Evaluation of the Therapeutical Effect of Matricaria Chamomilla Extract vs. Galantamine on Animal Model Memory and Behavior Using 18F-FDG PET/MRI.

The memory-enhancing activity of Matricaria chamomilla hydroalcoholic extract (MCE) is already being investigated by behavioral and biochemical assays in scopolamine-induced amnesia rat models, while the effects of scopolamine (Sco) on cerebral glucose metabolism are examined as well. Nevertheless, the study of the metabolic profile determined by an enriched MCE has not been performed before. The present experiments compared metabolic quantification in characteristic cerebral regions and behavioral characteristics for normal, only diseased, diseased, and MCE- vs. Galantamine (Gal)-treated Wistar rats. A memory deficit was induced by four weeks of daily intraperitoneal Sco injection. Starting on the eighth day, the treatment was intraperitoneally administered 30 min after Sco injection for a period of three weeks. The memory assessment comprised three maze tests. Glucose metabolism was quantified after the 18F-FDG PET examination. The right amygdala, piriform, and entorhinal cortex showed the highest differential radiopharmaceutical uptake of the 50 regions analyzed. Rats treated with MCE show metabolic similarity with normal rats, while the Gal-treated group shows features closer to the diseased group. Behavioral assessments evidenced a less anxious status and a better locomotor activity manifested by the MCE-treated group compared to the Gal-treated group. These findings prove evident metabolic ameliorative qualities of MCE over Gal classic treatment, suggesting that the extract could be a potent neuropharmacological agent against amnesia.

Aldose Reductase as a Key Target in the Prevention and Treatment of Diabetic Retinopathy: A Comprehensive Review.

The escalating global prevalence of diabetes mellitus (DM) over the past two decades has led to a persistent high incidence of diabetic retinopathy (DR), necessitating screening for early symptoms and proper treatment. Effective management of DR aims to decrease vision impairment by controlling modifiable risk factors including hypertension, obesity, and dyslipidemia. Moreover, systemic medications and plant-based therapy show promise in advancing DR treatment. One of the key mechanisms related to DR pathogenesis is the polyol pathway, through which aldose reductase (AR) catalyzes the conversion of glucose to sorbitol within various tissues, including the retina, lens, ciliary body and iris. Elevated glucose levels activate AR, leading to osmotic stress, advanced glycation end-product formation, and oxidative damage. This further implies chronic inflammation, vascular permeability, and angiogenesis. Our comprehensive narrative review describes the therapeutic potential of aldose reductase inhibitors in treating DR, where both synthetic and natural inhibitors have been studied in recent decades. Our synthesis aims to guide future research and clinical interventions in DR management.

Evaluating the Role of Breast Ultrasound in Early Detection of Breast Cancer in Low- and Middle-Income Countries: A Comprehensive Narrative Review.

Breast cancer, affecting both genders, but mostly females, exhibits shifting demographic patterns, with an increasing incidence in younger age groups. Early identification through mammography, clinical examinations, and breast self-exams enhances treatment efficacy, but challenges persist in low- and medium-income countries due to limited imaging resources. This review assesses the feasibility of employing breast ultrasound as the primary breast cancer screening method, particularly in resource-constrained regions. Following the PRISMA guidelines, this study examines 52 publications from the last five years. Breast ultrasound, distinct from mammography, offers advantages like radiation-free imaging, suitability for repeated screenings, and preference for younger populations. Real-time imaging and dense breast tissue evaluation enhance sensitivity, accessibility, and cost-effectiveness. However, limitations include reduced specificity, operator dependence, and challenges in detecting microcalcifications. Automatic breast ultrasound (ABUS) addresses some issues but faces constraints like potential inaccuracies and limited microcalcification detection. The analysis underscores the need for a comprehensive approach to breast cancer screening, emphasizing international collaboration and addressing limitations, especially in resource-constrained settings. Despite advancements, notably with ABUS, the primary goal is to contribute insights for optimizing breast cancer screening globally, improving outcomes, and mitigating the impact of this debilitating disease.

Small Scale, High Precision: Robotic Surgery in Neonatal and Pediatric Patients-A Narrative Review.

This narrative review explores the evolution and implications of robotic-assisted surgery in pediatric and neonatal cases, focusing on its advantages, drawbacks, and the specific diseases amenable to this innovative technology. Following PRISMA guidelines, 56 relevant articles from the past five years were selected, emphasizing advancements in precision, reduced trauma, and expedited recovery times for pediatric patients. Despite challenges like cost and training, ongoing research shapes pediatric robotic-assisted surgery, promising improved outcomes. The technology's benefits include enhanced precision, minimized scarring, and faster recovery, addressing the challenges in delicate pediatric procedures. Challenges encompass cost, training, and instrument design, but ongoing refinements aim to overcome these. This review underscores psychological and musculoskeletal considerations for patients and surgeons. While acknowledging limitations and preferred pathologies, this review outlines the transformative potential of robotic-assisted surgery in reshaping pediatric surgical care. This comprehensive assessment concludes that, despite challenges, ongoing advancements promise a future of enhanced precision and tailored care in pediatric surgery.

Differentiating Viral from Bacterial Pneumonia in Children: The Diagnostic Role of Lung Ultrasound-A Prospective Observational Study.

This prospective observational study aimed to investigate the utility of lung ultrasound (LUS) in diagnosing and managing pediatric respiratory infections, specifically focusing on viral, bacterial, and SARS-CoV-2 infections. Conducted over a period of 1 year and 8 months, this research involved 85 pediatric patients (showcasing a median age of 14 months) recruited based on specific criteria, including age, confirmed infection through multiplex PCR tests, and willingness to undergo LUS imaging. This study employed a 12-area scoring system for LUS examinations, utilizing the lung ultrasound score (LUSS) to evaluate lung abnormalities. The PCR examination results reveal diverse respiratory pathogens, with SARS-CoV-2, influenza, and bacterial co-infections being prominent among the cases. As an observational study, this study was not registered in the registry. Distinct LUS patterns associated with different pathogens were identified, showcasing the discriminatory potential of LUS in differentiating between viral and bacterial etiologies. Bacterial infections demonstrated more severe lung involvement, evident in significantly higher LUSS values compared with viral cases (p < 0.0001). The specific abnormalities found in bacterial superinfection can be integrated into diagnostic and management protocols for pediatric respiratory infections. Overall, this research contributes valuable insights into optimizing LUS as a diagnostic tool in pediatric pneumonia, facilitating more informed and tailored healthcare decisions.

Current Trends in Diagnosis and Treatment Approach of Diabetic Retinopathy during Pregnancy: A Narrative Review.

Diabetes mellitus during pregnancy and gestational diabetes are major concerns worldwide. These conditions may lead to the development of severe diabetic retinopathy during pregnancy or worsen pre-existing cases. Gestational diabetes also increases the risk of diabetes for both the mother and the fetus in the future. Understanding the prevalence, evaluating risk factors contributing to pathogenesis, and identifying treatment challenges related to diabetic retinopathy in expectant mothers are all of utmost importance. Pregnancy-related physiological changes, including those in metabolism, blood flow, immunity, and hormones, can contribute to the development or worsening of diabetic retinopathy. If left untreated, this condition may eventually result in irreversible vision loss. Treatment options such as laser therapy, intravitreal anti-vascular endothelial growth factor drugs, and intravitreal steroids pose challenges in managing these patients without endangering the developing baby and mother. This narrative review describes the management of diabetic retinopathy during pregnancy, highlights its risk factors, pathophysiology, and diagnostic methods, and offers recommendations based on findings from previous literature.

Stratifying Disease Severity in Pediatric COVID-19: A Correlative Study of Serum Biomarkers and Lung Ultrasound-A Retrospective Observational Dual-Center Study.

The COVID-19 pandemic, caused by SARS-CoV-2, has manifested distinct impacts on infants and children. This study delves into the intricate connection between lung ultrasound (LUS) findings and serum biomarkers in neonates and infants with COVID-19. Exploring factors contributing to the mild symptoms in this demographic, including immune responses and pre-existing immunity, the study spans 3 years and 9 months, involving 42 patients. Respiratory and gastrointestinal symptoms predominate, and LUS emerges as a vital, non-irradiating tool for evaluating pulmonary abnormalities. Serum biomarkers like CRP, procalcitonin, and cytokines provide key insights into the pathophysiology. Correlations reveal nuanced links between LUS score and clinical parameters, unveiling associations with hospitalization duration (rho = 0.49), oxygen saturation (rho = -0.88), and inflammatory markers, like ferritin (rho = 0.62), LDH (rho = 0.73), and D-dimer (rho = 0.73) with significance level (p < 0.05). The absence of large consolidations in LUS suggests unique pulmonary characteristics. The novelty of these findings lies in the comprehensive integration of LUS with serum biomarkers to assess and monitor the severity of lung involvement in neonates and infants affected by SARS-CoV-2. This approach offers valuable insights into disease severity, biomarker levels, the duration of hospitalization, and oxygen saturation, providing a multifaceted understanding of COVID-19's impact on this vulnerable population.

Tiny Lungs, Big Differences: Navigating the Varied COVID-19 Landscape in Neonates vs. Infants via Biomarkers and Lung Ultrasound.

Due to their susceptibilities, neonates and infants face unique SARS-CoV-2 challenges. This retrospective study will compare the illness course, symptoms, biomarkers, and lung damage in neonates and infants with SARS-CoV-2 infection from February 2020 to October 2023. This study was conducted at two hospitals in Timisoara, Romania, using real-time multiplex PCR to diagnose and lung ultrasonography (LUS) to assess lung involvement. Neonates had a more severe clinical presentation, an increased immune response, and greater lung involvement. Neonates had more PCR-positive tests (p = 0.0089) and longer hospital stays (p = 0.0002). In neonates, LDH, CRP, and ferritin levels were higher, indicating a stronger inflammatory response. Reduced oxygen saturation in neonates indicates respiratory dysfunction. The symptoms were varied. Infants had fever, cough, and rhinorrhea, while neonates had psychomotor agitation, acute dehydration syndrome, and candidiasis. This study emphasizes individualized care and close monitoring for neonatal SARS-CoV-2 infections. Newborn lung ultrasonography showed different variances and severity levels, emphasizing the need for targeted surveillance and therapy. Newborns have high lung ultrasound scores (LUSS), indicating significant lung involvement. Both groups had initial lung involvement, but understanding these modest differences is crucial to improving care for these vulnerable populations.

COVID-19 in Infants and Children under 2 Years-Could Lung Ultrasound Score Be Correlated with Biomarkers and Symptoms?

INTRODUCTION: It is already well known that infants and children infected with COVID-19 develop mild to moderate forms of the disease, with fever and oropharyngeal congestion being the most common symptoms. However, there are instances when patients claim to be experiencing respiratory symptoms. Because of the repeated lung examinations required in these situations, non-irradiating imaging techniques are preferred. This study's objective is to ascertain the value of lung ultrasonography (LUS) in the medical management of these specific cases. METHODS: Infants and children under two years old with SARS-CoV-2 infection were evaluated using LUS. Patients with other respiratory pathologies were excluded by using specific tests. The LUS score (LUSS) was correlated with biomarkers and clinical findings using the Mann-Whitney U test and Spearman's rank correlation rho. RESULTS: The LUSS for each patient varied from 1 to 8 points out of a maximum of 36 points. The arithmetic mean was 4.47 ± 2.36 (S.D), while the 95% CI for the arithmetic mean was 3.33 to 5.61. Sparse B-lines were present in all enrolled infants and children (100%), while only 36.84% developed alveolar syndrome (confluent B-lines). The lung changes were correlated with their biomarkers, specifically inflammatory markers. The correlation between LUSS and LDH, D-dimers, and IL-6 was a strongly positive one with rho = 0.55 (p = 0.001, 95% CI 0.13 to 0.80) between the LUSS and D-dimer levels and rho = 0.60 (p = 0.03, 95% CI 0.04 to 0.87) between LUSS and D-dimer levels at symptomatic infants and children (with respiratory involvement). CONCLUSIONS: Infants and children under the age of two are prone to develop mild forms of COVID-19 disease with a B-line pattern on LUS, although inflammatory markers have elevated blood levels. Despite the small sample, D-dimer levels and O2 saturation were correlated with LUSS in patients with respiratory involvement, while similar results were also found in the entire lot.

Hepatic arterial variations detected at multidetector computer tomography angiography in the Romanian population.

BACKGROUND: Our purpose was to determine the prevalence of normal hepatic vascularization and variations of the hepatic arteries using multidetector computed tomography (MDCT) angiography. These variants should be known before any surgery of the upper abdomen, the downside being that there aren't many studies on large groups of patients using high-specialized imaging. MATERIALS AND METHODS: This study was carried out on 4192 patients. We performed MDCT angiography on each one of the patients and had a specialized team observe the images. RESULTS: Using Michels' classification, the normal anatomy (type I) was present in 3392 (80.91%) cases, while abnormal hepatic arteries were observed in 800 (19.08%) cases. The variations were distributed as follows: type II in 40 (0.95%) cases, type III in 442 (10.54%) cases, type IV in 13 (0.31%) cases, type V in 285 (6.79%) cases, type VI in 12 (0.28%) cases, type VII in 3 (0.07%) cases, type VIII in 108 (2.57%) cases, type IX in 6 (0.14%) cases and type X in one case (0.02%). 170 (4.05%) unclassified cases were observed. Using Hiatt's classification, the variations were: type II in 325 (7.75%) cases, type III in 454 (10.83%) cases, type IV in 124 (2.95%) cases, type V in 6 cases (0.14%) and type VI in 69 (1.64%) cases. 102 (2.43%) unclassified cases were observed. CONCLUSIONS: We observed well-known variations of the hepatic arterial pattern and also found a large number of rare, unclassified cases.

Structural mechanism of a drug-binding process involving a large conformational change of the protein target.

Proteins often undergo large conformational changes when binding small molecules, but atomic-level descriptions of such events have been elusive. Here, we report unguided molecular dynamics simulations of Abl kinase binding to the cancer drug imatinib. In the simulations, imatinib first selectively engages Abl kinase in its autoinhibitory conformation. Consistent with inferences drawn from previous experimental studies, imatinib then induces a large conformational change of the protein to reach a bound complex that closely resembles published crystal structures. Moreover, the simulations reveal a surprising local structural instability in the C-terminal lobe of Abl kinase during binding. The unstable region includes a number of residues that, when mutated, confer imatinib resistance by an unknown mechanism. Based on the simulations, NMR spectra, hydrogen-deuterium exchange measurements, and thermostability measurements and estimates, we suggest that these mutations confer imatinib resistance by exacerbating structural instability in the C-terminal lobe, rendering the imatinib-bound state energetically unfavorable.

Could Biparametric MRI Replace Multiparametric MRI in the Management of Prostate Cancer?

Prostate cancer (PCa) is a worldwide epidemiological problem, since it is one of the most prevalent types of neoplasia among men, and the third-leading cause of cancer-related deaths, after lung and colorectal tumors. Unfortunately, the early stages of PCa have a wide range of unspecific symptoms. For these reasons, early diagnosis and accurate evaluation of suspicious lesions are crucial. Multiparametric MRI (mpMRI) is currently the imaging modality of choice for diagnostic screening and local staging of PCa, but also has a leading role in guiding biopsies and in treatment biparametric MRI (bpMRI) could partially replace mpMRI due to its lack of adverse reactions caused by contrast agents, relatively lower costs, and shorter acquisition time. Further, 31 relevant articles regarding the advantages and disadvantages of the aforementioned imaging techniques were scanned. As a result, while bpMRI has comparable accuracy in detecting PCa, its roles in the other steps of PCa management are limited.

Dynamics of integrin α5ß1, fibronectin, and their complex reveal sites of interaction and conformational change.

Integrin α5ß1 mediates cell adhesion to the extracellular matrix by binding fibronectin (Fn). Selectivity for Fn by α5ß1 is achieved through recognition of an RGD motif in the 10th type III Fn domain (Fn10) and the synergy site in the ninth type III Fn domain (Fn9). However, details of the interaction dynamics are unknown. Here, we compared synergy-site and Fn-truncation mutations for their α5ß1-binding affinities and stabilities. We also interrogated binding of the α5ß1 ectodomain headpiece fragment to Fn using hydrogen-deuterium exchange (HDX) mass spectrometry to probe binding sites and sites of integrin conformational change. Our results suggest the synergistic effect of Fn9 requires both specific residues and a folded domain. We found some residues considered important for synergy are required for stability. Additionally, we show decreases in fibronectin HDX are localized to a synergy peptide containing contacting residues in two ß-strands, an intervening loop in Fn9, and the RGD-containing loop in Fn10, indicative of binding sites. We also identified binding sites in the α5-subunit ß-propeller domain for the Fn9 synergy site and in the ß1-subunit ßI domain for Fn10 based on decreases in α5ß1 HDX. Interestingly, the dominant effect of Fn binding was an increase in α5ß1 deuterium exchange distributed over multiple sites that undergo changes in conformation or solvent accessibility and appear to be sites where energy is stored in the higher-energy, open-integrin conformation. Together, our results highlight regions important for α5ß1 binding to Fn and dynamics associated with this interaction.

Breast Cancer-How Can Imaging Help?

Breast cancer is the most common malignant disease among women, causing death and suffering worldwide. It is known that, for the improvement of the survival rate and the psychological impact it has on patients, early detection is crucial. For this to happen, the imaging techniques should be used at their full potential. We selected and examined 44 articles that had as subject the use of a specific imaging method in breast cancer management (mammography, ultrasound, MRI, ultrasound-guided biopsy, PET-CT). After analyzing their data, we summarized and concluded which are the best ways to use each one of the mentioned techniques for a good outcome. We created a simplified algorithm with easy steps that can be followed by radiologists when facing this type of neoplasia.

The Assessment of COVID-19 Pneumonia in Neonates: Observed by Lung Ultrasound Technique and Correlated with Biomarkers and Symptoms.

Newborns infected with SARS-CoV2 infection develop different symptoms in comparison with adults, but one thing is clear: some of the most common manifestations include cough and other respiratory symptoms that need to be evaluated. In these cases, lung ultrasound is a useful imaging technique that can evaluate the newborns' lung damage caused by COVID-19 pneumonia and can be used for the surveillance of the patients as well, being non-irradiating and easy to use. Nineteen neonates who were confirmed as having SARS-CoV2 infection were investigated using this imaging tool, and the results were compared and correlated with their symptoms and biomarkers. The mean of LUSS was 12.21 ± 3.56 (S.D), while the 95% CI for the arithmetic mean was 10.49-13.93. The difference of an independent t-test between the LUSS for the patient who presented cough and the LUSS for the patient without cough was -4.48 with an associated p-value of p = 0.02. The Pearson's correlation coefficient r = 0.89 (p = 0.03, 95% CI 0.0642 to 0.993) between the LUSS and IL-6 level showed a positive strong correlation. This reliable correlation between lung ultrasound score and inflammatory markers suggests that LUS could be used for monitoring inflammatory lung diseases in the future.

Von Willebrand factor A1 domain stability and affinity for GPIbα are differentially regulated by its O-glycosylated N- and C-linker.

Hemostasis in the arterial circulation is mediated by binding of the A1 domain of the ultralong protein von Willebrand factor (VWF) to GPIbα on platelets to form a platelet plug. A1 is activated by tensile force on VWF concatemers imparted by hydrodynamic drag force. The A1 core is protected from force-induced unfolding by a long-range disulfide that links cysteines near its N- and C-termini. The O-glycosylated linkers between A1 and its neighboring domains, which transmit tensile force to A1, are reported to regulate A1 activation for binding to GPIb, but the mechanism is controversial and incompletely defined. Here, we study how these linkers, and their polypeptide and O-glycan moieties, regulate A1 affinity by measuring affinity, kinetics, thermodynamics, hydrogen deuterium exchange (HDX), and unfolding by temperature and urea. The N-linker lowers A1 affinity 40-fold with a stronger contribution from its O-glycan than polypeptide moiety. The N-linker also decreases HDX in specific regions of A1 and increases thermal stability and the energy gap between its native state and an intermediate state, which is observed in urea-induced unfolding. The C-linker also decreases affinity of A1 for GPIbα, but in contrast to the N-linker, has no significant effect on HDX or A1 stability. Among different models for A1 activation, our data are consistent with the model that the intermediate state has high affinity for GPIbα, which is induced by tensile force physiologically and regulated allosterically by the N-linker.

Could Ultrasound Be Used as a Triage Tool in Diagnosing Fractures in Children? A Literature Review.

Fracture is one of the most frequent causes of emergency department visits in children, conventional radiography being the standard imaging tool used for following procedures and treatment. This imagistic method is irradiating and harmful, especially for children due to their high cell division rate. For this reason, we searched the literature to see if musculoskeletal ultrasound is a good alternative for diagnostic and follow-up regarding fractures in the pediatric population. After searching the databases using MeSH terms and manual filters, 24 articles that compare X-ray and ultrasound regarding their specificity and sensitivity in diagnosing fractures were included in this study. In the majority of the studied articles, the specificity and sensitivity of ultrasound are around 90-100%, and with high PPVs (positive predictive values) and NPVs (negative predictive values). Although it cannot replace conventional radiography, it is a great complementary tool in fracture diagnosis, having a sensitivity of nearly 100% when combined with clinical suspicion of fracture, compared with X-ray.

Protection of the Prodomain α1-Helix Correlates with Latency in the Transforming Growth Factor-ß Family.

The 33 members of the transforming growth factor beta (TGF-ß) family are fundamentally important for organismal development and homeostasis. Family members are synthesized and secreted as pro-complexes of non-covalently associated prodomains and growth factors (GF). Pro-complexes from a subset of family members are latent and require activation steps to release the GF for signaling. Why some members are latent while others are non-latent is incompletely understood, particularly because of large family diversity. Here, we have examined representative family members in negative stain electron microscopy (nsEM) and hydrogen deuterium exchange (HDX) to identify features that differentiate latent from non-latent members. nsEM showed three overall pro-complex conformations that differed in prodomain arm domain orientation relative to the bound growth factor. Two cross-armed members, TGF-ß1 and TGF-ß2, were each latent. However, among V-armed members, GDF8 was latent whereas ActA was not. All open-armed members, BMP7, BMP9, and BMP10, were non-latent. Family members exhibited remarkably varying HDX patterns, consistent with large prodomain sequence divergence. A strong correlation emerged between latency and protection of the prodomain α1-helix from exchange. Furthermore, latency and protection from exchange correlated structurally with increased α1-helix buried surface area, hydrogen bonds, and cation-pi bonds. Moreover, a specific pattern of conserved basic and hydrophobic residues in the α1-helix and aromatic residues in the interacting fastener were found only in latent members. Thus, this first comparative survey of TGF-ß family members reveals not only diversity in conformation and dynamics but also unique features that distinguish latent members.

Role of Diphosphonates Bone Scintigraphy in Correlation with Biomarkers for a Personalized Approach to ATTR Cardiac Amyloidosis in North-Eastern Romania.

Transthyretin cardiac amyloidosis (ATTR) is a rare cardiac protein deposition disease characterized by progressive thickening of both ventricles, the inter-atrial-ventricular septum and the atrioventricular valves. The gold standard method for diagnosing this rare pathology is endomyocardial biopsy. If this method cannot be used, the alternative is a mixture of clinical and paraclinical tests. Over the course of five years, we examined 58 patients suspected of cardiac amyloidosis based on electrocardiography and ultrasonography criteria, who had been sent for bone scintigraphy in order to determine the presence of ATTR cardiac amyloidosis. However, the final diagnosis was set by correlating the bone scan with genetic testing, free light chain dosage or soft tissue biopsy. Based on the final diagnosis we analyzed the patients' predominant biomarkers in order to determine a possible correlation between them. This analysis is designed to help the general practitioner set a possible cardiac amyloidosis diagnosis.

Is Lung Ultrasound Helpful in COVID-19 Neonates?-A Systematic Review.

BACKGROUND: The SARS-CoV-2 infection has occurred in neonates, but it is a fact that radiation exposure is not recommended given their age. The aim of this review is to assess the evidence on the utility of lung ultrasound (LUS) in neonates diagnosed with COVID-19. METHODS: A systematic literature review was performed so as to find a number of published studies assessing the benefits of lung ultrasound for newborns diagnosed with COVID and, in the end, to make a comparison between LUS and the other two more conventional procedures of chest X-rays or CT exam. The key terms used in the search of several databases were: "lung ultrasound", "sonography", "newborn", "neonate", and "COVID-19'. RESULTS: In total, 447 studies were eligible for this review, and after removing the duplicates, 123 studies referring to LU were further examined, but only 7 included cases of neonates. These studies were considered for the present research paper. CONCLUSIONS: As a non-invasive, easy-to-use, and reliable method for lung lesion detection in neonates with COVID-19, lung ultrasound can be used as a useful diagnosis tool for the evaluation of COVID-19-associated lung lesions. The benefits of this method in this pandemic period are likely to arouse interest in opening new research horizons, with immediate practical applicability.