remote areas with limited access to hygiene and sanitation. In this study, conducted in three endemic countries of West Africa where yaws remains a significant public health concern (Ghana, Cameroon, and Côte d'Ivoire), we aimed to assess the knowledge, attitudes, and practices related to yaws among community members, community health workers (CHWs), and traditional healers. The study revealed variations in the perception of causes of yaws among community members: the majority or participants in Ghana attributed yaws to germs (60.2%); in Cameroon the most reported form of transmission was contact with or drinking infected water sources (44.6%); and in Côte d'Ivoire both of these answers were also the most prevalent (60.3% germs and 93.% water sources). A substantial proportion of participants in Côte d'Ivoire also associated yaws with witchcraft and divine punishment (44.8%). Only a small proportion of individuals in Ghana and Côte d'Ivoire correctly identified contact with an infected person as a form of transmission (11.9% and 20.7%, respectively) and less than half in Cameroon (42.6%), although more than 98% of all participants reported avoidance behaviours towards yaws infected people due to fear of getting infected. Most participants expressed a preference for seeking care at hospitals (49.2%, 60.6%, 86.2%) or health care professionals including doctors and nurses (58.5%, 41,5% and 17.2%) if they were diagnosed with yaws, although a quarter of participants in Côte d'Ivoire also sought support from traditional healers. The CHWs interviewed were generally well-trained on yaws causes and treatment options, although they often reported low availability of treatment and diagnostic tests for yaws. Our findings underscore the need for community education, awareness campaigns, ongoing CHW training, and improved access to yaws treatment and diagnostic resources. The data also suggest that collaboration with traditional healers, who usually hold a highly esteemed position in the society, such as giving training on yaws causes and transmission or exchanging knowledge on treatment options, could be beneficial in certain regions, particularly in Côte d'Ivoire. Author summary: Yaws is a non-venereal ulcerative disease caused by the bacterium Treponema pallidum ssp. Pertenue. This disease is spread through skin-to-skin contact by someone with an infectious ulcer and is endemic in 13 countries, including Ghana, Cameroon and Ivory Coast. Oral azithromycin is the preferred treatment for yaws and the World Health Organization is currently deploying mass drug administration campaigns of azithromycin with the aim of global eradication of yaws. A cornerstone of this eradication campaign is reaching a population treatment coverage of over 90%, therefore education and awareness of the disease's natural history and management is paramount. In this study, we aimed to explore knowledge, attitudes and practices regarding yaws in Ghana, Côte d'Ivoire and Cameroon to understand the general understanding of the disease and the practices around it. We found that the route of transmission of yaws is generally not well understood, with most individuals incorrectly reporting sources like dirty drinking or washing water, and supernatural causes such as curses or witchcraft. Most respondents would attend hospitals or clinics if they had yaws for correct management, although traditional healers were also a popular choice. Community health workers reported a correct management of the disease, although low stock of tests and drug availability was reported. [ABSTRACT FROM AUTHOR]

The ongoing COVID-19 pandemic continues to pose significant challenges worldwide, despite widespread vaccination. Researchers are actively exploring antiviral treatments to assess their efficacy against emerging virus variants. The aim of the study is to employ M-polynomial, neighborhood M-polynomial approach and QSPR/QSAR analysis to evaluate specific antiviral drugs including Lopinavir, Ritonavir, Arbidol, Thalidomide, Chloroquine, Hydroxychloroquine, Theaflavin and Remdesivir. Utilizing degree-based and neighborhood degree sum-based topological indices on molecular multigraphs reveals insights into the physicochemical properties of these drugs, such as polar surface area, polarizability, surface tension, boiling point, enthalpy of vaporization, flash point, molar refraction and molar volume are crucial in predicting their efficacy against viruses. These properties influence the solubility, permeability, and bio availability of the drugs, which in turn affect their ability to interact with viral targets and inhibit viral replication. In QSPR analysis, molecular multigraphs yield notable correlation coefficients exceeding those from simple graphs: molar refraction (MR) (0.9860), polarizability (P) (0.9861), surface tension (ST) (0.6086), molar volume (MV) (0.9353) using degree-based indices, and flash point (FP) (0.9781), surface tension (ST) (0.7841) using neighborhood degree sum-based indices. QSAR models, constructed through multiple linear regressions (MLR) with a backward elimination approach at a significance level of 0.05, exhibit promising predictive capabilities highlighting the significance of the biological activity I C 50 (Half maximal inhibitory concentration). Notably, the alignment of predicted and observed values for Remdesivir's with obs p I C 50 = 6.01 ,pred p I C 50 = 6.01 ( p I C 50 represents the negative logarithm of I C 50 ) underscores the accuracy of multigraph-based QSAR analysis. The primary objective is to showcase the valuable contribution of multigraphs to QSPR and QSAR analyses, offering crucial insights into molecular structures and antiviral properties. The integration of physicochemical applications enhances our understanding of factors influencing antiviral drug efficacy, essential for combating emerging viral strains effectively. [ABSTRACT FROM AUTHOR]

Significance: Sickle cell disease (SCD) is the most common inherited diathesis affecting mostly underserved populations globally. SCD is characterized by chronic pain and fatigue, severe acute painful crises requiring hospitalization and opioids, strokes, multiorgan damage, and a shortened life span. Symptoms may appear shortly after birth, and, in less developed countries, most children with SCD die before attaining age 5. Hematopoietic stem cell transplant and gene therapy offer a curative therapeutic approach, but, due to many challenges, are limited in their availability and effectiveness for a majority of persons with SCD. A critical unmet need is to develop safe and effective novel targeted therapies. A wide array of drugs currently undergoing clinical investigation hold promise for an expanded pharmacological armamentarium against SCD. Recent Advances: Hydroxyurea, the most widely used intervention for SCD management, has improved the survival in the Western world and more recently, voxelotor (R-state-stabilizer), l-glutamine, and crizanlizumab (anti-P-selectin antibody) have been approved by the Food and Drug Administration (FDA) for use in SCD. The recent FDA approval emphasizes the need to revisit the advances in understanding the core pathophysiology of SCD to accelerate novel evidence-based strategies to treat SCD. The biomechanical breakdown of erythrocytesis, the core pathophysiology of SCD, is associated with intrinsic factors, including the composition of hemoglobin, membrane integrity, cellular volume, hydration, andoxidative stress. Critical Issues and Future Directions: In this context, this review focuses on advances in emerging nongenetic interventions directed toward the therapeutic targets intrinsic to sickle red blood cells (RBCs), which can prevent impaired rheology of RBCs to impede disease progression and reduce the sequelae of comorbidities, including pain, vasculopathy, and organ damage. In addition, given the intricate pathophysiology of the disease, it is unlikely that a single pharmacotherapeutic intervention will comprehensively ameliorate the multifaceted complications associated with SCD. However, the availability of multiple drug options affords the opportunity for individualized therapeutic regimens tailored to specific SCD-related complications. Furthermore, it opens avenues for combination drug therapy, capitalizing on distinct mechanisms of action and profiles of adverse effects. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a major and growing medical problem and its management is still challenging due to the coexistence of complications, co‐morbidity, and medication non‐adherence. HF patients who are adherent to their medication have fewer HF exacerbations, improved survival, and lower healthcare expenditure. Adherence to HF medication plays a pivotal role in attaining maximal therapeutic outcomes. The aim was to assess the medication adherence of heart failure patients at Debre Berhan Comprehensive Specialized Hospital (DBCSH). A pre‐post interventional study was undertaken from July 1, 2022, to December 31, 2022, at the medical referral clinic of DBCSH. The educational interventions were provided for 6 months. Medication adherence was determined using the Morisky Green Levin Medication Adherence Scale (MGLS). The data was entered into Epidata version 4.2.0 and analyzed using SPSS version 25.0 statistical software. Descriptive statistics and binary logistic regression analysis were performed. The strength of the association between predictor variables and outcome variables was determined using a 95% confidence interval and adjusted odd ratio. In the pre‐intervention phase, 54.6% of patients had medium medication adherence, while in the post‐intervention phase, 36.4% of patients had high medication adherence and 61.9% of patients had medium medication adherence. Following the intervention, medication cost (120, 50%), inadequate availability of drugs (75, 31%), and forgetfulness (30, 13%) were the main reasons for medication non‐adherence. The presence of co‐morbidity and the number of co‐morbidity (p <.05) were significantly associated with the occurrence of decreased medication adherence in the pre‐intervention phase. Interventions by pharmacists to educate HF patients about the nature of their disease and providing brochures to increase awareness of their medications have been shown to improve medication adherence. [ABSTRACT FROM AUTHOR]

Purpose: The primary objective of this study was to evaluate the associations between centre/country-based factors and two important process and outcome indicators in patients with hospital-acquired bloodstream infections (HABSI). Methods: We used data on HABSI from the prospective EUROBACT-2 study to evaluate the associations between centre/country factors on a process or an outcome indicator: adequacy of antimicrobial therapy within the first 24 h or 28-day mortality, respectively. Mixed logistical models with clustering by centre identified factors associated with both indicators. Results: Two thousand two hundred nine patients from two hundred one intensive care units (ICUs) were included in forty-seven countries. Overall, 51% (n = 1128) of patients received an adequate antimicrobial therapy and the 28-day mortality was 38% (n = 839). The availability of therapeutic drug monitoring (TDM) for aminoglycosides everyday [odds ratio (OR) 1.48, 95% confidence interval (CI) 1.03–2.14] or within a few hours (OR 1.79, 95% CI 1.34–2.38), surveillance cultures for multidrug-resistant organism carriage performed weekly (OR 1.45, 95% CI 1.09–1.93), and increasing Human Development Index (HDI) values were associated with adequate antimicrobial therapy. The presence of intermediate care beds (OR 0.63, 95% CI 0.47–0.84), TDM for aminoglycoside available everyday (OR 0.66, 95% CI 0.44–1.00) or within a few hours (OR 0.51, 95% CI 0.37–0.70), 24/7 consultation of clinical pharmacists (OR 0.67, 95% CI 0.47–0.95), percentage of vancomycin-resistant enterococci (VRE) between 10% and 25% in the ICU (OR 1.67, 95% CI 1.00–2.80), and decreasing HDI values were associated with 28-day mortality. Conclusion: Centre/country factors should be targeted for future interventions to improve management strategies and outcome of HABSI in ICU patients. [ABSTRACT FROM AUTHOR]

Expedited market access for novel and efficacious drugs is warranted for patients. Since 2020, Swissmedic (The Swiss Agency for Therapeutic Products) has been participating in Project Orbis, a collaborative parallel-review programme launched by the US Food and Drug Administration (FDA) in 2019 to expedite patient access to cancer drugs. This programme allows regulatory agencies to remain independent in their decisions. We aimed to evaluate the effect of the first 2 years of Project Orbis from the Swissmedic perspective. In this comparative analysis, we compared submission gap (time between submission at the FDA and Swissmedic), review time, approval and consensus decision rate, and the approved indications between Swissmedic and the FDA for marketing authorisation applications (MAAs) in oncology submitted to Swissmedic through Project Orbis (Orbis MAAs) or outside of Project Orbis (non-Orbis MAAs) from Jan 1, 2020, to Dec 31, 2021. Swissmedic review time was evaluated with a decision until June 30, 2022. For the decision comparison analysis, non-Orbis oncology MAAs submitted and evaluated from Jan 1, 2009, to Dec 31, 2018 (referred to as the pre-Orbis era) were also considered. Inferential statistics were done using Wilcoxon rank-sum test and the 95% CI for the median was based on binomial distribution. For each hypothesis testing, the significance level was set to 5%. No correction for multiple testing was performed. We analysed the submission gap, review time, and regulatory decision for 31 Orbis MAAs and 41 non-Orbis MAAs during the Orbis era. The median submission gap was 33·0 days (95% CI 19·0–57·0) for Orbis MAAs versus 168·0 days (56·0–351·0) for non-Orbis MAAs (p<0·0001). The median review time at Swissmedic was 235·5 days (198·0–264·0) for Orbis MAAs versus 314·0 days (279·0–354·0) for non-Orbis MAAs (p=0·0002). Approval rates at Swissmedic were consistent between Orbis MAAs (20 [77%] of 26) and non-Orbis MAAs (31 [76%] of 41). The rate of consensus decisions between Swissmedic and the FDA was 21 (81%) of 26 for Orbis MAAs and 31 (76%) of 41 for non-Orbis MAAs. Swissmedic approval rates were lower for indication extensions than for new active substances for Orbis MAAs (13 [72%] of 18 vs seven [88%] of eight) and non-Orbis MAAs (17 [71%] of 24 vs 14 [82%] of 17). Divergent decisions between agencies were predominantly observed for indication extensions (11 [73%] of 15 divergent decisions). During the pre-Orbis era, Swissmedic approved 61 (88%) of 69 MAAs for new active substances. Submission gap and review time for oncology applications at Swissmedic were significantly reduced by participation in Project Orbis, and approval consensus decisions were increased between agencies. These findings suggests that participating in Project Orbis could lead to faster patient access to drugs. None. [ABSTRACT FROM AUTHOR]

Heart failure poses a global health challenge affecting millions of individuals, and access to guideline-directed medical therapy is often limited. This limitation is frequently attributed to factors such as drug availability, slow adoption, clinical inertia, and delayed diagnosis. Despite international recommendations promoting the use of guideline-directed medical therapy for heart failure management, personalized approaches are essential in settings with resource constraints. In India, crucial treatments like angiotensin II receptor blocker neprilysin inhibitors and sodium-glucose co-transporter 2 inhibitors are not fully utilized despite their established safety and efficacy. To address this issue, an expert consensus involving 150 specialists, including cardiologists, nephrologists, and endocrinologists, was convened. They deliberated on patient profiles, monitoring, and adverse side effects and provided tailored recommendations for guideline-directed medical therapy in heart failure management. Stressing the significance of early initiation of guideline-directed medical therapy in patients with heart failure, especially with sodium-glucose co-transporter 2 inhibitors, the consensus also explored innovative therapies like vericiguat. To improve heart failure outcomes in resource-limited settings, the experts proposed several measures, including enhanced patient education, cardiac rehabilitation, improved drug access, and reforms in healthcare policies. [ABSTRACT FROM AUTHOR]

Physiologically based pharmacokinetic (PBPK) modelling in pregnancy is a relatively new approach that is increasingly being used to assess drug systemic exposure in pregnant women to potentially inform dosing adjustments. Physiological changes throughout pregnancy are incorporated into mathematical models to simulate drug disposition in the maternal and fetal compartments as well as the transfer of drugs across the placenta. This mini‐review gathers currently available pregnancy PBPK models for drugs commonly used during pregnancy. In addition, information about the main PBPK modelling platforms used, metabolism pathways, drug transporters, data availability and drug labels were collected. The aim of this mini‐review is to provide a concise overview, demonstrate trends in the field, highlight understudied areas and identify current gaps of PBPK modelling in pregnancy. Possible future applications of this PBPK approach are discussed from a clinical, regulatory and industry perspective. [ABSTRACT FROM AUTHOR]

Background: In 2016, Uganda added Hydroxyurea (HU) to the list of essential drugs to treat sickle cell disease SCD. However, Hydroxyurea utilization has been low for several countries in sub-Saharan Africa. This study examined patient-related barriers to hydroxyurea use among adolescent and adult patients with sickle cell disease in Mulago and Kiruddu hospitals, in Uganda. Methods: To understand the patient-related barriers to hydroxyurea use among adolescent and adult patients with sickle cell disease, we conducted a parallel convergent mixed methods study at outpatient departments of two national referral hospitals in Uganda from October 2022 to January 2023. The cross-sectional mixed-methods study employed both quantitative and qualitative methods. We collected survey data from a systematic sample of 259 participants and conducted individual interviews with a purposive sample of 40 participants (20 adolescents or their caregivers and 20 adult patients with SCD) and interviewed them individually on their knowledge, perceptions, barriers, and facilitators of HU utilization. Descriptive data were analyzed using Stata 16, whereas qualitative data were analyzed thematically using an inductive approach supported by NVivo 12 software. We triangulated data to determine the concordance of qualitative and quantitative data. Results: The study enrolled 40 participants for qualitative interviews and 259 patients for quantitative, with an average age of 16, over half being female, 46% having secondary education, and 96% unmarried. The prevalence of HU use was 78%. The study identified three themes as follows: Patient barriers at the individual including Inadequate knowledge about HU, Persistent pain, Poor adherence to HU, Poor communication with health care workers, and Psychosocial and emotional challenges. At the facility level, long queues and poor quality of care, drug-related side effects that affect HU, and drug stock-outs were reported. Myths, rumors, and misconceptions about HU, and gender-related barriers were reported to affect HU utilization at a community level. Facilitators for the use of HU and recommendations for improvement. Facilitators included perceived benefits, long duration on HU, information sharing by healthcare workers, availability of complementary drugs, confirmation of diagnosis, and availability of medication at public health facilities or private pharmacies. Patients suggested continuous adherence support, encouragement from healthcare workers, sensitization about benefits and risks, a peer-to-peer approach, and financial support for adolescents and women to start businesses to resolve financial problems. Conclusion: Implementing the use of HU has been challenging in Uganda and needs improvement. Facilitators to hydroxyurea use have been highlighted, though Patient-identified barriers at individual, facility, and community levels that need to be resolved. The experiences and insights shared by our participants provide invaluable guidance for increasing the uptake of HU. Further studies are needed to establish validated instruments to assess patients' pain communication and adherence to the HU regimen. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Drug-associated cues and drug dosage contribute to increased opioid seeking after abstinence" published in Scientific Reports. The original article contained errors in Figures 1, 2, and 5, including incorrect figure legends and reversed histograms. The correction provides the correct versions of the figures and legends. The article explores the impact of drug cues and dosage on opioid seeking behavior after a period of abstinence. [Extracted from the article]

Background: The National Drug Price Negotiation (NDPN) policy has entered a normalisation stage, aiming to alleviate, to some extent, the disease-related and economic burdens experienced by cancer patients. This study analysed the use and subsequent burden of anticancer medicines among cancer patients in a first-tier city in northeast China. Methods: We assessed the usage of 64 negotiated anticancer medicines using the data on the actual drug deployment situation, the frequency of medical insurance claims and actual medication costs. The affordability of these medicines was measured using the catastrophic health expenditure (CHE) incidence and intensity of occurrence. Finally, we used the defined daily doses (DDDs) and defined daily doses cost (DDDc) as indicators to evaluate the actual use of these medicines in the region. Results: During the study period, 63 of the 64 medicines were readily available. From the perspective of drug usage, the frequency of medical insurance claims for negotiated anticancer medicines and medication costs showed an increasing trend from 2018 to 2021. Cancer patients typically sought medical treatment at tertiary hospitals and purchased medicines at community pharmacies. The overall quantity and cost of medications for patients covered by the Urban Employee Basic Medical Insurance (UEBMI) were five times higher than those covered by the Urban and Rural Resident Medical Insurance (URRMI). The frequency of medical insurance claims and medication costs were highest for lung and breast cancer patients. Furthermore, from 2018 to 2021, CHE incidence showed a decreasing trend (2.85–1.60%) under urban patients' payment capability level, but an increasing trend (11.94%–18.42) under rural patients' payment capability level. The average occurrence intensities for urban (0.55–1.26 times) and rural (1.27–1.74 times) patients showed an increasing trend. From the perspective of drug utilisation, the overall DDD of negotiated anticancer medicines showed an increasing trend, while the DDDc exhibited a decreasing trend. Conclusion: This study demonstrates that access to drugs for urban cancer patients has improved. However, patients' medical behaviours are affected by some factors such as hospital level and type of medical insurance. In the future, the Chinese Department of Health Insurance Management should further improve its work in promoting the fairness of medical resource distribution and strengthen its supervision of the nation's health insurance funds. [ABSTRACT FROM AUTHOR]

Background: In recent years, a significant understanding of delivering optimal aerosol therapy and the availability of various drugs and devices have led to an increase in its use in clinical practice. There are only a few studies available regarding their use in critically ill patients from a few parts of the world. We aimed to study the practice pattern of aerosol therapy in critically ill patients from Indian intensive care units (ICUs). Methods: After ethical approval, this multi-centric prospective observational study was performed over a study period of four weeks. Newly admitted adult patients considered who had an artificial airway and/or ventilation (including non-invasive). Patients were followed up for the next 14 days or until ICU discharge/death (whichever came first) for details of each aerosol therapy, including ongoing respiratory support, drug type, and aerosol-generating device. Results: From the nine participating centers across India, 218 patients were enrolled. Of 218 enrolled patients, 72.48% received 4884 aerosols with 30.91 ± 27.15 (95%CI: 26.6-35.1) aerosols per patient over 1108 patient days. Approximately 62.7% during IMV, 30.2% during NIV, 2.3% in spontaneously breathing patients with an artificial airway during weaning, and 4.7% were given without an artificial airway after weaning or decannulation. In 59%, a single drug was used, and bronchodilators were the most frequent. The jet nebulizer was the most common, followed by the ultrasonic and vibrating mesh aerosol generator. The ventilator setting was changed in only 6.6% of the aerosol sessions with IMV and none with NIV. Conclusion: Aerosol therapy is frequently used with a wide variation in practices; bronchodilators are the most commonly used drugs, and jet nebulizers are the most widely used. [ABSTRACT FROM AUTHOR]

The article celebrates National Institute on Drug Abuse's 50 years of groundbreaking research on drugs and addiction, highlighting major advancements in understanding addiction's neurobiology, development of evidence-based prevention strategies, and innovative treatments including medications, immunotherapies, and neuromodulation. Topics include advances in addiction science, evidence-based prevention strategies, and innovative treatments like medications, immunotherapies, and neuromodulation.

The prevention and treatment of addiction (moderate to severe substance use disorder—SUD) have remained challenging because of the dynamic and complex interactions between multiple biological and social determinants that shape SUD. The pharmacological landscape is ever changing and the use of multiple drugs is increasingly common, requiring an unraveling of pharmacological interactions to understand the effects. There are different stages in the trajectory from drug use to addiction that are characterized by distinct cognitive and emotional features. These are directed by different neurobiological processes that require identification and characterization including those that underlie the high co-morbidity with other disorders. Finally, there is substantial individual variability in the susceptibility to develop SUD because there are multiple determinants, including genetics, sex, developmental trajectories and times of drug exposures, and psychosocial and environmental factors including commercial determinants that influence drug availability. Elucidating how these factors interact to determine risk is essential for identifying the biobehavioral basis of addiction and developing prevention and treatment strategies. Basic research is tasked with addressing each of these challenges. The recent proliferation of technological advances that allow for genetic manipulation, visualization of molecular reactions and cellular activity in vivo, multiscale whole brain mapping across the life span, and the mining of massive data sets including multimodality human brain imaging are accelerating our ability to understand how the brain functions and how drugs influence it. Here, we highlight how the application of these tools to the study of addiction promises to illuminate its neurobiological basis and guide strategies for prevention and treatment. [ABSTRACT FROM AUTHOR]

The article discusses the progress made in eliminating human African trypanosomiasis (HAT), a disease caused by Trypanosoma brucei gambiense. The incidence of HAT has remained below 1,000 new cases reported annually for the past five years, a significant achievement considering the estimated 300,000 people infected at the turn of the century. Seven out of 36 countries in sub-Saharan Africa have been validated by the World Health Organization (WHO) as having eliminated the disease as a public health problem. However, there are challenges in sustaining the elimination efforts, including the impact of the COVID-19 pandemic, funding constraints, and the need for robust surveillance. The article also discusses the importance of case detection, the availability of medicines for treatment, and tsetse fly control in the elimination campaign. The development of new tools, such as fexinidazole and acoziborole, shows promise in advancing the elimination efforts. The article emphasizes the need for continued collaboration and coordination among stakeholders to overcome the remaining hurdles and achieve the goal of eliminating HAT. [Extracted from the article]

Therapeutic approaches for triple-negative breast cancer (TNBC) have been continuously advancing, but inadequate control over release behavior, insufficient tumor selectivity, and limited drug availability continue to impede therapeutic outcomes in nanodrug systems. In this study, we propose a general hydrophobic antineoplastic delivery system, termed s patiotemporally- c ontrolled h ydrophobic a ntineoplastic d elivery s ystem (SCHADS) for enhanced TNBC treatment. The key feature of SCHADS is the formation of metastable photosensitive-antineoplastic complexes (PACs) through the self-assembly of hydrophobic drugs driven by photosensitive molecules. With the further decoration of tumor-targeting peptides coupled with the EPR effect, the PACs tend to accumulate in the tumor site tremendously, promoting drug delivery efficiency. Meanwhile, the disassembly behavior of the metastable PACs could be driven by light on demand to achieve in situ drug release, thus promoting chemotherapeutics availability. Furthermore, the abundant ROS generated by the photosensitizer could effectively kill tumor cells, ultimately realizing an effective combination of photodynamic and chemotherapeutic therapy. As an exemplary presentation, chlorin e6 has been chosen to drive the formation of PACs with the system xc− inhibitor sorafenib. Compared with pure drug treatment, the PACs with the above-described preponderances exhibit superior therapeutic effects both in vitro and in vivo and circumvent the side effects due to off-target. By manipulating the laser irradiation, the PACs-treated cell death mechanism could be dynamically regulated, thus providing the potential to remedy intrinsic/acquired resistance of tumor. Collectively, this SCHADS achieves spatio-temporal control of the drug that greatly enhances the availability of anticarcinogen and realizes synergistic antitumor effect in TNBC treatment, even ultimately being extended to the treatment of other types of tumors. A universal spatiotemporally-controlled hydrophobic antineoplastic delivery system via a photosensitizer-driven assembly-disassembly process was developed for enhanced treatment of TNBC. The photosensitive-antineoplastic complexes (PACs) could be precisely delivered to the tumor site via targeted guiding and EPR effect. In the presence of light, PACs disassemble in tumor sites leading to enhanced drug availability in situ. Notably, the photosensitive molecule generates abundant ROS and the antineoplastic drug suppresses GSH biosynthesis, achieving a synergistic therapeutic effect. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Dermatophytosis is a common and major public health concern worldwide. Despite the increasing availability of antifungal drugs, relapses and untreated cases of dermatophyte infections are reported. Therefore, novel antifungal agents are required. Aminopyrrolnitrin (APRN) shows promise for dermatophytosis treatment because of its antifungal activity. Objectives: This study aimed to assess the antifungal properties of APRN against Trichophyton verrucosum (T. verrucosum), in both laboratory settings and a guinea pig model. Methods: The minimum inhibitory concentrations (MICs) of APRN and enilconazole against T. verrucosum were determined according to the CLSI M38 method. The skins of 16 male guinea pigs were infected with 1.0 × 108 conidia of T. verrucosum and the animals were grouped into sets of four: negative control group (NC) received normal saline; positive control group (PC) received 2 μg/mL of enilconazole; and APRN4 and APRN8 received 4 and 8 μg/mL of APRN, respectively. Clinical, mycological and histological efficacies were measured after 10 days. Results: The MIC90 of APRN and enilconazole against T. verrucosum was 4 and 2 μg/mL, respectively. The clinical scores of PC, APRN4, and APRN8 were significantly lower than those of NC. Clinical and mycological efficacies were higher for APRN8, APRN4 and PC. No fungi were observed in the skin tissues of APRN4 and APRN8, while fungi were observed in 50% of the PC. Conclusion: APRN showed antifungal activity against T. verrucosum in vitro and in vivo and is a potential candidate for the treatment of dermatophytosis. [ABSTRACT FROM AUTHOR]

Background: An ambitious reform of the early access (EA) process was set up in July 2021 in France, aiming to simplify procedures and accelerate access to innovative drugs. Objective: This study analyzes the characteristics of oncology drug approvals through the EA process and its impact on real-life data for oncology patients. Methods: The number and characteristics of EA demands concerning oncology drugs submitted to the National Health Authority (HAS, Haute Autorité de Santé) were reviewed until 31 December 2022. A longitudinal retrospective study on patients treated with an EA oncology drug between 1 January 2019 and 31 December 2022 was also performed using the French nationwide claims database (Systeme National des Données de Santé [SNDS]) to assess the impact of the reform on the number of indications and patients, and the costs. Results: Among 110 published decisions, the HAS granted 88 (80%) EA indications within 70 days of assessment on average, including 46 (52%) in oncology (67% in solid tumors and 33% in hematological malignancies). Approved indications were mostly supported by randomized phase III trials (67%), whereas refused EA relied more on non-randomized (57%) trials. Overall survival was the primary endpoint of 28% of EA approvals versus none of denied EAs. In the SNDS data, the annual number of patients with cancer treated with an EA drug increased from 3137 patients in 2019 to 18,341 in 2022 (+ 484%), whereas the number of indications rose from 12 to 62, mainly in oncohematology (n = 17), lung (n = 12), digestive (n = 9) and breast cancer (n = 9). Reimbursement costs for EA treatments surged from €42 to €526 million (+ 1159%). Conclusion: The French EA reform contributed to enabling rapid access to innovations in a wide range of indications for oncology patients. However, the findings highlight ongoing challenges in financial sustainability, warranting continued evaluation and adjustments. [ABSTRACT FROM AUTHOR]

This article discusses the use of fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, in combination with other treatments for relapsed chronic immune thrombocytopenia (ITP). ITP is an autoimmune disorder characterized by low platelet counts. The study analyzed 15 adult patients who received fostamatinib in combination with prednisone or thrombopoietin receptor agonists (TPO-RAs). The results showed that the combination therapy was effective in achieving a response in 80% of patients, with 73% achieving a complete response. The treatment was generally well-tolerated, with no severe adverse events reported. However, further research is needed to determine the optimal schedule and feasibility of these combinations. [Extracted from the article]

Background: Since 2005, the healthcare system in Ethiopia has implemented policies to promote the provision of free maternal healthcare services. The primary goal of these policies is to enhance the accessibility of maternity care for women from various socioeconomic backgrounds. Additionally, the aim is to increase the utilization of maternity services, such as institutional deliveries, by removing financial obstacles that pregnant women may face. Even though maternity services are free of charge. The hidden cost has unquestionably been a key obstacle in seeking and utilizing health care services. Significant payments due to delivery services could create a heavy economic burden on households. Objectives: To determine the hidden cost of hospital-based delivery and associated factors among postpartum women attending public hospitals in Gamo zone, southern Ethiopia 2023. Methods: A facility-based cross-sectional study was conducted on 411 postpartum women in Gamo Zone Public Health Hospitals from December 1, 2022, to January 30, 2023. The systematic sampling technique was applied to reach study units. Data was collected using the Kobo Toolbox Data Collection Tool and exported to SPSS statistical software version 27 for analysis. Simple linear regression and multiple linear regression were done to see the association of variables. The significance level was declared at a P-value < 0.05 in the final model. Result: The median hidden cost of hospital-based delivery was 1142 Ethiopian birr (ETB), with a range (Q) of 2262 (504–2766) ETB. Monthly income of the family (β = 0.019), obstetrics complications (β = 0.033), distance from the health facility (β = 0.003), and mode of delivery (β = 0.072), were positively associated with the hidden cost of hospital-based delivery. While, rural residence (β = −0.041) was negatively associated with the outcome variable. Conclusion: This study showed the hidden cost of hospital based delivery was relatively high. Residence, monthly income of the family, obstetric complications, mode of delivery, and distance from the health facility were statistically significant. It is important to take these factors into account when designing health intervention programs and hospitals should prioritize the availability of essential drugs and medical supplies within their facilities to address direct medical costs in hospitals. [ABSTRACT FROM AUTHOR]

One major obstacle in the drug treatment of pancreatic ductal adenocarcinoma (PDAC) is its highly fibrotic tumor microenvironment, which is replete with activated pancreatic stellate cells (a‐PSCs). These a‐PSCs generate abundant extracellular matrix and secrete various cytokines to form biophysical and biochemical barriers, impeding drug access to tumor tissues. Therefore, it is imperative to develop a strategy for reversing PSC activation and thereby removing the barriers to facilitate PDAC drug treatment. Herein, by integrating chromatin immunoprecipitation (ChIP)‐seq, Assays for Transposase‐Accessible Chromatin (ATAC)‐seq, and RNA‐seq techniques, this work reveals that super‐enhancers (SEs) promote the expression of various genes involved in PSC activation. Disruption of SE‐associated transcription with JQ1 reverses the activated phenotype of a‐PSCs and decreases stromal fibrosis in both orthotopic and patient‐derived xenograft (PDX) models. More importantly, disruption of SEs by JQ1 treatments promotes vascularization, facilitates drug delivery, and alters the immune landscape in PDAC, thereby improving the efficacies of both chemotherapy (with gemcitabine) and immunotherapy (with IL‐12). In summary, this study not only elucidates the contribution of SEs of a‐PSCs in shaping the PDAC tumor microenvironment but also highlights that targeting SEs in a‐PSCs may become a gate‐opening strategy that benefits PDAC drug therapy by removing stromal barriers. [ABSTRACT FROM AUTHOR]

The logistics management information system (LMIS) plays a crucial role in effective record-keeping and reporting, ensuring efficient management of stock status and consumption data. A proficient LMIS improves accountability and supports informed logistic decisions in healthcare. Conversely, a subpar LMIS negatively affects essential medicine availability, compromising overall healthcare service efficiency. This study aimed to evaluate the status of the logistics management information system and the availability of non-program tracer drugs (NPTDs) in public health facilities within Bahir Dar City. This study employed an institutional-based cross-sectional study. Data were collected from February 20 to April 30, 2022 in 12 public health facilities located in Bahir Dar City. Structured questionnaire and data abstraction formats were used to gather pertinent data. After checking for completeness, the data were analyzed using Microsoft Excel and SPSS version 23. The primary analytical outcomes involved descriptive statistics, encompassing frequencies, averages, and percentages, which were subsequently presented in tables and figures. Bin card and Internal Facility Report and Resupply Form were the only blank LMIS tools available in all health facilities, while stock-record card was the least available, present in only 2(16.7%) facilities. Nine health facilities (75%) used self-prepared forms to request NPTDs from the Ethiopian Pharmaceutical Supply Agency (EPSA) at the end of the review period, whereas 7(58.3%) used official letters for emergency orders. Additionally, seven health facilities (58.3%) used the Health Commodities Management Information System On the day of the visit, 78.68% of NPTDs were available. Tetracycline eye ointment 1% had the longest stock-out duration, lasting for a mean 69.64 days. Rather than using the RRF, most of facilities opted for their own forms to request NPTDs from EPSA. While it is advisable for all health facilities to maintain continuous availability of tracer drugs, this study revealed that the current state of non-program tracer drug availability falls short of meeting this expectation. [ABSTRACT FROM AUTHOR]

Background: The co-administration of drugs known to interact greatly impacts morbidity, mortality, and health economics. This study aims to examine the drug–drug interaction (DDI) phenomenon with a large-scale longitudinal analysis of age and gender differences found in drug administration data from three distinct healthcare systems. Methods: This study analyzes drug administrations from population-wide electronic health records in Blumenau (Brazil; 133 K individuals), Catalonia (Spain; 5.5 M individuals), and Indianapolis (USA; 264 K individuals). The stratified prevalences of DDI for multiple severity levels per patient gender and age at the time of administration are computed, and null models are used to estimate the expected impact of polypharmacy on DDI prevalence. Finally, to study actionable strategies to reduce DDI prevalence, alternative polypharmacy regimens using drugs with fewer known interactions are simulated. Results: A large prevalence of co-administration of drugs known to interact is found in all populations, affecting 12.51%, 12.12%, and 10.06% of individuals in Blumenau, Indianapolis, and Catalonia, respectively. Despite very different healthcare systems and drug availability, the increasing prevalence of DDI as patients age is very similar across all three populations and is not explained solely by higher co-administration rates in the elderly. In general, the prevalence of DDI is significantly higher in women — with the exception of men over 50 years old in Indianapolis. Finally, we show that using proton pump inhibitor alternatives to omeprazole (the drug involved in more co-administrations in Catalonia and Blumenau), the proportion of patients that are administered known DDI can be reduced by up to 21% in both Blumenau and Catalonia and 2% in Indianapolis. Conclusions: DDI administration has a high incidence in society, regardless of geographic, population, and healthcare management differences. Although DDI prevalence increases with age, our analysis points to a complex phenomenon that is much more prevalent than expected, suggesting comorbidities as key drivers of the increase. Furthermore, the gender differences observed in most age groups across populations are concerning in regard to gender equity in healthcare. Finally, our study exemplifies how electronic health records' analysis can lead to actionable interventions that significantly reduce the administration of known DDI and its associated human and economic costs. [ABSTRACT FROM AUTHOR]

The objective of this study was to prepare and evaluate sodium alginate microbeads with calcium chloride as cross-linking agent for Clonidinehydrochloride by ionotropic gelation method. Clonidine hydrochloride a centrally acting sympatholytic and imidazoline-derivative hypotensiveagent; selective α2-adrenergic agonist. It stimulates alpha2-adrenergic receptors in the brainstem to decrease sympathetic nervous system outflow. It is also administered epidurally to treat pain. Microbeads offer numerous advantages for releasing one of the drugs or part of the samedrug immediately while remaining drug or parts of the same can be sustained release. Prepared microbeads were evaluated for particle size,polydispersity index, zeta potential, particle shape, surface morphology, entrapment efficiency and In-vitro drug release. The prepared beads were free flowing and white in colour. The drug loaded beads showed 72.9±2.4% to 94.6±2.6% drug entrapment, which was found to increase with increase in alginate concentration. In vitro drug release study of these microbeads indicated controlled release for Clonidine hydrochloride 83.46% release after 48 hours. Hence the observations of all results of the different batches, MBD 11 showed controlled release action and improved drug availability. From this study it could be concluded that the free flowing micro beads of Clonidine hydro chloride could be successfully prepared by ionotropic gelation technique with high entrapment efficiency and prolonged release characteristics. [ABSTRACT FROM AUTHOR]

Essential medicines or drugs are recognized as highly cost-effective components within contemporary healthcare, demonstrating significant potential for improving health outcomes. The provision of essential medicines directly impacts the functioning of healthcare facilities, resulting in financial hardship. This review aims to fill knowledge gaps by examining obstacles hindering access and utilization of essential medicines in India. This study conducted a comprehensive evidence synthesis, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to analyse articles on the availability and utilization of essential medicines in India. The search strategy included various databases and keywords. Published, peer-reviewed articles focusing on the National/State List of Essential Medicines and meeting specific criteria were considered. Data items included essential medicines, drug availability, utilization, and challenges. Data was extracted, synthesized, and analysed using thematic framework analysis. Out of 1,129 articles, 11 were selected for review. Studies consistently highlighted the inadequate availability of essential medicines in different Indian states. Availability of essential medicines varies in the range of 17-51 percent across major states of India. Stock-outs of medicines vary from 4 to 14 weeks. Governance issues including differential procurement mechanisms across states of India, hinder seamless availability of essential medicines. Other challenges included distribution and purchasing system inefficiencies, governance-related issues, and facility/user-level challenges impacting drug utilization. Disruptions in utilization were observed due to improper prescription practices and non-availability of affordable options. Accessibility and affordability also affected drug utilization. Issues with supply chain management and conflicting guidelines further contributed to the obstacles faced in ensuring availability and utilization of essential medicines in India. Ensuring the availability, accessibility, and affordability of essential medicines is of utmost importance. The public health system needs to strengthen its procurement and distribution management. Strengthening the logistics support for an efficient supply of essential medicines will reduce the time lag in receipt of drugs. Guidelines on essential drugs prepared by the National Health System Resource Centre need to be strictly adhered to and monitored in inventory management system. There is an urgent need to develop a sustainable model for achieving uniformity in the availability and utilization of essential medicines in India. [ABSTRACT FROM AUTHOR]

Combination therapy using two or more drugs with different mechanisms of action is an effective strategy for treating cancer. This is because of the synergistic effect of complementary drugs that enhances their effectiveness. However, this approach has some limitations, such as non-specific distribution of the drugs in the tumor and the occurrence of dose-dependent toxicity to healthy tissues. To overcome these issues, we have developed a folate receptor-mediated co-delivery system that improves the access of chemotherapy drugs to the tumor site. We prepared a nanoplatform by encapsulating paclitaxel (PTX) and curcumin (CUR) in poly(caprolactone)-poly(ethylene glycol)-poly(caprolactone) (PCL-PEG-PCL) co-polymer using a double emulsion method and coating nanoparticles with pH-responsive chitosan-folic acid (CS-FA) conjugate. The nanocarrier's physicochemical properties were studied, confirming successful preparation with appropriate size and morphology. PTX and CUR could be released synchronously in a controlled and acid-facilitated manner. The dual drug-loaded nanocarrier exhibited excellent anti-tumor efficiency in MDA-MB-231 cells in vitro. The active targeting effect of FA concluded from the high inhibitory effect of dual drug-loaded nanocarrier on MDA-MB-231 cells, which have overexpressed folate receptors on their surface, compared to Human umbilical vein endothelial cells (HUVEC). Overall, the nanoengineered folate receptor-mediated co-delivery system provides great potential for safe and effective cancer therapy. [ABSTRACT FROM AUTHOR]

Background Managing drug–food interactions may help to achieve the optimal action and safety profile of β-lactam antibiotics. Methods We conducted a systematic review with meta-analyses in adherence to PRISMA guidelines for 32 β-lactams. We included 166 studies assessing the impact of food, beverages, antacids or mineral supplements on the pharmacokinetic (PK) parameters or PK/pharmacodynamic (PK/PD) indices. Results Eighteen of 25 β-lactams for which data on food impact were available had clinically important interactions. We observed the highest negative influence of food (AUC or C max decreased by >40%) for ampicillin, cefaclor (immediate-release formulations), cefroxadine, cefradine, cloxacillin, oxacillin, penicillin V (liquid formulations and tablets) and sultamicillin, whereas the highest positive influence (AUC or C max increased by >45%) for cefditoren pivoxil, cefuroxime and tebipenem pivoxil (extended-release tablets). Significantly lower bioavailability in the presence of antacids or mineral supplements occurred for 4 of 13 analysed β-lactams, with the highest negative impact for cefdinir (with iron salts) and moderate for cefpodoxime proxetil (with antacids). Data on beverage impact were limited to 11 antibiotics. With milk, the extent of absorption was decreased by >40% for cefalexin, cefradine, penicillin G and penicillin V, whereas it was moderately increased for cefuroxime. No significant interaction occurred with cranberry juice for two tested drugs (amoxicillin and cefaclor). Conclusions Factors such as physicochemical features of antibiotics, drug formulation, type of intervention, and patient's health state may influence interactions. Due to the poor actuality and diverse methodology of included studies and unproportionate data availability for individual drugs, we judged the quality of evidence as low. [ABSTRACT FROM AUTHOR]

Background: Allergic diseases typically refer to a heterogeneous group of conditions primarily caused by the activation of mast cells or eosinophils, including atopic dermatitis (AD), allergic rhinitis (AR), and asthma. Asthma, AR, and AD collectively affect approximately one‐fifth of the global population, imposing a significant economic burden on society. Despite the availability of drugs to treat allergic diseases, they have been shown to be insufficient in controlling relapses and halting disease progression. Therefore, new drug targets are needed to prevent the onset of allergic diseases. Method: We employed a Mendelian randomization approach to identify potential drug targets for the treatment of allergic diseases. Leveraging 1798 genetic instruments for 1537 plasma proteins from the latest reported Genome‐Wide Association Studies (GWAS), we analyzed the GWAS summary statistics of Ferreira MA et al. (nCase = 180,129, nControl = 180,709) using the Mendelian randomization method. Furthermore, we validated our findings in the GWAS data from the FinnGen and UK Biobank cohorts. Subsequently, we conducted sensitivity tests through reverse causal analysis, Bayesian colocalization analysis, and phenotype scanning. Additionally, we performed protein‐protein interaction analysis to determine the interaction between causal proteins. Finally, based on the potential protein targets, we conducted molecular docking to identify potential drugs for the treatment of allergic diseases. Results: At Bonferroni significance (p < 3.25 × 10−5), the Mendelian randomization analysis revealed 11 significantly associated protein‐allergic disease pairs. Among these, the increased levels of TNFAIP3, ERBB3, TLR1, and IL1RL2 proteins were associated with a reduced risk of allergic diseases, with corresponding odds ratios of 0.82 (0.76–0.88), 0.74 (0.66–0.82), 0.49 (0.45–0.55), and 0.81 (0.75–0.87), respectively. Conversely, increased levels of IL6R, IL1R1, ITPKA, IL1RL1, KYNU, LAYN, and LRP11 proteins were linked to an elevated risk of allergic diseases, with corresponding odds ratios of 1.04 (1.03–1.05), 1.25 (1.18–1.34), 1.48 (1.25–1.75), 1.14 (1.11–1.18), 1.09 (1.05–1.12), 1.96 (1.56–2.47), and 1.05 (1.03–1.07), respectively. Bayesian colocalization analysis suggested that LAYN (coloc.abf‐PPH4 = 0.819) and TNFAIP3 (coloc.abf‐PPH4 = 0.930) share the same variant associated with allergic diseases. Conclusions: Our study demonstrates a causal association between the expression levels of TNFAIP3 and LAYN and the risk of allergic diseases, suggesting them as potential drug targets for these conditions, warranting further clinical investigation. [ABSTRACT FROM AUTHOR]

Drug efflux transporters of the ATP-binding-cassette superfamily play a major role in the availability and concentration of drugs at their site of action. ABCC2 (MRP2) and ABCG2 (BCRP) are among the most important drug transporters that determine the pharmacokinetics of many drugs and whose overexpression is associated with cancer chemoresistance. ABCC2 and ABCG2 expression is frequently altered during treatment, thus influencing efficacy and toxicity. Currently, there are no routine approaches available to closely monitor transporter expression. Here, we developed and validated a UPLC-MS/MS method to quantify ABCC2 and ABCG2 in extracellular vesicles (EVs) from cell culture and plasma. In this way, an association between ABCC2 protein levels and transporter activity in HepG2 cells treated with rifampicin and hypericin and their derived EVs was observed. Although ABCG2 was detected in MCF7 cell-derived EVs, the transporter levels in the vesicles did not reflect the expression in the cells. An analysis of plasma EVs from healthy volunteers confirmed, for the first time at the protein level, the presence of both transporters in more than half of the samples. Our findings support the potential of analyzing ABC transporters, and especially ABCC2, in EVs to estimate the transporter expression in HepG2 cells. [ABSTRACT FROM AUTHOR]

Many tumors have well-defined vulnerabilities, thus potentially allowing highly specific and effective treatment. There is a spectrum of actionable genetic alterations which are shared across various tumor types and, therefore, can be targeted by a given drug irrespective of tumor histology. Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies. Multiple lines of evidence suggest that this histology-independent approach is also reasonable for tumors carrying ALK and ROS1 translocations, biallelic BRCA1/2 inactivation and/or homologous recombination deficiency (HRD), strong HER2 amplification/overexpression coupled with the absence of other MAPK pathway-activating mutations, etc. On the other hand, some well-known targets are not agnostic: for example, PD-L1 expression is predictive for the efficacy of PD-L1/PD1 inhibitors only in some but not all cancer types. Unfortunately, the individual probability of finding a druggable target in a given tumor is relatively low, even with the use of comprehensive next-generation sequencing (NGS) assays. Nevertheless, the rapidly growing utilization of NGS will significantly increase the number of patients with highly unusual or exceptionally rare tumor-target combinations. Clinical trials may provide only a framework for treatment attitudes, while the decisions for individual patients usually require case-by-case consideration of the probability of deriving benefit from agnostic versus standard therapy, drug availability, associated costs, and other circumstances. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future. [ABSTRACT FROM AUTHOR]

Purpose Despite the recent success of Bruton's tyrosine kinase (BTK) inhibitors for the treatment of Waldenstrom macroglobulinemia (WM), their indefinite treatment duration ultimately tantamount to substantial financial and emotional burden. On the other hand, fixed duration of proteasome inhibitors (PI) have shown rapid and reasonable response in WM treatment. Despite the well-known synergism between PI and immunomodulatory drugs (IMiD), there is no trials evaluating such combination in WM. Materials and Methods Based on above, we designed this phase II study to investigate the efficacy and safety of 6 cycles of 28-day bortezomib-thalidomide-dexamethasone (VTD) regimen for treatment-naïve WM. Results A total of 15 patients were enrolled: major response rate was 64.3%, and overall response rate was 78.6%. During the median follow-up of 41 months, median progression-free survival (PFS) was 13 months and overall survival 40 months. For responders, median duration of response was 13 months and median PFS 19 months. The most common adverse event (AE) of any grade was constipation (57.1%). The most common grade = 3 AE was anemia (21.4%). Conclusion All in all, we hereby provide proof-of-concept that PI + IMiD may be an attractive backbone for fixed duration treatment. It should be noted that granting the same level of access to newer drugs globally is virtually impossible. Thus efforts to develop regimens using readily available drugs to yield similar or adequate treatment outcomes should not be disregarded. In this sense, we believe our study holds its place for its novelty and eloquently addresses achieving the daunting societal quest of health equity. [ABSTRACT FROM AUTHOR]

Fks1 is a unique enzyme that makes β-1,3-glucan, a key cell wall component. Blocking Fks1 kills fungi by damaging their cell wall. Fks1 enhances fungal virulence and host infection by contributing to pathogenesis and immune response, while β-1,3-glucan is a biomarker for fungal infections. Fks1 is a promising target for new antifungal drugs. Studies on echinocandins and ibrexafungerp have identified their binding sites and action mechanisms on Fks1. Improvements in existing drugs can increase their antifungal activity. Fks1 research is essential to develop better antifungal drugs. More studies on Fks1 are needed to understand its structure, function, and interaction with antifungal agents crucial for drug optimization and design. Fungal infections are a major threat to human health. The limited availability of antifungal drugs, the emergence of drug resistance, and a growing susceptible population highlight the critical need for novel antifungal agents. The enzymes involved in fungal cell wall synthesis offer potential targets for antifungal drug development. Recent studies have enhanced our focus on the enzyme Fks1, which synthesizes β-1,3-glucan, a critical component of the cell wall. These studies provide a deeper understanding of Fks1's function in cell wall biosynthesis, pathogenicity, structural biology, evolutionary conservation across fungi, and interaction with current antifungal drugs. Here, we discuss the role of Fks1 in the survival and adaptation of fungi, guided by insights from evolutionary and structural analyses. Furthermore, we delve into the dynamics of Fks1 modulation with novel antifungal strategies and assess its potential as an antifungal drug target. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic resulted in changes in prescription patterns and fillings for certain medications, but little is known about its impact on the dispensing of cardiovascular drugs. Trends in dispensing of cardiovascular drugs before and during the pandemic were examined using a population-based cohort in Norway. Using interrupted time series analyses and considering March 1, 2020 as the interruption point, the impact of the pandemic on defined daily dose dispensing of prescribed cardiovascular drugs was estimated in a population of adults with and without pre-existing cardiovascular disease from January 2018 to December 2021. All data were analyzed in 2023. In a total of 4,053,957 adults, 690,910 (17.0%) had pre-existing cardiovascular disease. Prior to the pandemic, there was a significant monthly increase in any cardiovascular drug dispensing among those with pre-existing cardiovascular disease (0.30 defined daily dose per month per adult), including prescription of diuretics, calcium channel blockers, and lipid-modifying agents. After controlling for preinterruption trends, there was a slight decrease in level change immediately after the start of the pandemic (2.5 defined daily dose per month per adult) but an increase in the postinterruption trend (0.06 defined daily dose per month per adult) for dispensing of cardiovascular prescriptions, although these changes were not significant. Although the COVID-19 pandemic did not appear to result in significant changes in patterns of cardiovascular drug dispensing in Norway, continued access to cardiovascular drugs remains important to prevent further related morbidity. [ABSTRACT FROM AUTHOR]

Background: In recent years, stimulant use has increased among persons who use opioids in the rural U.S., leading to high rates of overdose and death. We sought to understand motivations and contexts for stimulant use among persons who use opioids in a large, geographically diverse sample of persons who use drugs (PWUD) in the rural settings. Methods: We conducted semi-structured individual interviews with PWUD at 8 U.S. sites spanning 10 states and 65 counties. Content areas included general substance use, injection drug use, changes in drug use, and harm reduction practices. We used an iterative open-coding process to comprehensively itemize and categorize content shared by participants related to concurrent use. Results: We interviewed 349 PWUD (64% male, mean age 36). Of those discussing current use of stimulants in the context of opioid use (n = 137, 39%), the stimulant most used was methamphetamine (78%) followed by cocaine/crack (26%). Motivations for co-use included: 1) change in drug markets and cost considerations; 2) recreational goals, e.g., seeking stronger effects after heightened opioid tolerance; 3) practical goals, such as a desire to balance or alleviate the effects of the other drug, including the use of stimulants to avoid/reverse opioid overdose, and/or control symptoms of opioid withdrawal; and 4) functional goals, such as being simultaneously energized and pain-free in order to remain productive for employment. Conclusion: In a rural U.S. cohort of PWUD, use of both stimulants and opioids was highly prevalent. Reasons for dual use found in the rural context compared to urban studies included changes in drug availability, functional/productivity goals, and the use of methamphetamine to offset opioid overdose. Education efforts and harm reduction services and treatment, such as access to naloxone, fentanyl test strips, and accessible drug treatment for combined opioid and stimulant use, are urgently needed in the rural U.S. to reduce overdose and other adverse outcomes. [ABSTRACT FROM AUTHOR]

Notable progress in basic, translational and clinical nephrology research has been made over the past five decades. Nonetheless, many challenges remain, including obstacles to the early detection of kidney disease, disparities in access to care and variability in responses to existing and emerging therapies. Innovations in drug development, research technologies, tissue engineering and regenerative medicine have the potential to improve patient outcomes. Exciting prospects include the availability of new drugs to slow or halt the progression of chronic kidney disease, the development of bioartificial kidneys that mimic healthy kidney functions, and tissue engineering techniques that could enable transplantable kidneys to be created from the cells of the recipient, removing the risk of rejection. Cell and gene therapies have the potential to be applied for kidney tissue regeneration and repair. In addition, about 30% of kidney disease cases are monogenic and could potentially be treated using these genetic medicine approaches. Systemic diseases that involve the kidney, such as diabetes mellitus and hypertension, might also be amenable to these treatments. Continued investment, communication, collaboration and translation of innovations are crucial to realize their full potential. In addition, increasing sophistication in exploring large datasets, implementation science, and qualitative methodologies will improve the ability to deliver transformational kidney health strategies. Despite notable progress in basic, clinical and translational nephrology research in the past 50 years, many challenges remain. In this Review, the authors provide an overview of the current status and future directions in nephrology research and patient care. Key points: In the past 5 decades, notable progress has been made in basic, translational and clinical nephrology research. Remaining challenges in nephrology include obstacles to the early detection of kidney disease, inconsistency in access to care and variability in responses to established and emerging therapies. A new approach to medical research based on close collaboration between basic and clinical scientists and clinicians is fundamental to ensure patient-centred care and improve clinical outcomes. Deeper understanding and analyses of individual patients, including use of genetic profiles, biomarkers and sophisticated imaging technologies, can aid prediction of disease progression, identify risk factors and enable tailoring of treatment plans. Promising future approaches to the treatment of kidney diseases include cell and gene therapies, xenotransplantation and bioartificial kidneys. In-depth knowledge of the values and preferences of patients, such as their treatment goals, communication preferences, cultural beliefs and financial considerations, is essential to improving kidney care; disadvantaged populations must receive specific attention to avoid widening health inequities. [ABSTRACT FROM AUTHOR]

An important public concern about the impact of recreational cannabis legalization is how it may affect adolescent cannabis use. Prior research on this issue has primarily focused on the implications of medical cannabis legalization for adolescents and used data that cover a relatively short post-legalization period. This study extends this line of research by examining the relationship between recreational cannabis legalization and adolescent cannabis use in Washington State, using the National Survey of Drug Use and Health (NSDHU) data from 2005 to 2019. Based on a quasi-experimental research design, this study found some evidence suggesting a positive effect of recreational legalization on the prevalence of adolescent cannabis use and cannabis initiation. Findings suggest the need to create a cannabis regulatory environment that minimizes adolescent access to this drug. [ABSTRACT FROM AUTHOR]

The precision oncology paradigm challenges the feasibility and data generalizability of traditional clinical trials. Consequently, an unmet need exists for practical approaches to test many subgroups, evaluate real-world drug value, and gather comprehensive, accessible datasets to validate novel biomarkers. Real-world data (RWD) are increasingly recognized to have the potential to fill this gap in research methodology. Established applications of RWD include informing disease epidemiology, pharmacovigilance, and healthcare quality assessment. Currently, concerns regarding RWD quality and comprehensiveness, privacy, and biases hamper their broader application. Nonetheless, RWD may play a pivotal role in supplementing clinical trials, enabling conditional reimbursement and accelerated drug access, and innovating trial conduct. Moreover, purpose-built RWD repositories may support the extension or refinement of drug indications and facilitate the discovery and validation of new biomarkers. This perspective explores the potential of leveraging RWD to advance oncology, highlights its benefits and challenges, and suggests a path forward in this evolving field. [ABSTRACT FROM AUTHOR]

Background: People who use drugs experience pain at two to three times the rate of the general population and yet continue to face substantial barriers to accessing appropriate and adequate treatment for pain. In light of the overdose crisis and revised opioid prescribing guidelines, we sought to identify factors associated with being denied pain medication and longitudinally investigate denial rates among people who use drugs. Methods: We used multivariable generalized estimating equations analyses to investigate factors associated with being denied pain medication among people who use drugs reporting pain in three prospective cohort studies in Vancouver, Canada. Analyses were restricted to study periods in which participants requested a prescription for pain from a healthcare provider. Descriptive statistics detail denial rates and actions taken by participants after being denied. Results: Among 1168 participants who requested a prescription for pain between December 2012 and March 2020, the median age was 47 years and 63.0% were male. Among 4,179 six-month observation periods, 907 (21.7%) included a report of being denied requested pain medication. In multivariable analyses, age was negatively associated with prescription denial (adjusted odds ratio [AOR] = 0.98, 95% confidence interval [CI]:0.97–0.99), while self-managing pain (AOR = 2.48, 95%CI:2.04–3.00), experiencing a non-fatal overdose (AOR = 1.51, 95%CI:1.22–1.88), engagement in opioid agonist therapy (AOR = 1.32, 95%CI:1.09–1.61), and daily use of heroin or other unregulated opioids (AOR = 1.32, 95%CI:1.05–1.66) were positively associated with being denied. Common actions taken (n = 895) after denial were accessing the unregulated drug supply (53.5%), doing nothing (30.6%), and going to a different doctor/emergency room (6.1%). The period following the introduction of new prescribing guidelines was not associated with a change in denial rates. Conclusions: A substantial proportion of people who use drugs continue to be denied prescriptions for pain, with such denial associated with important substance use-related harms, including non-fatal overdose. Guidelines specific to the pharmaceutical management of pain among people who use drugs are needed. [ABSTRACT FROM AUTHOR]

Objective: The debate surrounding access to medicines in Nigeria has become increasingly necessary due to the high cost of essential medicine drugs and the prevalence of counterfeit medicines in the country. The Nigerian government has proposed the implementation of the National Health Insurance Scheme (NHIS) to address these issues and guarantee universal access to essential medicines. Access was investigated using the 3 A's (accessibility, affordability, and availability). This paper investigates whether the NHIS is a viable pathway to sustained access to medicines in Nigeria. Design: This was a cross-sectional study using a mixed-methods design. Both qualitative and quantitative methods were utilized for the study. Setting: This study was conducted at NHIS-accredited public and private facilities in Enugu State. Participants: 296 randomly selected enrollees took part in the quantitative component, while, 6 participants were purposively selected for the qualitative component, where in-depth interviews (IDIs) were conducted face-to-face with NHIS desk officers in selected public and private health facilities. Results: The quantitative findings showed that 94.9% of respondents sought medical help. Our data shows that 78.4% of the respondents indicated that the scheme improved their access to care (accessibility, affordability, and availability). The qualitative results from the NHIS desk officers showed that respondents across all the socio-economic groups reported that the NHIS had marginally improved access to medicine over the years. It was also observed that most of the staff in NHIS-accredited facilities were not adequately trained on the scheme's requirements and that most times, essential drugs were not readily available at the accredited facilities. Conclusion: The study findings revealed that although the NHIS has successfully expanded access to medicines, there remain several challenges to its effective implementation and sustainability. Additionally, the scheme's coverage of essential medicines is could be improved even more, leading to reduced access to needed drugs for many Nigerians. A focus on the 3As for the scheme means that all facility categories (private and public) and their interests (where necessary) must be considered in further planning of the scheme to ensure that things work out well. [ABSTRACT FROM AUTHOR]

To eliminate multidrug-resistant bacteria of Acinetobacter baumannii, we screened 1100 Food and Drug Administration-approved small molecule drugs and accessed the broxyquinoline (Bq) efficacy in combination with various metal ions. Antibacterial tests demonstrated that the prepared Zn(Bq)2 complex showed ultralow minimum inhibitory concentration of ~0.21 micrograms per milliliter with no resistance after 30 passages. We then constructed the nano zeolitic imidazolate framework-8 (ZIF-8) as a drug carrier of Zn(Bq)2 and also incorporated the photosensitizer chlorin e6 (Ce6) to trace and boost the antibacterial effect. To further ensure the stable and targeted delivery, we genetically engineered outer membrane vesicles (OMVs) with the ability to selectively target A. baumannii. By coating the ZnBq/Ce6@ZIF-8 core with these OMV, the resulted drug (ZnBq/Ce6@ZIF-8@ OMV) exhibited exceptional killing efficacy (>99.9999999%) of A. baumannii. In addition, in vitro and in vivo tests were also respectively carried out to inspect the remarkable efficacy of this previously unknown nanodrug in eradicating A. baumannii infections, including biofilms and meningitis. [ABSTRACT FROM AUTHOR]

Background: Availability and accessibility of Antiretroviral drugs (ARV's) improve the lives of People living with HIV (PLHIV) by improving client's immune system to overcome infections and prevent the development of AIDS and other HIV complications. Combination therapy, early initiation of ART, newer ART drugs, single dosage and drug affordability significantly contribute in the reduction of viral multiplication and suppression of HIV to undetectable plasma levels. Methods: A retrospective longitudinal study design study was conducted from 1st October, 2018 to 30th June 2022 in all supported HIV care and treatment health facilities in Tanga region which were supported by Amref Health Africa, Tanzania. The participants were HIV adult patients aged 15 years and above on ART and attended the clinic at least once after ART initiation. Viral load suppression levels are defined with viral load <1,000 HIV RNA copies/ml (viral load suppression). Cox proportional hazard regression models were employed to identify risk factors for virological failure. P values were two-sided, and we considered a P<0.05 to be statistically significant. Results: Fifty-nine thousand five hundred three adult clients >15 years whom were on ART were included in the analysis to determine the level of plasma Viral Load suppression after being on ART. Female 41,304 (69.4%) and male 18,199 (30.6%). Only four percent (2,290) were found to be unsuppressed i.e having plasma Viral Load >1,000cp/ml while 96% (57,213) were virally suppressed. Several factors were independently associated with virologic failure that included; age between 15 - <25 years (HR: 2.82, 95% CI 1.96 – 4.04), BMI <18.5 (HR: 1.69, 95% CI 1.23 – 2.30), advanced WHO stage IV (HR: 1.60, 95% CI 1.12 – 2.24), CD4 cell count <350 (HR: 2.61, 95% CI 2.12 – 3.23), poor adherence (HR: 1.98, 95% CI 1.80 – 2.18) and not using DTG based drug (HR: 11.8, 95% CI 9.74 – 14.3). Conclusion: Virologic failure was observed in this study among clients with young age, advanced WHO stage IV, not using DTG based regimen, poor drug adherence and second line regime. To improve Viral Load Suppression among these clients; the existing HIV intervention strategies should be taken care by targeting the identified risk factors. [ABSTRACT FROM AUTHOR]

This article discusses the effects of opioid withdrawal on striatal dopamine levels. The study found that in laboratory rats exposed to morphine injections, extracellular dopamine concentrations decreased in the ventral striatum during withdrawal, but increased in the dorsal striatum during naloxone-triggered withdrawal. These findings suggest that withdrawal symptoms can become paired with opioid availability, enhancing the incentive salience of the drug and promoting conditioned approach. The article also explores the implications of these findings for addiction treatment, suggesting that a medication that offsets the aversive effects of withdrawal while diminishing dopamine surges could be beneficial. [Extracted from the article]

In this paper, I raise some doubts about Nicole Hassoun's account of the obligations of states, pharmaceutical firms, and consumers with regard to global health, presented in Global Health Impact. I argue that it is not necessarily the case, as Hassoun claims, that if states are just, and therefore satisfy all of their obligations, then consumers will not have strong moral reasons, and perhaps obligations, to make consumption choices that are informed by principles and requirements of justice. This is because there may be justice‐based limits on what states can permissibly and feasibly do both to promote access to existing drugs for all of those who need them, and to promote research and development for new drugs that could treat diseases that primarily affect the global poor. One important upshot of my argument is that there can be reasons for organizations like the Global Health Impact Organization to exist, and to do the kind of work that Hassoun argues is potentially valuable in our deeply unjust world, even in much less unjust worlds in which states and firms largely, or even entirely, comply with their obligations. [ABSTRACT FROM AUTHOR]

Intravenous administration of drugs is frequently employed to achieve rapid and effective systemic effects. However, it is undesirable to administer drugs into the tissue as a result of extravasation of the intravenous cannula. Both the closed extremities to which the IV route is applied due to the surgical method to be applied make it difficult to access the vascular access during surgery and the use of pressurised instruments in the administration of drugs through the IV route makes the work of the anaesthetist difficult. In addition, patients cannot report their pain due to unconsciousness. In the operating theater and intensive care unit for anesthesia practice, induction, fluid therapy, nutrition, etc., although rare, difficulty in vascular access maintenance and drug extravasation cause serious complications in many procedures. This study aimed to emphasize the importance of perioperative anesthetic drug extravasation and its physiopathology by presenting current information. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance poses a severe threat, particularly in developing countries where the ready availability of drugs and increased consumption lead to improper antibiotic usage, thereby causing a surge in resistance levels compared to developed areas. Despite the past success of antibiotics, their effectiveness diminishes with regular use, posing a significant threat to medical efficacy. Pseudomonas aeruginosa, an opportunistic pathogen, triggers various infection-related issues, occurring on occasions including chronic wounds, burn injuries, respiratory problems in cystic fibrosis, and corneal infections. Targeting the quorum sensing (QS) of P. aeruginosa emerges as a strategic approach to combat infections caused by this bacterium. The objective of this study was to check the effect of antimycobacterial drugs against the potential QS targets in P. aeruginosa and identify lead candidates. The antimycobacterial drugs were first examined for the toxicological and pharmacokinetic profile. By virtual screening through molecular docking, delamanid and pretomanid stood out as major candidates. The binding energies of delamanid and pretomanid with LasR were determined to be −8.3 and −10.9 kcal/mol, respectively. The detailed analysis of the complexes of lead compounds were examined through molecular dynamics simulations. The molecular simulations data validated a sustained interaction of lead drugs with target proteins (PqsR, LasI, and LasA) in a physiological environment. The negligible changes in the secondary structure of proteins in presence of hit antimycobacterial drugs further strengthened the stability of the complexes. These findings highlight the potential repurposing of delamanid and pretomanid, specifically in targeting P. aeruginosa quorum-sensing mechanisms. [ABSTRACT FROM AUTHOR]

Immunocompromised patients account for an increasing proportion of the typical intensive care unit (ICU) case-mix. Because of the increased availability of new drugs for cancer and auto-immune diseases, and improvement in the care of the most severely immunocompromised ICU patients (including those with hematologic malignancies), critically ill immunocompromised patients form a highly heterogeneous patient population. Furthermore, a large number of ICU patients with no apparent immunosuppression also harbor underlying conditions altering their immune response, or develop ICU-acquired immune deficiencies as a result of sepsis, trauma or major surgery. While infections are associated with significant morbidity and mortality in immunocompromised critically ill patients, little specific data are available on the incidence, microbiology, management and outcomes of ICU-acquired infections in this population. As a result, immunocompromised patients are usually excluded from trials and guidelines on the management of ICU-acquired infections. The most common ICU-acquired infections in immunocompromised patients are ventilator-associated lower respiratory tract infections (which include ventilator-associated pneumonia and tracheobronchitis) and bloodstream infections. Recently, several large observational studies have shed light on some of the epidemiological specificities of these infections—as well as on the dynamics of colonization and infection with multidrug-resistant bacteria—in these patients, and these will be discussed in this review. Immunocompromised patients are also at higher risk than non-immunocompromised hosts of fungal and viral infections, and the diagnostic and therapeutic management of these infections will be covered. Finally, we will suggest some important areas of future investigation. [ABSTRACT FROM AUTHOR]

Chemotherapeutic efficacy for pancreatic cancer is severely compromised by limited drug availability to tumor cells. Herein, we constructed a cancer cell membrane-fused liposome containing a siATG5-loaded calcium phosphate (CaP) core, termed CLip@siATG5. Through cancer cell membrane camouflage, the liposomes evaded immune clearance, actively infiltrated tumor tissues, and were preferentially taken up by homotypic tumor cells. Then, siATG5 escaped from the endosomes and was liberated in the cytoplasm, mainly benefiting from CaP dissolution-induced endosome rupture and liposome disassembly in acidic endosomes. The released siATG5 silenced autophagy protein 5 (ATG5) to inhibit autophagy, starving tumor cells. An alternative nutrient procurement pathway, macropinocytosis, was then upregulated in the cells, leading to increased uptake of the albumin-bound chemotherapeutic agent (nanoparticle albumin-bound paclitaxel (Nab-PTX)). Finally, in a murine pancreatic cancer model, CLip@siATG5 combined with Nab-PTX exerted superior efficacy to a twofold dose of Nab-PTX while avoiding its toxicity. Overall, we justified enhancing chemotherapeutic delivery by modulating the pancreatic cancer cell metabolism, which will enlighten the development of more effective chemotherapeutic adjuvants for pancreatic cancer in the future. CLip@siATG5 sequentially overcomes multiple barriers and effectively delivers siATG5 to pancreatic cancer cells. Then, cancer cells are pushed to transfer from autophagy to macropinocytosis, swallowing massive cytotoxic albumin-bound chemotherapeutics (Nab-PTX). [Display omitted] • Cancer cell membrane camouflage enabled the CLip@siATG5 to evade the MPS uptake and be preferentially taken up by the homotypic cancer cells. • Calcium phosphate (CaP) core dissolution in acid endosomes promoted siATG5 release in the cytoplasm. • CLip@siATG5 could deliver a sufficient concentration of siATG5 to in vivo pancreatic cancer cells for autophagy inhibition. • CLip@siATG5 pushed pancreatic cancer cells to transfer from autophagy to macropinocytosis and take up massive Nab-PTX. [ABSTRACT FROM AUTHOR]

Introduction: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. After corticosteroids with or without intravenous immune globulin (first-line treatment), second-line treatment options include rituximab, splenectomy, thrombopoietin receptor agonists (TPO-RAs), and fostamatinib. In Canada, the choice of second-line therapy is influenced by access to medications. The goals of this narrative review are to 1) summarize the evidence for the use of TPO-RAs and other second-line therapies in ITP and 2) highlight differences in public funding criteria for TPO-RAs across provinces and territories in Canada. Methods: We conducted a literature review of second-line therapies for ITP. We solicited information on public funding programs for TPO-RAs in Canada from health care providers, pharmacists, and provincial ministries of health. Results: Head-to-head trials involving TPO-RAs, rituximab, splenectomy, and fostamatinib are lacking. There is substantial evidence of effect for TPO-RAs in improving platelet count levels, health-related quality of life, bleeding, and fatigue from placebo-controlled trials and observational studies; however, access to TPO-RAs through provincial funding programs in Canada is variable. Splenectomy failure is a prerequisite for the funding of TPO-RAs in Ontario, Manitoba, and Saskatchewan, but not in Alberta or Quebec. Other provinces either do not have access to public funding or funding is provided on a case-by-case basis. Discussion: TPO-RAs are effective second-line therapies for the treatment of ITP; however, access is variable across Canada, which results in health disparities and poor uptake of international treatment guidelines. [ABSTRACT FROM AUTHOR]

(1) Background: Radiation-induced thrombocytopenia (RIT) often occurs in cancer patients undergoing radiation therapy, which can result in morbidity and even death. However, a notable deficiency exists in the availability of specific drugs designed for the treatment of RIT. (2) Methods: In our pursuit of new drugs for RIT treatment, we employed three deep learning (DL) algorithms: convolutional neural network (CNN), deep neural network (DNN), and a hybrid neural network that combines the computational characteristics of the two. These algorithms construct computational models that can screen compounds for drug activity by utilizing the distinct physicochemical properties of the molecules. The best model underwent testing using a set of 10 drugs endorsed by the US Food and Drug Administration (FDA) specifically for the treatment of thrombocytopenia. (3) Results: The Hybrid CNN+DNN (HCD) model demonstrated the most effective predictive performance on the test dataset, achieving an accuracy of 98.3% and a precision of 97.0%. Both metrics surpassed the performance of the other models, and the model predicted that seven FDA drugs would exhibit activity. Isochlorogenic acid A, identified through screening the Chinese Pharmacopoeia Natural Product Library, was subsequently subjected to experimental verification. The results indicated a substantial enhancement in the differentiation and maturation of megakaryocytes (MKs), along with a notable increase in platelet production. (4) Conclusions: This underscores the potential therapeutic efficacy of isochlorogenic acid A in addressing RIT. [ABSTRACT FROM AUTHOR]

Canada has one of the most complex and rigorous drug approval and public reimbursement processes and is, unfortunately, one of the countries with the longest delays in drug access. To assess the overall impact of systemic delays in access to cancer therapy, a targeted literature review (TLR) was performed to identify studies associated with the clinical, economic, and quality of life impacts of delayed access to oncology drugs. Using MEDLINE/PubMed databases and snowballing, four unique records met the eligibility criteria. Results revealed that clinical outcomes were the most impacted by systemic delays in access to oncology drugs (e.g., life years lost, overall survival, and progression-free survival). The four articles retrieved by the TLR specifically illustrated that a substantial number of life years could potentially be saved by increasing systemic efficiency regarding the development, approval, and reimbursement processes of new drugs for advanced malignancies. It is imperative that initiatives are put in place to improve the performance and speed of Canadian drug regulatory and health technology assessment (HTA) processes, especially for new cancer therapeutics. The proposed solutions in this paper include better coordination between HTA and Canadian payers to harmonize coverage decisions, international collaborations, information sharing, and national standards for timeliness in oncology drug access. [ABSTRACT FROM AUTHOR]