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Musculoskeletal modeling, typically implemented using marker-based systems in laboratory environments, is commonly used for noninvasive estimations of loads. Inertial measurement units (IMUs) have become an alternative for the evaluation of kinematics. However, estimates of spine joint contact forces using IMUs have yet to be thoroughly evaluated. Dynamics tasks and static postures from activities of daily living were captured on 11 healthy subjects using both systems simultaneously. Spine kinematics obtained from IMU- and marker-based systems and L4–L5 joint contact forces were compared. Lateral bending resulted in a weak agreement with significant differences between the 2 systems (P =.02, average root mean-squared error = 4.81), whereas flexion–extension and axial rotation exhibited the highest agreement with no significant differences (P <.05, average root mean-squared error = 5.51 and P <.31, average root mean-squared error = 5.08, respectively). All tasks showed excellent correlations (R2 =.76–.99) in estimated loads between systems. Differences in predicted loads at the L4–L5 were only observed during flexion–extension (1041 N vs 947 N, P =.0004) and walking with weights (814 N vs 727 N, P =.004). Different joint reaction force outcomes were obtained in 2 of the 8 tasks between systems, suggesting that IMUs can be robust tools allowing for convenient and less expensive evaluations and for longitudinal assessments inside and outside the laboratory setting. [ABSTRACT FROM AUTHOR]

Many studies have shown that personalized exergames have a positive effect on promoting regular and proper exercise. However, there is no consensus on the design characteristics and evaluation of exergames. This systematic review of published research literature aimed to explore the general characteristics, personalization characteristics, and evaluation of personalized exergames for middle-aged and older people. We screened published studies in the Web of Science, Scopus, PubMed, ACM, and IEEE Xplore databases, extracted data, and performed a thematic analysis according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews checklist. Three main themes and nine subthemes were generated from 24 included papers. Moreover, a personalization model (FACTS) and evaluation system (PMSS) of exergames were developed. Personalized exergames had potential positive effects on motivating middle-aged and older people to exercise and improve their health, particularly physical, mental, and social health. However, more fine-grained studies on personalized exergames are necessary in the future. [ABSTRACT FROM AUTHOR]

This canine in vivo study assessed the effect of recombinant human platelet-derived growth factor (rhPDGF) on the healing of periapical tissues following apical surgery. From a total of 96 premolar teeth, 64 teeth from six beagle dogs (2 years old) were classified as experimental and were randomly assigned to four experimental groups (16 teeth per group). After having the pulp extirpated, leaving teeth open to the oral cavity for 1 week, and sealing with an immediate restorative material for 8 weeks, nonsurgical endodontic treatment was performed. A split-mouth design was used, and intra-animal randomization of treatment sides was applied to the groups as follows: apical curettage + 1.5-mm root-end resection (Group 1); apicoectomy + mineral trioxide aggregate (MTA) root-end filling (Group 2); apicoectomy + MTA root-end filling + rhPDGF (Group 3); and apical curettage + rhPDGF (Group 4). The animals were sacrificed 24 months after apical surgery, and histologic and µCT analyses were performed for bone volume loss (BVL). Group 1 showed partial resolution of the periapical lesions without signs of tissue regeneration (BVL: 49.09 ± 10.97 mm3). Group 2 had minimal bone regeneration and showed cementum reformation in 9 teeth, with no direct attachment to the MTA (BVL: 35.34 ± 10.97 mm3). Group 3 showed regeneration of all damaged apical tissues without direct contact between the cementum and MTA (BLV: 4.51 ± 1.55 mm3). Group 4 showed regeneration of PDL, bone, and cementum and attachment of functional cementum fibers (BVL: 2.82 ± 2.3 mm3). The difference in BVL was statistically significant only for Groups 1 and 2 (P < .05). rhPDGF may help regenerate apical tissue structures following apical surgery. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effect of continuous perioperative clopidogrel treatment on the osseointegration of titanium implants. Materials and Methods: A total of 32 New Zealand rabbits were randomly divided between two groups: a clopidogrel group (n = 16) and a control group (n = 16). For 1 week prior to the surgical placement of a titanium implant in their medial femoral condyle, rabbits in the clopidogrel group received 3 mg/kg of clopidogrel daily, and the control group received only the vehicle. This treatment was continued for another 6 weeks postoperatively. At 6 weeks, the rabbits were euthanized and postmortem histologic and histomorphometric evaluation of the implants was performed. Results: The surgical procedures and postoperative period were uneventful and well tolerated by all animals without any surgical wound dehiscence, signs of infection, or other complication. No implant failure was observed in any of the groups. Histomorphometric analysis showed that bone-to-implant contact (BIC) was 48.77% for the clopidogrel group and 34.65% for the control group, with statistically significant difference between them (P < .001). Moreover, clopidogrel group had significantly greater bone tissue density (40.52% vs 28.74%, respectively; P <.001) and mean trabecular thickness (284.7 μm vs 180.7 μm, respectively; P < .001) in proximity to the implant surface than the control group, while the mean trabecular number had no difference between groups (1.56 vs 1.60, respectively; P = .961). Conclusions: The present study showed that continuous clopidogrel treatment does not negatively affect osseointegration, but rather promotes it in terms of BIC and bone density around the titanium implants. Further studies on the effect of the P2Y12 receptor and its antagonists on peri-implant bone homeostasis may provide useful information or applications for long-term success of dental implant therapy. [ABSTRACT FROM AUTHOR]

Purpose: To review experimental peri-implantitis studies using rat models and summarize different peri-implantitis induction techniques and evaluate their effectiveness. Materials and Methods: Electronic searches were conducted by two independent examiners to address the following issues. Meta-analyses explored the marginal bone loss (MBL) of four types of peri-implantitis induction methods in rats. The detailed induction tactics--such as the implant design, implant size, surgical process, time cost, induction methods, and endpoint measurements--were summarized. Results: Of the 18 included studies, 38.9% of the studies placed implants at the maxillary first molar, and 44.4% placed them at the alveolar ridge region anterior to the maxillary first molar. As for the induction method, the numbers of published studies on ligature methods, bacterial inoculation, and bacterial lipopolysaccharide inoculation were equally high among all selected studies. The total implant survival rate at the end was 160 out of 213 implants (75.11%). Eight studies with high pooled heterogeneity (I2 = 98, P < .01) in the meta-analysis reported an overall MBL (µ-CT) of 0.47 mm (95% CI = 0.14 to 0.81). A subgroup analysis estimated an MBL of 0.31 mm (95% CI = 0.12 to 0.50) for bacterial inoculation and 0.66 mm (95% CI = 0.07 to 1.26) for the ligature method. Histopathologic analysis revealed that peri-implantitis in rats was similar to peri-implantitis lesions in humans. Conclusions: Implant placement at the maxillary first molar with bacterial inoculation and the silk ligature method to build peri-implantitis rat models is reliable to use for research on peri-implantitis. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effect of supraphysiologic administration of testosterone in an early and late model of implant osseointegration in rat tibiae. Materials and Methods: A total of 40 rats were randomly allocated into four groups (n = 10/group), which were divided according to the type of experiment and time of osseointegration: (1) vehicle (14 days), (2) testosterone (14 days), (3) vehicle (42 days), and (4) testosterone (42 days). Testosterone cypionate (7.5 mg/kg) administration started 4 weeks before implant placement, and the injections were performed daily until euthanasia. Machined-surface titanium implants (2.2 mm in diameter and 4 mm high) were placed bilaterally in the tibia of animals 28 days after the first testosterone injection. At days 14 and 42 after implant placement, euthanasia was performed and the tibiae were harvested to perform biomechanical evaluation and histomorphometric analysis of bone-to-implant contact (BIC%) and bone between the threads (BBT%). Results: There was no statistical difference in the removal torque of the implants between the groups treated with the vehicle (control group) or testosterone (P > .05). At 14 days of osseointegration, the BIC% and BBT% did not differ between vehicle or testosterone groups (P > .05), while at 42 days, both the BIC% and BBT% were significantly reduced by testosterone compared to the vehicle group (P < .05). Conclusions: Testosterone cypionate in supraphysiologic dose impaired late-phase osseointegration in rat tibiae. [ABSTRACT FROM AUTHOR]

It is not currently possible to directly and noninvasively measure in vivo patellofemoral joint contact force during dynamic movement; therefore, indirect methods are required. Simple models may be inaccurate because patellofemoral contact forces vary for the same knee flexion angle, and the patellofemoral joint has substantial out-of-plane motion. More sophisticated models use 3-dimensional kinematics and kinetics coupled to a subject-specific anatomical model to predict contact forces; however, these models are time consuming and expensive. We applied a principal component analysis prediction and regression method to predict patellofemoral joint contact forces derived from a robust musculoskeletal model using exclusively optical motion capture kinematics (external approach), and with both patellofemoral and optical motion capture kinematics (internal approach). We tested this on a heterogeneous population of asymptomatic subjects (n = 8) during ground-level walking (n = 12). We developed equations that successfully capture subject-specific gait characteristics with the internal approach outperforming the external. These approaches were compared with a knee-flexion based model in literature (Brechter model). Both outperformed the Brechter model in interquartile range, limits of agreement, and the coefficient of determination. The equations generated by these approaches are less computationally demanding than a musculoskeletal model and may act as an effective tool in future rapid gait analysis and biofeedback applications. [ABSTRACT FROM AUTHOR]

In this narrative review, we explore developments in the field of computational musculoskeletal model personalization using the Physiome and Musculoskeletal Atlas Projects. Model geometry personalization; statistical shape modeling; and its impact on segmentation, classification, and model creation are explored. Examples include the trapeziometacarpal and tibiofemoral joints, Achilles tendon, gastrocnemius muscle, and pediatric lower limb bones. Finally, a more general approach to model personalization is discussed based on the idea of multiscale personalization called scaffolds. [ABSTRACT FROM AUTHOR]

Purpose: To compare bone substitutes composed of glycated collagen with synthetic micro-sized (1 to 10 µm) hydroxyapatite (OB) vs non-cross-linked collagen matrix with large-particle (250 to 1,000 µm) bovine-derived hydroxyapatite (BOC). Materials and Methods: The P1 to P4 premolars were bilaterally extracted from the mandibles of 19 Beagle dogs. After 21 days, osteotomies were created in each dog that received OB or BOC and were covered with a collagen membrane or were left untreated. The animals were randomly divided into three groups based on sacrifice time (4, 12, or 24 weeks). The right and left hemimandibles were trimmed to facilitate imaging and histology, and all tissues were placed in 10% neutral-buffered formalin. Microcomputed tomography (MicroCT 40 Scanner, Scanco) was used to analyze bone sections. Bone volume, residual material volume, and bone mineral density were determined for each treatment site (OB and BOC) based on a volume of interest that encompassed the original defect. Additionally, blinded histopathologic assessment (based on the ISO 10993-6 scoring system) and histomorphometry were performed on sections ground to < 100 µm thick and stained with Stevenel's blue. Results: No clinical side effects were noted. No statistical differences were observed for OB vs BOC regarding the mineral volume percentage. Compared to OB, BOC had significantly higher mean mineralization densities at 12 weeks (P < .01), but this difference did not extend to 24 weeks. For residual grafting material, bone maturation, alveolar ridge restoration, and inflammatory response, OB showed a residual amount of bone graft and no statistical differences compared to BOC. Conclusion: Both OB and BOC represent valid treatment options for critically sized bone defects. Both bone fillers outperformed the sham-operated, ungrafted (empty) control, demonstrating statistically improved bone growth and ridge restoration. [ABSTRACT FROM AUTHOR]

Stochastic differential equations (SDE) are a powerful tool to model biological regulatory processes with intrinsic and extrinsic noise. However, numerical simulations of SDE models may be problematic if the values of noise terms are negative and large, which is not realistic for biological systems since the molecular copy numbers or protein concentrations should be non-negative. To address this issue, we propose the composite Patankar-Euler methods to obtain positive simulations of SDE models. A SDE model is separated into three parts, namely, the positive-valued drift terms, negative-valued drift terms, and diffusion terms. We first propose the deterministic Patankar-Euler method to avoid negative solutions generated from the negative-valued drift terms. The stochastic Patankar-Euler method is designed to avoid negative solutions generated from both the negative-valued drift terms and diffusion terms. These Patankar-Euler methods have the strong convergence order of a half. The composite Patankar-Euler methods are the combinations of the explicit Euler method, deterministic Patankar-Euler method, and stochastic Patankar-Euler method. Three SDE system models are used to examine the effectiveness, accuracy, and convergence properties of the composite Patankar-Euler methods. Numerical results suggest that the composite Patankar-Euler methods are effective methods to ensure positive simulations when any appropriate stepsize is used. [ABSTRACT FROM AUTHOR]

Purpose: To study the effect of BMP-2 on the volumetric and histometric changes in peri-implant defect treatments in animal models. Materials and Methods: An electronic search of four databases and a manual search of peer-reviewed journals for relevant articles were performed. Animal studies with data that compared the volumetric and/or histometric outcomes of peri-implant defect treatment with and without the use of BMP-2 were included. Meta-analyses were performed to analyze the weighted mean difference (WMD) and confidence interval (CI) for the recorded variables. Results: After completing the search process, 21 randomized controlled trials were included. The results of the metaanalyses showed that the WMD of bone-to-implant contact (%BIC) with 4 to 8 weeks and 12 to 24 weeks of follow-up was 15.50% (95% CI = 3.28% to 27.72%, P = .01) and 16.17% (95% CI = 11.17% to 21.16%, P < .00001), respectively, favoring the BMP-2 group. The WMD for the percentage of defect fill with 4 to 8 weeks and 12 to 24 weeks of follow-up was 15.88% (95% CI = 3.90% to 27.86%, P = .009) and 10.48% (95% CI = 0.95% to 20.02%, P = .03), respectively, favoring the BMP-2 group. The WMD for the vertical bone gain with 8 to 16 weeks of follow-up was 1.63 mm (95% CI = 0.58 to 2.67 mm, P = .002), also favoring the BMP-2 group. Conclusion: This review demonstrated that the use of BMP-2 in treating periimplant defects showed better clinical and histometric outcomes than defects not treated with BMP-2 in animal models. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most diagnosed cancer in women. Its pathogenesis includes several pathways in cancer proliferation, apoptosis, and metastasis. Some clinical data have indicated the association between coffee consumption and decreased cancer risk. However, little data is available on the effect of coffee on breast cancer cells in vitro and in vivo. Methods: In our study, we assessed the effect of Turkish coffee and Fridamycin-H on different pathways in breast cancer, including apoptosis, proliferation, and oxidative stress. A human breast cancer cell line (MCF-7) was treated for 48 h with either coffee extract (5% or 10 v/v) or Fridamycin-H (10 ng/ml). Ehrlich solid tumors were induced in mice for in vivo modeling of breast cancer. Mice with Ehrlich solid tumors were treated orally with coffee extract in drinking water at a final concentration (v/v) of either 3%, 5%, or 10% daily for 21 days. Protein expression levels of Caspase-8 were determined in both in vitro and in vivo models using ELISA assay. Moreover, P-glycoprotein and peroxisome proliferator-activated receptor gamma (PPAR-γ) protein expression levels were analyzed in the in vitro model. β-catenin protein expression was analyzed in tumor sections using immunohistochemical analysis. In addition, malondialdehyde (MDA) serum levels were analyzed using colorimetry. Results: Both coffee extract and Fridamycin-H significantly increased Caspase-8, P-glycoprotein, and PPAR-γ protein levels in MCF-7 cells. Consistently, all doses of in vivo coffee treatment induced a significant increase in Caspase-8 and necrotic zones and a significant decrease in β- catenin, MDA, tumor volume, tumor weight, and viable tumor cell density. Conclusion: These findings suggest that coffee extract and Fridamycin-H warrant further exploration as potential therapies for breast cancer. [ABSTRACT FROM AUTHOR]

Background: Studies have shown that Averrhoa carambola L. possesses therapeutic potential for diabetes and related complications. However, the specific beneficial effects and molecular mechanisms of 2-dodecyl-6-meth-oxycyclohexa-2,5-diene-1,4-dione (DMDD) isolated from Averrhoa carambola L. on diabetic nephropathy (DN) require further investigation. Methods: 80 C57BL/6 J male mice were subjected to a 1-week adaptive feeding, followed by a high-fat diet and intraperitoneal injection of 100 mg/kg streptozotocin (STZ) to construct an in vivo DN model. Additionally, human renal proximal tubular epithelial cells (HK-2) induced by high glucose (HG) were used as an in vitro DN model. The expression levels of epithelial-mesenchymal transition (EMT), endoplasmic reticulum stress (ERS), and autophagy-related proteins in renal tubular cells were detected by Western Blot, flow cytometry, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) staining. Transcriptome analysis revealed was conducted to elucidate the specific mechanism of by which DMDD mitigates DN by inhibiting ERS and autophagy. HK-2 cells were transfected with IRE1α overexpression lentivirus to reveal the role of IRE1α overexpression in HG-induced HK-2. Results: The experimental data showed that DMDD significantly reduced blood glucose levels and improved renal pathological alterations in DN mice. Additionally, DMDD inhibited the calcium (Ca2+) pathway, manifested by decreased autophagosome formation and downregulation of LC3II/I, Beclin-1, and ATG5 expression. Moreover, in HG-induced HK-2 cells, DMDD suppressed the overexpression of GRP78, CHOP, LC3II/I, Beclin1, and ATG5. Notably, IRE1α overexpression significantly increased autophagy incidence; however, DMDD treatment subsequently reduced the expression of LC3II/I, Beclin1, and ATG5. Conclusion: DMDD effectively inhibits excessive ERS and autophagy, thereby reducing renal cell apoptosis through the IRE1α pathway and Ca 2+ pathway. [ABSTRACT FROM AUTHOR]

Richards in [35] proposed a modification of the logistic model to model growth of biological populations. In this paper, we give a new representation (or characterization) of the solution to the Richards‐type fractional differential equation Dαy(t)=y(t)·(1+a(t)yβ(t))$$ {\mathcal{D}}&amp;#x0005E;{\alpha }y(t)&amp;#x0003D;y(t)\cdotp \left(1&amp;#x0002B;a(t){y}&amp;#x0005E;{\beta }(t)\right) $$ for t≥0$$ t\ge 0 $$, where a:[0,∞)→ℝ$$ a:\left[0,\infty \right)\to \mathrm{\mathbb{R}} $$ is a continuously differentiable function on [0,∞),α∈(0,1)$$ \left[0,\infty \right),\alpha \in \left(0,1\right) $$ and β$$ \beta $$ is a positive real constant. The obtained representation of the solution can be used effectively for computational and analytic purposes. This study improves and generalizes the results obtained on fractional logistic ordinary differential equation. [ABSTRACT FROM AUTHOR]

Background: Accurately measuring energy expenditure during physical activity outside of the laboratory is challenging, especially on a large scale. Thigh-worn accelerometers have gained popularity due to the possibility to accurately detect physical activity types. The use of machine learning techniques for activity classification and energy expenditure prediction may improve accuracy over current methods. Here, we developed a novel composite energy expenditure estimation model by combining an activity classification model with a stride specific energy expenditure model for walking, running, and cycling. Methods: We first trained a supervised deep learning activity classification model using pooled data from available adult accelerometer datasets. The composite energy expenditure model was then developed and validated using additional data based on a sample of 69 healthy adult participants (49% female; age = 25.2 ± 5.8 years) who completed a standardised activity protocol with indirect calorimetry as the reference measure. Results: The activity classification model showed an overall accuracy of 99.7% across all five activity types during validation. The composite model for estimating energy expenditure achieved a mean absolute percentage error of 10.9%. For running, walking, and cycling, the composite model achieved a mean absolute percentage error of 6.6%, 7.9% and 16.1%, respectively. Conclusions: The integration of thigh-worn accelerometers with machine learning models provides a highly accurate method for classifying physical activity types and estimating energy expenditure. Our novel composite model approach improves the accuracy of energy expenditure measurements and supports better monitoring and assessment methods in non-laboratory settings. [ABSTRACT FROM AUTHOR]

Background: Chronic alcohol users often exhibit an increased minimum alveolar concentration (MAC) of sevoflurane, yet the specific mechanism remains unclear. It has been reported that ethanol exposure can upregulate the protein expression and enzyme activity of cytochrome P450 2E1 (CYP2E1). CYP2E1 is a key enzyme that converts 2–5% of sevoflurane into equimolar amounts of hexafluoroisopropanol (HFIP) and F−. This study aims to explore whether ethanol exposure could alter sevoflurane metabolism through CYP2E1 modulation, potentially explaining the increased MAC observed in alcohol users. Methods: Eighty adult male Sprague-Dawley (SD) rats were randomly divided into two groups and received either 50% ethanol (dose: 3 g/kg) or 0.9% saline twice daily by gavage. After 1, 2, 3, and 4 weeks of gavage, ten rats were randomly selected from each group to undergo 1-hour anesthesia with 2.3% sevoflurane. Blood samples were collected after anesthesia to measure the concentration of free HFIP using gas chromatography. Additionally, the left lobe tissue of the liver was collected for the analysis of CYP2E1 protein expression by Western blot and CYP2E1 enzyme activity by colorimetric assay. Correlations between these parameters were analyzed using Pearson's correlation. Results: In the ethanol group, CYP2E1 expression, activity, and the concentration of free HFIP were significantly higher at all time points compared to the control group (P < 0.05), except for protein expression in the first week (P > 0.05). Within-group comparisons indicated no significant changes in any of the parameters for the control group (P > 0.05). In the ethanol group, there was no difference in free HFIP concentration between the first and second weeks (P > 0.05), but a significant increase was observed in the third and fourth weeks (P < 0.01); protein expression and enzyme activity significantly varied over time, especially showing a notable increase from the first to the third and fourth weeks (P < 0.05). Correlation analysis revealed strong positive correlations between free HFIP concentration and CYP2E1 activity (r = 0.7898), free HFIP concentration and CYP2E1 expression (r = 0.8418), and CYP2E1 activity and expression (r = 0.8740), all with P < 0.001. Conclusions: Ethanol exposure increased both the expression and enzymatic activity of CYP2E1, consequently enhancing the metabolism of sevoflurane. [ABSTRACT FROM AUTHOR]

Background: Ameloblastoma and odontogenic keratocyst (OKC) are odontogenic tumors that develop from remnants of odontogenic epithelium. Both display locally invasive growth characteristics and high predilection for recurrence after surgical removal. Most ameloblastomas harbor BRAFV600E mutation while OKCs are associated with PATCH1 gene mutation but distinctive indicators of ameloblastoma growth characteristics relative to OKC are still unclear. The aim of this study was to assess hub genes that underlie ameloblastoma growth characteristics using bioinformatic analysis, ameloblastoma samples and mouse xenografts of human epithelial-derived ameloblastoma cells. Methods: RNA expression profiles were extracted from GSE186489 gene expression dataset acquired from Gene Expression Ominibus (GEO) database. Galaxy and iDEP online analysis tools were used to identify differentially expressed genes that were further characterized by gene ontology (GO) and pathway analysis using ShineyGO. The protein-protein interaction (PPI) network was constructed for significantly upregulated differentially expressed genes using online database STRING. The PPI network visualization was performed using Cytoscape and hub gene identification with cytoHubba. Top ten nodes were selected using maximum neighborhood component, degree and closeness algorithms and analysis of overlap was performed to confirm the hub genes. Epithelial-derived ameloblastoma cells from conventional ameloblastoma were transplanted into immunocompromised mice to recreate ameloblastoma in vivo based on the mouse xenograft model. The top 3 hub genes FN1, COL I and IGF-1 were validated by immunostaining and quantitative analysis of staining intensities to ameloblastoma, OKC samples and mouse ameloblastoma xenografts tissues. Results: Seven hub genes were identified among which FN1, COL1A1/COL1A2 and IGF-1 are associated with extracellular matrix organization, collagen binding, cell adhesion and cell surface interaction. These were further validated by positive immunoreactivity within the stroma of ameloblastoma samples but both ameloblastoma xenograft and OKC displayed only FN1 and IGF-1 immunoreactivity while COL 1 was unreactive. The expression levels of both FN1 and IGF-1 were much lower in OKC relative to ameloblastoma. Conclusion: This study further validates a differentially upregulated expression of matrix proteins FN1, COL I and IGF-1 in ameloblastoma relative to OKC. It suggests that differential stromal architecture and growth characteristics of ameloblastoma relative to OKC could be an interplay of differentially upregulated genes in ameloblastoma. [ABSTRACT FROM AUTHOR]

Effective analysis of single-cell RNA sequencing (scRNA-seq) data requires a rigorous distinction between technical noise and biological variation. In this work, we propose a simple feature selection model, termed "Differentially Distributed Genes" or DDGs, where a binomial sampling process for each mRNA species produces a null model of technical variation. Using scRNA-seq data where cell identities have been established a priori, we find that the DDG model of biological variation outperforms existing methods. We demonstrate that DDGs distinguish a validated set of real biologically varying genes, minimize neighborhood distortion, and enable accurate partitioning of cells into their established cell-type groups. Author summary: Single-cell omics technologies measure tens of thousands of genes in up to millions of individual cells. Yet, the sheer dimensionality of the data poses a challenge to its intelligibility. A typical first step in reducing the dimensionality is to apply a feature selection model that distinguishes real biological signals from technical noise. Yet without an appropriate model of technical noise, feature selection can introduce bias into the downstream analysis of the data. In this work, we demonstrate that, in the analysis of single-cell RNA sequencing data, the standard approach of finding Highly Variable Genes (HVGs) induces severe distortion and bias into the analysis of data, when compared to true biological variation that is known a priori. To address this issue, we present a new feature selection model and demonstrate that our model outperforms existing methods in its ability to accurately identify real biological variation. [ABSTRACT FROM AUTHOR]

Radiomics offers a noninvasive avenue for predicting clinicopathological factors. However, thorough investigations into a robust breast cancer outcome-predicting model and its biological significance remain limited. This study develops a robust radiomic model for prognosis prediction, and further excavates its biological foundation and transferring prediction performance. We retrospectively collected preoperative dynamic contrast-enhanced MRI data from three distinct breast cancer patient cohorts. In FUSCC cohort (n = 466), Lasso was used to select features correlated with patient prognosis and multivariate Cox regression was utilized to integrate these features and build the radiomic risk model, while multiomic analysis was conducted to investigate the model's biological implications. DUKE cohort (n = 619) and I-SPY1 cohort (n = 128) were used to test the performance of the radiomic signature in outcome prediction. A thirteen-feature radiomic signature was identified in the FUSCC cohort training set and validated in the FUSCC cohort testing set, DUKE cohort and I-SPY1 cohort for predicting relapse-free survival (RFS) and overall survival (OS) (RFS: p = 0.013, p = 0.024 and p = 0.035; OS: p = 0.036, p = 0.005 and p = 0.027 in the three cohorts). Multiomic analysis uncovered metabolic dysregulation underlying the radiomic signature (ATP metabolic process: NES = 1.84, p-adjust = 0.02; cholesterol biosynthesis: NES = 1.79, p-adjust = 0.01). Regarding the therapeutic implications, the radiomic signature exhibited value when combining clinical factors for predicting the pathological complete response to neoadjuvant chemotherapy (DUKE cohort, AUC = 0.72; I-SPY1 cohort, AUC = 0.73). In conclusion, our study identified a breast cancer outcome-predicting radiomic signature in a multicenter radio-multiomic study, along with its correlations with multiomic features in prognostic risk assessment, laying the groundwork for future prospective clinical trials in personalized risk stratification and precision therapy. [ABSTRACT FROM AUTHOR]

The abnormal reduction of kelp production occurred in Rongcheng area of the Yellow Sea in 2021, which is closely related to the red tide. However, the relationship between the red tide event and the hydrodynamic environment remains unclear. In response to these issues, this study established a coupled physical-biological model which coupling the ROMS dynamic model with the RED_TIDE biological model for the Yellow Sea and Bohai Sea region, and discussed driving factors of this red tide. Based on this coupled model, various factors influencing the development of red tide were investigated, with a focus on analyzing the key factors contributing to the occurrence of the red tide event in the northern sea area of the Shandong Peninsula in 2021. The aggregation of dinoflagellate cells triggers red tide events. The distribution characteristics and concentration changes of dinoflagellate cells were studied by designing simulation experiments under different conditions to reflect the contributions of various influencing factors to red tide. According to observation data and simulation experiments, this study explored the effects of factors such as light conditions, tides, Yellow River runoff and wind field on the distribution and concentration of dinoflagellate cells. The variation of wind field can promote the proliferation and aggregation of dinoflagellate cells, serving as key factors in triggering red tide. The occurrence of red tide is a complex ecological phenomenon influenced by multiple factors, necessitating the comprehensive consideration of these factors to more accurately predict and prevent red tide events. [ABSTRACT FROM AUTHOR]

Genomics methods have uncovered patterns in a range of biological systems, but obscure important aspects of cell behavior: the shapes, relative locations, movement, and interactions of cells in space. Spatial technologies that collect genomic or epigenomic data while preserving spatial information have begun to overcome these limitations. These new data promise a deeper understanding of the factors that affect cellular behavior, and in particular the ability to directly test existing theories about cell state and variation in the context of morphology, location, motility, and signaling that could not be tested before. Rapid advancements in resolution, ease-of-use, and scale of spatial genomics technologies to address these questions also require an updated toolkit of statistical methods with which to interrogate these data. We present a framework to respond to this new avenue of research: four open biological questions that can now be answered using spatial genomics data paired with methods for analysis. We outline spatial data modalities for each open question that may yield specific insights, discuss how conflicting theories may be tested by comparing the data to conceptual models of biological behavior, and highlight statistical and machine learning-based tools that may prove particularly helpful to recover biological understanding. [ABSTRACT FROM AUTHOR]

Subarachnoid hemorrhage (SAH) is a severe subtype of hemorrhagic stroke. The molecular mechanisms of its secondary brain damage remain obscure. To investigate the alterations in gene and metabolite levels following SAH, we construct the transcriptome and metabolome profiles of the rat cerebral cortex post-SAH using whole transcriptome sequencing and untargeted metabolomics assays. Transcriptomic analysis indicated that there were 982 differentially expressed genes (DEGs) and 540 differentially expressed metabolites (DEMs) between the sham group and SAH 1d, and 292 DEGs and 254 DEMs between SAH 1d and SAH 7d. Most notably, DEGs were predominantly involved in the activation of immune and inflammatory pathways, particularly the Complement and coagulation cascades, TNF signaling pathway, and NOD-like receptor signaling pathway. Metabolic analysis revealed that the metabolic pathways of Arginine and proline, Arachidonic acid, Folate biosynthesis, Pyrimidine, and Cysteine and methionine were remarkably affected after SAH. Metabolites of the above pathways are closely associated not only with immune inflammation but also with oxidative stress, endothelial cell damage, and blood-brain barrier disruption. This study provides new insights into the underlying pathologic mechanisms of secondary brain injury after SAH and further characterization of these aberrant signals could enable their application as potential therapeutic targets for SAH. [ABSTRACT FROM AUTHOR]

Background: The effect of swimming on bone health remains unclear, namely due to discrepant findings between studies in humans and animal models. Objective: The aim of this systematic review and meta-analysis is to identify the available evidence on the effects of swimming on bone mass, geometry and microarchitecture at the lumbar spine, femur and tibia in both humans and rodent animal models. Methods: The study followed PRISMA guidelines and was registered at PROSPERO (CRD4202236347 and CRD42022363714 for human and animal studies). Two different systematic literature searches were conducted in PubMed, Scopus and Web of Science, retrieving 36 and 16 reports for humans and animal models, respectively. Results: In humans, areal bone mineral density (aBMD) was similar between swimmers and non-athletic controls at the lumbar spine, hip and femoral neck. Swimmers' tibia diaphysis showed a higher cross-sectional area but lower cortical thickness. Inconsistent findings at the femoral neck cortical thickness were found. Due to the small number of studies, trabecular microarchitecture in human swimmers was not assessed. In rodent models, aBMD was found to be lower at the tibia, but similar at the femur. Inconsistent findings in femur diaphysis cross-sectional area were observed. No differences in femur and tibia trabecular microarchitecture were found. Conclusion: Swimming seems to affect bone health differently according to anatomical region. Studies in both humans and rodent models suggest that tibia cortical bone is negatively affected by swimming. There was no evidence of a negative effect of swimming on other bone regions, both in humans and animal models. [ABSTRACT FROM AUTHOR]

Training in anastomosis is fundamental in neurosurgery due to the precision and dexterity required. Biological models, although realistic, present limitations such as availability, ethical concerns, and the risk of biological contamination. Synthetic models, on the other hand, offer durability and standardized conditions, although they sometimes lack anatomical realism. This study aims to evaluate and compare the efficiency of anastomosis training models in the intra-extracranial cerebral bypass procedure, identifying those characteristics that enhance optimal microsurgical skill development and participant experience. A neurosurgery workshop was held from March 2024 to June 2024 with 5 vascular techniques and the participation of 22 surgeons. The models tested were the human placenta, the Wistar rat, the chicken wing artery, the nasogastric feeding tube, and the UpSurgeOn Mycro simulator. The scales used to measure these models were the Main Characteristics Score and the Evaluation Score. These scores allowed us to measure, qualitatively and quantitatively, durability, anatomical similarity, variety of simulation scenarios, risk of biological contamination, ethical considerations and disadvantages with specific infrastructure. The human placenta model, Wistar rat model, and UpSurgeOn model were identified as the most effective for training. The human placenta and Wistar rat models were highly regarded for anatomical realism, while the UpSurgeOn model excelled in durability and advanced simulation scenarios. Ethical and cost implications were also considered. The study identifies the human placenta and UpSurgeOn models as optimal for training in intra-extracranial bypass procedures, emphasizing the need for diverse and effective training models in neurosurgery. [ABSTRACT FROM AUTHOR]

Objective This study aimed to establish a screening model for differentiating anti-synthetase syndrome (ASS) from other ANA-associated rheumatic diseases (AARDs) using a combination of cytoplasmic and non-cytoplasmic ANA (ncANA) patterns. Methods : This retrospective observational study included patients with AARDs such as SLE, SSc, SS, MCTD and PM/DM who underwent ANA screening between April 2012 and December 2021. Variables included age, sex, ANA patterns (Cytoplasmic and ncANA) and titres. Logistic regression analysis of Cytoplasmic and ncANA patterns was performed to differentiate ASS from other AARDs. Result : The 981 diagnosed cases of AARDs consisted of SS (n  = 451), SSc (n  = 264), SLE (n  = 201), PM/DM (n  = 104), MCTD (n  = 52) and ASS, including PM/DM (n  = 64). Of these, 155 patients had ≥2 overlapping diseases; however, there was no overlap between AARDs and ASS. ASS is more likely to occur when the cytoplasmic titre is positive and the ncANA <320. Receiver operating characteristic analysis of the Cytoplasmic and ncANA range revealed an area under the receiver operating characteristic curve of 0.885 (95% CI: 0.844–0.927). Conclusion : It is important to detect cytoplasmic patterns as an ANA screening test for ASS diagnosis, even if the titre is low. Additionally, combining the cytoplasmic and ncANA patterns yields more accurate ASS screening results. [ABSTRACT FROM AUTHOR]

Purpose: Ulcerative colitis (UC) is a serious health problem with increasing morbidity and prevalence worldwide. The pathogenesis of UC is complex, currently believed to be influenced by genetic factors, dysregulation of the host immune system, imbalance in the intestinal microbiota, and environmental factors. Currently, UC is typically managed using aminosalicylates, immunosuppressants, and biologics as adjunctive therapies, with the risk of relapse and development of drug resistance upon discontinuation. Therefore, further research into the pathogenesis of UC and exploration of potential treatment strategies are necessary to improve the quality of life for affected patients. According to previous studies, Lactobacillus paracasei Jlus66 (Jlus66) reduced inflammation and may help prevent or treat UC. Methods: We used dextran sulfate sodium (DSS) to induce a mouse model of UC to assess the effect of Jlus66 on the progression of colitis. During the experiment, we monitored mouse body weight, food and water consumption, as well as rectal bleeding. Hematoxylin-eosin staining was performed to assess intestinal pathological damage. Protein imprinting and immunohistochemical methods were used to evaluate the protein levels of nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and tight junction (TJ) proteins in intestinal tissues. Fecal microbiota was analyzed based on partial 16S rRNA gene sequencing. Results: Jlus66 supplementation reduced the degree of colon tissue damage, such as colon shortening, fecal occult blood, colon epithelial damage, and weight loss. Supplementation with Jlus66 reduced DSS-induced upregulation of cytokine levels such as TNF-α, IL-1β, and IL-6 (p < 0.05). The NF-κB pathway and MAPK pathway were inhibited, and the expression of TJ proteins (ZO-1, Occludin, and Claudin-3) was upregulated. 16S rRNA sequencing of mouse cecal contents showed that Jlus66 effectively regulated the structure of the intestinal biota. Conclusion: In conclusion, these data indicate that Jlus66 can alter the intestinal biota and slow the progression of UC, providing new insights into potential therapeutic strategies for UC. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the effects of different ω-3 polyunsaturated fatty acid (PUFA) enriched diets, including a novel renewable plant source of ω-3 fatty acids (Buglossoides arvensis), on the development and progression of rheumatoid arthritis (RA). Methods: RA was induced in mice consuming experimental diets using the K/BxN model. The experimental diets consisted of either a western control diet (control), diets containing B. arvensis oil or fish oil. The effects of the diets on platelets, platelet microvesicles (PMVs), and inflammatory markers such as clinical index, ankle thickness and cytokine/chemokine release were measured. Results: While ω-3 PUFA-enriched diets did not prevent the development of arthritis in the K/BxN model, a significant decrease in ankle swelling was observed compared to the control group. Platelets isolated from mice consuming either low content of B. arvensis oil or fish oil diets exhibited significantly decreased PMVs production compared to mice consuming the control diet. Conclusion: Our study provides insight into the contribution of ω-3 PUFA supplementation in modulating the pro-inflammatory phenotype of platelets in RA pathology. Furthermore, our study suggests that low concentrations of dietary B. arvensis oil may have similar anti-inflammatory potential seen with dietary fish oil supplementation. [ABSTRACT FROM AUTHOR]

Objective: Peri‐implantitis is one of the most common complications of implants. However, its pathogenesis has not been clarified. In recent years, mouse models are gradually being used in the study of peri‐implantitis. This review aims to summarize the methods used to induce peri‐implantitis in mice and their current applications. Method: Articles of peri‐implantitis mouse models were collected. We analyzed the various methods of inducing peri‐implantitis and their application in different areas. Results: Most researchers have induced peri‐implantitis by silk ligatures. Some others have induced peri‐implantitis by Pg gavage and LPS injection. Current applications of peri‐implantitis mouse models are in the following areas: investigation of pathogenesis and exploration of new interventions, comparison of peri‐implantitis with periodontitis, the interaction between systemic diseases and peri‐implantitis, etc. Conclusion: Silk ligature for 2–4 weeks, Pg gavage for 6 weeks, and LPS injection for 6 weeks all successfully induced peri‐implantitis in mice. Mice have the advantages of mature gene editing technology, low cost, and short time to induce peri‐implantitis. It has applications in the study of pathogenesis, non‐surgical treatments, and interactions with other diseases. However, compared with large animals, mice also have a number of disadvantages that limit their application. [ABSTRACT FROM AUTHOR]

Objectives: The underlying mechanisms of burning mouth syndrome (BMS) remain unclear leading to challenges and unsatisfactory management. Current treatments focus primarily on symptom relief, with few consistently achieving a 50% reduction in pain. This review aims to explore animal models of BMS to gain a better understanding of the underlying mechanisms and to discuss potential and existing knowledge gaps. Methods: A comprehensive review of PubMed®, Google Scholar, and Scopus was performed to assess advances and significant gaps of existing rodent models that mimic BMS‐related symptoms. Results: Rodent models of BMS involve reproduction of dry‐tongue, chorda tympani transection, or overexpression of artemin protein. Existing preclinical models tend to highlight one specific etiopathogenesis and often overlook sex‐ and hormone‐specific factors. Conclusion: Combining aspects from various BMS models could prove beneficial in developing comprehensive experimental designs and outcomes encompassing the multifaceted nature of BMS. [ABSTRACT FROM AUTHOR]

Objective: The limited understanding of the molecular mechanism for oral submucosal fibrosis (OSF) poses challenges to the development of effective prevention and treatment strategies. The lack of suitable animal models is a major hindrance. Therefore, this study aimed to address this issue by comparing commonly used arecoline‐induced water drinking and injection mouse models. Materials and Methods: The mice were subjected to two protocols: receiving 2 mg/mL arecoline in drinking water and 4 mg/mL arecoline saline solution injections every other day. Tissues were collected at regular 4‐week intervals, with a final time point of 20 weeks. Stereo microscopy and histomorphological analysis were performed on live and harvested tissues, respectively. Results: During arecoline treatment, collagen deposition and myofibroblast proliferation progressively increased in both models. Changes in the collagen I/III ratio indicated that both models exhibited characteristics of the early and intermediate stages of OSF after 20 weeks of arecoline induction. The water‐drinking model also demonstrated multi‐organ fibrosis involving the tongue, lungs, and small intestine. Conclusion: Both the water drinking and injection mouse models effectively induced OSF, but the water‐drinking model better mirrored the observed pathogenesis in patients with OSF. These models provide valuable tools for investigating the mechanisms underlying OSF. [ABSTRACT FROM AUTHOR]

Background: Here, we evaluated whether the histone lysine demethylase 5B (JARID1B), is involved in osteogenic phenotype commitment of periodontal ligament cells (PDLCs), by considering their heterogeneity for osteoblast differentiation. Materials and Methods: Epigenetic, transcriptional, and protein levels of a gene set, involved in the osteogenesis, were investigated by performing genome‐wide DNA (hydroxy)methylation, mRNA expression, and western blotting analysis at basal (without osteogenic induction), and at the 3rd and 10th days of osteogenic stimulus, in vitro, using PDLCs with low (l) and high (h) osteogenic potential as biological models. Results: h‐PDLCs showed reduced levels of JARID1B, compared to l‐PDLCs, with significant inversely proportional correlations between RUNX2 and RUNX2/p57. Epigenetically, a significant reduction in the global H3K4me3 content was observed only in h‐PDLCs. Immunoblotting data reveal a significant reduction in the global H3K4me3 content, at 3 days of induction only in h‐PDLCs, while an increase in the global H3K4me3 content was observed at 10 days for both PDLCs. Additionally, positive correlations were found between global H3K4me3 levels and JARID1B gene expression. Conclusions: Altogether, our results show the crucial role of JARID1B in repressing PDLCs osteogenic phenotype and this claims to pre‐clinical protocols proposing JARID1B as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Introduction: Clinical heterogeneity is one of the biggest challenges for researchers studying underlying neurobiological mechanisms in Autism Spectrum Disorder (ASD). We aimed to use polyinosinic-polycytidylic acid [Poly (I:C)] induced maternal immune activation mice model to investigate the behavioral variation and the role of brain circuits related to symptom clusters in ASD. For this purpose, behavioral tests were applied to offsprings and regional thickness was measured from histological brain sections in medial prefrontal cortex, hippocampus and striatum. Methods: Pups of intraperitoneal Poly (I:C)-applied mothers (n: 14) and phosphate buffered saline-applied mothers (n: 6) were used for this study. We used three chamber socialization test and social memory test to evaluate social behavior deficit in mice. Marble burying test was used for assessing stereotypic behavior and new object recognition test for learning and cognitive flexibility. Three subgroups (n: 4 for each) were determined according to behavioral test parameters. Regional thickness was measured in medial prefrontal cortex, hippocampus and striatum and compared between subgroups. Results: We detected that the behavioral differences were distributed in a spectrum as expected in the clinic and also detected increased hippocampus thickness in the stereotypic behavior dominant Poly (I:C) subgroup. Conclusion: Poly (I:C) induced maternal immune activation model creates the behavioral variation and cortical development differences that are seen in relation with symptom groups in ASD. [ABSTRACT FROM AUTHOR]

A transition from nonhuman animal models to engineered microphysiological systems (MPS), such as organoids and organ-on-achip technologies, would signal a paradigm shift in biomedical research. Despite MPS' potential to more accurately model human physiology, reduce high failure rates of drugs in clinical trials, and limit unnecessary animal use, widespread adoption is hampered by public opinion and lack of scalability, standardization, and current regulatory uptake. This article suggests how 5 key concepts (awareness, access, education, application, and rewards) could help address these barriers. These concepts are part of a framework that underscores a need to integrate MPS into mainstream biomedical research and to better promote ethical responsibility for the means of biomedical innovation. [ABSTRACT FROM AUTHOR]

Historically, most discussions about nonhuman animal experimentation consider what has become known as the 3 R's: refinement, reduction, and replacement. Refinement and reduction receive the most attention, but recent modeling advances suggest that suitable replacement of nonhuman animal testing would bolster human research and increase translatability to human health outcomes. This article discusses these modeling advances and advocates their use, especially as replacements to nonpredictive nonhuman animal protocols, and discusses growing momentum in biomedical research communities and federal agencies that favors replacement of animal testing. [ABSTRACT FROM AUTHOR]

Nonhuman animals used in biomedical research frequently suffer and are harmed as part of their use as experimental models. The Institutional Animal Care and Use Committee (IACUC) of a given institution is meant to ensure that research protocols follow federal guidelines, but research protocols such as those described in this case can generate unnecessary suffering; this problem suggests limitations of IACUCs' capacity to protect nonhuman animals' welfare. This commentary on the case considers how to more fully protect nonhuman animals used in scientific research and identifies barriers to more comprehensive protection of nonhuman animals' welfare. [ABSTRACT FROM AUTHOR]

If we assume that nonhuman animals experience pain or distress, then ethically justifying human-centered research with only nonhuman animals as subjects likely requires that the research's benefits to humans must, at least, outweigh harms suffered by the nonhuman animals. Yet this reasoning does not seem to account well for the ethical view that nonhuman animals are morally valuable in their own right. This commentary on a case considers this ethical tension and discusses how clinician-researchers should navigate it. This commentary also suggests why clinician-researchers' reasoning about the nature and scope of their obligations to nonhuman animals extends beyond governing regulations and federal oversight, which is silent on or ambiguous about nonhuman animals as morally valuable in their own right. [ABSTRACT FROM AUTHOR]

The International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee aims to improve the use of drugs in older adults and develop new therapeutic approaches for the syndromes and diseases of old age through advocacy, education, and research. In the present paper, we propose strategies relevant to drug development and evaluation, spanning preclinical and the full range of clinical studies. Drugs for older adults need to consider not only age, but also other characteristics common in geriatric patients, such as multimorbidity, polypharmacy, falls, cognitive impairment, and frailty. The IUPHAR Geriatric Committee's position statement on 'Measurement of Frailty in Drug Development and Evaluation' is included, highlighting 12 key principles that cover the spectrum of translational research. We propose that where older adults are likely to be major users of a drug, that frailty is measured at baseline and as an outcome. Preclinical models that replicate the age, frailty, duration of exposure, comorbidities, and co‐medications of the proposed patients may improve translation. We highlight the potential application of recent technologies, such as physiologically based pharmacokinetic–pharmacodynamic modeling informed by frailty biology, and Artificial Intelligence, to inform personalized medicine for older patients. Considerations for the rapidly aging populations in low‐ and middle‐income countries related to health‐care and clinical trials are outlined. Involving older adults, their caregivers and health‐care providers in all phases of research should improve drug development, evaluation, and outcomes for older adults internationally. [ABSTRACT FROM AUTHOR]

Objective: Glucocorticoid‐induced tumor necrosis factor receptor superfamily–related protein (GITR), with its ligand (GITRL), plays an important role in CD4+ T cell–mediated autoimmunity. This study aimed to investigate the underlying mechanisms of GITRL in primary Sjögren syndrome (pSS). Methods: Patients with pSS and healthy controls were recruited. Serum GITRL and Th17‐related cytokines were determined. RNA sequencing was performed to decipher key signal pathways. Nonobese diabetes (NOD) mice were adopted as experimental Sjögren models and recombinant adeno‐associated virus (rAAV) transduction was conducted to verify the therapeutic potentials of targeting GITRL in vivo. Results: Serum GITRL was significantly higher in patients with pSS and showed a positive correlation with leukopenia, thrombocytopenia, autoantibodies, lung involvement, and disease activity. Serum GITRL was correlated with Th17‐related cytokines. GITRL promoted the expansion of Th17 and Th17.1 cells. Expansion of granulocyte‐macrophage colony‐stimulating factor positive (GM‐CSF+) CD4+ T cells induced by GITRL could be inhibited by blockade of GITRL. Moreover, GM‐CSF could stimulate GITRL expression on monocytes. RNA sequencing revealed mammalian target of rapamycin complexes 1 (mTORC1) might be the key modulator. The increased phosphorylation of S6 and STAT3 and the expansion of Th17 and Th17.1 cells induced by GITRL were effectively inhibited by rapamycin, suggesting a GITRL–mTORC1–GM‐CSF positive loop in pathogenic Th17 response in pSS. Administration of an rAAV vector expressing short hairpin RNA targeting GITRL alleviated disease progression in NOD mice. Conclusion: Our results identified the pathogenic role of GITRL in exacerbating disease activity and promoting pathogenic Th17 response in pSS through a GITRL–mTORC1–GM‐CSF loop. These findings suggest GITRL might be a promising therapeutic target in the treatment of pSS. [ABSTRACT FROM AUTHOR]

Serum creatinine in neonates follows complex dynamics due to maturation processes, most pronounced in the first few weeks of life. The development of a mechanism‐based model describing complex dynamics requires high expertise in pharmacometric (PMX) modeling and substantial model development time. A recently published machine learning (ML) approach of low‐dimensional neural ordinary differential equations (NODEs) is capable of modeling such data from newborns automatically. However, this efficient data‐driven approach in itself does not result in a clinically interpretable model. In this work, an approach to deriving an interpretable model with reasonable PMX‐type functions is presented. This "translation" was applied to derive a PMX model for serum creatinine in neonates considering maturation processes and covariates. The developed model was compared to a previously published mechanism‐based PMX model whereas both models had similar mechanistic structures. The developed model was then utilized to simulate serum creatinine concentrations in the first few weeks of life considering different covariate values for gestational age and birth weight. The reference serum creatinine values derived from these simulations are consistent with observed serum creatinine values and previously published reference values. Thus, the presented NODE‐based ML approach to model complex serum creatinine dynamics in newborns and derive interpretable, mathematical‐statistical components similar to those in a conventional PMX model demonstrates a novel, viable approach to facilitate the modeling of complex dynamics in clinical settings and pediatric drug development. [ABSTRACT FROM AUTHOR]

The rapid growth in the use of pediatric physiologically based pharmacokinetic (PBPK) models, particularly for regulatory applications, has focused emphasis on model verification and ensuring system parameters are robust, including how these change with age. Uncertainty remains regarding the ontogeny of some enzymes and transporters, in this study 2 published ontogeny profiles for hepatic CYP3A4 were compared. Clinical pharmacokinetic data on 4 intravenously administered CYP3A4 substrates (alfentanil, fentanyl, midazolam, and sildenafil) used across the pediatric age range was collected from the literature. The PBPK models were verified in the adult population and then used to compare the Salem and a modified Upreti ontogeny profiles for CYP3A4 in terms of parent drug clearance and area under the curve from birth onward. Overall, the modified Upreti ontogeny profile resulted in 15 out of 17 age‐related predictions within 2‐fold and 12 out of 17 predictions within 1.5‐fold ranges of observed values, for the Salem ontogeny these values were 12 out of 17 and 8 out of 17, respectively. The Upreti ontogeny profile performed better than Salem, average fold error and absolute average fold error were 1.14 and 1.35 compared to 1.56 and 1.90, respectively. Identifying the optimal CYP3A4 ontogeny is important for regulatory use of PBPK especially given the number of drugs cleared by this enzyme. This study broadens the evidence from previous studies that Upreti is more favorable than Salem, but further work is needed especially in the neonatal and early infant age range. [ABSTRACT FROM AUTHOR]

Since the Open Source Initiative laid the foundation for the open source software environment in 1998, the popularity of free and open source software has been steadily increasing. Model‐informed drug discovery and development (MID3), a key component of pharmaceutical research and development, heavily makes use of computational models which can be developed using various software including the Open Systems Pharmacology (OSP) software (PK‐Sim/MoBi), a free and open source software tool for physiologically based pharmacokinetic (PBPK) modeling. In this study, we aimed to investigate the impact, application areas, and reach of the OSP software as well as the relationships and collaboration patterns between organizations having published OSP‐related articles between 2017 and 2023. Therefore, we conducted a bibliometric analysis of OSP‐related publications and a social network analysis of the organizations with which authors of OSP‐related publications were affiliated. On several levels, we found evidence for a significant growth in the size of the OSP community as well as its visibility in the MID3 community since OSP's establishment in 2017. Specifically, the annual publication rate of PubMed‐indexed PBPK‐related articles using the OSP software outpaced that of PBPK‐related articles using any software. Our bibliometric analysis and network analysis demonstrated that the expansion of the OSP community was predominantly driven by new authors and organizations without prior connections to the community involving the generation of research clusters de novo and an overall diversification of the network. These findings suggest an ongoing evolution of the OSP community toward a more segmented, diverse, and inclusive network. [ABSTRACT FROM AUTHOR]

Background: Robot-assisted procedures are increasingly common, and several systems are available for thoraco-abdominal surgery. Specific structured training is necessary, while access to these systems is still limited. This study aimed to assess surgeons' skill progress during consecutive training days of a curriculum with exposure to different robotic systems. Methods: This prospective observational study enrolled 47 surgeons with anonymized analysis of SimNow™ simulator performance scores and dedicated questionnaires after written consent. The primary outcome was the overall score, based on economy of motion, time to complete the exercise, and penalty for errors. Course participants in 2022–2023 had chosen 2 full hands-on days on Da Vinci® consoles with either virtual reality (VR) simulation training using the SimNow (n = 21, 44.7%) or digestive surgery procedures with a live animal model (n = 26, 55.3%). In all participants, training on Da Vinci® systems included console functions and principles of docking, camera, and instrument use for console and procedural training. They additionally had access to introductory dry-lab and VR simulator exercises on the Versius, HugoTMRAS, and Dexter systems and to VR exercises on the ROBOTiS simulator. Results: The participants (16F/31M, median age 40 years, range 29–58) from various surgical specialties (general/visceral/vascular) had no (n = 35, 74.5%) or little (n = 12, 25.5%) robotic experience including bedside assistance only and 20 (42.6%) had robotic simulator experience. The demographic variables fully completed by 44/47 participants (93.6%) and choice of module had no significant impact on the primary outcome. The considerable performance improvement from days 1 to 2 was exemplified by a significantly increased economy of motion and decreased amount of excessive force. Conclusion: Robotic surgical training is increasingly complex with several systems on the market. Within a dedicated robotic surgery curriculum and based on integrated performance metrics, a significant improvement of skill levels was observed in a relatively short period of time. [ABSTRACT FROM AUTHOR]

Background: Simulation-based training plays a significant role in surgical education, especially in minimally invasive pediatric surgery and urology. This study aimed to evaluate a novel 3D-printed model as training tool for endoscopic injection of bulking agent. Methods: Forty-three attendees and ten teaching faculty members were invited to complete a post hoc questionnaire after completing training sessions using the Fish Tank Simulation Model (FTSM). The survey consisted of a 7-question 5-point Likert scale to assess the model's realism (face validity) and its effectiveness as training tool (content validity). Results: Regarding the training status, 20/53 (37.7%) participants were fellow and/or specialist in pediatric surgery and 33/53 (62.3%) were surgeons in training. Their level of confidence in endoscopic injection procedure was defined as novice (< 10 procedures per year) in 33/53 (62.3%), intermediate (10–20 procedures per year) in 10/53 (18.9%), and expert (> 20 procedures per year) in 10/53 (18.9%). Regarding both face validity and content validity assessments, no statistically significant differences were found between scores given by novice vs intermediate/expert groups. Similarly, no statistically significant differences emerged between scores given by participant vs faculty groups assessing the content validity of the FTSM. The FTSM was considered a good teaching tool for beginners by 44/53 (83%) and for pediatric surgeons/urologists by 38/53 (71.7%). Conclusions: The 3D-printed Fish Tank Simulation Model proved to be a valuable, high-fidelity, easily accessible, cost-effective, hygienic, and domestic-use training tool for pediatric surgeons/urologists conducting the procedure. The model's user-friendly design and realistic environment enhanced learning opportunities for trainees, regardless of their experience level or training status. Nevertheless, further development is necessary, particularly in enhancing the realism of the ureteral hiatus and reproducing more complex anatomy, to make it beneficial for the training of advanced surgeons. [ABSTRACT FROM AUTHOR]

Background: Anastomotic leakage (AL) is a dreaded complication following colorectal cancer surgery, impacting patient outcome and leads to increasing healthcare consumption as well as economic burden. Bowel perfusion is a significant modifiable factor for anastomotic healing and thus crucial for reducing AL. Aims: The study aimed to calculate a cut-off value for quantified laser speckle perfusion units (LSPUs) in order to differentiate between ischemic and well-perfused tissue and to assess inter-observer reliability. Methods: LSCI was performed using a porcine ischemic small bowel loop model with the PerfusiX-Imaging® system. An ischemic area, a well-perfused area, and watershed areas, were selected based on the LSCI colormap. Subsequently, local capillary lactate (LCL) levels were measured. A logarithmic curve estimation tested the correlation between LSPU and LCL levels. A cut-off value for LSPU and lactate was calculated, based on anatomically ischemic and well-perfused tissue. Inter-observer variability analysis was performed with 10 observers. Results: Directly after ligation of the mesenteric arteries, differences in LSPU values between ischemic and well-perfused tissue were significant (p < 0.001) and increased significantly throughout all following measurements. LCL levels were significantly different (p < 0.001) at both 60 and 120 min. Logarithmic curve estimation showed an R2 value of 0.56 between LSPU and LCL values. A LSPU cut-off value was determined at 69, with a sensitivity of 0.94 and specificity of 0.87. A LCL cut-off value of 3.8 mmol/L was found, with a sensitivity and specificity of 0.97 and 1.0, respectively. There was no difference in assessment between experienced and unexperienced observers. Cohen's Kappa values were moderate to good (0.52–0.66). Conclusion: Real-time quantification of LSPUs may be a feasible intraoperative method to assess tissue perfusion and a cut-off value could be determined with high sensitivity and specificity. Inter-observer variability was moderate to good, irrespective of prior experience with the technique. [ABSTRACT FROM AUTHOR]

Background: Artificial intelligence (AI) has the potential to enhance surgical practice by predicting anatomical structures within the surgical field, thereby supporting surgeons' experiences and cognitive skills. Preserving and utilising nerves as critical guiding structures is paramount in rectal cancer surgery. Hence, we developed a deep learning model based on U-Net to automatically segment nerves. Methods: The model performance was evaluated using 60 randomly selected frames, and the Dice and Intersection over Union (IoU) scores were quantitatively assessed by comparing them with ground truth data. Additionally, a questionnaire was administered to five colorectal surgeons to gauge the extent of underdetection, overdetection, and the practical utility of the model in rectal cancer surgery. Furthermore, we conducted an educational assessment of non-colorectal surgeons, trainees, physicians, and medical students. We evaluated their ability to recognise nerves in mesorectal dissection scenes, scored them on a 12-point scale, and examined the score changes before and after exposure to the AI analysis videos. Results: The mean Dice and IoU scores for the 60 test frames were 0.442 (range 0.0465–0.639) and 0.292 (range 0.0238–0.469), respectively. The colorectal surgeons revealed an under-detection score of 0.80 (± 0.47), an over-detection score of 0.58 (± 0.41), and a usefulness evaluation score of 3.38 (± 0.43). The nerve recognition scores of non-colorectal surgeons, rotating residents, and medical students significantly improved by simply watching the AI nerve recognition videos for 1 min. Notably, medical students showed a more substantial increase in nerve recognition scores when exposed to AI nerve analysis videos than when exposed to traditional lectures on nerves. Conclusions: In laparoscopic and robot-assisted rectal cancer surgeries, the AI-based nerve recognition model achieved satisfactory recognition levels for expert surgeons and demonstrated effectiveness in educating junior surgeons and medical students on nerve recognition. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a severe complication of acute respiratory distress syndrome (ARDS). Emerging studies have revealed the effects of pyrrolidine dithiocarbamate (PDTC) on improving surgery-induced cognitive impairment. The major aim of the study was to investigate whether PDTC protected against ARDS-induced cognitive dysfunction and to identify the underlying mechanisms involved. The rat model of ARDS was established by intratracheal instillation of lipopolysaccharide (LPS), followed by treatment with PDTC. The cognitive function of rats was analyzed by the Morris Water Maze, and pro-inflammatory cytokines were assessed by quantitative real-time PCR, enzyme-linked immunosorbent assay, and western blot assays. A dual-luciferase reporter gene assay was performed to identify the relationship between miR-181c and its target gene, TAK1 binding protein 2 (TAB2). The results showed that PDTC improved cognitive impairment and alleviated neuroinflammation in the hippocampus in LPS-induced ARDS model. Furthermore, we demonstrated that miR-181c expression was downregulated in the hippocampus of the ARDS rats, which was restored by PDTC treatment. In vitro studies showed that miR-181c alleviated LPS-induced pro-inflammatory response by inhibiting TAB2, a critical molecule in the nuclear factor (NF)-κB signaling pathway. PDTC improves cognitive impairment in LPS-induced ARDS by regulating miR-181c/NF-κB axis-mediated neuroinflammation, providing a potential opportunity for the treatment of this disease. [ABSTRACT FROM AUTHOR]

Objective: To identify and disseminate research priorities for the headache field that should be areas of research focus during the next 10 years. Background: Establishing research priorities helps focus and synergize the work of headache investigators, allowing them to reach the most important research goals more efficiently and completely. Methods: The Headache Research Priorities organizing and executive committees and working group chairs led a multistakeholder and international group of experts to develop headache research priorities. The research priorities were developed and reviewed by clinicians, scientists, people with headache, representatives from headache organizations, health‐care industry representatives, and the public. Priorities were revised and finalized after receiving feedback from members of the research priorities working groups and after a public comment period. Results: Twenty‐five research priorities across eight categories were identified: human models, animal models, pathophysiology, diagnosis and management, treatment, inequities and disparities, research workforce development, and quality of life. The priorities address research models and methods, development and optimization of outcome measures and endpoints, pain and non‐pain symptoms of primary and secondary headaches, investigations into mechanisms underlying headache attacks and chronification of headache disorders, treatment optimization, research workforce recruitment, development, expansion, and support, and inequities and disparities in the headache field. The priorities are focused enough that they help to guide headache research and broad enough that they are widely applicable to multiple headache types and various research methods. Conclusions: These research priorities serve as guidance for headache investigators when planning their research studies and as benchmarks by which the headache field can measure its progress over time. These priorities will need updating as research goals are met and new priorities arise. Plain Language Summary: The American Headache Society led a large, international, multistakeholder process to identify headache research topics that should be prioritized during the next 10 years. With input from headache clinicians, scientists, people with headache, representatives from headache organizations, health‐care industry representatives, and the public, 25 research priorities within 8 categories were identified. These research priorities can help guide headache researchers when planning their studies and as benchmarks by which the headache field can measure its progress over time. [ABSTRACT FROM AUTHOR]

Objective: Our aim was to survey astrocyte and microglial activation across four brain regions in a mouse model of chronic migraine. Background: Chronic migraine is a leading cause of disability, with higher rates in females. The role of central nervous system neurons and glia in migraine pathophysiology is not fully elucidated. Preclinical studies have shown abnormal glial activation in the trigeminal nucleus caudalis of male rodents. No current reports have investigated glial activation in both sexes in other important brain regions involved with the nociceptive and emotional processing of pain. Methods: The mouse nitroglycerin model of migraine was used, and nitroglycerin (10 mg/kg) or vehicle was administered every other day for 9 days. Prior to injections on days 1, 5, and 9, cephalic allodynia was determined by periorbital von Frey hair testing. Immunofluorescent staining of astrocyte marker, glial fibrillary protein (GFAP), and microglial marker, ionized calcium binding adaptor molecule 1 (Iba1), in male and female trigeminal nucleus caudalis, periaqueductal gray, somatosensory cortex, and nucleus accumbens was completed. Results: Behavioral testing demonstrated increased cephalic allodynia in nitroglycerin‐ versus vehicle‐treated mice. An increase in the percent area covered by GFAP+ cells in the trigeminal nucleus caudalis and nucleus accumbens, but not the periaqueductal gray or somatosensory cortex, was observed in response to nitroglycerin. No significant differences were observed for Iba1 staining across brain regions. We did not detect significant sex differences in GFAP or Iba1 quantification. Conclusions: Immunohistochemical analysis suggests that, at the time point tested, immunoreactivity of GFAP+ astrocytes, but not Iba1+ microglia, changes in response to chronic migraine‐associated pain. Additionally, there do not appear to be significant differences between males and females in GFAP+ or Iba1+ cells across the four brain regions analyzed. Plain Language Summary: The aim of this study was to determine if supportive immune cells in the brains of males and females are altered in an animal model of chronic migraine. Mice in the chronic migraine group showed significant activation of astrocytes, but not microglia, in male and female mice in pain and emotion‐processing brain regions. These results suggest that some supportive cells in the brain may play a role in regulating chronic migraine. [ABSTRACT FROM AUTHOR]

Different biological models can be evaluated using mathematical models in both qualitative and quantitative ways. A fractional bone mineralization model involving Caputo’s fractional derivative is presented in this work. The fractional mathematical model is beneficial because of its memory carrying property. An appropriate fractional order of the derivative can be chosen that is more closely related to experimental or actual data. The dynamical system of equations for the process of bone mineralization is examined qualitatively and quantitatively in this article. A numerical simulation has been performed for the model. The model’s parameters have undergone sensitivity analysis and their effects on the model variables have been explored. By studying the mineralization patterns in bone, different diseases can be cured, and it can also be examined how the deviations from healthy mineral distributions lead to specific bone diseases. [ABSTRACT FROM AUTHOR]

Considering the established pharmacokinetics and toxicity profiles, drug repurposing has emerged as an alternative therapeutic approach for treating cancer. Mefloquine has previously demonstrated inhibitory effects on multiple cancer types. This study aims to explore the impact of mefloquine on nasopharyngeal carcinoma (NPC). We found that mefloquine, at pharmacologically achievable concentrations, displayed anti-NPC activity while sparing normal counterparts. Mefloquine inhibits proliferation and induces death by reducing the levels of Cyclin A2, Bcl-2, and Bcl-xL. Intriguingly, we observed an increase in the levels of the anti-apoptotic protein Mcl-1. Mefloquine exerts its effects on NPC cells by inducing lysosomal-mediated ROS production, and the heightened expression of Mcl-1 is a consequence of ROS generation in mefloquine-treated NPC cells. The combination of an Mcl-1 inhibitor with mefloquine synergistically inhibits NPC growth in mice without causing substantial toxicity. These findings demonstrate the effectiveness and limited toxicity of mefloquine as a monotherapy and in combination with an Mcl-1 inhibitor. Our research underscores the promise of the mefloquine and Mcl-1 inhibitor combination as a potential treatment for NPC. Additionally, the elevation of Mcl-1 is a compensatory response in cells exposed to oxidative stress, offering a potential target to overcome resistance induced by pro-oxidant therapies. [ABSTRACT FROM AUTHOR]