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PURPOSE: Intraoperative laxity assessments in total knee arthroplasty (TKA) are subjective, with few studies comparing against standardised preoperative and postoperative assessments. This study compares coronal knee laxity in TKA patients awake and anaesthetised, preprosthesis and postprosthesis implantation, evaluating relationships to patient-reported outcome measures. METHODS: A retrospective analysis of 49 TKA joints included preoperative and postoperative computed tomography scans, stress radiographs and knee injury and osteoarthritis outcome score (KOOS) questionnaire results preoperatively and 12 months postoperatively. The imaging was used to assess functional laxity (FL) in awake patients, whereas computer navigation measured intraoperative surgical laxity (SL) preimplantation and postimplantation, with patients anaesthetised. Varus and valgus stress states and their difference, joint laxity, were measured. RESULTS: SL was greater than FL in both preimplantation [8.1° (interquartile range, IQR 2.0°) and 3.8° (IQR 2.9°), respectively] and postimplantation [3.5° (IQR 2.3°) and 2.5° (IQR 2.7°), respectively]. Preimplantation, SL was more likely than FL to categorise knees as correctable to ±3° of the mechanical axis. Preoperative FL correlated with KOOS Symptoms (r = 0.33, p = .02) and quality of life (QOL) (r = 0.38, p = .01), whereas reducing medial laxity with TKA enhanced postoperative QOL outcomes (p = .02). CONCLUSIONS: Functional coronal knee laxity assessment of awake patients is generally lower than intraoperative surgical assessments of anaesthetised patients. Preoperative SL may result in overcorrection of coronal TKA alignment, whereas preoperative FL better predicts postoperative patient outcomes and reflects the patients' native and tolerable knee laxity. Preoperative FL assessment can be used to guide surgical planning. LEVEL OF EVIDENCE: Level II.

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BACKGROUND: Pediatric epilepsy is a complicated neuropsychiatric disorder that is characterized by recurrent seizures and unusual synchronized electrical activities within brain tissues. It has a substantial effect on the quality of life of children, thus understanding of the hereditary considerations influencing epilepsy susceptibility and the response to antiepileptic medications is crucial. This study focuses on assessing the correlation of the ABCB1, ABCC2, CYP1A2, and CYP2B6 genetic polymorphisms with the susceptibility to epileptic seizures and their contributions to antiepileptic medication throughout the course of the disease. METHODS: This study included 134 Egyptian epileptic children, comprising 67 drug-responsive and 67 drug-resistant patients, along with 124 healthy controls matching for age, gender, and geographical district. Genotyping of the rs2032582, rs717620, rs2273697, rs762551, and rs3745274 variants was performed using the PCR technique. Statistical analyses, including haplotype, multivariate, logistic regression, and bioinformatics approaches, were conducted to evaluate the associations within the disease. RESULTS: The ABCC2*rs717620 (T allele) revealed an increased risk of epilepsy compared to healthy controls (OR = 2.12, p-value < 0.001), with the rs717620 (C/T + T/T genotypes) showing significant differences between drug-responsive and drug-resistant patients (p-value < 0.05). Moreover, the ABCC2*rs2273697 (A allele) indicated a decreased risk of epileptic seizures compared to healthy controls (OR = 0.51, p-value = 0.033), with the rs2273697 (G/A + A/A genotypes) indicating a significant association with drug-resistant patients (OR = 0.21, p-value = 0.002). The rs717620*T/rs2273697*G haplotype was significantly correlated with an elevated risk of epileptic seizures within drug-responsive patients (OR = 2.26, p-value = 0.019). Additionally, the CYP1A2*rs762551 (A allele) represented a protective effect against epilepsy susceptibility (OR = 0.50, p-value < 0.001), with the rs762551 (G/A + A/A genotypes) disclosing a substantial association with a decreased risk of epileptic seizures among drug-resistant patients compared to drug-responsive patients (OR = 0.07, p-value < 0.001). Conversely, the ABCB1*rs2032582 (G allele) and the CYP2B6*rs3745274 (T allele) did not attain a significant difference with the epilepsy risk compared to healthy controls (p-value > 0.05). CONCLUSIONS: The findings of our study emphasize the importance of pharmacogenetic screening in epilepsy research, particularly regarding to drug-resistant patients. The ABCC2*rs717620 variant conferred a significant correlation with elevated risk of epileptic seizures, while the ABCC2*rs2273697 and CYP1A2*rs762551 variants confirmed their contributions as protective markers against epilepsy development. Conversely, the ABCB1*rs2032582 and CYP2B6*rs3745274 alleles were not considered as independent risk factors with the course of epilepsy disease.

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Sarcomas are commonly misdiagnosed, and treatment delays negatively impact patient outcomes. The purpose of this study is to explore patient threshold for and timeline to medical evaluation, to identify providers most likely to be contacted first, and to assess general sarcoma knowledge in Minnesota's general population. Voluntary participants were recruited at the 2015 and 2022 Minnesota State Fair to complete a three-part survey. Part 1 assessed evaluation timeline and provider choice, part 2 evaluated sarcoma knowledge via a ten-question survey, and part 3 documented demographics. Responses were electronically recorded, and results were tabulated. Overall, 2124 participants completed some or all of the survey. Part 1: Participants indicated they would seek more urgent treatment for a painful mass compared to a non-painful mass (p < 0.001). The majority (77%) of participants indicated a family medicine physician would be their first contact for painful and non-painful masses. Part 2: There was no difference in overall score (percent correct) when comparing results from 2015 (mean = 40%) to 2022 (mean = 42%) (p = 0.183). Overall, 16% (349/2117) of participants had no correct responses. Individuals who self-identified as Hispanic or Latino ethnicity and a non-White race performed worse (p < 0.001). In general, scores improved with increased education and those with a graduate or professional degree had an estimated 2.515-point increase in score compared to participants with some high school education or high school diploma/general education diploma (p < 0.001). Participants with a healthcare background scored better (p < 0.001). Pain is a driving factor for patient-initiated evaluation, and primary care providers are the most likely first contact for patients. General sarcoma awareness remains low, even among those with advanced degrees and healthcare experience. Ongoing educational efforts are warranted for both the general public and healthcare communities in Minnesota.

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BACKGROUND: The human cytochrome P450 (CYP) superfamily encompasses different categories of isoenzymes that contribute to multiple metabolic processes involving drug detoxification, cellular signaling, and the proliferation of malignant tissues. Using genetic technology, customized bioinformatic analysis, and meta-analysis design, the main goal of this study was to identify the association between the CYP1A2*rs762551 variant and the susceptibility to breast carcinoma (BRCA). METHODS: The case-control study was conducted based on 104 BRCA women and 102 healthy controls. Using the TaqMan allelic discrimination assay, the CYP1A2 (rs762551; c.-9-154 C>A) variant was genotyped. Bioinformatic frameworks and logistic regression analysis were used to assess the involvement of this genetic variant in BRCA development. A meta-analysis design was accomplished based on our case-control study and other previously published records. Publication bias, heterogeneity between studies, and trial sequential analysis (TSA) were analyzed. RESULTS: The CYP1A2*rs762551 variant conferred protection against BRCA development under allelic (OR = 0.48, p-value < 0.001), dominant (OR = 0.34, p-value < 0.001), and recessive (OR = 0.44, p-value = 0.011) models. However, this intronic variant was correlated with a decreased risk of BRCA among late-onset menopause women compared to other cases. Bioinformatic analysis confirmed that this genetic variant has a functional impact on the progression of tumorgenesis. Moreover, this meta-analysis design included 12922 BRCA women and 15603 healthy controls. Our findings disclosed the contribution of the CYP1A2*rs762551 variant with protection against cancer development among Caucasian females under allelic (OR = 0.75, p-value = 0.025), and dominant (OR = 0.58, p-value = 0.015) models. CONCLUSIONS: This case-control study confirmed the contribution of the CYP1A2*rs762551 variant with decreased risk of BRCA development among Egyptian subjects. Moreover, BRCA women with late-onset menopause conferred protection against cancer progression compared to other subjects. Our findings identified that this meta-analysis design achieved protection against BRCA development among Caucasian women compared to other ethnicities.

Asunto(s)

Neoplasias de la Mama , Citocromo P-450 CYP1A2 , Predisposición Genética a la Enfermedad , Femenino , Humanos , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Citocromo P-450 CYP1A2/genética , Polimorfismo de Nucleótido Simple

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Neosporosis is a proven disease of farm animals and dogs caused by Neospora caninum. This cross-sectional study investigates N. caninum prevalence and seroprevalence among 268 dogs. Nc5 gene PCR was carried out on dog faeces and confirmed by sequencing. Seroprevalence was detected using an indirect fluorescent antibody test (IFAT). Three age groups, gender, locality (Amman, Irbid, and Zarqa Governorates), dog type (stray, pet, and breeding), place of living (indoor/outdoor), food type (raw/cooked), having diarrhoea, having abortion in the area, and having animals nearby were tested as independent variables for associations with positivity to N. caninum using univariate and multivariable logistic regression analyses. The true prevalence of N. caninum was 34.3% (95% CI 28.4, 40.5) using the Nc5-PCR test. The true seroprevalence rate of N. caninum among dogs in Jordan was 47.9% (95% CI 41.4, 54.5) using IFAT. The sequenced isolates of Nc5-PCR products (n = 85) matched three N. caninum strains, namely, NcHareGre (n = 70, 82.4%, 95% CI 72.6-89), NC MS2 (n = 14, 16.5%, 95% CI 9.3-26.1), and L218 (n = 1, 1.2%, 95% CI 0.03-6.4). The three strains were isolated previously from three different countries and continents. N. caninum shedding is associated with abortion among dogs and animals in the area (odds ratio = 3.6). In Amman and Zarqa, living indoors reduced seroprevalence at 0.45, 0.24, and 0.02 odds ratios, respectively. Jordan shares three molecular N. caninum strains with three different countries and continents.

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Coccidiosis , Enfermedades de los Perros , Heces , Neospora , Animales , Perros , Neospora/genética , Neospora/inmunología , Neospora/aislamiento & purificación , Enfermedades de los Perros/epidemiología , Enfermedades de los Perros/parasitología , Coccidiosis/epidemiología , Coccidiosis/veterinaria , Coccidiosis/parasitología , Estudios Seroepidemiológicos , Jordania/epidemiología , Estudios Transversales , Femenino , Masculino , Heces/parasitología , Prevalencia , Anticuerpos Antiprotozoarios/sangre , Reacción en Cadena de la Polimerasa/veterinaria , Técnica del Anticuerpo Fluorescente Indirecta/veterinaria

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BACKGROUND: Patients with low HEART (History, Electrocardiogram, Age, Risk factors, and Troponin level) risk scores who are discharged from the emergency department (ED) may present clinical challenges and diagnostic dilemmas. The use of downstream non-invasive stress imaging (NISI) tests in this population remains uncertain. Therefore, this study aims to investigate the value of NISI in risk stratification and predicting cardiac events in patients with low-risk HEART scores (LRHSs). METHODS: We prospectively included 1384 patients with LRHSs between March 2019 and March 2021. All the patients underwent NISI (involving myocardial perfusion imaging/stress echocardiography). The primary endpoints included cardiac death, non-fatal myocardial infarction and unplanned coronary revascularisation. Secondary endpoints encompassed cardiovascular-related admissions or ED visits. RESULTS: The mean patient age was 64±14 years, with 670 (48.4%) being women. During the 634±104 days of follow-up, 58 (4.2%) patients experienced 62 types of primary endpoints, while 60 (4.3%) developed secondary endpoints. Multivariable Cox models, adjusted for clinical and imaging variables, showed that diabetes (HR: 2.38; p=0.008), HEART score of 3 (HR: 1.32; p=0.01), history of coronary artery disease (HR: 2.75; p=0.003), ECG changes (HR: 5.11; p<0.0001) and abnormal NISI (HR: 16.4; p<0.0001) were primary endpoint predictors, while abnormal NISI was a predictor of secondary endpoints (HR: 3.05; p<0.0001). CONCLUSIONS: NISI significantly predicted primary cardiac events and cardiovascular-related readmissions/ED visits in patients with LRHSs.

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Dolor en el Pecho , Ecocardiografía de Estrés , Servicio de Urgencia en Hospital , Humanos , Femenino , Masculino , Persona de Mediana Edad , Medición de Riesgo/métodos , Estudios Prospectivos , Dolor en el Pecho/diagnóstico , Dolor en el Pecho/etiología , Ecocardiografía de Estrés/métodos , Anciano , Imagen de Perfusión Miocárdica/métodos , Factores de Riesgo , Pronóstico , Estudios de Seguimiento , Valor Predictivo de las Pruebas , Electrocardiografía , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/diagnóstico por imagen

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BACKGROUND: Although positron emission tomography (PET) imaging is well established for its diagnostic role in cardiac sarcoidosis, less is known about the prognostic value of PET and its use in risk stratification for major adverse cardiac events (MACE). OBJECTIVES: The goal of this study was to perform a systematic review and meta-analysis looking at the prognostic value of PET imaging in patients with cardiac sarcoidosis. METHODS: Study investigators systematically searched EMBASE (Excerpta Medica dataBASE), MEDLINE, PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL (Cumulative Index to Nursing and Allied Health Literature), ClinicalTrials.gov, and the European Union Clinical Trial Registry for cardiac sarcoidosis and PET imaging. The primary outcome of interest was MACE. RESULTS: The search revealed 3,010 records, of which 55 studies were included. This represented 5,250 patients. Factors associated with MACE included the following: the combination of abnormal fluorodeoxyglucose (FDG) uptake and perfusion defect, which had an OR of 2.86 (95% CI: 1.74-4.71; P < 0.0001); abnormal perfusion or FDG uptake, which had an OR of 2.69 (95% CI: 1.67-4.33); abnormal FDG uptake, which had an OR of 2.61 (95% CI: 1.51-4.50); focal abnormal right ventricular uptake, which had an OR of 6.27 (95% CI: 3.19-12.32; P < 0.00001); and a lack of response to immunosuppression on serial PET, which had an OR of 8.43 (95% CI: 3.25-21.85; P < 0.0001). A QUIPS (Quality in Prognostic Studies) tool analysis found a low to moderate risk of bias, particularly given the small sample sizes in the individual studies. CONCLUSIONS: Multiple cardiac PET parameters provide risk stratification value in cardiac sarcoidosis. Focal right ventricular uptake and a lack of response to immunosuppressive therapy on serial PET imaging were particularly predictive of MACE.

Asunto(s)

Cardiomiopatías , Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Sarcoidosis , Humanos , Sarcoidosis/diagnóstico por imagen , Cardiomiopatías/diagnóstico por imagen , Medición de Riesgo , Pronóstico , Factores de Riesgo , Femenino , Masculino , Persona de Mediana Edad , Radiofármacos/administración & dosificación , Anciano , Adulto , Imagen de Perfusión Miocárdica/métodos , Fluorodesoxiglucosa F18/administración & dosificación

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Atomoxetine is a psychostimulant drug used for the treatment of attention-deficit/hyperactivity disorder (ADHD) symptoms in people with autism. Herein, eco-friendly fluorescent carbon quantum dots (CQDs) were synthesized using black-eyed pea beans and characterized for the purpose of quantifying atomoxetine in pharmaceutical capsules and human plasma. The selectivity of these CQDs towards atomoxetine was improved by functionalizing their surface with an atomoxetine-tetraphenylborate ion complex. The quantification of atomoxetine is based on measuring the fluorescence quenching of the functionalized CQDs in response to varying concentrations of atomoxetine. The Stern-Volmer plot was employed to investigate the mechanism through which atomoxetine quenches the fluorescence intensity of the CQDs. The outcomes indicated a dynamic quenching mechanism. The applied method was optimized and validated in compliance with ICH requirements, resulting in excellent linearity across the concentration range of 50-800 ng/mL. The developed method was successfully used to quantify atomoxetine in pharmaceutical dosage form and human plasma with acceptable accuracy and precision outcomes. In addition, the method was applied for clinical pharmacokinetic study of atomoxetine in the plasma of children diagnosed with both autism and ADHD. Atomoxetine was rapidly absorbed after a single oral dose of 10 mg, reaching maximum concentration within two hours and having a half-life (t1/2) of 3.11 h. Moreover, the method demonstrates a notable degree of eco-friendliness, as evidenced by two greenness evaluation metrics; Green Analytical Procedure Index (GAPI) and Analytical GREEnness (AGREE).

Asunto(s)

Clorhidrato de Atomoxetina , Colorantes Fluorescentes , Puntos Cuánticos , Espectrometría de Fluorescencia , Clorhidrato de Atomoxetina/farmacocinética , Clorhidrato de Atomoxetina/sangre , Humanos , Puntos Cuánticos/química , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacocinética , Espectrometría de Fluorescencia/métodos , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/sangre , Niño , Masculino , Trastorno Autístico/tratamiento farmacológico , Reproducibilidad de los Resultados , Límite de Detección

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Intrahepatic cholestasis is a common clinical form of hepatobiliary injury characterized by the intrahepatic accumulation of toxic bile acids. Besides its antidiabetic activity, the dipeptidyl peptidase IV inhibitor sitagliptin (SG) has been recently assigned diverse pharmacological activities and therapeutic potential against different disorders owing to its emerging antioxidant and anti-inflammatory properties. The current study explored the potential hepatoprotective effect of SG on α-naphthyl isothiocyanate (ANIT)-induced cholestatic liver injury (CLI) in mice and investigate its possible targeted signaling pathways. Mice received SG (10 and 20 mg/kg) for four consecutive days, two days before and after a single oral administration of ANIT (75 mg/kg). Our results revealed that SG administration remarkably prevented ANIT-induced histopathological lesions in the liver and maintained hepatic functions and oxidative/antioxidant balance. Ultimately, SG counteracted the inflammatory response in the liver, as indicated by the marked suppression of hepatic expression of NF-κB, TNF-α, and IL-6. Moreover, it inhibited the endoplasmic reticulum (ER) stress response in the liver. These beneficial effects of SG were accompanied by upregulation of SIRT1, p-AMPK, and Nrf2 expressions while downregulating keap1 expression in the liver. In conclusion, this study is the first to demonstrate the ability of SG to protect against ANIT-induced CLI through modulating multiple signaling cascades, including SIRT1/AMPK, Nrf2/keap1, and NF-кB, which resulted in enhanced antioxidant capacity and repressed inflammatory and ER stress responses in the liver.

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1-Naftilisotiocianato , Proteínas Quinasas Activadas por AMP , Estrés del Retículo Endoplásmico , Factor 2 Relacionado con NF-E2 , FN-kappa B , Estrés Oxidativo , Sirtuina 1 , Fosfato de Sitagliptina , Animales , Sirtuina 1/metabolismo , Estrés Oxidativo/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Fosfato de Sitagliptina/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Masculino , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , FN-kappa B/metabolismo , 1-Naftilisotiocianato/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Inflamación/prevención & control , Inflamación/metabolismo , Colestasis Intrahepática/inducido químicamente , Colestasis Intrahepática/tratamiento farmacológico , Colestasis Intrahepática/prevención & control , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología

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ABSTRACT: Facial grimacing is used to quantify spontaneous pain in mice and other mammals, but scoring relies on humans with different levels of proficiency. Here, we developed a cloud-based software platform called PainFace ( http://painface.net ) that uses machine learning to detect 4 facial action units of the mouse grimace scale (orbitals, nose, ears, whiskers) and score facial grimaces of black-coated C57BL/6 male and female mice on a 0 to 8 scale. Platform accuracy was validated in 2 different laboratories, with 3 conditions that evoke grimacing-laparotomy surgery, bilateral hindpaw injection of carrageenan, and intraplantar injection of formalin. PainFace can generate up to 1 grimace score per second from a standard 30 frames/s video, making it possible to quantify facial grimacing over time, and operates at a speed that scales with computing power. By analyzing the frequency distribution of grimace scores, we found that mice spent 7x more time in a "high grimace" state following laparotomy surgery relative to sham surgery controls. Our study shows that PainFace reproducibly quantifies facial grimaces indicative of nonevoked spontaneous pain and enables laboratories to standardize and scale-up facial grimace analyses.

Asunto(s)

Expresión Facial , Ratones Endogámicos C57BL , Dimensión del Dolor , Programas Informáticos , Animales , Ratones , Femenino , Programas Informáticos/normas , Dimensión del Dolor/métodos , Dimensión del Dolor/normas , Masculino , Dolor/diagnóstico

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Futibatinib is a powerful inhibitor of fibroblast growth factor receptors that impedes its phosphorylation and subsequently leading to a reduction in in cell viability across various cell lines. Futibatinib was approved for initial use as an effective treatment for several diseases, including non-small cell lung cancer and breast cancer. Herein, a novel selective fluorescence probe was created for futibatinib quantification in various matrices, including pharmaceutical formulation and human plasma. The technique primarily depends on futibatinib's chemical conversion into a fluorescent product through a reaction with trimethylamine and bromoacetyl bromide. The created fluorescent probe exhibits maximum emission peak at 338 nm upon excitation at 248 nm. The method provided a low detection limit of 0.120 ng/mL and maintained a linear concentration-dependent relationship across the range of 1-200 ng/mL. High sensitivity, accuracy and precision were demonstrated for futibatinib quantification in pharmaceutical formulation and spiked plasma matrix by the method, which was validated in accordance with ICH requirements.

Asunto(s)

Límite de Detección , Espectrometría de Fluorescencia , Humanos , Espectrometría de Fluorescencia/métodos , Reproducibilidad de los Resultados , Colorantes Fluorescentes/química

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Celecoxib and tramadol have been combined in a novel FDA-approved medication to address acute pain disorders requiring opioid treatment when other analgesics proved either intolerable or ineffective. The absorbance spectra of celecoxib and tramadol exhibit significant overlap, posing challenges for their individual quantification. This study introduces a spectrophotometric quantification approach for celecoxib and tramadol using a principle component regression assistive model to assist resolving the overlapped spectra and quantifying both drugs in their binary mixture. The model was constructed by establishing calibration and validation sets for the celecoxib and tramadol mixture, employing a five-level, two-factor experimental design, resulting in 25 samples. Spectral data from these mixtures were measured and preprocessed to eliminate noise in the 200-210 nm range and zero absorbance values in the 290-400 nm range. Consequently, the dataset was streamlined to 81 variables. The predicted concentrations were compared with the known concentrations of celecoxib and tramadol, and the errors in the predictions were evidenced calculating root mean square error of cross-validation and root mean square error of prediction. Validation results demonstrate the efficacy of the models in predicting outcomes; recovery rates approaching 100 % are demonstrated with relative root mean square error of prediction (RRMSEP) values of 0.052 and 0.164 for tramadol and celecoxib, respectively. The selectivity was further evaluated by quantifying celecoxib and tramadol in the presence of potentially interfering drugs. The model demonstrated success in quantifying celecoxib and tramadol in laboratory-prepared tablets, producing metrics consistent with those reported in previously established spectrophotometric methods.

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Celecoxib , Análisis de Componente Principal , Espectrofotometría , Tramadol , Celecoxib/análisis , Celecoxib/química , Tramadol/análisis , Espectrofotometría/métodos , Calibración , Reproducibilidad de los Resultados , Formas de Dosificación , Analgésicos Opioides/análisis

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For cancer therapy, the focus is now on targeting the chemotherapy drugs to cancer cells without damaging other normal cells. The new materials based on bio-compatible magnetic carriers would be useful for targeted cancer therapy, however understanding their effectiveness should be done. This paper presents a comprehensive analysis of a dataset containing variables x(m), y(m), and U(m/s), where U represents velocity of blood through vessel containing ferrofluid. The effect of external magnetic field on the fluid flow is investigated using a hybrid modeling. The primary aim of this research endeavor was to construct precise and dependable predictive models for velocity, utilizing the provided input variables. Several base models, including K-nearest neighbors (KNN), decision tree (DT), and multilayer perceptron (MLP), were trained and evaluated. Additionally, an ensemble model called AdaBoost was implemented to further enhance the predictive performance. The hyper-parameter optimization technique, specifically the BAT optimization algorithm, was employed to fine-tune the models. The results obtained from the experiments demonstrated the effectiveness of the proposed approach. The combination of the AdaBoost algorithm and the decision tree model yielded a highly impressive score of 0.99783 in terms of R2, indicating a strong predictive performance. Additionally, the model exhibited a low error rate, as evidenced by the root mean square error (RMSE) of 5.2893 × 10-3. Similarly, the AdaBoost-KNN model exhibited a high score of 0.98524 using R2 metric, with an RMSE of 1.3291 × 10-2. Furthermore, the AdaBoost-MLP model obtained a satisfactory R2 score of 0.99603, accompanied by an RMSE of 7.1369 × 10-3.

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Hypertension and hyperlipidemia are two common conditions that require effective management to reduce the risk of cardiovascular diseases. Among the medications commonly used for the treatment of these conditions, valsartan and pitavastatin have shown significant efficacy in lowering blood pressure and cholesterol levels, respectively. In this study, synchronous spectrofluorimetry coupled to chemometric analysis tools, specifically concentration residual augmented classical least squares (CRACLS) and spectral residual augmented classical least squares (SRACLS), was employed for the determination of valsartan and pitavastatin simultaneously. The developed models exhibited excellent predictive performance with relative root mean square error of prediction (RRMSEP) of 2.253 and 2.1381 for valsartan and pitavastatin, respectively. Hence, these models were successfully applied to the analysis of synthetic samples and commercial formulations as well as plasma samples with high accuracy and precision. Besides, the greenness and blueness profiles of the determined samples were also evaluated to assess their environmental impact and analytical practicability. The results demonstrated excellent greenness and blueness scores with AGREE score of 0.7 and BAGI score of 75 posing the proposed method as reliable and sensitive approach for the determination of valsartan and pitavastatin with potential applications in pharmaceutical quality control, bioanalytical studies, and therapeutic drug monitoring.

Asunto(s)

Quinolinas , Espectrometría de Fluorescencia , Valsartán , Quinolinas/química , Quinolinas/sangre , Valsartán/química , Valsartán/sangre , Análisis de los Mínimos Cuadrados

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Hepatitis C Virus (HCV) is a significant health concern affecting a large portion of the global population and is a major cause of acute liver diseases, including cirrhosis. The variability in the HCV genome mainly results from the rapid replication facilitated by the NS5B polymerase, making it a prime target for anti-HCV drug development. This study explores potential compounds from marine bacteria that could inhibit the HCV NS5B polymerase by virtual screening, analyzing the energetics, and dynamic behavior of target-compound complexes. Virtual screening with the Lipinski filter was employed to select compounds from the marine bacteria database that demonstrated strong binding affinity to NS5B. The top four (CMNPD27216, CMNPD21066, CMNPD21065, and CMNPD27283) compounds, ranked by their re-docking scores, underwent additional evaluation. Molecular dynamics simulations for 200 ns were conducted to assess the dynamic stability of these complexes in a solvent environment. Furthermore, methods such as MM-GBSA, PCA, and free energy landscape analysis were used to analyze the system's energetics and identify stable conformations by locating transition states. The findings suggest that these compounds exhibit promising binding capabilities to HCV polymerase and could be considered for future experimental validation.

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We investigated the effect of confinement on the phase behavior of hexane in nanopores of mesoporous silica at varying pore diameters and temperatures using a patented gravimetric apparatus. The adsorption and desorption isotherms were experimentally measured, and the capillary condensation and evaporation pressures were calculated from the isotherms. The results show that, for all pore sizes and temperatures utilized here, the confinement of fluids significantly lowers the vapor-liquid phase transition pressures. However, its evaporation, i.e., liquid-vapor phase transition, occurs at a lower pressure than its capillary condensation counterpart. The experimental findings demonstrate that the confinement effect becomes weaker in wider nanopores due to the reduced solid-fluid interactions in larger spaces. Furthermore, it is evident from isotherms that hexane rapidly approaches a supercritical-like state at high temperatures when confined in smaller pores, resulting in an ambiguous vapor-liquid phase transition. In contrast, this behavior disappears in larger pores at similar temperatures. Moreover, the present study compares the fully gravimetric adsorption method against the thermogravimetric approach. The results show that the fully gravimetric method, which directly measures the mass of the adsorbed or condensed fluids, provides significant advantages over the thermogravimetric counterpart. The findings of this study are expected to be of fundamental interest to a wide range of science and engineering communities concerned about the behavior of heavier hydrocarbons in various industrial applications, and modeling the confined phase behavior of fluids and developing robust equations of state (EOS).

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Biomedical research in the US has long been conducted in a public-private (PP) "ecosystem." Today, especially with gene therapies and genome editing-based medicine, publicly funded researchers frequently hand off their research to the private sector for clinical development, often to small, venture capital-funded startups in which they have a financial interest. This trend raises ethical questions about conflicts of interest, effectiveness of regulatory oversight, and justice in therapy access, that we are addressing in a multi-year, multidisciplinary study of the evolving governance of genome editing. This paper draws on interviews with scientists working across the PP divide and their private sector business and financial partners. We find little concern about potential ethical dilemmas, with two exceptions expressed by public sector scientists: concerns about inequitable access to treatments due to disparities in wealth, ethnicity, and health insurance benefits; and about whether their private collaborators' profit motive may affect their research objectives.

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INTRODUCTION: The aim of this study is to analyze the diagnostic value of global longitudinal strain (GLS) in detecting inducible myocardial ischemia in patients with chest pain undergoing treadmill contrast-enhanced stress echocardiography (SE). METHODS: We retrospectively enrolled all patients who underwent invasive coronary angiography after treadmill contrast-enhanced SE. Rest and peak-stress myocardial GLS, segmental LS, and LS of 4-chamber (CH), 2-CH, and 3-CH views were reported. Luminal stenosis of more than 70% or fractional flow reserve (FFR) of < 0.8 was considered significant. RESULTS: In total 33 patients were included in the final analysis, among whom sixteen patients (48.4%) had significant coronary artery stenosis. Averaged GLS, 3-CH, and 4-CH LS were significantly lower in patients with critical coronary artery stenosis compared to those without significant stenosis (-17.1 ± 7.1 vs. -24.2 ± 7.2, p = 0.041), (-18.2 ± 8.9 vs. -24.6 ± 8.2, p = 0.045) and (-14.8 ± 6.2 vs. -22.8 ± 7.8, p = 0.009), respectively. Receiver operating characteristic (ROC) analysis of ischemic and non-ischemic segments demonstrated that a cut-off value of -20% of stress LS had 71% sensitivity and 60% specificity for ruling out inducible myocardial ischemia (Area under the curve was AUC = 0.72, P < 0.0001). CONCLUSION: Myocardial LS measured with treadmill contrast-enhanced stress echocardiography demonstrates potential value in identifying patients with inducible myocardial ischemia.

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Medios de Contraste , Angiografía Coronaria , Estenosis Coronaria , Ecocardiografía de Estrés , Valor Predictivo de las Pruebas , Humanos , Masculino , Femenino , Ecocardiografía de Estrés/métodos , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Medios de Contraste/administración & dosificación , Estenosis Coronaria/fisiopatología , Estenosis Coronaria/diagnóstico por imagen , Reproducibilidad de los Resultados , Contracción Miocárdica , Función Ventricular Izquierda , Isquemia Miocárdica/fisiopatología , Isquemia Miocárdica/diagnóstico por imagen , Reserva del Flujo Fraccional Miocárdico

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The aim of this research is to prepare and identify functionalized carboxymethylcellulose/mesoporous silica nanohydrogels (CMC/NH2-MCM-41) for obtaining a pH-sensitive system for the controlled release of drugs. The beads of CMC/NH2-MCM-41 nanocomposites were prepared by dispersing NH2-MCM-41 in a CMC polymer matrix and crosslinking with ferric ions (Fe3+). The SEM analysis of samples revealed enhancement in surface porosity of the functionalized nanohydrogel beads compared to the conventional beads. Swelling of the prepared functionalized nanohydrogels was evaluated at various pH values including pH = 7.35-7.45 (simulated body fluid or healthy cells), pH = 6 (simulated intestinal fluid), and pH = 1.5-3.5 (simulated gastric fluid). The swelling of CMC/MCM-41 and CMC/NH2-MCM-41 nanohydrogels at the pH values of simulated body fluid and simulated intestinal fluid is much higher than that of simulated gastric fluid, indicating successful synthesis of pH-sensitive nanohydrogels for drug delivery. The drug loading results showed that drug release in the CMC/NH2-MCM-41 system is much slower than that in the CMC/MCM-41 system. The results of the survival studies for the manufactured systems showed a very good biocompatibility of the designed drug delivery systems for biological applications. By coating the surface of functionalized mesopores with CMC hydrogel, we were able to develop a pH-sensitive intelligent drug delivery system.

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Carboximetilcelulosa de Sodio , Doxorrubicina , Portadores de Fármacos , Liberación de Fármacos , Hidrogeles , Metformina , Naproxeno , Hidrogeles/química , Carboximetilcelulosa de Sodio/química , Concentración de Iones de Hidrógeno , Metformina/química , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Naproxeno/química , Portadores de Fármacos/química , Dióxido de Silicio/química , Sistemas de Liberación de Medicamentos , Humanos , Diseño de Fármacos , Porosidad

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Knee arthroplasty technique is constantly evolving and the opportunity for surgeons to practice new techniques is currently highly dependent on the availability of cadaveric specimens requiring certified facilities. The high cost, limited supply, and heterogeneity of cadaveric specimens has increased the demand for synthetic training models, which are currently limited by a lack of biomechanical fidelity. Here, we aimed to design, manufacture, and experimentally validate a synthetic knee surgical training model which reproduces the flexion dependent varus-valgus (VV) and anterior-posterior (AP) mechanics of cadaveric knees, while maintaining anatomic accuracy. A probabilistic finite element modeling approach was employed to design physical models to exhibit passive cadaveric VV and AP mechanics. Seven synthetic models were manufactured and tested in a six-degree-of-freedom hexapod robot. Overall, the synthetic models exhibited cadaver-like VV and AP mechanics across a wide range of flexion angles with little variation between models. In the extended position, two models showed increased valgus rotation (<0.5°), and three models showed increased posterior tibial translation (<1.7 mm) when compared to the 95% confidence interval (CI) of cadaveric measurements. At full flexion, all models showed VV and AP mechanics within the 95% CI of cadaveric measurements. Given the repeatable mechanics exhibited, the knee models developed in this study can be used to reduce the current reliance on cadaveric specimens in surgical training.