Therapy For Disease Research Articles

Effect of rosuvastatin versus atorvastatin on new-onset diabetes mellitus in patients treated with high-intensity statin therapy for coronary artery disease: a post-hoc analysis from the LODESTAR randomized clinical trial

BackgroundThe impact of rosuvastatin versus atorvastatin on new-onset diabetes mellitus (NODM) among patients treated with high-intensity statin therapy for coronary artery disease (CAD) remains to be clarified. This study aimed to evaluate the risk of NODM in patients with CAD treated with rosuvastatin compared to atorvastatin in the randomized LODESTAR trial.MethodsIn the LODESTAR trial, patients with CAD were randomly assigned to receive either rosuvastatin or atorvastatin using a 2-by-2 factorial randomization. In this post-hoc analysis, the 3-year incidence of NODM was compared between rosuvastatin and atorvastatin treatment in the as-treated population with high-intensity statin therapy as the principal population of interest.ResultsAmong 2932 patients without diabetes mellitus at baseline, 2377 were included in the as-treated population analysis. In the as-treated population with high-intensity statin therapy, the incidence of NODM was not significantly different between the rosuvastatin and atorvastatin groups (11.4% [106/948] versus 8.8% [73/856], hazard ratio [HR] = 1.32, 95% confidence interval [CI] = 0.98 to 1.77, P = 0.071). When the risk of NODM with rosuvastatin versus atorvastatin was assessed according to the achieved low-density lipoprotein cholesterol (LDL-C) level, the risk of NODM began to increase at a LDL-C level below 70 mg/dL. The incidence of NODM was significantly greater in the rosuvastatin group than it was in the atorvastatin group when the achieved LDL-C level was < 70 mg/dL (13.9% versus 8.0%; HR = 1.79, 95% CI 1.18 to 2.73, P = 0.007).ConclusionsAmong CAD patients receiving high-intensity statin therapy, the incidence of NODM was not significantly different between rosuvastatin and atorvastatin. However, a drug effect of the statin type on NODM was observed when the achieved LDL-C level was < 70 mg/dL.Trial registrationClinicalTrials.gov, Identifier: NCT02579499.Graphical abstract

Shared decision-making in selecting modality of renal replacement therapy confers better patient prognosis after the initiation of dialysis.

The effect of shared decision-making (SDM) regarding the choice of renal replacement therapy (RRT) for chronic kidney disease (CKD) patients on their mortality after the induction of dialysis therapy has not been adequately investigated. Patients who initiated dialysis at our hospital were divided into two groups according to whether they participated in SDM in the outpatient clinic, and survival analysis was performed. We also examined the effect of SDM in the outpatient clinic on mortality. Of the 554 patients, 123 (22.2%) were in the SDM group. The survival rate was significantly higher in the SDM group (p = 0.001, log-rank test). Multivariate analysis excluding ADL, which competed with SDM, showed that SDM was significantly associated with mortality (HR 0.593, 95% CI: 0.353-0.997, p = 0.049). SDM regarding RRT selection in the outpatient clinic may be associated with a better patient prognosis after dialysis induction.

Active Surface-Enhanced Raman Spectroscopy (SERS): A Novel Concept for Enhancing Signal Contrast in Complex Matrices Using External Perturbation.

Noninvasive detection of surface-enhanced Raman spectroscopy (SERS) signals from deep within tissue represents a common challenge in many biological and clinical applications including disease diagnosis and therapy monitoring. Such signals are typically weak and not readily discernible from often much larger Raman and fluorescence background signals (e.g., from surrounding tissue). Consequently, suboptimal sensitivity in the detection of SERS signals is often achieved in these situations. Similar issues can arise in SERS measurements in other diffusely scattering samples and complex matrices. Here, we propose a novel concept, active SERS, for the efficient retrieval of SERS signals from deep within complex matrices such as biological tissues that mitigates these issues. It relies on applying an external perturbation to the sample to alter the SERS signal from nanoparticles (NPs) deep inside the matrix. A measurement with and without, or before and after, such perturbation then can provide powerful contrasting data enabling an effective elimination of the matrix signals to reveal more clearly the desired SERS signal without the interfering background and associated artifacts. The concept is demonstrated using ultrasound (US) as an external source of perturbation and SERS NPs inserted deep within a heterogeneous tissue phantom mimicking a cluster of NPs accumulated within a small target lesion. The overall SERS signal intensity induced by the applied US perturbation decreased by ∼21% and the SERS signal contrast was considerably improved by eliminating subtraction artifacts present in a conventional measurement performed at a neighboring spatial location in a heterogeneous tissue sample. Although the technique was demonstrated with SERS gold NPs with a standard Raman label, it is envisaged that active SERS NPs (both the nanoscale metal geometry and Raman label) could be specifically designed to deliver an augmented response to the external stimulus to further enhance the achievable SERS signal contrast and yield even greater improvement in detection sensitivity. The method was demonstrated using transmission Raman spectroscopy; however, it is also applicable to other Raman implementations including spatially offset Raman spectroscopy and conventional Raman spectroscopy performed both at depth and at surfaces of complex matrices.

Advancements and challenges in CAR T cell therapy in autoimmune diseases.

Chimeric antigen receptor (CAR) T cells are highly effective at targeting and eliminating cells of the B cell lineage. CAR T cell therapy has become a standard-of-care treatment for patients with relapsed or refractory B cell malignancies. In addition, the administration of genetically modified T cells with the capacity to deplete B cells and/or plasma cells has tremendous therapeutic potential in autoimmune diseases. In the past few years, CD19-based and B cell maturation antigen (BCMA)-based CAR T cell therapies have been applied to various B cell-mediated autoimmune diseases including systemic lupus erythematosus, idiopathic inflammatory myopathy, systemic sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis and multiple sclerosis. The scientific rationale behind this approach is that deep depletion of B cells, including autoreactive B cell clones, could restore normal immune function, referred to as an immune reset. In this Review, we discuss important aspects of CAR T cell therapy in autoimmune disease, including considerations relating to patient selection, safety, efficacy and medical management. These considerations are based on the early experiences of CAR T cell therapy in autoimmune diseases, and as the field of CAR T cell therapy in autoimmune diseases continues to rapidly evolve, these issues will remain subject to ongoing refinement and adaptation.

Potential Add-On Benefits of Dietary Intervention in the Treatment of Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of renal failure. The pathogenesis of the disease encompasses several pathways and metabolic alterations, including the hyperactivation of mTOR and suppression of AMPK signaling pathways, as well as mitochondrial dysfunction. This metabolic reprogramming makes epithelial cyst-lining cells highly dependent on glucose for energy and unable to oxidize fatty acids. Evidence suggests that high-carbohydrate diets may worsen the progression of ADPKD, providing the rationale for treating ADPKD patients with calorie restriction and, in particular, with ketogenic dietary interventions, already used for other purposes such as in overweight/obese patients or in the treatment of refractory epilepsy in children. Preclinical studies have demonstrated that calorie restriction may prevent and/or slow disease progression by inducing ketosis, particularly through increased beta-hydroxybutyrate (BHB) levels, which may modulate the metabolic signaling pathways altered in ADKPK. In these patients, although limited, ketogenic intervention studies have shown promising beneficial effects. However, larger and longer randomized controlled trials are needed to confirm their tolerability and safety in long-term maintenance and their additive role in the therapy of polycystic kidney disease.

Clonal hematopoiesis, cardiovascular events and treatment benefit in 63,700 individuals from five TIMI randomized trials.

Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with an increased risk of cardiovascular (CV) disease in the general population. Currently, it is unclear whether this association is observed in large clinical trial cohorts with a high burden of existing CV disease or whether CV therapies can mitigate CHIP-associated CV risk. To address these questions, we studied 63,700 patients from five randomized trials that tested established therapies for CV disease, including treatments targeting the proteins PCSK9, SGLT2, P2Y12 and FXa. During a median follow-up of 2.5 years, 7,453 patients had at least one CV event (CV death, myocardial infarction (MI), ischemic stroke or coronary revascularization). The adjusted hazard ratio (aHR) for CV events for CHIP+ patients was 1.07 (95% CI: 0.99-1.16, P = 0.08), with consistent risk estimates across each component of CV risk. Significant heterogeneity in the risk of MI was observed, such that CHIP+ patients had a 30% increased risk of first MI (aHR = 1.31 (1.05-1.64), P = 0.02) but no increased risk of recurrent MI (aHR = 0.94 (0.79-1.13), Pint = 0.008), as compared to CHIP- patients. Moreover, no significant heterogeneity in treatment effect between individuals with and without CHIP was observed for any of the therapies studied in the five trials. These results indicate that in clinical trial populations, CHIP is associated with incident but not recurrent coronary events and that the presence of CHIP does not appear to identify patients who will derive greater benefit from commonly used CV therapies.

Dendritic cells transfected with DNA constructs encoding CCR9, IL-10, and type II collagen demonstrate induction of immunological tolerance in an arthritis model

IntroductionRestoring immune tolerance is a promising area of therapy for autoimmune diseases. One method that helps restore immunological tolerance is the approach using tolerogenic dendritic cells (tolDCs). In our study, we analyzed the effectiveness of using dendritic cells transfected with DNA constructs encoding IL-10, type II collagen, and CCR9 to induce immune tolerance in an experimental model of arthritis.MethodsDendritic cell cultures were obtained from bone marrow cells of Balb/c mice. Dendritic cells (DCs) cultures were transfected with pmaxCCR9, pmaxIL-10, and pmaxCollagen type II by electroporation. The phenotype and functions of DCs were studied using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Migration of electroporated DCs was assessed in vitro. Induction of antigen-collagen induced arthritis (ACIA) was carried out according to the protocol in Balb/c mice. DCs were then administered to ACIA mice. The development of arthritis was monitored by measuring paw swelling with a caliper at different time points. The immunological changes were assessed by analyzing the content of antibodies to type II collagen using enzyme immunoassay. Additionally, a histological examination of the joint tissue was conducted, followed by data analysis.The results are as followsDCs were obtained, characterized by reduced expression of CD80, CD86, and H-2Db (MHC class I), increased expression of CCR9, as well as producing IL-10 and having migratory activity to thymus cells. Transfected DCs induced T-regulatory cells (T-reg) and increased the intracellular content of IL-10 and TGF-β in CD4+T cells in their co-culture, and also suppressed their proliferative activity in response to antigen. The administration of tolDCs transfected with DNA constructs encoding type II collagen, IL-10, and CCR9 to mice with ACIA demonstrated a reduction in paw swelling, a reduction in the level of antibodies to type II collagen, and a regression of histological changes.ConclusionThe study presents an approach by which DCs transfected with DNA constructs encoding epitopes of type II collagen, IL-10 and CCR9 promote the development of antigen-specific tolerance, control inflammation and reduce the severity of experimental arthritis through the studied mechanisms: induction of T-reg, IL-10, TGF-β.

The Double-Edged Sword of Extremely High Prices for Gene Therapies in Sickle Cell Disease.

This Viewpoint discusses the high cost of new gene therapies for sickle cell disease, the challenges these costs pose for health care access, and new policy approaches to ensure fair reimbursement for payers and manufacturers without further increasing health care costs or barriers to access for underserved populations.

Cell‐Anchored Lead‐Free Piezoelectric KNN NPs Resisting Washout for Low‐Intensity Ultrasound Driven Neuromodulation

AbstractPiezoelectric nanomaterials for wireless neuromodulation is a promising alternative to traditional electrical stimulation. However, the low‐avidity between piezoelectric nanomaterials and cellular membranes leads to low efficiency of electrical signal transmission, which requires high‐intensity thresholds of ultrasound stimulation (US). Here, lead‐free piezoelectric (K,Na)NbO3 (KNN) nanoparticles (NPs) with cholesterol coating (KNNC) are presented, in which Cholesterol can be accommodated in the membrane and make them append on the plasma membrane. Compared to non‐modified nanoparticles, cell‐anchored KNNC NPs highly resist convective washout owing to high affinity of cholesterol to biological membranes, which enables highly efficient wireless electrical stimulation to activate cell impulses under low‐intensity ultrasound. Meanwhile, after perfusion washing, the KNNC NPs distributed around the cells are washed away, while part of KNNC NPs remain on the surface of cell membrane still can induce significant Ca2+ influx under US, similar to the group without washing, indicating the KNNC NPs appended on the cell play a major role in wireless electrical stimulation. Furthermore, the highly efficient electrical transmission of KNNC enables neural differentiation of stem cells in regulating synaptic plasticity by modulating Ca2+ influx, demonstrating that KNNC NPs offer a perspective toward minimally invasive wireless neuromodulation therapies for neurological diseases.

Clinical Evidence Supporting FDA Approval of Gene and RNA Therapies for Rare Inherited Conditions.

Gene and RNA therapies have potential to transform the treatment of rare inherited diseases, but there are concerns about the evidence supporting their use and high costs. We analyze the evidence supporting Food and Drug Administration (FDA) approval of gene and RNA therapies for rare inherited diseases and discuss implications for clinical practice and policy. We conducted a qualitative analysis of FDA documents outlining the basis of approval for gene and RNA therapies approved for rare inherited diseases between 2016 and 2023. For each drug, we gathered five characteristics of the evidence supporting FDA approval (no phase 3 trial, nonrandomized, no clinical endpoint, lack of demonstrated benefit, and significant protocol deviation) and four characteristics of the FDA approval process (prior rejection or complete response, negative committee vote, discrepancy between label and trial population, and boxed warning). The main outcome was the number of drugs with each characteristic. Between 2016 and 2023, 19 gene and RNA therapies received FDA approval to treat rare inherited diseases. The most common limitations in the evidence supporting approval of these drugs were nonrandomized studies (8/19, 42%), no clinical endpoint (7/19, 37%), lack of demonstrated benefit or inconsistent results (4/19, 21%), and no phase 3 trial (4/19, 21%). Half (3/6) of accelerated approvals and 57% (5/9) of drugs with breakthrough designation had nonrandomized trials, and gene therapies with one-time dosing were overrepresented (5/7, 71%) among the drugs with nonrandomized trials. Five of six accelerated approvals (83%) and five of nine pediatric drugs (56%), most of which were indicated for Duchenne muscular dystrophy, had no clinical endpoint. Four of nine (44%) pediatric drugs and four of six (67%) accelerated approvals failed to demonstrate benefit compared with none of the nonpediatric drugs and none of the traditional approvals. Five drugs, which all had different indications and represented a mix of RNA and gene therapies, did not have any of these evidence characteristics. Among drugs that received prior rejections or negative committee opinions, all four had nonrandomized trials and lacked a clinical endpoint, and 75% (3/4) lacked demonstrated benefit. Five of nine (56%) pediatric drugs were indicated for broader age groups according to the drug label compared with the trial populations. Of the three drugs with boxed warnings, two had pediatric indications and nonrandomized studies, and one had no phase 3 trial. Issues related to trial design, outcome, and data integrity in the evidence supporting FDA approval of rare inherited disease gene and RNA therapies raise questions about whether this evidence is adequate to inform prescribing decisions. Gene and RNA therapies with accelerated approval and pediatric indications were overrepresented among drugs lacking clinical endpoints or demonstrated benefit and should be the focus of efforts to reduce uncertainty in the evidence.

Dynamic chest radiographic evaluation of the effects of tiotropium/olodaterol combination therapy in chronic obstructive pulmonary disease: the EMBODY study protocol for an open-label, prospective, single-centre, non-controlled, comparative study

IntroductionTo date, there is limited evidence on the effects of bronchodilators on respiratory dynamics in chronic obstructive pulmonary disease (COPD). Dynamic chest radiography (DCR) is a novel radiographic modality that...

A dual methodology employing ion-pair chromatography and built-in UV spectrophotometry for quantifying recently approved combination of mometasone and indacaterol in a novel combined metered dose inhaler: assessing the greenness, carbon footprint, blueness, and whiteness

Developing analytical techniques that align with green and sustainable chemistry principles is crucial in today's scientific landscape. This work introduces two innovative approaches for the simultaneous quantification of indacaterol (IND) and mometasone (MOM), a recently approved combination therapy for chronic obstructive pulmonary disease. These methods—rapid isocratic ion pair chromatography (IPC) and UV–visible spectrophotometry—demonstrate improved environmental sustainability, cost-effectiveness, and versatility compared to existing techniques. The optimized 4-min IPC method achieved excellent resolution (retention times 2.18 ± 0.1 min for IND and 3.95 ± 0.1 min for MOM), peak symmetry, and sensitivity. It utilizes a low-cost ion pair mobile phase of acetonitrile and acidified water containing 0.025% sodium dodecyl sulfate (50:50% v/v), making it suitable for laboratories with standard chromatographic instruments. The spectrophotometric approach offers two procedures: first derivative and ratio derivative methods. These serve as simplified, low-cost alternatives for resource-limited laboratories without access to advanced instruments. Both techniques feature simplified protocols that minimize extraction and fractionation steps. Comprehensive validation confirmed outstanding accuracy (98–102%) and precision (%2 <). Sustainability assessments using ComplexGAPI, AGREE, carbon footprint, BAGI, and RGB12 tools demonstrated enhanced environmental performance compared to existing methods. The IPC and spectrophotometry methods achieved greenness scores of 0.81 and 0.85, respectively, surpassing the 0.63–0.67 range of reported techniques. Additionally, they showed lower carbon footprints of 0.035 and 0.022 kg CO2 equivalent emissions per sample, compared to 0.079–0.092 kg for conventional procedures. The application of novel "blueness" and "whiteness" concepts using BAGI and RGB12 algorithms further confirmed superior sustainability, with scores of 87.5 & 90 for blueness and 88.1 & 89.8 for whiteness. Successfully applied to quantify IND and MOM in combined capsules, this work provides a model for eco-friendly pharmaceutical analysis that maintains high analytical reliability while improving sustainability metrics.

Meeting Report: 2023 Muscular Dystrophy Association Summit on ‘Safety and Challenges in Gene Therapy of Neuromuscular Diseases’

This meeting report summarizes the presentations and discussions held at the summit on Challenges in Gene Therapy hosted by the Muscular Dystrophy Association (MDA) in 2023. Topics covered include safety issues, mitigation strategies and practical considerations pertaining to the clinical translation of gene therapies for neuromuscular disease. The listing of actionable recommendations will assist in overall efforts in the field to achieve safe and efficacious translation of gene therapies for neuromuscular disease patients.

The Roles of RNA N6-methyladenosine Modifications in Systemic Lupus Erythematosus.

N6-methyladenosine (m6A) modification is the most widespread RNA internal modification involved in RNA metabolism. M6A regulators consist of writers, erasers and readers. They exert their function by methylation, demethylation and recognization respectively, participating in cell biology and immune responses. Previously, the focus of m6A modification is its effect on tumor progress. Currently, extensive m6A-related studies have been performed in autoimmune diseases, such as RA, IBD and SLE, revealing that the unique influence of m6A modification in autoimmunity is undeniable. In this review, we summarize the function of m6A regulators, analyze their roles in pathogenic immune cells, summarize the m6A modification in SLE, and provide the potential m6A-targeting therapies for autoimmune diseases.

Impact of guideline directed medical therapy on myocardial function in adults with congenital heart disease

BackgroundGuideline-directed heart failure therapy with angiotensin receptor blocker/neprilysin inhibitor (ARNi) and sodium-glucose transporter inhibitors (SGLT2i) has been incrementally beneficial in improving outcomes in heart failure patients. ObjectiveEvaluate the feasibility and efficacy of guideline-directed medical therapy (GDMT) in adults congenital heart disease (ACHD) patients. MethodsIn a retrospective cohort study, 46 ACHD patients with either New York Heart Association (NYHA) Class II symptoms or systemic ejection fraction (EF) <45%, optimized on a combination of beta-blocker (BB), ARNi, mineralocorticoid receptor antagonist (MRA) and SGLT2i were evaluated. ResultsForty-six patients with a mean age 42.6 ± 12.1 years prescribed GDMT were identified. Twenty-eight (61%) were male, 20 (43%) had a systemic right ventricle (RV) and 9 (20%) had single-ventricle physiology. Over the optimization period, 20 (43%) were sustained on ARNi and 42 (91%) on SGLT2i in addition to treatment with BB and MRA. Over a period of 45 weeks, echocardiography parameters for left ventricle (LV) ejection fraction (EF) (+7.5%, p = 0.006), systemic ventricle (SV) velocity time integral (VTI) (+1.9 cm, p = 0.012) and LV global longitudinal strain (GLS) (−2.5%, p = 0.005) improved when 3–4 medications were used versus 1–2 medications alone. The use of either ARNi or SGLT2i (+8.1%, p = 0.017) or in combination (+7.0%, p = 0.043) increased LVEF compared to the use of neither medication. ConclusionCombination GDMT is beneficial in improving myocardial characteristics in ACHD patients with systemic RV and LV.

Recent advances in measuring the effects of diet on gastrointestinal physiology: Sniffing luminal gases and fecal volatile organic compounds.

Despite the huge pool of ideas on how diet can be manipulated to ameliorate or prevent illnesses, our understanding of how specific changes in diet influence the gastrointestinal tract is limited. This review aims to describe two innovative investigative techniques that are helping lift the veil of mystery about the workings of the gut. First, the gas-sensing capsule is a telemetric swallowable device that provides unique information on gastric physiology, small intestinal microbial activity, and fermentative patterns in the colon. Its ability to accurately measure regional and whole-gut transit times in ambulant humans has been confirmed. Luminal concentrations of hydrogen and carbon dioxide are measured by sampling through the gastrointestinal tract, and such application has enabled mapping of the relative amounts of fermentation of carbohydrates in proximal-versus-distal colon after manipulation of the types and amounts of dietary fiber. Second, changes in the smell of feces, via analysis of volatile organic compounds, occur in response to the diet, and by the presence and therapy of irritable bowel syndrome and inflammatory bowel disease. Such information is likely to aid our understanding of what dietary change can do to the colonic luminal microenvironment, and may value-add to diagnosis and therapeutic design. In conclusion, such methodologies enable a more complete physiological profile of the gastrointestinal tract to be created. Systematic description in various cohorts and effects of dietary interventions, particularly when co-ordinated with the analysis of microbiome, are needed.

Revolutionary breakthrough: FDA approves CASGEVY, the first CRISPR/Cas9 gene therapy for sickle cell disease

Sickle cell disease (SCD) is a hereditary hemoglobinopathy resulting from a β-globin chain mutation that causes abnormal hemoglobin (HbS) polymerization and leads to severe complications. Current treatment options primarily focus on symptom management, with limited curative potential. Recently, Casgevy, the first CRISPR/Cas9-based gene therapy for SCD, has received breakthrough FDA approval. Clinical trials have shown that Casgevy administered to patients aged older than or equal to 12 years enables precise modifications in hematopoietic stem cells, resulting in elevated fetal hemoglobin (HbF) levels and a significant reduction in vaso-occlusive events. Unlike conventional treatments, this therapy offers a curative approach and eliminates the need for recurrent transfusions and transplants, thereby improving the quality of life of patients with SCD. Casgevy has emerged as a beacon of hope for SCD patients and signifies a potential paradigm shift in SCD management due to its safety, curative potential, and transformative impact, positioning it as a groundbreaking intervention. Nevertheless, ethical considerations surrounding CRISPR technology and regulatory frameworks must be addressed to ensure responsible application and equitable access to this one-time gene editing therapy. As the authors celebrate this scientific advancement, sustained interdisciplinary collaboration and ethical scrutiny are essential to navigating the evolving landscape of CRISPR technology in medicine. This review aims to provide a detailed insight into the application of Casgevy, challenges associated with its application, future prospects of this therapy, and its comparison with existing treatment options for SCD.

Isavuconazole as prophylaxis and therapy for invasive fungal diseases: a real-life observational study.

Isavuconazole is a relatively new antifungal agent indicated for the management of various invasive fungal diseases (IFDs), including invasive aspergillosis. Information on real-world experience with isavuconazole is scarce. This retrospective observational study aimed to describe the usage of isavuconazole in clinical practice with an in-depth evaluation of individual isavuconazole exposure. Patients treated with isavuconazole were evaluated based on retrospective data, including therapeutic drug monitoring (TDM) data and efficacy and safety data. Additionally, we calculated the individual isavuconazole exposure described by the average AUC24 over the first 7 days of treatment by means of non-linear mixed-effects modelling and compared this with the currently desired lower target AUC of 60 mg·h/L. Ninety-nine patients treated with isavuconazole were evaluated. In our real-life cohort, isavuconazole was often deployed off-label in patients with non-classical host factors and infections with non-Aspergillus and non-Mucorales species. Isavuconazole was most often chosen for its safety profile, even after prior triazole treatment with manifestations of toxicity. TDM and subsequent dosage adjustments were frequently performed. The individual average AUC24 over 7 days was above 60 mg·h/L in 29 out of 77 (37.7%) patients. This overview provides practical insights that can aid clinicians in the management of their patients with IFD. Our study shows that isavuconazole was used in a diverse patient population and was well tolerated overall. Individual isavuconazole exposure reflected by the average AUC24 over the first 7 days of treatment was generally low and variable. Dosage adjustments following TDM were frequently performed. Our experience shows that isavuconazole is a feasible alternative after prior azole treatment.

Potential of extracellular vesicles in the pathogenesis, diagnosis and therapy for parasitic diseases.

Parasitic diseases have a significant impact on human and animal health, representing a major hazard to the public and causing economic and health damage worldwide. Extracellular vesicles (EVs) have long been recognized as diagnostic and therapeutic tools but are now also known to be implicated in the natural history of parasitic diseases and host immune response modulation. Studies have shown that EVs play a role in parasitic disease development by interacting with parasites and communicating with other types of cells. This review highlights the most recent research on EVs and their role in several aspects of parasite-host interactions in five key parasitic diseases: Chagas disease, malaria, toxoplasmosis, leishmaniasis and helminthiases. We also discuss the potential use of EVs as diagnostic tools or treatment options for these infectious diseases.

Molecular Docking of Phytomolecules of Grain Amaranth (Amaranthus hypochondriacus) with AKR1C3Protein Involved in Prostate Cancer in Human Beings

Abstract: This study focuses on exploring how the bioactive compounds found in amaranth— phytol, squalene, and α-tocopherol—could potentially offer medicinal benefits in the context of prostate cancer. The investigation involves a docking study with AKRC13, an important target linked to the control of prostate cancer, aiming to uncover their potential effects against this disease. Costeffective and efficient cancer treatment options are crucial because of the high expenses associated with current cancer therapies as well as their side effects. Amaranth (Amaranthus hypochondriacus) is a pseudocereal crop abundant in squalene, α-tocopherol, and phytol, which shows promising foodbased therapy for various diseases, including cancer. Prostate cancer has been a significant contributor to mortality globally, but the introduction of relugolix has emerged as a crucial therapeutic intervention in its treatment. Hence, this study was conducted to investigate the interactions between grain amaranth bioactive compounds squalene, phytol, and α-tocopherol with AKRC13 protein utilizing a molecular docking approach facilitated by Autodock Vina software. Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB-PDB) (http://www.rcsb.org/) was used for retrieving the 3D crystal structure of the target protein, AKRC13 (PDB ID: 7c7f). The 3D structure of bioactive compounds squalene, phytol, and α-tocopherol were retrieved from the PubChem database, following which Open-Babel was used to change the format from .sdf to .pdb. Furthermore, pharmacokinetics characteristics were also considered along with Lipinski’s rule of five using SwissADME (http://www. Swiss adme.ch/index.php) and pkCSM (http://structure.bioc.cam.ac.uk/pkcsm), indicating their potential as a drug candidate in the initial stage. The potential anticancer properties of the ligands were predicted using PASS software. Following the completion of the docking study, it became evident that α-tocopherol demonstrated the most significant binding energy, followed by squalene and phytol, in comparison to the established drug, relugolix. This implies that the chosen bioactive compounds might possess enzyme-inhibiting properties, indicating their potential for further in vivo anticancer screening using model organisms. The findings serve as stepping stones for advancing the potential use of the discussed bioactive compounds as a potential drug candidate for prostate cancer.