ABSTRACT
BACKGROUND: Lack of trust in artificial intelligence (AI) models in medicine is still the key blockage for the use of AI in clinical decision support systems (CDSS). Although AI models are already performing excellently in systems medicine, their black-box nature entails that patient-specific decisions are incomprehensible for the physician. Explainable AI (XAI) algorithms aim to "explain" to a human domain expert, which input features influenced a specific recommendation. However, in the clinical domain, these explanations must lead to some degree of causal understanding by a clinician. RESULTS: We developed the CLARUS platform, aiming to promote human understanding of graph neural network (GNN) predictions. CLARUS enables the visualisation of patient-specific networks, as well as, relevance values for genes and interactions, computed by XAI methods, such as GNNExplainer. This enables domain experts to gain deeper insights into the network and more importantly, the expert can interactively alter the patient-specific network based on the acquired understanding and initiate re-prediction or retraining. This interactivity allows us to ask manual counterfactual questions and analyse the effects on the GNN prediction. CONCLUSION: We present the first interactive XAI platform prototype, CLARUS, that allows not only the evaluation of specific human counterfactual questions based on user-defined alterations of patient networks and a re-prediction of the clinical outcome but also a retraining of the entire GNN after changing the underlying graph structures. The platform is currently hosted by the GWDG on https://rshiny.gwdg.de/apps/clarus/.
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Decision Support Systems, Clinical , Physicians , Humans , Artificial Intelligence , Neural Networks, Computer , Algorithms , TolnaftateSubject(s)
Models, Statistical , Tolnaftate , Humans , Data Interpretation, Statistical , Treatment OutcomeABSTRACT
The eye is a complex organ with a unique physiology and anatomy. Using novel nanosystems is expected to enhance ocular drug permeation and retention. Hence, this work aimed to study the potential of flexosomes as an ocular delivery system to enhance the corneal permeation and antifungal activity of Tolnaftate (TOL). Different flexosomes formulae were formulated using ethanol injection method, employing a 31.22 full factorial design. The studied formulation variables were: X1: amount of stearyl amine, X2: hydration volume and X3: type of edge activator. Encapsulation efficiency, particle size and zeta potential were selected as dependent variables. FX5 was selected as the optimal TOL flexosomes and showed encapsulation efficiency of 66.08 ± 11.38%, particle size of 154.99 ± 29.11 nm and zeta potential of 42.95 ± 0.64 mV. FX5 was subjected to further ex vivo and in vivo studies which showed that TOL flux was significantly increased through FX5 compared to TOL suspension. Draize test and histopatholoigal tests assured that FX5 is safe to be used for eye.. The in vivo fungal susceptibility testing using Aspergillus niger demonstrated the superior and more durable antifungal activity of FX5 than TOL suspension. Hence, FX5 can be considered as promising nanocarrier for safe and efficient ocular TOL delivery.
Subject(s)
Antifungal Agents , Tolnaftate , Antifungal Agents/pharmacology , Administration, Cutaneous , Cornea , Particle Size , Drug Carriers , Drug Delivery Systems/methodsABSTRACT
Introduction: Paracoccidioidomycosis is a systemic mycosis endemic in Latin America. Climate change and host migration emphasize the need to optimize this infection diagnosis. Objective: To evaluate the implementation of Paracoccidioides spp. DNA detection in the mycological diagnosis of patients with suspected paracoccidioidomycosis. Materials and methods: It is a retrospective study with laboratory data from patients with clinical suspicion of paracoccidioidomycosis, who consulted a university hospital from a non-endemic area. Results: We analyzed the laboratory results of samples from 19 patients with suspected paracoccidioidomycosis. Seventeen out of 19 patients were born in or had visited an endemic area in Latin America. Fourteen adult male patients were confirmed to have paracoccidioidomycosis by conventional diagnosis: the direct examination was positive in 12 samples while fungal growth was found only in 4. Anti-Paracoccidioides spp. antibodies were detected in 10 patients, 8 of them with proven paracoccidioidomycosis. Nested PCR for Paracoccidioides spp. detection was performed on clinical samples from 14 patients, and positive results were obtained for 9 out of 10 patients with the conventional diagnosis of paracoccidioidomycosis. Conclusions: The incorporation of molecular techniques to detect Paracoccidioides spp. DNA complements the conventional diagnosis of paracoccidioidomycosis. This tool allows the prescription of antifungal treatment in those cases where the fungus is not observed in the clinical samples.
Introducción: La paracoccidioidomicosis es una micosis sistémica y endémica en Latinoamérica. El cambio climático y el movimiento migratorio del huésped enfatizan la necesidad de optimizar el diagnóstico de esta infección. Objetivo: Evaluar la implementación de la detección de ADN de Paracoccidioides spp. al diagnóstico micológico de pacientes con sospecha de paracoccidioidomicosis. Materiales y métodos. Estudio retrospectivo con datos de laboratorio de pacientes con sospecha de paracoccidioidomicosis en un hospital de área no endémica. Resultados: Se analizaron los resultados de las muestras de 19 pacientes con sospecha clínica de paracoccidioidomicosis. El 90 % de los pacientes había nacido o visitado un área endémica de esta micosis en Latinoamérica. En 14 pacientes varones adultos se confirmó paracoccidioidomicosis por diagnóstico convencional. El examen directo fue positivo en 12 pacientes con enfermedad comprobada y en 4 de ellos se obtuvo crecimiento del hongo. Se detectaron anticuerpos contra Paracoccidioides spp. en ocho pacientes con la enfermedad. Se realizó PCR anidada con muestras de 14 pacientes para detectar ADN de Paracoccidioides spp. En 9 de los 10 pacientes con diagnóstico convencional de paracoccidioidomicosis se obtuvo una prueba de PCR positiva. Conclusiones: La implementación de técnicas moleculares para detectar ADN de Paracoccidioides spp. complementa el diagnóstico convencional de paracoccidioidomicosis y permite instaurar el tratamiento antifúngico, sobre todo en los casos clínicos donde no se observa la presencia del hongo en las muestras clínicas. La migración actual de poblaciones humanas dificulta el diagnóstico de paracoccidioidiomicosis y otras infecciones endémicas, por lo que se requiere optimizar el diagnostico micológico en los laboratorios clínicos para tratar pacientes con este tipo micosis desatendida.
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Hospitals , Tolnaftate , Polymerase Chain ReactionABSTRACT
Introduction: Sporotrichosis is an implantation mycosis caused by Sporothrix spp. It is distributed worldwide and can be found in vegetation and soil. The most frequent route of infection is by trauma with elements contaminated with fungal propagules. Since domestic cats are the most affected animals and can transmit this infection to humans, sporotrichosis is considered a zoonosis. Clinical presentations include nodular lymphangitis, fixed cutaneous, pulmonary (rare), and disseminated (exceptional). Objectives: To analyze the epidemiology of sporotrichosis in Argentina during 2010 and 2022. To describe the clinical presentation, diagnostic methods, and treatment of cases diagnosed during this period. To know the circulating genotypes and to observe possible associations with the geographic location where the infection was acquired. Materials and methods: Analytical, retrospective, and observational study. We analyzed the medical records of patients with sporotrichosis from 12 health institutions in Argentina, between 2010 and 2022. Results: We present 54 cases in which the most frequent clinical form was nodular lymphangitis, and the treatment of choice was itraconazole. Conventional diagnosis was made in all cases. Culture of clinical samples was more sensitive than direct examination because it allowed the isolation of Sporothrix spp. in all 54 cases. Molecular identification was performed in 22 cases, with Sporothrix schenkii sensu stricto being the most frequently isolated species. Conclusions: This study allowed to know the epidemiology of this mycosis in Argentina, as well as the availability of diagnostic methods and the treatment of choice.
Introducción: La esporotricosis es una micosis de implantación causada por Sporothrix spp. Este se encuentra distribuido mundialmente y se puede encontrar en la vegetación y en el suelo. La ruta más frecuente de adquisición de la infección es por traumatismos con elementos contaminados con propágulos del hongo. Los gatos domésticos son los animales más afectados y pueden transmitirla a los humanos, por lo que es considerada una zoonosis. Las formas clínicas incluyen: la linfangítica nodular, la cutánea fija, la pulmonar (poco habitual) y la diseminada (excepcional). Objetivo: Analizar la epidemiología de la esporotricosis en Argentina entre los años 2010 y 2022. Describir la presentación clínica, los métodos de diagnóstico y el tratamiento de los casos diagnosticados en este período. Conocer los genotipos circulantes y observar su relación con el lugar geográfico de adquisición de la infección. Materiales y métodos. Se llevó a cabo un estudio analítico, retrospectivo y observacional, en el que se analizaron las historias clínicas de los pacientes con esporotricosis de 12 instituciones de salud de Argentina, entre los años 2010 y 2022. Resultados: Se presentan 54 casos en los que la forma clínica más frecuente fue la linfangítica nodular y el tratamiento de elección fue el itraconazol. En todos los casos se realizó diagnóstico convencional. El cultivo de las muestras clínicas resultó más sensible que el examen directo, ya que permitió el desarrollo de Sporothrix spp. en los 54 casos. En 22 casos se hizo identificación molecular y Sporothrix schenkii sensu stricto fue la especie más frecuentemente aislada. Conclusiones: Este estudio permitió conocer la epidemiología de esta micosis en Argentina, así como la disponibilidad de métodos diagnósticos y el tratamiento de elección.
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Itraconazole , Tolnaftate , Animals , Argentina/epidemiology , ZoonosesABSTRACT
Introduction. Medical device colonization by pathogenic microorganisms is a risk factor for increasing infections associated with health care and, consequently, the morbidity and mortality of intubated patients. In Colombia, fungal colonization of endotracheal tubes has not been described, and this information could lead to new therapeutic options for the benefit of patients. Objective. To describe the colonizing fungi of the endotracheal tubes from patients in the intensive care unit, along with its antifungal sensitivity profile. Materials and methods. We conducted a descriptive, observational study in two health centers for 12 months. Endotracheal tubes were collected from patients in intensive care units. Samples were processed for culture, fungi identification, and antifungal sensitivity profile assessment. Results. A total of 121 endotracheal tubes, obtained from 113 patients, were analyzed: 41.32 % of the tubes were colonized by Candida albicans (64.62%), C. nonalbicans (30.77%), Cryptococcus spp. (3.08%) or molds (1.54%). All fungi evaluated showed a high sensitivity to antifungals, with a mean of 91%. Conclusion. Fungal colonization was found in the endotracheal tubes of patients under invasive mechanical ventilation. The antifungal sensitivity profile in these patients was favorable. A clinical study is required to find possible correlations between the colonizing microorganisms and infectivity.
Introducción. La colonización por microorganismos patógenos de los dispositivos médicos usados en las unidades de cuidados intensivos es un factor de riesgo para el aumento de infecciones asociadas con la atención en salud y, por lo tanto, al de la morbilidad y la mortalidad de los pacientes intubados. En Colombia, no se ha descrito la colonización por hongos de los tubos endotraqueales, con lo cual se podrían considerar nuevas opciones terapéuticas para el beneficio de los pacientes. Objetivo. Describir los hongos que colonizan los tubos endotraqueales de los pacientes en unidades de cuidados intensivos, junto con su perfil de sensibilidad a los antifúngicos. Materiales y métodos. Se realizó un estudio observacional, descriptivo, en dos centros hospitalarios durante 12 meses. Se recolectaron tubos endotraqueales de pacientes de las unidades de cuidados intensivos. Estos fueron procesados para cultivar e identificar hongos, y para establecer su perfil de sensibilidad a los antifúngicos. Resultados. Se analizaron 121 tubos endotraqueales obtenidos de 113 pacientes. De estos, el 41,32 % se encontró colonizado por los hongos Candida albicans (64,61 %), C. no-albicans (30,77 %), Cryptococcus spp. (3,08 %) o mohos (1,54 %). Todos los hongos evaluados presentaron una gran sensibilidad a los antifúngicos, con un promedio del 91 %. Conclusión. Se encontró colonización fúngica en los tubos endotraqueales de pacientes con asistencia respiratoria mecánica. El perfil de sensibilidad en estos pacientes fue favorable. Se requiere un estudio clínico para correlacionar los microorganismos colonizadores y su capacidad de generar infección.
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Candida albicans , Granisetron , Colombia , TolnaftateABSTRACT
We describe a rare case of fungal peritoneal dialysis (PD) peritonitis caused by the ascomycete fungus Neurospora sitophila (N. sitophila). The patient had little response to initial antibiotics and PD catheter removal was necessary for source control. The fungal biomarker ß-d-glucan (BDG) was positive prior to N. sitophila being cultured and remained positive for 6 months after discharge. Use of BDG early in the assessment of PD peritonitis may reduce time to definitive therapy in fungal peritonitis.
Subject(s)
Mycoses , Neurospora , Peritoneal Dialysis , Peritonitis , Humans , Peritoneal Dialysis/adverse effects , Peritonitis/diagnosis , Peritonitis/drug therapy , Peritonitis/etiology , Biomarkers , TolnaftateABSTRACT
Simple and rapid stability indicating High Performance Liquid Chromatography-Photo Diode Array (HPLC-PDA) method was developed and validated for the estimation of tolnaftate in the presence of its forced degradation products. The method employed SunQSil C18 column (250 mm × 4.6 mm, 5 µm) as stationary phase and acetonitrile:water (85:15, v/v) as mobile phase. Retention time of tolnaftate was 6.9 min. Acid and alkali hydrolysis, oxidation, photo degradation and thermal degradation studies were carried out to evaluate the degradation behavior of tolnaftate. The developed and optimized method was validated as per International Conferences on Harmonization (ICH) guidelines. Limit of detection and limit of quantitation were found to be 0.092 and 0.276 µg/mL, respectively. Linearity was observed in a concentration range of 0.276-6 µg/mL with R2 = 0.9936. %Recovery was found to be between 98.28% and 100.71%. The developed and validated Reversed Phase-High Performance Liquid Chromatography (RP-HPLC) method was successfully applied for quantification of tolnaftate in in-house topical solution. Major base and oxidative degradation products were identified and characterized by liquid chromatography-electrospray ionization mass spectrometry. The probable mechanisms for the formation of degradation products were predicted based on the fragmentation pattern of degradation products. The in silico dermal penetration predictions and carcinogenicity of degradation products were evaluated by using QikProp and CarcinoPred-EL functionality.
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Spectrometry, Mass, Electrospray Ionization , Tolnaftate , Chromatography, High Pressure Liquid/methods , Drug Stability , Chromatography, Liquid/methods , Spectrometry, Mass, Electrospray Ionization/methodsABSTRACT
Mud volcanoes are the most dynamic and unstable sedimentary structures in the areas of tectonic compression like the subduction zones. In this study, we comprehensively analyzed the distribution of minerals as well as diversity, abundance and metabolic potential of the microbial communities of major mud volcanic groups across Taiwan namely Chu-kou Fault (CKF), Gu-ting-keng Anticline (GTKA), Chi-shan Fault (CSF), and Longitudinal Valley Fault (LVF). The mud volcano fluids recorded relatively higher Na and Cl contents than the other elements, particularly in the CKF and GTKA groups. The highest microbial diversity and richness were observed in the CSF group, followed by the GTKA group, whereas the lowest microbial diversity was observed in the CKF and LVF groups. Proteobacteria were common in all the sampling sites, except WST-7 and WST-H (Wu-Shan-Ting) of the CSF group, which were abundant in Chloroflexi. The halophilic genus Alterococcus was abundant in the Na-and Cl-rich CL-A sites of the CKF group. Sulfurovum was dominant in the CLHS (Chung-Lun hot spring) site of the CKF group and was positively correlated with sulfur/thiosulfate respiration, which might have resulted in a higher expression of these pathways in the respective group. Aerobic methane-oxidizing microbial communities, such as Methylobacter, Methylomicrobium, Methylomonas, and Methylosoma, constituted a dominant part of the LVF and CSF groups, except for the YNH-A and YNH-B (Yang-Nyu-Hu) sites. The WST-7 and JS sites were abundant in both methane-producing and methane-oxidizing microbial communities. The LGH-F1 (Lei-Gong-Huo) site was dominated by both methanotrophic and methylotrophic genera, such as Methylomicrobium and Methylophaga, respectively. Methylotrophy, methanotrophs, and hydrocarbon-degrading pathways were more abundant in the LVF and CSF groups but not in the remaining groups. The results of this study extend our knowledge of the diversity, abundance, and metabolic functions of prokaryotes in major terrestrial mud volcanoes in Taiwan.
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Geologic Sediments , Microbiota , Geologic Sediments/chemistry , RNA, Ribosomal, 16S , Bacteria , Tolnaftate , Taiwan , Phylogeny , Methane/analysis , Minerals/metabolismABSTRACT
We reinterpret the instrumented difference-in-differences (iDID) under a linear instrumental variables (IV) model. Under the linear IV model, we show why iDID is a clear improvement over two existing methods, difference-in-differences (DID) and a cross-sectional, IV analysis. We also re-express some of the assumptions of iDID using familiar, regression-based identification assumptions. We conclude with a method inspired by the linear IV model that can potentially remedy the weak identification problem in iDID.
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Tolnaftate , Cross-Sectional Studies , Linear ModelsABSTRACT
We discuss Ye et al. 2022, which combines instrumental variables methods with difference in differences. First, we compare the paper to other works in the difference in differences literatures and argue that the main contribution lies in the multiply robust estimation approach. Then, we reformulate the causal assumptions in Ye et al. 2022 in the usual theoretical framework of the instrumental variables literature. This clarifies in which sense the difference in differences design can weaken the standard instrumental variable conditions.
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Tolnaftate , CausalityABSTRACT
CONTEXT: The mechanisms by which osteopathic cranial manipulative medicine (OCMM) promotes health and healing have yet to be fully elucidated. One commonly utilized OCMM technique, compression of the fourth ventricle (CV4), has been theorized to balance autonomic nervous system (ANS) activity. There is growing evidence that the ANS also plays a significant mechanistic role in acupuncture. Potential connections between OCMM and acupuncture meridian theory largely remain unknown. OBJECTIVES: By measuring specific electrical parameters at acupuncture points that have been shown to correlate with ANS activity, the objectives of this study were to: 1) determine if CV4 has any influence on the bioelectric properties of the acupuncture meridian system; and 2) determine if CV4 affects the ANS. METHODS: A total of 77 males and females ages 18-78 years, all volunteers recruited by local flyers and personal or phone contact, were randomized into CV4 (n=40) and Sham (n=37) groups. All CV4 participants were treated by the same physician utilizing standard CV4 protocol. The Sham treatment, performed by a different physician, consisted of the supine participant's occiput resting passively on the physician's finger pads for a similar duration as those in the CV4 group. Among several devices developed to assess ANS activity at acupuncture points, evidence suggests that the Apparatus for Meridian Identification (AMI) is the most accurate and valid. Utilizing the AMI, bioelectric skin parameters were measured immediately before and after CV4 or Sham treatments. Student's or Welch's t tests and Wilcoxon tests were utilized for analysis of normally and non-normally distributed data, respectively. RESULTS: Statistical significance was determined with a p value less than 0.05. Sham treatments showed insignificant (p=0.754) before vs. after differences in ANS activity measured at acupuncture points, whereas CV4 treatment significantly (p=0.00015) affected ANS activity. CONCLUSIONS: This research suggests that CV4 has demonstrable biophysical effects on the acupuncture meridian system occurring via the ANS, and that the underlying mechanisms of OCMM and acupuncture may be related. Further studies are needed to clarify this.
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Acupuncture Therapy , Manipulation, Osteopathic , Male , Female , Humans , Adolescent , Young Adult , Adult , Middle Aged , Aged , Tolnaftate , Fourth Ventricle , Acupuncture PointsABSTRACT
Background: Baichanting (BCT),a traditional Chinese medicine prescription, is a combination of Acanthopanax senticosus, Paeonia lactiflora, and Uncaria three herbs, which has the effect of benefiting the kidney and calming the liver. The study was aimed at investigating the protective effect of BCT against Parkinson's disease using an integrated strategy of network pharmacology and brain metabolomics. Materials and Methods: By integrating network pharmacology with metabolomic research, the protective effect of BCT against PD was investigated using a transgenic mouse model for α-synuclein. The metabolite level and gene level components of BCT that might be anti-PD were separated out. Indicators of behavior and pharmacodynamics were employed to gauge the effectiveness of BCT on PD in the preliminary stages. Network pharmacology, which may be the target of BCT, screened the active substances and target genes. The use of metabolomics to identify potential biomarkers of PD, and then through network pharmacology and metabolic pathways to determine their regulatory enzymes and regulatory genes, improve the pathway mechanism of the disease, has important guiding significance for the in-depth study of the pathogenesis of PD. Results: 101 putative target genes were identified by the network pharmacology analysis in relation to the treatment of PD with BCT. According to the functional enrichment analysis, the proposed mechanism was primarily related to the transport of neurotransmitters, the metabolism of arachidonic acid, dopamine, and alpha-amino acids, as well as the transport of dopamine and the negative regulation of amino acid transport. 25 distinct endogenous metabolites were shown to be potential biomarkers for the BCT for treating PD based on metabolomics. These metabolites were mostly implicated in the important methionine and cysteine, tyrosine, histidine, and arginine and proline metabolic pathways. These results somewhat agreed with those of the network pharmacology analysis. Conclusions: In conclusion, this study showed that BCT could delay the occurrence and development of PD by improving the brain metabolic disorder of α-Syn mice, which revealed the mechanism of BCT through multitarget and multipathway treatment, and provided a new explanation for the mechanism of anti-PD action. Our research, on the other hand, demonstrated that the network pharmacology-integrated metabolomics approach was a potent tool for discovering the active ingredients and mechanisms underlying the pharmacological effects of traditional Chinese medicine.
Subject(s)
Drugs, Chinese Herbal , Parkinson Disease , Animals , Mice , Tolnaftate , Parkinson Disease/drug therapy , Dopamine , Network Pharmacology , Metabolomics/methods , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Biomarkers/metabolism , Brain/metabolismABSTRACT
We investigated the sediment carbon (C) stocks, sequestration and sources in tidal flats and their adjacent mangroves in two coastal wetlands in Hong Kong (the Mai Po Nature Reserve (MPNR) and Ting Kok (TK)), part of a megacity of â¼20 million. At both locations, the C stock of tidal flats was lower than that of mangroves. In MPNR, tidal flats indicated a higher C burial rate (75.2 g C m-2 yr-1) compared to mangroves (64.3 g C m-2 yr-1). The C of tidal flats mainly originated from mangroves and riverine sources, while those in deeper sediments (below 60 cm) in the mangroves originated from the tidal flats. In TK, the C of tidal flats was dominated by oceanic sources. Our study indicates that tidal flats are also important in coastal C sequestration. On highly urbanized coasts, tidal flats and their connected mangroves can play a critical role for C mitigation.
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Carbon Sequestration , Wetlands , Carbon , Hong Kong , TolnaftateABSTRACT
Silk fibroin (SF) is a natural polymeric biomaterial widely used in the preparation of drug delivery systems. Herein, silk fibroin peptide (SFP) was self-assembled into nanofibers, encapsulated a poorly water-soluble drug baicalein (SFP/BA NFs), and then used to protect against cisplatin-induced acute kidney injury (AKI). Specifically, the SFP/BA NFs significantly enhanced the aqueous dispersity, storage stability, and in vitro antioxidant activity of BA. SFP/BA NFs increased the drug uptake and localization to mitochondria. In vitro results demonstrated that SFP/BA NFs can relieve the cisplatin-induced HK-2 cell damage, and inhibit the cisplatin-induced accumulation of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) disruption. Mechanism studies demonstrated that SFP/BA NFs may exert nephroprotective effects by inhibiting both the cisplatin-induced DNA damage and the cGAS/STING pathway activation. In vivo results showed that cisplatin treatment resulted in decreased body weight, increased serum creatinine (SCr), and increased blood urea nitrogen (BUN) levels, while SFP/BA NFs reversed the above symptoms. Furthermore, SFP/BA NFs reversed the cisplatin-induced abnormal changes of antioxidant enzymes (e.g., SOD and GSH), and inhibited the cisplatin-induced DNA damage as well as the activation of cGAS/TING. Above all, our results revealed the potential of SFP/BA NFs to protect against cisplatin-induced AKI.
Subject(s)
Acute Kidney Injury , Fibroins , Nanofibers , Acute Kidney Injury/chemically induced , Acute Kidney Injury/drug therapy , Acute Kidney Injury/prevention & control , Antioxidants/pharmacology , Antioxidants/therapeutic use , Apoptosis , Biocompatible Materials/therapeutic use , Cisplatin/pharmacology , Creatinine , Fibroins/chemistry , Flavanones , Humans , Kidney/metabolism , Nanofibers/chemistry , Nucleotidyltransferases/pharmacology , Nucleotidyltransferases/therapeutic use , Peptides/chemistry , Reactive Oxygen Species/metabolism , Superoxide Dismutase , Tolnaftate/adverse effects , Water/pharmacologyABSTRACT
Fungal keratitis (FK) is a devastating ocular disease that can cause corneal opacity and blindness if not treated effectively. Tolnaftate (TOL) is a selective fungicidal drug against Aspergillus spp. which are among the most common causes of mycotic keratitis. TOL is lipophilic drug with low water solubility and permeation which act as obstacles for its clinical ocular efficacy. Hence, this study aimed to statistically optimize a novel polymeric pseudorotaxanes (PSRs) containing TOL for enhancing its ocular permeability and antifungal effect. For achieving this goal, a full 31.22 factorial design was fashioned for preparing and optimizing TOL-PSRs using film hydration technique. Three formulation variables were studied: drug amount (X1), weight ratio of Pluronics to HPßCD (X2) and Pluronic system (X3). Entrapment efficiency percent (EE%) (Y1), particle size (PS) (Y2) and zeta potential (ZP) (Y3) were set as dependent variables. The selected optimal TOL-PSRs (PSR1) showed EE% of 71.55 ± 2.90%, PS of 237.05 ± 12.80 nm and ZP of -32.65 ± 0.92 mV. In addition, PSR1 was compared to conventional polymeric mixed micelles (PMMs) and both carriers significantly increased the drug flux and resulted in higher amount permeated per unit area in 8 h compared to drug suspension. The histopathological studies assured the safety of PSR1 for ocular use. The in vivo susceptibility testing using Aspergillus niger confirmed that PSR1 displayed sustained antifungal activity up to 24 h. The obtained results revealed the admirable potential of PSR1 to be used as novel nanocarriers for promoting TOL ocular delivery.
Subject(s)
Eye Infections, Fungal , Keratitis , Rotaxanes , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Drug Carriers/therapeutic use , Drug Delivery Systems/methods , Eye Infections, Fungal/drug therapy , Humans , Keratitis/drug therapy , Keratitis/microbiology , Particle Size , Permeability , Poloxamer , Polymers , Rotaxanes/therapeutic use , Tolnaftate/therapeutic useABSTRACT
BACKGROUND: Wasting and stunting commonly coexist, sup-posedly due to biological and social mechanisms. In under-five children, low-ponderosity is defined as <-2SD of WHO standards for either weight for height (wasted) or body mass index for age (thin) metrics. Unlike body mass index for age, weight for height ignores physiological changes in ponderosity with age, resulting in overestimation of wasting in comparison to thinness in under-5 populations with high stunting prevalence. This suggests a plausi- ble statistical explanation for the wasting-stunting association. AIM: To test the null hypothesis that wasting-stunting (WaSt) and thinness-stunting (ThSt) associations are similar. METHODS: Demographic Health Survey datasets (2010-2020) from South and South-East Asia (7 countries) and Sub-Saharan Africa (13 countries) were evaluated. WaSt and ThSt asso-ciations were estimated as odds ratio (OR) for individual data-sets, which was pooled (random-effects meta-analysis). Strati-fied analyses were done for sex, age and region. RESULT: Young infants (0-6 months) comprised 8-14% of under-five children, with equal representation of boys and girls. Participants, especially Asians, were mostly shorter with lower ponderosity than WHO standards. WaSt prevalence was higher than ThSt in the 6-59 months age group, but lower in young infants. Pooled WaSt estimates were not significant: Asia (OR 0.95; 95% CI 0.75-1.14), Africa (1.17; 0.95-1.40), and combined (1.09; 0.93-1.24). In contrast, pooled ThSt associations were significantly negative: Asia (0.63; 0.50-0.76), Africa (0.82; 0.68-0.96), and combined (0.75; 0.65-0.85). In girls, these associations were attenuated for WaSt (0.96; 0.8-1.1), but enhanced for ThSt (0.6; 0.5-0.7). CONCLUSION: WaSt and ThSt associations are dissimilar. This suggests a primary statistical explanation for the reported was-ting-stunting association, originating from ignoring physiological changes with age.
Subject(s)
Thinness , Wasting Syndrome , Infant , Child , Male , Female , Humans , Thinness/epidemiology , Body Mass Index , Tolnaftate , Growth Disorders/epidemiology , Body Height , Prevalence , Wasting Syndrome/epidemiologyABSTRACT
The treatment of invasive aspergillosis caused by cryptic species remains a challenge due to the lack of randomised clinical trials and investigation of the efficacy and safety of different therapeutic strategies. We aimed to evaluate the in vitro activity of 23 conventional and new antifungal drugs against 54 clinical and environmental Aspergillus oryzae isolates by using the Clinical and Laboratory Standards Institute (CLSI) standard M38-A3. The lowest geometric mean MIC values were found for luliconazole and lanoconazole (0.001 µg/ml), followed by anidulafungin (0.104 µg/ml), posaconazole (0.15 µg/ml), itraconazole (0.37 µg/ml), efinaconazole (0.5 µg/ml), voriconazole (0.51 µg/ml), tavaborole (0.72 µg/ml), and amphotericin B (0.79 µg/ml). In contrast, ketoconazole, terbinafine, econazole, tioconazole, ravuconazole, miconazole, nystatin, clotrimazole, griseofulvin, sertaconazole, natamycin, tolnaftate, and fluconazole had no or low activity. Further studies are required to determine how well this in vitro activity translates into in vivo efficacy.