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Background The dispersible fixed-dose combination drug has been recommended as the mainstay of treatment for TB in children. However, more needs to be known about its effect on treatment. This study aimed to assess the effectiveness of the formulation on treatment adherence among children with TB. Methods A historical cohort design was used to assess and compare adherences of old loose non-dispersible and new dispersible fixed-dose anti-TB drugs, using a convergent parallel mixed-method approach for data collection. Determinants of treatment adherence were assessed using binary logistic regression. Results The proportion of children with good treatment adherence was higher in the new dispersible formulation group (82 [64.6%]) relative to the proportion among the loose non-dispersible formulation group (29 [23.4%]). Reports of forgetfulness, travelling and pill burden were significantly higher among those with poor adherence in the loose non-dispersible formulation group. Significant predictors of treatment adherence were acceptability (adjusted OR [AOR]=4.1, p=0.013, 95% CI 1.342 to 12.756), travelling from treatment areas (AOR=8.9, p=0.002, 95% CI 2.211 to 35.771) and forgetfulness (AOR=74.0, p<0.001, 95% CI 23.319 to 234.725). Conclusions The determinants of treatment adherence are multifactorial. In addition to ensuring universal access to the drug, flexible referral in case of travelling and ensuring treatment partners' participation to minimise forgetfulness to take pills, are essential. [ABSTRACT FROM AUTHOR]

Background: In addition to the drugs that have been known for decades, several hundred mainly synthetic substances have been identified as drugs for the first time in the last 20 years. Aim of the work: Presentation of the various groups of substances and their psychotropic effects, the epidemiology of their use and the legal and social background of this development. Material: Narrative literature review. Results: The most important new psychoactive substances (NPS) are synthetic cannabinoids, synthetic stimulants (cathinones), halluginogens and new synthetic opioids (NSO), in particular fentanyl and related substances. The new substances do not have any qualitatively new psychotropic effects. They were brought onto the market in particular as substitutes for substances subject to the Narcotics Act but are often associated with dangerous side effects and even mortality. The increasing availability of these substances has gone hand in hand with the establishment of the Internet as a source of knowledge (e.g. for synthesis routes) and as a marketplace. Substance group-related regulations have also been established in Germany (New Psychoactive Substances Act). In Germany the prevalence of NPS use is significantly lower than that of cannabis; however, there are indications that the production and distribution of synthetic drugs is more profitable for drug dealers than with conventional plant-based drugs, such as heroin. In the USA, for example, NSOs are the primarily drugs used for opioid addiction. Discussion: It remains to be seen whether NPS and NSOs will replace conventional drugs. The availability of synthetic drugs is more difficult to reduce than that of plant-based drugs. Harm reduction measures should be expanded, e.g., early warning systems for new drugs, drug checking and naloxone programs. [ABSTRACT FROM AUTHOR]

This article discusses the use of long-acting injectables (LAIs) as a treatment option for adolescents diagnosed with bipolar disorder. The study focuses on four adolescent patients with similar symptoms of bipolar disorder who underwent treatment with a LAI antipsychotic. The results showed positive responses to the treatment, with a decline in symptoms over time. The article emphasizes the importance of medication adherence in managing bipolar disorder and highlights the benefits of LAIs in promoting stability and reducing the impact of the illness on daily life. It also emphasizes the need for comprehensive measures, such as education, family support, and regular monitoring, to effectively manage bipolar disorder in adolescents. [Extracted from the article]

Background: Direct-to-consumer (DTC) pharmacies sell generic prescription drugs, often at lower prices than traditional retail pharmacies; however, not all drugs are available, and prices vary. Objective: To determine the availability and cost of generic drugs at DTC pharmacies. Design: Cross-sectional study. Setting: Five national DTC pharmacies in April and May 2023. Participants: Each qualifying form of 100 generic drugs with the highest cost-per-patient (expensive) and the 50 generic drugs with the highest number of patients (common) in Medicare Part D in 2020 Main Measures: Availability of these drugs and the lowest DTC pharmacy price for a standardized drug strength and supply (e.g., 30 pills), compared to GoodRx retail pharmacy prices. Key Results: Of the 118 expensive generic dosage forms, 94 (80%) were available at 1 or more DTC pharmacies; out of 52 common generic dosage forms, 51 (98%) were available (p < 0.001). Of the 88 expensive generics available in comparable quantities and strengths across pharmacies, 42 (47%) had the lowest cost at Amazon, 23 (26%) at Mark Cuban Cost Plus Drug Company, 13 (14%) at Health Warehouse, and 12 (13%) at Costco; for 51 common generic formulations, 16 (31%) had the lowest cost at Costco, 14 (27%) at Amazon, 10 (20%) at Walmart, 6 (12%) at Health Warehouse, and 5 (10%) at Mark Cuban Cost Plus Drug Company. For the 77 expensive generics with available GoodRx retail pharmacy prices, the median cost savings at DTC pharmacies were $231 (95% CI, $129–$792) or 76% (IQR, 53–91%); for 51 common generics, savings were $19 (95% CI, $10–$34) or 75% (IQR, 67–83%). Conclusions: Many of the most expensive generic drugs are unavailable at direct-to-consumer pharmacies. Meanwhile, less expensive, commonly used generics are widely available, but drug prices vary by pharmacy and savings are modest, requiring patients to shop around for the lowest cost. [ABSTRACT FROM AUTHOR]

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are mainly found in the small intestine and pancreas. The course of the disease in patients is highly variable and depends on the degree of differentiation (G1–G3) of the neoplasm. The potential for metastasis formation of GEP-NEN is high even with good differentiation (G1). Lymph node metastases and, in many cases, liver metastases are also often found. Less common are bone metastases or peritoneal carcinomas. The treatment of these GEP-NENs is surgical, whenever possible. If an R0 resection with removal of all lymph node and liver metastases is successful, the prognosis of the patients is excellent. Patients with diffuse liver or bone metastases can no longer be cured by surgery alone. The long-term survival of these patients is nowadays possible due to the availability of drugs (e.g., somatostatin analogues, tyrosine kinase inhibitors), peptide receptor radionuclide therapy (PRRT) and liver-directed procedures, with a good quality of life. [ABSTRACT FROM AUTHOR]

This commentary discusses the impact of the COVID-19 pandemic on low- and middle-income countries, referred to as "have not" countries. These countries have faced challenges in obtaining and affording pandemic vaccines and antiviral agents. The author suggests an alternative approach of treating the host response to infection with a combination of generic statins and ACE inhibitors or ARBs, which target the endothelial dysfunction underlying COVID-19. Observational studies and clinical trials are needed to better prepare these countries for treating COVID-19 and future pandemics. The commentary also highlights the need for a pluralistic approach that considers both randomized controlled trials and observational studies in understanding treatment efficacy. The availability of inexpensive generic drugs in "have not" countries could have a significant impact on global equity. [Extracted from the article]

Comprehensive information on genetic alterations in salivary gland cancer (SGC) is limited. This study aimed to elucidate the genetic and clinical characteristics of patients with SGC using the Center for Cancer Genomics and Advanced Therapeutics (C‐CAT) database, a Japanese national genomic database. We analyzed data of 776 patients with SGC registered in the C‐CAT database between June 1, 2019, and June 30, 2023. Adenoid cystic carcinoma was the most common histologic type, followed by salivary duct carcinoma (SDC) and adenocarcinoma not otherwise specified. Genetic data of 681 patients receiving FoundationOne® CDx were analyzed. We identified specific features of the combination of TP53 and CDKN2A alterations among the histological types. Specific LYN amplification was mainly detected in carcinoma ex pleomorphic adenoma and myoepithelial carcinoma. For SDC, the frequency of ERBB2 and BRAF alterations were higher in cases with metastatic lesions than in those with primary lesions. Although 28.6% patients were offered recommended treatment options, only 6.8% received the recommended treatments. This study highlights the differences in genetic alterations among the histological types of SGC, with comprehensive genomic profiling tests revealing lower drug accessibility. These findings could contribute to the development of personalized treatment for patients with SGC. [ABSTRACT FROM AUTHOR]

Optimized dosages provide a secure foundation for the development of well‐tolerated and effective oncology drugs. Project Optimus, an initiative within the Oncology Center of Excellence, strives to reform the dosage optimization and dosage selection paradigm in oncology. This initiative stems from the availability of targeted drugs and from the demand for more tolerable dosages from patients, caregivers, and advocates. Reforming dosage optimization for oncology drugs requires a paradigm shift from the one employed for cytotoxic chemotherapy to one that understands and considers the unique attributes of targeted therapy, immunotherapy, and cellular therapy. Limited characterization of dosage during drug development may result in (1) patients not staying on a therapy long‐term due to poor tolerability, (2) failure to establish positive benefit–risk in clinical trials for regulatory approval (3) withdrawal of drugs from the market (4) removal of indications of drugs from the market. Timely access to drugs is important for all patients with cancer, so it is vital to iteratively analyze all nonclinical and clinically relevant data at each stage of development and leverage quantitative approaches, innovative trial designs, and regulatory support to arrive at dosages with favorable benefit–risk. This review highlights the key challenges and opportunities to embracing this new paradigm and realizing the full potential of new oncology therapies. [ABSTRACT FROM AUTHOR]

The construction of a chemical library based on natural products is a promising method for the synthesis of natural product‐like compounds. In this study, we synthesized a terpenoid alkaloid‐like compound library based on the humulene skeleton. Our strategy, which enables access to diverse ring systems such as 11‐membered monocyclic, oxabicyclic, and medium‐sized aza ring‐containing scaffolds, involves the introduction of a nitrogen atom, an intermolecular C−O bond formation via Lewis acid‐mediated epoxide‐opening transannulation, and a ring‐reconstruction strategy based on olefin metathesis. A cheminformatics analysis based on their structural and physicochemical properties revealed that the synthesized compounds have high three‐dimensionality and high natural product likeness scores but with structural novelty. The usefulness of the terpenoid alkaloid‐like compound library for drug discovery and the accessibility to structure‐activity relationship studies were validated by performing an assay for osteoclast‐specific tartrate‐resistant acid phosphatase activity, resulting in the identification of a seed compound for bone‐resorptive diseases such as osteoporosis. [ABSTRACT FROM AUTHOR]

Background: The national volume-based procurement (NVBP) policy has significantly decreased prices and increased the accessibility of NVBP drugs. Nevertheless, issues such as heightened adverse reactions and suboptimal efficacy have arisen. Concerns regarding the quality of low-cost medications and the absence of long-term research have been widely recognized. This has led to caution among patients with late-life depression (LLD) due to their delicate health and the severity of their condition. This study evaluated the choice intention for NVBP drugs and associated factors in older patients with LLD. Methods: A weighted sample of 408 participants between December 2022 and March 2023 were included. Data were collected via face-to-face interviews and questionnaires. To identify significant associated factors of choice intention, a multilevel logistic regression model was employed. Results: Over half (53.68%) of older patients with LLD intended to choose NVBP drugs. Associated factors included self-assessed poor economy, higher out-of-pocket expenses, monthly household income exceeding CNY 6000, absence of other non-communicable chronic diseases, ordinary registration, urban employee medical insurance, no requirements for brand-name drugs, adverse reactions after using NVBP drugs, and rejection of physicians' recommendation for NVBP drugs. The interaction effect between the real economic condition and patients self-assessed economy significantly influences choice intention for NVBP drugs. Among 124 patients with self-assessed poor economy, 75 showed a higher intention to use NVBP drugs. In these patients, age, medical insurance reimbursement, and brand awareness were significantly associated with choice intention. Conclusion: Economic factors, physical conditions, medical needs, and physician recommendations significantly influenced the choice intention for NVBP drugs. The choice intention can be improved by strengthening physician-patient communication, increasing the scope and proportion of medical insurance reimbursement, improving substitution studies, and conducting post-marketing re-evaluations of NVBP drugs. [ABSTRACT FROM AUTHOR]

Background: Economic and health care restraints strongly impact on drug prescription for chronic diseases. We aimed to identify potential factors for prescription behavior in chronic disease. Multiple sclerosis was chosen as a model disease due to its chronic character, incidence, and high socioeconomic impact. Methods: Germany was used as a model country as the health-care system is devoid of economic and drug availability restraints. German statutory health insurance data were analyzed retrospectively. The impact of number of university hospitals and neurologists as well as the gross domestic product (GDP) as potential factors on prescriptions of platform and high-efficacy disease-modifying therapies (DMTs) was analyzed. Results: Prescription of platform DMTs increased over time in almost all federal states with varying degree of increase. Univariate regression analysis showed that the prescription volume of platform DMTs positively correlated with the number of university hospitals and neurologists, as well as the GDP per federal state. Stepwise forward regression analysis including all potential factors indicated a statistically significant model for platform DMT (R² = 0.55; 95%-CI [0.28, 0.82]; p=0.001) revealing GDP as the main contributor. This was confirmed in the independent analysis. Conclusion: This study illustrates that even without overt drug prescription inequity, access to medication is not evenly distributed and depends on economic strength and regional medical care density. [ABSTRACT FROM AUTHOR]

This cross-sectional study surveyed veterinarians and facility managers to characterise the use of antimicrobials in laboratory rodent facilities within Australia and New Zealand. Most facilities (71%) reported routine administration of antimicrobials. The indications for antibiotic use reflected those described in publications and differed significantly to reasons for use in non-laboratory animals. Antimicrobials used include those of critical importance to human health, and access to these drugs is unregulated, as prescription-only classes are ordered through research catalogues, without human or veterinary physician prescriptions. The ways in which antimicrobials are used in Australian and New Zealand rodent facilities are likely contributing to antimicrobial resistance within rodent populations, particularly as they are largely administered in drinking water, risking subtherapeutic dosing. Much antimicrobial use reported is unnecessary and could be replaced with changes to husbandry and handling. The generation of resistance in both pathogenic and commensal microbes may also represent a work health and safety issue for humans working with these animals. Reported disposal of antimicrobials included discharge into wastewater, without inactivation, and some respondents reported disposal of substrate, or soiled bedding, nesting material, and disposable enrichment items, from treated animals and medicated feed into landfill, without prior inactivation. Environmental contamination with resistant microbes and antimicrobials is a significant driver of antimicrobial resistance. As such, significant opportunities exist to implement judicious and responsible use of antimicrobials within research rodent facilities in Australia and New Zealand, with a particular focus on instituting aseptic surgery, optimising dosing regimens, and inactivation of medicated water and substrate before disposal. [ABSTRACT FROM AUTHOR]

Introduction: Clinical mastitis (CM) treatment decision-making is a multifaceted process that remains relatively understudied, despite CM being one of the most prevalent diseases on dairy farms worldwide, contributing greatly to the use of antimicrobials in the dairy industry. This study aimed to gain insights into decision-making mechanisms employed by dairy farmers in British Columbia and Alberta, Canada, when dealing with CM. Methods: Interviews were held with 15 dairy farmers in the Canadian provinces of British Columbia and Alberta and analyzed using reflexive thematic analysis to develop both the decision-pathway and overarching themes influencing the CM decisions by farmers in this region. Results and discussion: The analysis generated a decision-making process that begins with identification and classification of CM, guided by visual characteristics of milk and the udder, available milk production and quality data, presence of systemic signs, and additional diagnostics. Subsequently, CM cases are assessed based on the likelihood of cure, value of the cow, and herd goals to decide whether antimicrobial treatment is desired. Next, a treatment choice is made by evaluating severity and urgency of the case, availability of drugs and timing of the case. Finally, definition of treatment success and progression over time following the treatment decision guides the termination of treatment. Three overarching themes were generated that shape the decision-making process: 'Personal attributes', including personal approach and experiential knowledge; 'Inter-actor dynamics', such as shared decision-making and dynamics among producers, veterinarians, and milkers; and 'Moving beyond protocols', which highlights the dynamic nature of mastitis decision-making. These insights have the potential to inform the development of effective interventions to improve CM antimicrobial use that align with the reality of farming operations within Western Canada, and potentially beyond. [ABSTRACT FROM AUTHOR]

Several new classes of medications for diabetes have recently become available newer medication classes have been increasing in use. It is unclear how their utilization varied across provinces and how the COVID-19 pandemic may have affected these trends. Our objective was to investigate Canada-wide and province-specific trends in diabetes medication dispensed by drug class over time, while also examining the impact of the COVID-19 pandemic and related restrictions on diabetes medication dispensing. We conducted a repeated cross-sectional analysis study. Data were obtained from IQVIA's CompuScript database for Canada-wide prescription dispensing patterns in primary care from January 2018 to December 2021. Drug classes of interest were biguanides dipeptidyl peptidase 4 inhibitors, sulfonylurea's, insulins, sodium-glucose co-transporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists. We examined trends before and after the onset of the pandemic with special attention to changes during periods of high COVID-19 activity. Most drug classes displayed a stable number of prescriptions each month throughout, except for glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors, which demonstrated a consistent pattern of increased dispensing. Sodium-glucose co-transporter inhibitors and glucagon-like peptide-1 receptor agonists exhibited the greatest growth over the examined period, of 7.9% and 5.0% increases, respectively. For sodium-glucose co-transporter 2 inhibitors, Prince Edward Island (4.0%) displayed the greatest growth while Ontario showed the least (2.5%). For glucagon-like peptide-1 receptor analogs, Saskatchewan (11.3%) displayed the greatest growth and Newfoundland the least (4.5%). The pandemic did not impact overall dispensing trends. However, spikes in COVID-19 cases corresponded to changes in dispensing for most drug classes. Important variations across Canada in guideline-recommended medication classes seems to be increasing over time. This is likely due to differing formulary listing and access to drug coverages. If so, future research could explore national formulary harmonization across Canada and health outcomes for patients with diabetes. [ABSTRACT FROM AUTHOR]

Liver fibrosis, characterized by excessive extracellular matrix deposition, is driven by activated hepatic stellate cells (HSCs). Due to the limited availability of anti-fibrotic drugs, the research on therapeutic agents continues. Here we have investigated Moringa oleifera Lam. (MO), known for its various bioactive properties, for anti-fibrotic effects. This study has focused on 1-phenyl-2-pentanol (1-PHE), a compound derived from MO leaves, and its effects on LX-2 human hepatic stellate cell activation. TGF-β1-stimulated LX-2 cells were treated with MO extract or 1-PHE, and the changes in liver fibrosis markers were assessed at both gene and protein levels. Proteomic analysis and molecular docking were employed to identify potential protein targets and signaling pathways affected by 1-PHE. Treatment with 1-PHE downregulated fibrosis markers, including collagen type I alpha 1 chain (COL1A1), collagen type IV alpha 1 chain (COL4A1), mothers against decapentaplegic homologs 2 and 3 (SMAD2/3), and matrix metalloproteinase-2 (MMP2), and reduced the secretion of matrix metalloproteinase-9 (MMP-9). Proteomic analysis data showed that 1-PHE modulates the Wnt/β-catenin pathway, providing a possible mechanism for its effects. Our results suggest that 1-PHE inhibits the TGF-β1 and Wnt/β-catenin signaling pathways and HSC activation, indicating its potential as an anti-liver-fibrosis agent. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a chronic hematologic malignancy that remains incurable, because most patients eventually relapse or become refractory to current treatments. MM is a major health problem, with a globally increasing incidence. While, increase in the choice of MM treatment, including new immunotherapies (bispecific monoclonal antibodies and chimeric antigen receptor (CAR)-T cell therapy), may allow to further improve MM patients' outcomes, some non-therapy-related key issues may represent a pre-requisite towards improving MM outcomes in the next few years. This includes, the necessity of real-world evidence data, of a better definition of frailty, of a dynamic disease risk assessment, of a better definition of high-risk disease, broader accessibility to novel drugs, and to ensure diversity and representation of underrepresented groups. These key issues will be discussed in the current perspective review. [ABSTRACT FROM AUTHOR]

AbstractA major shortcoming in the treatment of mesangial cell-associated diseases such as IgA nephropathy, diabetic nephropathy, or lupus nephritis, which frequently progress to end-stage renal disease, is poor drug availability in the glomerular mesangium. Drug delivery via active targeting of nanoparticles, using ligands attached to the particle surface for target cell recognition to increase the biodistribution to the mesangium, is a promising strategy to overcome this hurdle. However, although several glomerular tissue targeting approaches have been described, so far no study has demonstrated the particles’ ability to deliver sufficient drug amounts combined with an appropriate nanoparticle target retention time to trigger relevant biological effects in the mesangium. In our study, we encapsulated erastin, a ferroptosis-inducing model compound, into adenovirus-mimetic, mesangial cell-targeting nanoparticles, enabling the direct visualisation of biological effects through ferroptosis-dependent histological changes. By intravital microscopy and analysis of histological sections, we were not only able to localise the injected particles over 10 days within the target cells but also to demonstrate biological activity in the renal glomeruli. In conclusion, we have characterised adenovirus-mimetic nanoparticles as a highly suitable drug delivery platform for the treatment of mesangial cell-associated diseases and additionally provided the basis for a potential renal disease model. [ABSTRACT FROM AUTHOR]

Access to antibiotic medications is critical to achieving the Sustainable Development Goal for good health and well-being. However, non-prescribed and informal sources are implicated as the most common causes of inappropriate antibiotic access practices, resulting in untargeted therapy, which leads to antibiotic resistance. Hence, knowing antibiotic access practices at the community level is essential to target misuse sources. In this study, 2256 household representatives were surveyed between July and September 2023 to examine their antibiotic access practices. Of 1245 household members who received antibiotics, 45.6% did so inappropriately. Non-prescribed antibiotic access was more common among urban residents and individuals not enrolled in health insurance schemes. This means of antibiotic access was also more common among individuals concerned about distance, drug availability, and healthcare convenience at public facilities. In addition, women and rural individuals were more likely to get antibiotics from unauthorized sources. Unrestricted antibiotic dispensing practices in urban areas enabled their non-prescribed access, while unlicensed providers prevailed with this access practice in rural areas. In this regard, personal behaviors and healthcare-related gaps such as the lack of health insurance, inconvenience, and drug unavailability have led community members to seek antibiotics from unofficial and non-prescribed sources. Targeting the identified behavioral and institutional factors can enhance antibiotic access through prescriptions, hence reducing antibiotic resistance. [ABSTRACT FROM AUTHOR]

Dabigatran etexilate (DABE) is a lipophilic double alkyl ester prodrug of dabigatran (DAB) which is a serine protease inhibitor used clinically as an anticoagulant. Recently, translocation of serine protease enzymes, including trypsin, from the gut into the mesenteric lymph and then blood has been associated with organ failure in acute and critical illnesses (ACIs). Delivery of DABE into mesenteric lymph may thus be an effective strategy to prevent organ failure in ACIs. Most drugs access the mesenteric lymph in low quantities following oral administration, as they are rapidly transported away from the intestine via the blood. Here, we examine the potential to deliver DABE into the mesenteric lymph by promoting association with lymph lipid transport pathways via co-administration with a lipid-based formulation (LBF). A series of self-emulsifying LBFs were designed and tested in vitro for their potential to form stable DABE loaded emulsions and keep DABE solubilised and stable over time in simulated gastrointestinal conditions. The LBFs were found to form fine emulsions with a droplet size of 214 ± 30 nm and DABE was stable in the formulation. The stability of DABE in vitro in simulated intestinal conditions, plasma and lymph samples was also evaluated to ensure stability in collected samples and to evaluate whether the prodrug is likely to release active DAB. Ultimately, a highly uniform and stable self-emulsifying Type III A LBF of DABE was chosen for progression into in vivo studies in male Sprague Dawley rats to confirm the lymphatic uptake and plasma pharmacokinetics. Both in vitro and in vivo in plasma and lymph, DABE was rapidly converted to an intermediate and DAB. The main species present in vivo in both plasma and lymph was DAB and mass transport of DABE and DAB in lymph was minimal (∼0.5 % of dose). Importantly, the concentration of DABE in lymph was substantially (20–176 fold) higher than in plasma, supporting that if the prodrug were stable and did not convert to DAB in the intestine, it would be lymphatically transported. Future studies will therefore focus on optimizing the design of the prodrug and formulation to improve stability during absorption and further promote lymphatic uptake. [Display omitted] • Dabigatran etexilate (DABE) was formulated into a novel stable lipid-based formulation to enhance its lymphatic uptake. • The lipid-based formulation provided protection against degradation of DABE in simulated intestinal digestion conditions. • DABE showed some lymphatic uptake following intestinal administration in the lipid-based formulation but this appeared limited by intestinal instability of DABE. [ABSTRACT FROM AUTHOR]

Compared to other forms of drug administration, the use of Transdermal Drug Delivery Systems (TDDSs) offers significant advantages, including uniform drug release profiles that contribute to lower side effects and higher tolerability, avoidance of direct exposure to the gastrointestinal tract, better patient compliance due to their non-invasive means of application and others. Mesoporous silica membranes are of particular interest in this regard, due to their chemical stability and their tunable porous system, with adjustable pore sizes, pore volumes and surface chemistries. While this allows for fine-tuning and, thus, the development of optimized TDDSs with high loading capacities and the desired release profile of a given drug, its systemic availability also relies on skin penetration. In this paper, using a TDDS based on mesoporous silica membranes in Franz cell experiments on porcine skin, we demonstrate surprisingly substantial drug loss during skin penetration. Drug passage through porcine skin was found to be dependent on the age and pre-treatment of the skin. pH and temperature were major determinants of drug recovery rates as well, indicating drug loss in the skin by enzymatic metabolization. Regarding the TDDS, higher loading obtained by SO3H surface modification of the mesoporous silica membranes reduced drug loss. Still, high loss rates in the skin were determined for different drugs, including anastrozole, xylazine and imiquimod. We conclude that, beyond the fine-tuned drug release profiles from the mesoporous silica membrane TDDS, remarkably high drug loss in the skin is a major issue for achieving desired skin penetration and, thus, the systemic availability of drugs. This also poses critical requirements for defining an optimal TDDS based on mesoporous silica membranes. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, the use of alternative animal models to vertebrates for the study of infectious processes and antimicrobial drug development has become a major challenge in experimentation. Insects, in particular Galleria mellonella, may represent a good model for preclinical studies, as their response to infections allows for the preliminary selection of molecules with biological activity in a potential sepsis event. However, discordant data are often reported in the literature, and this is often due to the different methods implemented in many laboratories. The aim of this work was therefore to develop a standard protocol for infection with a Gram-positive bacterium, as we consider it important to apply these unified methodologies in order to obtain reproducible data. Our results made it possible to define a correct growth curve of Micrococcus luteus and, in parallel, an infection methodology that would provide consistent and repeatable data. We are therefore confident that this work can be a support for preclinical studies on model insects, as a link between the development of new drugs and its availability for patients. The aim of this work was to develop an experimental protocol for the infection of Galleria mellonella with Gram-positive bacteria. Some physiological characteristics of these insects are comparable to those of vertebrates, therefore allowing the replacement of mammals in the preclinical phases of drug development. G. mellonella Linnaeus 1758 (Lepidoptera: Pyralidae) is accepted as an alternative model for the study of infectious diseases. Since data on infection procedures with different bacterial strains are scarce and sometimes conflicting, also due to different and non-uniform protocols, we developed an experimental protocol that would allow for controlled and repeatable infections, using the Gram-positive bacterium GRAS (Generally Regarded As Safe) Micrococcus luteus. After analyzing the morphology and defining the growth rate of M. luteus, doses of between 101 and 106 CFU/larvae were administered to late-stage larvae. The survival rate of the larvae was monitored up to 7 days and the LD50 determined. The bacterial clearance capacity of the larvae after injection with 103 and 105 CFU/larvae was assessed by hemolymph bacterial load analysis. The results made it possible to define the growth curve of M. luteus correlated with the CFU count; based on the LD50 (103.8 CFU/larvae) calculated on the survival of G. mellonella, infections were carried out to evaluate the immune efficiency of the larvae in bacterial clearance. This protocol, standardized on G. mellonella larvae, could provide a functional tool to study the course of bacterial infections. [ABSTRACT FROM AUTHOR]

This article explores the challenges of treating epilepsy and the high prevalence of treatment failure. It suggests that a lack of understanding of why medications fail or why side effects occur is a major obstacle to successful treatment. The article emphasizes the need to identify the basis for treatment failure in order to develop more effective treatments. It also discusses different patterns of treatment failure and highlights the need for new approaches to discovery and a better understanding of treatment failure mechanisms. [Extracted from the article]

The World Health Organization (WHO) recently prequalified a new dispersible and more palatable paediatric formulation of the antischistosome drug praziquantel (PZQ). Now there is a need for implementation research to address current scientific evidence, tools, and operational strategy gaps to facilitate its deployment. Endemic countries need strategies and road maps for accessing, delivering, and scaling up adoption of this new formulation. Schistosomiasis is the second most important parasitic disease of public health importance in Africa, affecting over 50 million children aged < 5 years old. Schistosomiasis control has focused on treating school-aged children (>6 years) and adults through mass drug administration (MDA). Following the recent development of a paediatric praziquantel (PZQ) formulation for children aged <5 years, there are now concerted efforts to determine optimal and effective ways to integrate treatment of these children into national schistosomiasis control programmes. In this opinion article we outline the pathway for successful drug access, delivery, and mainstreaming of the new formulation in endemic country health systems. Effective and sustained paediatric schistosomiasis treatment is an important target of the 2030 World Health Organization (WHO) neglected tropical diseases (NTDs) roadmap. Schistosomiasis is the second most important parasitic disease of public health importance in Africa, affecting over 50 million children aged < 5 years old. Schistosomiasis control has focused on treating school-aged children (≥6 years) and adults through mass drug administration (MDA). Following the recent development of a paediatric praziquantel (PZQ) formulation for children aged <5 years, there are now concerted efforts to determine optimal and effective ways to integrate treatment of these children into national schistosomiasis control programmes. In this opinion article we outline the pathway for successful drug access, delivery, and mainstreaming of the new formulation in endemic country health systems. Effective and sustained paediatric schistosomiasis treatment is an important target of the 2030 World Health Organization (WHO) neglected tropical diseases (NTDs) roadmap. [ABSTRACT FROM AUTHOR]

The article focuses on the FDA (U.S. Food and Drug Administration) regulatory considerations for oncology drug development, particularly emphasizing the Accelerated Approval (AA) program. It examines the challenges and opportunities within the current competitive oncology landscape, including the need for early dose optimization, representation of ethnic diversity in clinical trials, and the impact of various FDA initiatives such as Project Optimus and Project Equity on drug approval processes.

Adverse childhood experiences (ACEs) are associated with a wide range of health problems and health‐compromising behaviors, including drug use, but are understudied in sub‐Saharan Africa. Further, some data suggest that some types of ACEs are more strongly associated with outcomes than others. We investigated associations between different types of ACEs and recent drug use among 2,011 women living in Katsina State, Nigeria. This community‐based survey included questions on ACE exposure, modifiable individual‐level risk and promotive factors, and past‐year drug use. Tobacco, cannabis, and the nonmedical use of cough syrup with codeine and tramadol were the most frequently used drugs. Logistic regressions revealed that across most drugs, ACEs reflecting abuse, neglect, and household dysfunction, but not community violence, increased the likelihood of drug use, odds ratios (ORs) = 1.30–3.10. Ease of access to drugs, ORs = 1.33–2.98, and personal religiosity, ORs = 1.19–2.27, also enhanced the risk of drug use, and higher depressive affect was associated with codeine, OR = 1.27, and tramadol use, ORs = 2.42. Practicing religious rites, ORs = 0.38–0.70; disapproval of drug use, ORs = 0.36–0.57; and perceived harm from drug use, ORs = 0.54–0.71, reduced the likelihood of drug use. Efforts to prevent abuse, neglect, and household dysfunction; reduce access to drugs; treat depression; and increase disapproval and harm associated with drug use may reduce drug use in the context of ACE exposure. [ABSTRACT FROM AUTHOR]

Generic drugs seem a promising alternative to decrease healthcare costs. However, on one hand, doctors express reluctance toward this kind of drug, and on the other hand, existing literature remains silent about factors explaining their prescribing behavior. The current study mobilizes the Health Belief Model to offer a better understanding of the factors that hinder the prescription of generic drugs by doctors in terms of benefits, barriers, perceived susceptibility, perceived severity, self-efficacy, and action cues. Twenty-four in-depth interviews were conducted with doctors from different specialties. Projective techniques were used including Chinese portrait, completion test, completion task, and association tests. Data analysis was processed using Sphinx software. The paper offers practical recommendations for health authorities and pharmaceutical firms to better promote generics. Increasing the prescription of generic drugs, compared to branded drugs, may increase patient access to affordable drug treatments, decrease healthcare costs and establish rational utilization of medicines. Generic drugs prescription may consequently play an essential role in improving the quality of life. [ABSTRACT FROM AUTHOR]

Disparities in Latinx sexual minority men (LSMM) pre-exposure prophylaxis (PrEP) initiation and adherence demonstrate the need for innovative strategies to improve outcomes along the PrEP Care Continuum. The purpose of this study was to examine physical and virtual risk venue co-attendance among LSMM of varying stages of PrEP use living in South Florida, an Ending the HIV Epidemic (EHE) priority jurisdiction. Venue co-attendance may be leveraged to support equitable dissemination and implementation (D&I) of HIV and drug use preventive interventions to LSMM. Ninety-four LSMM completed surveys on PrEP use and identified physical and virtual sexual and drug risk venues (where men seek sex partners and/or have sex or access or use drugs). Bivariate analyses examined differences in demographics and venue endorsement by PrEP status. Exponential random graph models examined endorsement of venues by PrEP status. One-mode projection visualizations portray the structure of venue co-attendance networks by PrEP status. Participants identified 49 physical and virtual sexual and drug risk venues. A homophily effect of PrEP status on venue endorsement was identified for both sexual and drug risk venues. Network size and density differed by PrEP status and whether the venue was identified as a sexual or drug risk location. Online dating apps, bars, and saunas had the highest centrality in each network type suggesting their potential role in implementing preventive programming. This study identified specific sexual and drug risk venues that may be leveraged to both disseminate targeted PrEP and harm reduction information and to implement interventions to improve PrEP uptake and adherence among LSMM living in EHE priority jurisdictions. [ABSTRACT FROM AUTHOR]

This study investigates the factors influencing the lack of Braille-embossed labels in Chinese pharmaceutical product packaging. To this end, this study constructs an evolutionary game model of multi-participant behaviour in drug production regulation and conducts simulation based on the perspective of stakeholders in order to study the evolutionary steady state of regulatory authorities, pharmaceutical companies, and visually impaired individuals and the influence of each parameter variable on the choice of strategic behaviour of the participants. The simulation results show that in the legal framework of China, administrative penalties, the production subsidy rate, and the Basic Medical Insurance (BMI) reimbursement rate are the main drivers of the system's evolution towards a steady state. Reduced costs of drugs with Braille-embossed packaging is a prerequisite for the visually impaired to purchase such drugs, and the key for the whole system to converge to a stable state therefore lies in the BMI reimbursement rate for drugs with Braille-embossed packaging. This paper suggests that the Chinese government should improve the law enforcement mechanism for the regulation of the production of drugs with Braille-embossed packaging; increase the type and intensity of administrative penalties as well as production subsidies, tax incentives, and compliance incentives for pharmaceutical companies; and provide higher BMI reimbursement rates for the visually impaired. The results of the study provide valuable insights to improve accessibility to drugs and build a barrier-free environment for ensuring medication safety in China and other developing countries. [ABSTRACT FROM AUTHOR]

After European Medicines Agency (EMA) approval, national pricing and reimbursement procedures are necessary to guarantee access to drugs, based on the willingness to pay and the recognition of therapeutic value. These can result in delays in drug availability for patients, even for those with important unfmet needs for whom it may be necessary and ethical to ensure access. The objective of this study was to evaluate the use of ruxolitinib for patients with graft-versus-host disease (GvHD) after EMA approval at the University Hospital of Catania. We analysed data about the use of ruxolitinib in patients with GvHD, describing their basic characteristics, their outcomes and the cost of the treatment. In the reference period, 24 ruxolitinib treatments were started according to the Summary of Product Characteristic. The average treatment duration was 10 months. Twenty patients showed a response, maintained over time, with no adverse reactions. The total expenditure amounts to EUR 963,424. The use of ruxolitinib in a real population confirms its role in an important therapeutic need. The quantification of costs requires a reflection on the sustainability of early access to medicines authorised by the EMA for serious diseases and in the absence of therapeutic alternatives. [ABSTRACT FROM AUTHOR]

Macrocyclic drugs can address an increasing range of molecular targets but enabling central nervous system (CNS) access to these drugs has been viewed as an intractable problem. We designed and synthesized a series of quinolinium-modified cyclosporine derivatives targeted to the mitochondrial cyclophilin D protein. Modification of the cation to enable greater delocalization was confirmed by x-ray crystallography of the cations. Critically, greater delocalization improved brain concentrations. Assessment of the compounds in preclinical assays and for pharmacokinetics identified a molecule JP1-138 with at least 20 times the brain levels of a non-delocalized compound or those reported for cyclosporine. Levels were maintained over 24 hours together with low hERG potential. The paradigm outlined here could have widespread utility in the treatment of CNS diseases. [ABSTRACT FROM AUTHOR]

Background: The treatment of multidrug-resistant tuberculosis (MDR-TB) and pre-extensively drug-resistant tuberculosis (pre-XDR-TB) remains challenging due to the limited availability of effective drugs. Linezolid has emerged as a promising therapeutic option for these cases. However, its long-term use can lead to complications such as peripheral and optic neuropathies. Acupuncture, a cornerstone of traditional Chinese medicine, has been shown to be effective in the treatment of peripheral neuropathy (PN). This study examines the potential benefits of acupuncture in the treatment of linezolid-induced peripheral neuropathy (LIPN). Methods: Four patients, aged 27 to 60 years, diagnosed with LIPN, underwent daily acupuncture treatments. The main endpoint was to assess the efficacy of acupuncture in reducing neuropathic pain associated with LIPN in patients. This was primarily measured using changes in the Short Form McGill Pain Questionnaire (SF-MPQ) scores before and after acupuncture treatment. Results: Three of the patients experienced significant symptom remission, while one experienced marginal improvement. Treatments ranged from 7 to 18 sessions. Specifically, the first patient reported substantial relief with a score reduction from 33 to 13; the second patient observed minimal change; the third patient's score decreased dramatically from 10 to 2 after eight sessions; the last patient had a score reduction from 21 to 12 after five sessions, but did not continue treatment for a second assessment. Conclusion: Acupuncture is a promising therapeutic approach for LIPN. However, larger and more thorough studies are needed to determine its full potential. [ABSTRACT FROM AUTHOR]

Although gender differences in the prevalence of substance use disorders (SUD) have been well-characterized, little is known about when gender differences emerge along the continuum of substance use. Understanding the contribution of gender to risk at key transition points across this continuum is needed to identify potential mechanisms underlying gender differences and to inform improved gender-responsive interventions. To characterize gender differences in the progression of cannabis, cocaine, and heroin use, the current study used data from the United States-based 2015–2019 National Survey on Drug Use and Health to quantify gender differences in: (1) perceived access to drugs, (2) lifetime drug use among individuals with at least some access, and (3) past-year SUD among those who had ever used each drug. Logistic regressions were conducted for each drug to examine gender differences across all three stages, controlling for sociodemographic factors and survey year. Compared to women, men had higher odds of reporting access to and lifetime use of all three drug types. Men also had higher odds of past-year cannabis and cocaine use disorders compared to women. Results suggest gender differences emerge in the earliest stage of drug use (access) and may accumulate across the stages of use. The magnitude of gender differences varied across stages, with the largest differences observed for odds of drug initiation among those with perceived access to each drug. Longitudinal data will be needed to confirm these findings and to provide insight into potential contributors to gender-specific risk and intervention targets across the continuum of drug use severity. • It is unclear when gender differences emerge in the progression of drug use. • Men have higher odds of perceived access to cannabis, cocaine, and heroin. • Of those with access, men have substantially higher odds of drug initiation. • Men have higher odds of a past-year cocaine or cannabis use disorder. • Men and women have similar odds of past-year heroin use disorder. [ABSTRACT FROM AUTHOR]

Background We present a novel simulation method for generating connected differential expression signatures. Traditional methods have struggled with the lack of reliable benchmarking data and biases in drug–disease pair labeling, limiting the rigorous benchmarking of connectivity-based approaches. Objective Our aim is to develop a simulation method based on a statistical framework that allows for adjustable levels of parametrization, especially the connectivity, to generate a pair of interconnected differential signatures. This could help to address the issue of benchmarking data availability for connectivity-based drug repurposing approaches. Methods We first detailed the simulation process and how it reflected real biological variability and the interconnectedness of gene expression signatures. Then, we generated several datasets to enable the evaluation of different existing algorithms that compare differential expression signatures, providing insights into their performance and limitations. Results Our findings demonstrate the ability of our simulation to produce realistic data, as evidenced by correlation analyses and the log2 fold-change distribution of deregulated genes. Benchmarking reveals that methods like extreme cosine similarity and Pearson correlation outperform others in identifying connected signatures. Conclusion Overall, our method provides a reliable tool for simulating differential expression signatures. The data simulated by our tool encompass a wide spectrum of possibilities to challenge and evaluate existing methods to estimate connectivity scores. This may represent a critical gap in connectivity-based drug repurposing research because reliable benchmarking data are essential for assessing and advancing in the development of new algorithms. The simulation tool is available as a R package (General Public License (GPL) license) at https://github.com/cgonzalez-gomez/cosimu. [ABSTRACT FROM AUTHOR]

Hepatitis C virus infection affects over 58 million individuals and is responsible for 290,000 annual deaths. The infection spread in the past via blood transfusion and iatrogenic transmission due to the use of non-sterilized glass syringes mostly in developing countries (Cameroon, Central Africa Republic, Egypt) but even in Italy. High-income countries have achieved successful results in preventing certain modes of transmission, particularly in ensuring the safety of blood and blood products, and to a lesser extent, reducing iatrogenic exposure. Conversely, in low-income countries, unscreened blood transfusions and non-sterile injection practices continue to play major roles, highlighting the stark inequalities between these regions. Currently, injection drug use is a major worldwide risk factor, with a growing trend even in low- and middle-income countries (LMICs). Emerging high-risk groups include men who have sex with men (MSM), individuals exposed to tattoo practices, and newborns of HCV-infected pregnant women. The World Health Organization (WHO) has proposed direct-acting antiviral (DAA) therapy as a tool to eliminate infection by interrupting viral transmission from infected to susceptible individuals. However, the feasibility of this ambitious and overly optimistic program generates concern about the need for universal screening, diagnosis, linkage to care, and access to affordable DAA regimens. These goals are very hard to reach, especially in LMICs, due to the cost and availability of drugs, as well as the logistical complexities involved. Globally, only a small proportion of individuals infected with HCV have been tested, and an even smaller fraction of those have initiated DAA therapy. The absence of an effective vaccine is a major barrier to controlling HCV infection. Without a vaccine, the WHO project may remain merely an illusion. [ABSTRACT FROM AUTHOR]

Drug poisoning is an important area of study in South Africa as a treatable cause of mortality. While research has been conducted on poisoning, there is a paucity of literature on the availability of antidotes in South Africa. The objectives of this study were to assess the availability of antidotes in selected teaching hospitals in the Southern Gauteng City-Region and to explore doctors' experiences of antidote supply. The availability of antidotes in the emergency departments (EDs) and pharmacies was assessed and recorded using a data sheet that was completed in person at each of the teaching hospitals. A questionnaire exploring experiences of antidote supply was distributed to 126 doctors working in the EDs. Our results indicate that N-acetylcysteine, atropine, diazepam, clonazepam, sodium bicarbonate, vitamin K, calcium gluconate, naloxone, ethanol, and pyridoxine were present in all EDs; activated charcoal was present in 80%; lorazepam, glycopyrrolate, and calcium chloride in 60%; freeze-dried plasma in 40%; glucagon and desferrioxamine in 20%; and fresh frozen plasma, hydroxocobalamin, sodium nitrite, sodium thiosulfate, sodium calcium edetate, and intralipid were not present in any of the EDs. Doctors reported organophosphate poisoning and paracetamol overdose as the most common drug poisonings (81.7% and 14.3% of 126 respondents, respectively). Most doctors experienced no supply issues for N-acetylcysteine, calcium gluconate, sodium bicarbonate, or pyridoxine (85.7%, 83.3%, 87.3%, and 75.4% of 126 respondents, respectively). The antidotes to the most common poisonings reported by doctors were present in all EDs. However, concerns were raised about consistency of supply, which will be an important avenue for further research. [ABSTRACT FROM AUTHOR]

Purpose: An expanded access clinical trials (EACTs) provides exceptional patient access to investigational new drugs for life-threatening diseases for which no effective treatment exists. Based on public information, we have studied EACTs since 2016, when the EACT system was launched in Japan. In this study, we investigated the reality of EACTs by interviewing pharmaceutical companies and clarifying how they view them. Patients and Methods: We conducted semi-structured interviews with 10 pharmaceutical companies developing new drugs. This study aims to clarify the status of EACTs, so we selected pharmaceutical companies that develop innovative drugs for which they may perform EACTs (however, experience in conducting EACTs was optional). Results: All those surveyed were aware of EACTs. Twelve access clinical trials were conducted, and the EACT implementation rate for pivotal clinical trials was 2.5%. The most common reason for implementing an EACT was "requests from physicians and medical institutions" (nine companies, 90.0%), and the most common reason for not implementing an EACT was "the applicability of the system" (five companies). Improvements to EACTs were identified by eight companies (80.0%); financial assistance by six companies (60.0%); reducing the scope of data to be collected and simplifying the procedure by six companies (60.0%). Seven companies (70.0%) responded that a Single Patient Investigational New Drug Application should be conducted, suggesting that the system should be revised. Conclusion: An interview survey of ten pharmaceutical companies developing new drugs in Japan regarding expanded access clinical trials indicated that there were issues with the system. Many wished to improve the system by establishing a single patient access system, supporting resources, and simplifying procedures. Based on our interviews with 10 Japanese pharmaceutical companies, it was found that the system needed to be improved by introducing a single patient access system, providing supporting resources, and simplifying procedures. In Japan, about eight years have passed since EACT was established, and it appears a revision of the EACT legislation is due. [ABSTRACT FROM AUTHOR]

Solid organ transplant (SOT) recipients are particularly susceptible to infections caused by multidrug-resistant organisms (MDRO) and are often the first to be affected by an emerging resistant pathogen. Unfortunately, their prevalence and impact on morbidity and mortality according to the type of graft is not systematically reported from high-as well as from low and middle-income countries (HIC and LMIC). Thus, epidemiology on MDRO in SOT recipients could be subjected to reporting bias. In addition, screening practices and diagnostic resources may vary between countries, as well as the availability of new drugs. In this review, we aimed to depict the burden of main Gram-negative MDRO in SOT patients across HIC and LMIC and to provide an overview of current diagnostic and therapeutic resources. [ABSTRACT FROM AUTHOR]

Ropeginterferon-alfa2b (ropegIFNα2b) is a long-acting IFN formulation with broad FDA/EMA approval as a therapy of polycythemia vera (PV) with no symptomatic splenomegaly. There is currently lack of information on the real-world patient selection, including the impact of local reimbursement policies, and drug management, particularly: type/timing of screening and follow-up tests; absolute/relative contraindications to therapy; ropegIFNα2b dose and combinations with hydroxyurea. As a sub-analysis of the PV-ARC retrospective study (NCT06134102), we here report our monocenter experience with ropegIFNα2b in the period from January 2021, corresponding to drug availability outside clinical trial, and December 2023. Among the 149 patients with EMA/FDA indication, only 55 (36.9%) met the local reimbursement criteria and 18 (12.1%) received ropegIFNα2b. Thanks to appropriate screening, relative/absolute contraindications to ropegIFNα2b were detected and managed in a multidisciplinary manner. Efficacy and safety of ropegIFNα2b was confirmed, with 3 cases of early molecular response. General use of low ropegIFNα2b dose, with frequent need for hydroxyurea combinations, was noted. This real-world experience suggests a significant impact of local regulations on drug prescription and the need for greater real-world data collection on ropegIFNα2b in PV patients. Also, it describes appropriate multidisciplinary screening and monitoring procedures during ropegIFNα2b therapy. [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]

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]

Duration of overall survival in patients with cancer has lengthened due to earlier detection and improved treatments. However, these improvements have created challenges in assessing the impact of newer treatments, particularly those used early in the treatment pathway. As overall survival remains most decision-makers' preferred primary endpoint, therapeutic innovations may take a long time to be introduced into clinical practice. Moreover, it is difficult to extrapolate findings to heterogeneous populations and address the concerns of patients wishing to evaluate everyday quality and extension of life. There is growing interest in the use of surrogate or interim endpoints to demonstrate robust treatment effects sooner than is possible with measurement of overall survival. It is hoped that they could speed up patients' access to new drugs, combinations, and sequences, and inform treatment decision-making. However, while surrogate endpoints have been used by regulators for drug approvals, this has occurred on a case-by-case basis. Evidence standards are yet to be clearly defined for acceptability in health technology appraisals or to shape clinical practice. This article considers the relevance of the use of surrogate endpoints in cancer in the UK context, and explores whether collection and analysis of real-world UK data and evidence might contribute to validation. [ABSTRACT FROM AUTHOR]

The number of new HIV cases worldwide has gradually declined; however, South African adolescent females and young women continue to account for the most infections. Although the availability and accessibility of antiretroviral drugs have improved the survival rates of women, some still transmit HIV to their children despite the availability of HIV prevention interventions, resulting in a dual responsibility for the care of themselves and their infected children. This study aims to explore the challenges experienced by caregivers of HIV-infected children in Limpopo Province. The study employed qualitative, exploratory, and descriptive designs, and data was collected from 12 caregivers through semi-structured interviews. Data were analysed using Tesch's eight steps of analysis. The study identified three challenges facing caregivers of HIV-positive children. Caregivers struggled with disclosure and stigma, finding it difficult to reveal the child's HIV status. The burden of care was significant, including the management of the child's unstable health, ensuring compliance with treatment, and attending frequent hospital visits. The unemployment rate posed a financial burden, particularly in arranging hospital travel costs and providing adequate nutrition to HIV-infected children. These challenges highlight the need for increased support for caregivers of HIV-infected children, including education and awareness campaigns to reduce stigma. Policymakers should consider providing financial support to caregivers. A holistic, multisectoral approach involving healthcare, education, social services, and policymakers is essential. [ABSTRACT FROM AUTHOR]

The European Medicines Agency (EMA) and European national/regional health technology assessment (HTA) organizations consider the availability of existing treatments when evaluating a new drug. Since disagreement about the availability of alternative treatments may impact patient access to new drugs, this study aimed to investigate whether the EMA and HTA organizations agreed on the availability of alternative treatments and whether a lack of alternative treatments was associated with HTA organizations' added benefit assessment outcomes. For 97 innovative drugs authorized in 2019–2021 (excluding vaccines and diagnostic tools), assessments by the EMA and AEMPS (Spain), AIFA (Italy), HAS (France), IQWiG/G‐BA (Germany), NICE (England and Wales), and ZIN (the Netherlands) were identified. Until 1 June 2022, 429 HTA drug‐indication combinations were identified for these 97 drugs, of which 205 exactly matched the EMA's indication. For those, the overall agreement between the EMA and HTA organizations on whether alternative treatments were available was 87%. The agreement of HTA organizations with the EMA on whether available treatments were either pharmacological on‐label, pharmacological off‐label, or non‐pharmacological was 87%, 21%, and 57%, respectively. For all 429 HTA drug‐indication combinations, absence of alternative treatments as considered by HTA organizations was associated with a higher chance to provide added benefit: risk ratio 1.8 (95%‐CI 1.4–2.3). In conclusion, although there was high overall agreement between the EMA and HTA organizations about whether alternative treatments exist, there were differences in the types of treatment considered. Parallel joint scientific consultations could inform drug developers about relevant alternative treatments to facilitate patient access to innovative drugs. [ABSTRACT FROM AUTHOR]

Background: Despite the availability of chemotherapy drugs such as 5-fluorouracil (5-FU), the treatment of some cancers such as gastric cancer remains challenging due to drug resistance and side effects. This study aimed to investigate the effect of celastrol in combination with the chemotherapy drug 5-FU on proliferation and induction of apoptosis in human gastric cancer cell lines (AGS and EPG85-257). Materials and Methods: In this in vitro study, AGS and EPG85-257 cells were treated with different concentrations of celastrol, 5-FU, and their combination. Cell proliferation was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The synergistic effect of 5-FU and celastrol was studied using Compusyn software. The DNA content at different phases of the cell cycle and apoptosis rate was measured using flow cytometry. Results: Co-treatment with low concentrations (10% inhibitory concentration (IC10)) of celastrol and 5-FU significantly reduced IC50 (p < 0.05) so that 48 h after treatment, IC50 was calculated at 3.77 and 6.9 μM for celastrol, 20.7 and 11.6 μM for 5-FU, and 5.03 and 4.57 μM for their combination for AGS and EPG85-257 cells, respectively. The mean percentage of apoptosis for AGS cells treated with celastrol, 5-FU, and their combination was obtained 23.9, 41.2, and 61.9, and for EPG85-257 cells 5.65, 46.9, and 55.7, respectively. In addition, the 5-FU and celastrol-5-FU combination induced cell cycle arrest in the synthesis phase. Conclusions: Although celastrol could decrease the concentration of 5-fluorouracil that sufficed to suppress gastric cancer cells, additional studies are required to arrive at conclusive evidence on the anticancer effects of celastrol. [ABSTRACT FROM AUTHOR]

Purpose: To characterize trends in use of and expenditure for the intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents aflibercept, ranibizumab, and bevacizumab among the population enrolled in Original Medicare from 2014 to 2019. Methods: The Centers for Medicare and Medicaid Services Physician and Other Supplier Public Use File was used to extract Medicare Part B fee-for-service outpatient injection claims data submitted by ophthalmologists. Multivariable linear regression models were used to evaluate the association between reimbursement, ophthalmologist availability, and agent administration rate. Results: Between 2014 and 2019, 17,588,995 intravitreal injection claims were filed by 4218 US ophthalmologists. Medicare costs for anti-VEGF injections increased from 2.51 B USD in 2014 to 4.02 B USD in 2019. Increased state-level ophthalmologist availability and incremental increases in average reimbursement amounts were found to be significantly associated with a 6.8-fold variation in 2019 overall anti-VEGF injection rates across states. Conclusions: Medicare injection rates and costs for anti-VEGF injections have both increased between 2014 and 2019, largely driven by increased aflibercept use. There is a significant association between ophthalmologist availability and anti-VEGF injection rate on the state level, suggesting access to care may contribute to the observed state-level disparities in intravitreal injection rates. Further characterization of factors contributing to the state-level variation in injection rates of individual anti-VEGF agents may help inform interventions promoting equitable access to and use of these drugs. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a challenging treatment landscape, due to its complex pathogenesis and limited availability of clinical drugs. Ferroptosis, an iron-dependent form of programmed cell death (PCD), stands distinct from apoptosis, necrosis, autophagy, and other cell death mechanisms. Recent studies have increasingly highlighted the role of iron deposition, reactive oxygen species (ROS) accumulation, oxidative stress, as well as systemic Xc- and glutamate accumulation in the antioxidant system in the pathogenesis of amyotrophic lateral sclerosis. Therefore, targeting ferroptosis emerges as a promising strategy for amyotrophic lateral sclerosis treatment. This review introduces the regulatory mechanism of ferroptosis, the relationship between amyotrophic lateral sclerosis and ferroptosis, and the drugs used in the clinic, then discusses the current status of amyotrophic lateral sclerosis treatment, hoping to provide new directions and targets for its treatment. [ABSTRACT FROM AUTHOR]

This study analyzed measures aggregated at the school level to identify key predictors of drinking alcohol, binge drinking, smoking cigarettes, and using marijuana. Using data collected from 6th through 12th grade students between 2011 and 2015, we identify school-level variables that predict school-level prevalence in the subsequent year. Data included prior year assessments of: (1) school-wide prevalence, (2) perceived ease of access to drugs, (3) perceived adult disapproval of drug use, (4) perceived peer disapproval of drug use, and (5) perceived prevalence of drug use. We regressed grade-level behaviors on predictor variables from the previous school year. In middle schools, prior grade prevalence and prior grade perceived norms were significant predictors of subsequent grade prevalence. For high schools, prior year prevalence, aggregated peer norms, and perceived ease of access predicted subsequent use. These analyses provide evidence that a school's culture is predictive of changes in prevalence over time. [ABSTRACT FROM AUTHOR]