Geometry-Driven Fabrication of Mini-Tablets via 3D Printing: Correlating Release Kinetics with Polyhedral Shapes.

The aim of this study was to fabricate mini-tablets of polyhedrons containing theophylline using a fused deposition modeling (FDM) 3D printer, and to evaluate the correlation between release kinetics models and their geometric shapes. The filaments containing theophylline, hydroxypropyl cellulose (HPC), and EUDRAGIT RS PO (EU) could be obtained with a consistent thickness through pre-drying before hot melt extrusion (HME). Mini-tablets of polyhedrons ranging from tetrahedron to icosahedron were 3D-printed using the same formulation of the filament, ensuring equal volumes. The release kinetics models derived from dissolution tests of the polyhedrons, along with calculations for various physical parameters (edge, SA: surface area, SA/W: surface area/weight, SA/V: surface area/volume), revealed that the correlation between the Higuchi model and the SA/V was the highest (R2 = 0.995). It was confirmed that using 3D- printing for the development of personalized or pediatric drug products allows for the adjustment of drug dosage by modifying the size or shape of the drug while maintaining or controlling the same release profile.

Unraveling the Potential of Attentive Bi-LSTM for Accurate Obesity Prognosis: Advancing Public Health towards Sustainable Cities.

The global prevalence of obesity presents a pressing challenge to public health and healthcare systems, necessitating accurate prediction and understanding for effective prevention and management strategies. This article addresses the need for improved obesity prediction models by conducting a comprehensive analysis of existing machine learning (ML) and deep learning (DL) approaches. This study introduces a novel hybrid model, Attention-based Bi-LSTM (ABi-LSTM), which integrates attention mechanisms with bidirectional Long Short-Term Memory (Bi-LSTM) networks to enhance interpretability and performance in obesity prediction. Our study fills a crucial gap by bridging healthcare and urban planning domains, offering insights into data-driven approaches to promote healthier living within urban environments. The proposed ABi-LSTM model demonstrates exceptional performance, achieving a remarkable accuracy of 96.5% in predicting obesity levels. Comparative analysis showcases its superiority over conventional approaches, with superior precision, recall, and overall classification balance. This study highlights significant advancements in predictive accuracy and positions the ABi-LSTM model as a pioneering solution for accurate obesity prognosis. The implications extend beyond healthcare, offering a precise tool to address the global obesity epidemic and foster sustainable development in smart cities.

Synergistic effects of copper and oxygen vacancies in enhancing the efficacy of partially crystalline CuMnxOy catalyst for ozone decomposition.

To tackle the challenge of ground-level ozone pollution, this study proposed a potential catalytic design approach for ozone decomposition using Cu-Mn bimetallic oxide. This approach is grounded in an understanding of the intrinsic reactivity for catalyst and incorporates a novel potassium-driven low-temperature oxidation process for catalyst synthesis. The research highlights the creation of a highly reactive Cu-Mn oxide phase with extensive defect coverage, leading to significantly increased reaction rates. It also identifies the MnO2(100) facet as a crucial active phase, where oxygen vacancies simultaneously enhance O3 adsorption and decomposition, albeit with a concurrent risk of O2 poisoning due to the stabilization of adsorbed O2. Crucially, the incorporation of Cu offsets the effects of oxygen vacancies, influencing conversion rates and lessening O2 poisoning. The synergistic interplay between Cu and oxygen vacancies elevates the performance of the defect-rich Cu-Mn oxide catalyst. By combining computational and experimental methods, this study not only advances the understanding of the Cu-Mn oxide system for ozone decomposition but also contributes valuable insights into developing more efficient catalysts to mitigate ozone pollution.

SARS-CoV-2 infection exacerbates the cellular pathology of Parkinson's disease in human dopaminergic neurons and a mouse model.

While an association between Parkinson's disease (PD) and viral infections has been recognized, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on PD progression remains unclear. Here, we demonstrate that SARS-CoV-2 infection heightens the risk of PD using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons and a human angiotensin-converting enzyme 2 (hACE2) transgenic (Tg) mouse model. Our findings reveal that SARS-CoV-2 infection exacerbates PD susceptibility and cellular toxicity in DA neurons pre-treated with human preformed fibrils (hPFFs). Additionally, nasally delivered SARS-CoV-2 infects DA neurons in hACE2 Tg mice, aggravating the damage initiated by hPFFs. Mice infected with SARS-CoV-2 display persisting neuroinflammation even after the virus is no longer detectable in the brain. A comprehensive analysis suggests that the inflammatory response mediated by astrocytes and microglia could contribute to increased PD susceptibility associated with SARS-CoV-2. These findings advance our understanding of the potential long-term effects of SARS-CoV-2 infection on the progression of PD.

Interleukin 38 improves insulin resistance in hyperlipidemic skeletal muscle cells via PPARδ/SIRT1-mediated suppression of STAT3 signaling and oxidative stress.

The cytokine interleukin-38 (IL-38), a recently discovered member of the IL-1 family, has been shown to regulate inflammation and improve hepatic endoplasmic reticulum stress and lipid metabolism in individuals with obesity. However, its impact on insulin signaling in skeletal muscle cells and the underlying mechanisms remain unclear. In vitro obesity models were established using palmitate treatment, and Western blot analysis was performed to assess target proteins. Commercial kits were used to measure glucose uptake in cultured myocytes. Our study showed that IL-38 treatment alleviated the impairment of insulin signaling, including IRS-1 and Akt phosphorylation, and increased glucose uptake in palmitate-treated C2C12 myocytes. Increased levels of STAT3-mediated signaling and oxidative stress were observed in these cells following palmitate treatment, and these effects were reversed by IL-38 treatment. In addition, IL-38 treatment upregulated the expression of PPARδ, SIRT1 and antioxidants. Knockdown of PPARδ or SIRT1 using appropriate siRNAs abrogated the effects of IL-38 on insulin signaling, oxidative stress, and the STAT3-dependent pathway. These results suggest that IL-38 alleviates insulin resistance by inhibiting STAT3-mediated signaling and oxidative stress in skeletal muscle cells through PPARδ/SIRT1. This study provides fundamental evidence to support the potential use of IL-38 as a safe therapeutic agent for the treatment of insulin resistance and type 2 diabetes.

Contemporary multimodality non-invasive cardiac imaging protocols for tetralogy of Fallot.

Tetralogy of Fallot is the most prevalent cyanotic congenital heart disease, requiring lifelong multimodality non-invasive cardiac imaging, such as echocardiography, cardiothoracic computed tomography, and cardiac magnetic resonance imaging. As imaging techniques continuously evolve and are gradually integrated into clinical practice, there is a critical need to update multimodality imaging protocols. Over the last two decades, cardiothoracic computed tomography imaging techniques have advanced remarkably, significantly enhancing its role in evaluating patients with tetralogy of Fallot. In this review, we describe contemporary multimodality non-invasive cardiac imaging protocols for tetralogy of Fallot, emphasizing the expanding role of cardiothoracic computed tomography. Additionally, we present standardized reporting forms designed to facilitate the clinical adoption of these protocols.

Large-scale cross-ancestry genome-wide meta-analysis of serum urate.

Hyperuricemia is an essential causal risk factor for gout and is associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to genome-wide association studies of serum urate, the genetic architecture of serum urate requires exploration. A large-scale cross-ancestry genome-wide association meta-analysis of 1,029,323 individuals and ancestry-specific meta-analysis identifies a total of 351 loci, including 17 previously unreported loci. The genetic architecture of serum urate control is similar between European and East Asian populations. A transcriptome-wide association study, enrichment analysis, and colocalization analysis in relevant tissues identify candidate serum urate-associated genes, including CTBP1, SKIV2L, and WWP2. A phenome-wide association study using polygenic risk scores identifies serum urate-correlated diseases including heart failure and hypertension. Mendelian randomization and mediation analyses show that serum urate-associated genes might have a causal relationship with serum urate-correlated diseases via mediation effects. This study elucidates our understanding of the genetic architecture of serum urate control.

Evaluating cardiovascular disease risk stratification using multiple-polygenic risk scores and pooled cohort equations: insights from a 17-year longitudinal Korean cohort study.

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, caused by a complex interplay of genetic and environmental factors. This study aimed to evaluate the combined efficacy of multi-polygenic risk scores and pooled cohort equations (PCE) for predicting future CVD risks in the Korean population. In this longitudinal study, 7,612 individuals from the Ansan and Ansung cohorts were analyzed over a 17-year follow-up period. The participants were genotyped using the Korea Biobank Array, and quality-controlled genetic data were subjected to imputation analysis. The weighted sum of the PRSs (wPRSsum) was calculated using PRS-CS with summary statistics from myocardial infarction, ischemic stroke, coronary artery disease, and hypertension genome-wide association studies. The recalibrated PCE was used to assess clinical risk, and the participants were stratified into risk groups based on the wPRSsum and PCE. Associations between these risk scores and incident CVD were evaluated using Cox proportional hazards models and Kaplan-Meier analysis. The wPRSsum approach showed a significant association with incident CVD (HR = 1.15, p = 7.49 × 10-5), and the top 20% high-risk genetic group had an HR of 1.50 (p = 5.04 × 10-4). The recalibrated PCE effectively differentiated between the low and high 10-year CVD risk groups, with a marked difference in survival rates. The predictive models constructed using the wPRSsum and PCE demonstrated a slight improvement in prediction accuracy, particularly among males aged <55 years (C-index = 0.640). We demonstrated that while the integration of wPRSsum with PCE did not significantly outperform the PCE-only model (C-index: 0.703 for combined and 0.704 for PCE-only), it provided enhanced stratification of CVD risk. The highest risk group, identified through the combination of high wPRSsum and PCE scores, exhibited an HR of 4.99 for incident CVD (p = 1.45 × 10-15). These findings highlight the potential of integrating genetic risk assessments with traditional clinical tools for effective CVD risk stratification. Although the addition of wPRSsum to the PCE provided a marginal predictive improvement, it proved valuable in identifying high-risk individuals and supporting personalized treatment strategies. This study reinforces the utility of multi-PRS in conjunction with clinical risk assessment tools, paving the way for more tailored approaches for CVD prevention and management in diverse populations.

Energy Storage Performance of Electrode Materials Derived from Manganese Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) are porous materials assembled using metal and organic linkers, showing a high specific surface area and a tunable pore size. Large portions of metal open sites in MOFs can be exposed to electrolyte ions, meaning they have high potential to be used as electrode materials in energy storage devices such as supercapacitors. Also, they can be easily converted into porous metal oxides by heat treatment. In this study, we obtained high energy storage performance by preparing electrode materials through applying heat treatment to manganese MOFs (Mn-MOFs) under air. The chemical and structural properties of synthesized and thermally treated Mn-MOFs were measured by Fourier-transform infrared spectroscopy (FTIR), Raman spectroscopy, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and transmission electron microscopy (TEM). The surface area and porosity were investigated by nitrogen adsorption/desorption isotherms. The electrochemical properties were studied by cyclic voltammetry (CV) and galvanostatic charge-discharge (GCD) using a three-electrode cell. It was found that Mn-MOF electrodes that underwent heat treatment at 400 °C under air consisted of Mn2O3 with high specific surface area and porosity. They also showed a superior specific capacitance of 214.0 F g-1 and an energy density value of 29.7 Wh kg-1 (at 0.1 A g-1) compared to non-treated Mn-MOFs.

2024 Consensus Statement on Coronary Stenosis and Plaque Evaluation in CT Angiography From the Asian Society of Cardiovascular Imaging-Practical Tutorial (ASCI-PT).

The Asian Society of Cardiovascular Imaging-Practical Tutorial (ASCI-PT) is an instructional initiative of the ASCI School designed to enhance educational standards. In 2021, the ASCI-PT was convened with the goal of formulating a consensus statement on the assessment of coronary stenosis and coronary plaque using coronary CT angiography (CCTA). Nineteen experts from four countries conducted thorough reviews of current guidelines and deliberated on eight key issues to refine the process and improve the clarity of reporting CCTA findings. The experts engaged in both online and on-site sessions to establish a unified agreement. This document presents a summary of the ASCI-PT 2021 deliberations and offers a comprehensive consensus statement on the evaluation of coronary stenosis and coronary plaque in CCTA.

Evaluation of Two Commercial Kits for Qualitative Detection of SARS-CoV-2 Antigens in Nasopharyngeal Specimens.

BACKGROUND: Two rapid antigen tests (RATs) for COVID-19 targeting the nucleocapsid protein of SARS-CoV-2 were compared with real-time RT-PCR as the reference method. METHODS: Ninety-six nasopharyngeal swab samples, comprising 56 positive and 40 negative samples confirmed through rRT-PCR were collected and retested to determine the reliability of the two nasopharyngeal RATs. RESULTS: The overall sensitivity and specificity of both RATs were 64.3% (95% confidence interval 50.4 - 76.6%) and 100% (95% confidence interval 91.2 - 100%), respectively. Cohen's kappa coefficient of agreement of both RATs to rRT-PCR was 0.600 (95% confidence interval 0.457 - 0.743) (p < 0.001), showing almost perfect agreement when the Ct values were less than 25 in rRT-PCR. A significant difference in Ct values between true positives and false negatives was observed (Mann-Whitney-Wilcoxon test; p < 0.001). CONCLUSIONS: Compared to rRT-PCR, RATs have fewer false negatives. In suspected COVID-19 cases, negative RAT results should be retested using either RAT or rRT-PCR.

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

Assessment of Feasibility and Interscan Variability of Short-time Cardiac MRI for Cardiotoxicity Evaluation in Breast Cancer.

Purpose To investigate the feasibility and interscan variability of short-time cardiac MRI protocol after chemotherapy in individuals with breast cancer. Materials and Methods A total of 13 healthy female controls (mean age, 52.4 years ± 13.2 [SD]) and 85 female participants with breast cancer (mean age, 51.8 years ± 9.9) undergoing chemotherapy prospectively underwent routine breast MRI and short-time cardiac MRI using a 3-T scanner with peripheral pulse gating in the prone position. Interscan, intercoil, and interobserver reproducibility and variability of native T1 and extracellular volume (ECV), as well as ventricular functional parameters, were measured using the intraclass correlation coefficient (ICC), standard error of measurement (SEM), or coefficient of variation (CoV). Results Left ventricular functional parameters had excellent interscan reproducibility (ICC ≥ 0.80). Left ventricular ejection fraction showed low interscan variability in control and chemotherapy participants (SEM, 2.0 and 1.2; CoV, 3.1 and 1.9, respectively). Native T1 showed excellent interscan (ICC, 0.75) and intercoil (ICC, 0.81) reproducibility in the control group and good interscan reproducibility (ICC, 0.72 and 0.73, respectively) in the participants undergoing immediate and remote chemotherapy. Interscan reproducibility for ECV was excellent in the control group and in the remote chemotherapy group (ICC, 0.93 and 0.88, respectively) and fair in the immediate chemotherapy group (ICC, 0.52). In the regional analysis, interscan repeatability and variability of native T1 and ECV were superior in the anteroseptum or inferoseptum than in other segments in the immediate chemotherapy group. Native T1 and ECV had good to excellent interobserver agreement across all groups. Conclusion Short-time cardiac MRI showed excellent results for interscan, intercoil, and interobserver reproducibility and variability for ventricular functional or tissue characterization parameters, suggesting that this modality is feasible for routine surveillance of cardiotoxicity evaluation in individuals with breast cancer. Keywords: Cardiac MRI, Heart, Cardiomyopathy ClinicalTrials.gov registration no. NCT03301389 Supplemental material is available for this article. © RSNA, 2024.

Changes in dementia treatment patterns associated with changes in the National Policy in South Korea among patients with newly diagnosed Alzheimer's disease between 2011 and 2017: results from the multicenter, retrospective CAPTAIN study.

BACKGROUND: The South Korean government has been actively involved in plans to combat dementia, implementing a series of national strategies and plans since 2008. In July 2014, eligibility for mandatory long-term care insurance (LTCI) was extended to people with dementia enabling access to appropriate long-term care including the cognitive function training program and home nursing service. This study aimed to investigate changes in treatment patterns for Alzheimer's disease (AD) between July 2011 and June 2017 which spanned the 2014 revision. METHODS: This multicenter, retrospective, observational study of patients with newly diagnosed AD analyzed electronic medical records from 17 general hospitals across South Korea. Based on their time of AD diagnosis, subjects were categorized into Cohort 1 (1 July 2011 to 30 June 2014) and Cohort 2 (1 July 2014 to 30 June 2017). RESULTS: Subjects (N=3,997) divided into Cohorts 1 (n=1,998) and 2 (n=1,999), were mostly female (66.4%) with a mean age of 84.4 years. Cohort 1 subjects were significantly older (P<0.0001) and had a lower number of comorbidities (P=0.002) compared with Cohort 2. Mean Mini-Mental State Examination (MMSE) scores in Cohorts 1 and 2 at the time of AD diagnosis or start of initial treatment were 16.9 and 17.1, respectively (P=0.2790). At 1 year, mean MMSE scores in Cohorts 1 and 2 increased to 17.9 and 17.4, respectively (P=0.1524). Donepezil was the most frequently administered medication overall (75.0%), with comparable rates between cohorts. Rates of medication persistence were ≥98% for acetylcholinesterase inhibitor or memantine therapy. Discontinuation and switch treatment rates were significantly lower (49.7% vs. 58.0%; P<0.0001), and mean duration of initial treatment significantly longer, in Cohort 2 vs. 1 (349.3 vs. 300.2 days; P<0.0001). CONCLUSIONS: Comparison of cohorts before and after revision of the national LTCI system for dementia patients found no significant difference in mean MMSE scores at the time of AD diagnosis or start of initial treatment. The reduction in the proportion of patients who discontinued or changed their initial treatment, and the significant increase in mean duration of treatment, were observed following revision of the LTCI policy which enabled increased patient access to long-term care.

Higher order neurocognition in pediatric brain tumor survivors: What can we learn from white matter microstructure?

BACKGROUND: Pediatric brain tumor survivors (PBTS) experience neurocognitive late effects, including problems with working memory, processing speed, and other higher order skills. These skill domains are subserved by various white matter (WM) pathways, but not much is known about these brain-behavior links in PBTS. This study examined the anterior corona radiata (ACR), inferior fronto-occipital fasciculi (IFOF), and superior longitudinal fasciculi (SLF) by analyzing associations among diffusion metrics and neurocognition. PROCEDURE: Thirteen PBTS and 10 healthy controls (HC), aged 9-14 years, completed performance-based measures of processing speed and executive function, and parents rated their child's day-to-day executive skills. Children underwent magnetic resonance imaging (MRI) with diffusion weighted imaging that yielded fractional anisotropy (FA) and mean diffusivity (MD) values. Independent samples t-tests assessed group differences on neurocognitive and imaging measures, and pooled within-group correlations examined relationships among measures across groups. RESULTS: PBTS performed more poorly than HC on measures of processing speed, divided attention, and shifting (d = -1.08 to -1.44). WM microstructure differences were significant in MD values for the bilateral SLF and ACR, with PBTS showing higher diffusivity (d = 0.75 to 1.21). Better processing speed, divided attention, and shifting were associated with lower diffusivity in the IFOF, SLF, and ACR, but were not strongly correlated with FA. CONCLUSIONS: PBTS demonstrate poorer neurocognitive functioning that is linked to differences in WM microstructure, as evidenced by higher diffusivity in the ACR, SLF, and IFOF. These findings support the use of MD in understanding alterations in WM microstructure in PTBS and shed light on potential functions of these pathways.

High-Throughput Manufacturing of Multimodal Epidermal Mechanosensors with Superior Detectability Enabled by a Continuous Microcracking Strategy.

Non-invasive human-machine interactions (HMIs) are expected to be promoted by epidermal tactile receptive devices that can accurately perceive human activities. In reality, however, the HMI efficiency is limited by the unsatisfactory perception capability of mechanosensors and the complicated techniques for device fabrication and integration. Herein, a paradigm is presented for high-throughput fabrication of multimodal epidermal mechanosensors based on a sequential "femtosecond laser patterning-elastomer infiltration-physical transfer" process. The resilient mechanosensor features a unique hybrid sensing layer of rigid cellular graphitic flakes (CGF)-soft elastomer. The continuous microcracking of CGF under strain enables a sharp reduction in conductive pathways, while the soft elastomer within the framework sustains mechanical robustness of the structure. As a result, the mechanosensor achieves an ultrahigh sensitivity in a broad strain range (GF of 371.4 in the first linear range of 0-50%, and maximum GF of 8922.6 in the range of 61-70%), a low detection limit (0.01%), and a fast response/recovery behavior (2.6/2.1 ms). The device also exhibits excellent sensing performances to multimodal mechanical stimuli, enabling high-fidelity monitoring of full-range human motions. As proof-of-concept demonstrations, multi-pixel mechanosensor arrays are constructed and implemented in a robot hand controlling system and a security system, providing a platform toward efficient HMIs.

Trend of nontuberculous mycobacteria species and minimal inhibitory concentration in a referral laboratory in Korea from 2013 to 2019.

BACKGROUND: This study investigated the trends of nontuberculous mycobacterial (NTM) isolates and the minimal inhibitory concentrations (MIC) of antimicrobial agents in Korea. METHODS: Data from 2013 to 2019 were collected from 69 medical institutions through 12 branches of the Korean Institute of Tuberculosis. NTM identification was conducted using the Advansure Mycobacteria Genoblot assay. The MIC of antibiotics against NTM species were measured using the broth microdilution method according to the Clinical and Laboratory Standards Institute guidelines. RESULTS: Over seven years, 86,194 NTM identifications were requested, with an annual increase from 8034 in 2013-17,229 in 2019. The most frequently identified NTM species were M. intracellulare (33,467; 47.3%) and M. avium (19,818; 27.2%), followed by M. abscessus (6858; 9.4%) and M. massiliense (3156; 4.3%). Regarding the antimicrobial agents, imipenem exhibited the greatest difference in MIC between M. intracellulare and M. avium, whereas clarithromycin showed the most significant difference between M. abscessus and M. massiliense. No notable changes were observed in the annual MIC distribution of most antibacterial agents, except for clarithromycin in M. abscessus. CONCLUSIONS: The prevalence of NTM in Korea is gradually increasing, and follow-up studies on NTM isolates identified as the causative agents of infection are needed.

Markedly Increased Mean Platelet Volume in Bacterial Meningitis.

BACKGROUND: Differentiating bacterial and viral meningitis is crucial, and this study explored the potential of mean platelet volume (MPV) as a marker for differentiation. METHODS: Blood samples were collected from patients with central nerve system related manifestations, and MPV was tested. Cerebrospinal fluid samples were obtained and bacterial culture and the FilmArray ME panel were performed. The distribution of MPV was compared between groups. RESULTS: The study included 8 patients in the bacterial meningitis group and 12 patients in the viral meningitis group. The bacterial meningitis group showed a significantly higher median MPV of 10.9 (9.2 - 11.6) fL compared to the viral meningitis group with 8.4 (8.1 - 8.8) fL (p < 0.0001). CONCLUSIONS: MPV could serve as a diagnostic indicator to differentiate between bacterial and viral meningitis. Larger studies are needed to validate these findings.