Search Results (457)

Topical drug administration is a common method of delivering medications to the eye to treat various ocular conditions, including glaucoma, dry eye, and inflammation. Drug efficacy following topical administration, including the drug’s distribution within the eye, absorption and elimination rates, and physiological responses can be predicted using physiologically based pharmacokinetic (PBPK) modeling. High-resolution computational models of the eye are desirable to improve simulations of drug delivery; however, these approaches can have long run times. In this study, a fast-running computational quasi-3D (Q3D) model of the human tear film was developed to account for absorption, blinking, drainage, and evaporation. Visualization of blinking mechanics and flow distributions throughout the tear film were enabled using this Q3D approach. Average drug absorption throughout the tear film subregions was quantified using a high-resolution compartment model based on a system of ordinary differential equations (ODEs). Simulations were validated by comparing them with experimental data from topical administration of 0.1% dexamethasone suspension in the tear film (R² = 0.76, RMSE = 8.7, AARD = 28.8%). Overall, the Q3D tear film model accounts for critical mechanistic factors (e.g., blinking and drainage) not previously included in fast-running models. Further, this work demonstrated methods toward improved computational efficiency, where central processing unit (CPU) time was decreased while maintaining accuracy. Building upon this work, this Q3D approach applied to the tear film will allow for more seamless integration into full-body models, which will be an extremely valuable tool in the development of treatments for ocular conditions. Full article

Background/Objectives: Current dosing recommendations for piperacillin/tazobactam suggest adjustments only for patients with creatinine clearance (CrCl) below 40 mL/min, potentially neglecting the variability in drug exposure among patients with a CrCl greater than 40 mL/min. This study aimed to develop a population pharmacokinetic (PK) model for piperacillin/tazobactam and explore optimal dosage regimens tailored by renal function and pathogen susceptibility. Methods: Twelve healthy adults received a single intravenous dose of piperacillin/tazobactam (4 g/0.5 g). Population PK models were developed using nonlinear mixed-effects modeling. Monte Carlo simulations were conducted to identify optimal dosing regimens across various renal functions and MIC levels, guided by pharmacodynamic targets defined as the percentage of time that free drug concentrations exceed the minimum inhibitory concentration (fT_>MIC). Results: PK profiles of both drugs were best described by two-compartment models. Estimated glomerular filtration rate (eGFR) adjusted by body surface area and body weight were identified as significant covariates influencing drug clearance and peripheral volume of distribution. Simulations showed that the standard dosing regimen (4/0.5 g q6h with 30 min infusion) achieved a 90% probability of target attainment (PTA) for 50%fT_>MIC at MIC values up to 4 mg/L in patients with normal renal function. However, this regimen often did not achieve a 90% PTA for stringent targets (100%fT_>MIC, 100%fT_>4MIC) or higher MICs, particularly in patients with eGFR ≥ 130 mL/min. Conclusions: These findings suggest current dosing regimens may be inadequate and highlight the potential of alternative strategies, such as extended or continuous infusion, which warrant further investigation in clinical populations to optimize therapeutic outcomes. Full article

Background: Foreign bodies (FBs) within the masticatory space are a rare but significant complication of oral and maxillofacial procedures. Despite advancements in orthognathic surgery, instrument breakage and accidental loss can lead to challenging secondary procedures. Clinical experience with retained foreign bodies in the masticatory space following orthognathic surgery and related dental procedures is summarized. Methods: A retrospective search was conducted in the surgical and radiological database of a tertiary referral center for maxillofacial surgery, covering procedures from January 2017 to December 2024. Patients were included if they had undergone orthognathic surgery and presented with a retained FB in the masticatory space confirmed through imaging. Clinical records, operative notes, imaging studies, and follow-up data were reviewed. Results: Out of 2092 procedures, four patients (0.19%) were identified. Two FBs were related to broken surgical instruments during orthognathic surgery (a suture needle and a burr fragment), while two were fractured local anesthesia needles during third molar extraction under local anesthesia. All FBs were located in deep compartments of the masticatory space (paramandibular or pterygopalatine region). Surgical retrieval via transoral approach under general anesthesia was successful in all cases. One patient experienced transient facial nerve dyskinesia; no long-term complications or recurrences were noted. Conclusions: Retained foreign bodies in the masticatory space are infrequent yet warrant prompt recognition and surgical management to mitigate the risk of infection, nerve damage, and repeated procedures. Thorough instrument checks, proper technique, and advanced imaging modalities are crucial for minimizing these complications in orthognathic surgery. Full article

Background: Obesity has been implicated in the pathogenesis and progression of several malignancies, including papillary thyroid carcinoma (PTC), but its role in tumor aggressiveness remains controversial. This study aimed to investigate the association between adiposity, as measured by body mass index (BMI), and histopathological features of aggressiveness in patients with PTC. Methods: This single-center retrospective study included 298 consecutive adult patients diagnosed with PTC between 2016 and 2021 at an endocrine referral center. Patients were stratified based on BMI into normal weight (<25 kg/m²) and overweight/obese (≥25 kg/m²) groups. Clinical, metabolic, and histopathological data were compared between the two groups. Results: Overweight/obese patients had significantly higher rates of hypertension, type 2 diabetes, fasting glucose, and triglycerides, as well as lower high-density lipoprotein cholesterol (all p < 0.01). Tumor size was similar between groups, with over 85% of tumors measuring ≤ 1 cm (microcarcinomas) and no significant difference in the proportion of tumors > 1 cm (p = 0.582). There were no significant differences in multifocality (p = 0.269) or extrathyroidal extension (ETE) (p = 0.826). Lymph node metastases occurred in 34% of normal weight and 28% of overweight/obese patients, without a statistically significant difference (p = 0.402). Lymph node compartment involvement did not significantly differ between groups (p = 0.160). Conclusions: Despite being associated with adverse metabolic profiles, higher BMI was not linked to tumor aggressiveness in patients with predominantly early-stage PTC. As the incidence of obesity and PTC continues to rise, these findings highlight the need for further research into early-stage PTC biology and more precise risk measures of adiposity beyond BMI alone. Full article

The intervertebral disc, an anatomical compartment interposed between vertebral bodies, plays a key role in spine flexibility and compression loading. It comprises three tissues: the nucleus pulposus, the annulus fibrosus, and the end plates. Degeneration-related changes in the extracellular matrix of the nucleus pulposus upon ageing or pathological conditions prompted the present investigation into the impact of proteoglycan reduction, the main constituent of the healthy nucleus pulposus, on its physicochemical properties and cellular phenotypical changes. To mimic the native extracellular matrix, three-dimensional NP-mimicking constructs were developed using a biomimetic hydrogel composed of collagen type I, collagen type II, and proteoglycans. This system was fabricated using a bottom-up approach, employing highly pure monomeric collagen types I and II, which were induced to form a reconstituted fibrillar structure closely resembling the natural NP microenvironment. A comprehensive physicochemical characterization was conducted at varying proteoglycan percentages using scanning electron microscopy (SEM), FTIR, rheological tests, and water retention property analysis. The effect of microenvironment changes on the phenotype of nucleus pulposus cells was studied by their encapsulation within the various collagen–proteoglycan hydrogels. The morphological and immunochemistry analysis of the cells was performed to study the cell–matrix adhesion pathways and the expression of the cellular regulator hypoxia-inducible factor 1 alpha. These were linked to the analysis of the synthesis of healthy or pathological extracellular matrix components. The findings reveal that the reduction in proteoglycan content in the nucleus pulposus tissue triggers a pathological pathway, impairing the rheological and water retention properties. Consequently, the cell phenotypes are altered, inducing the synthesis of collagen type I rather than securing the natural physiological remodelling process by the synthesis of collagen type II and proteoglycans. Identifying the proteoglycan content threshold that triggers these pathological phenotypical changes could provide new diagnostic markers and early therapeutic strategies for intervertebral disc degeneration. Full article

Lipids play vital roles in insect physiology, functioning as energy reserves, membrane constituents, and cuticular protectants. However, few studies have examined the anatomical distribution of lipids in blood-feeding Diptera and compared the compositions of the cuticular and internal compartments. This study analyzes the qualitative and quantitative profiles of free fatty acids (FFAs) in the female Tabanus bovinus, a hematophagous horsefly species, across different anatomical regions, including the head, wings, legs, thorax, and abdomen. The surface and internal lipid fractions were isolated using petroleum ether/dichloromethane extraction followed by sonication. GC-MS revealed the presence of 21 FFAs, including 16 saturated (C7:0, C8:0, C9:0, C10:0, C11:0, C12:0, C13:0, C14:0, C15:0, C16:0, C17:0, C18:0, C19:0, C20:0, C22:0, C24:0) and five unsaturated (C16:1, C18:2, C18:1, C20:5, C20:4). The head and wings showed the highest concentrations of cuticular FFAs. At the same time, internal lipid stores were most prominent in the thorax and abdomen (but four times lower than in the head cuticle), reflecting their role in energy storage and reproduction. All cuticular and internal extracts were dominated by C16:0, C18:0, and C18:1. Notably, several FFAs were undetected in specific compartments: C10:0 from inside the head, C11:0 and C13:0 from inside all examined body parts, C19:0 was absent from inside the head, wings and legs, while C20:5 and C20:4 were absent from both the cuticular and internal lipid pools of the wings. Interestingly, our analysis of the cuticle on the thorax and abdomen together revealed that both C13:0 and C19:0 were present only on the dorsal side, i.e., absent from the ventral side. These absences suggest a selective lipid metabolism tailored to the functional and ecological demands of T. bovinus females. Our findings suggest that the absence of specific compounds from individual body parts may serve as an indicator of physiological specialization. This work provides new insights into lipid compartmentalization in Tabanidae and offers a framework for future comparative and ecological lipidomics studies in insects. Full article

Background: Vitamin D has anti-inflammatory and immunomodulatory properties that may influence the pathophysiology of endometriosis. This study investigated the association between vitamin D levels and endometriosis, and vitamin D receptor (VDR) expression in endometriotic tissue. Methods: A cross-sectional study was conducted involving 36 patients with endometriosis and 72 healthy control women, matched for age and BMI. Serum 25-hydroxyvitamin D levels were measured and categorized into four statuses (normal, insufficiency, deficiency, and severe deficiency). Endometriotic tissue samples were examined for VDR expression using immunohistochemistry and qualitatively quantified using histo-scores (H-scores). Endometriosis severity was assessed using the revised criteria of the American Society for Reproductive Medicine (rASRM). Results: No statistically significant difference in vitamin D levels between the groups (20.45 vs. 21.10 ng/dL, p = 0.190) was observed, even after adjusting for residence, body sunscreen use, pregnancy, and contraceptive use. VDR expression exhibited significantly higher H-scores in endometriotic epithelial cells than in stromal cells (209.51 vs. 73.32; p < 0.001). Additionally, the VDR H-score in both cell compartments showed no significant difference according to vitamin D status. No statistically significant association was found between vitamin D levels, VDR expression, or disease severity. The odds of severe endometriosis were 2.17 (95% CI: 0.14–33.80) for vitamin D insufficiency and 4.33 (95% CI: 0.24–115.67) for deficiency compared with normal vitamin D. Conclusions: There was no statistically significant association between vitamin D levels and endometriosis and VDR. Full article

Background/Objectives: This study aimed to characterize the pharmacokinetic profiles of clobazam (CLB) and its active metabolite, N-desmethylclobazam (N-CLB), by establishing a population pharmacokinetic (PPK) model in Chinese children with epilepsy to propose individualized dosing regimens that achieve better clinical outcomes. Methods: This study examined plasma samples collected from 103 pediatric patients with refractory epilepsy undergoing CLB treatment. The plasma concentrations of CLB and its active metabolite N-CLB were measured. The developmental characteristics, CYP2C19 genotype, concomitant medications, and liver and kidney function indicators of the children with epilepsy were considered potential factors affecting the pharmacokinetic characteristics of CLB and N-CLB and analyzed using a PPK modeling approach. Results: A total of 156 samples were attained for PPK model development. The pharmacokinetic profiles of CLB and N-CLB were described using a tandem one-compartment model with first-order elimination. Body weight and CYP2C19 genotype showed statistical significance for CLB and/or N-CLB clearance. The N-CLB/CLB metabolic ratios of AUC_24h, C_min, and C_max in a steady state were as follows: normal metabolizers (NMs) < intermediated metabolizers (IMs) < poor metabolizers (PMs). The final model achieved good prediction performance and stability. Monte Carlo simulations demonstrated that the trough concentrations of CLB and N-CLB in children with epilepsy could reach satisfactory target values under varying dose regimens in CYP2C19 NMs and IMs, whereas there was a failure to achieve the desired trough concentrations of CLB and N-CLB simultaneously in CYP2C19 PMs due to the accumulation of N-CLB. Conclusions: Body weight and CYP2C19 genotype had an impact on CLB and/or N-CLB clearance in children with epilepsy. To ensure safe treatment, it is recommended to use the concentration of N-CLB as the target indicator for therapeutic drug monitoring and dose adjustments in CYP2C19 PMs. These results provide evidence for guiding the precise use of CLB. Full article

Background/Objectives: This study aims to assess dietary quality among Chinese pregnant women across three gestational trimesters using different assessment indices while investigating the relationship between dietary patterns and longitudinal alterations in maternal body composition parameters and bone mineral density (BMD) during pregnancy. Methods: A total of 556 healthy pregnant women were recruited. Dietary intake was assessed utilizing a semi-quantitative food frequency questionnaire (FFQ). Diet quality was evaluated through three indices: the Dietary Balance Index for Pregnant Women (DBI-P), the Dietary Inflammatory Index (DII), and the Eastern Health Diet Index (EHDI). Multiple linear regression models and mediation analyses were constructed to elucidate the relationships between dietary indices, body composition parameters, and BMD. Results: In the first trimester, excessive dietary intake was associated with increased maternal fat mass but reduced BMD, while insufficient intake correlated with declines in muscle mass, water compartments, and inorganic salt levels. Pro-inflammatory diets further exacerbated reductions in non-fat body composition, including protein and muscle mass. By the second trimester, low-quality diets continued to negatively affect muscle mass and water balance, whereas no significant dietary effects on body composition or BMD were observed in the third trimester. Mediation analyses revealed that body composition partially mediated the relationship between dietary imbalance and reduced BMD. Conclusions: Unbalanced, pro-inflammatory, and low-quality diets during early-to-mid pregnancy contribute to adverse changes in maternal body composition and bone health, especially in the first and second trimesters, with the DBI-P index demonstrating superior applicability for assessing dietary impacts in Chinese pregnant women. Full article

Background/Objectives: The relationship between body mass index (BMI) and endometriosis symptoms or lesion types remains unclear. This study investigates the association between BMI and symptom severity as well as the anatomical distribution of endometriosis using the #ENZIAN classification. Methods: A retrospective analysis was conducted on 219 patients with histologically confirmed endometriosis who underwent laparoscopic surgery at a tertiary endometriosis center in 2021. Preoperative symptom data were collected using standardized questionnaires. Patients were grouped by BMI categories based on WHO criteria. Endometriosis was classified intraoperatively using the #ENZIAN system. Statistical analyses included chi-square tests and one-way ANOVA. Results: Patients with low/normal BMI (<25 kg/m², n = 150) reported significantly higher intensity of chronic pelvic pain (CPP) compared to those with overweight/obesity (≥25 kg/m², n = 69; p = 0.0026). When stratified into four BMI groups, dyspareunia was significantly less frequent in obese patients (p = 0.0306), and high-intensity CPP was less common in both underweight and obese categories compared to normal-weight patients (p = 0.0069). Infertility rates increased significantly with higher BMI (p = 0.00001). No significant differences in the distribution of endometriosis lesions across #ENZIAN compartments were observed in relation to BMI. Conclusions: Our findings indicate that BMI does not significantly influence the anatomical distribution of endometriosis lesions as defined by the #ENZIAN classification, but it does correlate with some symptom intensity and infertility. These results suggest that while BMI may not predict disease localization, it plays a role in shaping the clinical phenotype of endometriosis. Full article

The pharmacology of antimicrobial agents comprises pharmacodynamics and pharmacokinetics. Pharmacodynamics refers to studying drugs’ mode of action on their molecular targets at various concentrations and the resulting effect(s). Pharmacokinetics refers to studying the way(s) in which drugs enter the body and are distributed to their targets in various compartments (such as tissues) and how local drug concentrations are modified in time, such as by metabolism or excretion. Pharmacodynamics and pharmacokinetics constitute pivotal knowledge for establishing the breakpoints used to identify the appropriate antimicrobial agents for infection therapy. Antibiotic resistance is the biological force opposing antimicrobials’ pharmacological effects. However, we do not have a term similar to pharmacology for microbial antibiotic resistance reactions. Here, we propose the new scientific field of antechology (from the classic Greek antechó, resistance), studying the dynamics and kinetics of antibiotic resistance molecules which oppose the effect of antimicrobial drugs. Antechodynamics refers to the study of the molecular mechanisms through which antibiotic molecules are chemically modified or degraded by particular bacterial resistance enzymes (primary effectors) or drive the modification of an antibiotic’s target inhibition sites through molecules released by antibiotic action on the microorganism (secondary effectors). Antechokinetics refers to the study of the processes leading to bacterial spatial cellular (subcellular, pericellular, extracellular) localizations of the molecules involved in antibiotic detoxifying mechanisms. Molecules’ local concentrations change over time due to their production, their degradation, and ultimately their excretion rates. We will examine the antechodynamics and antechokinetics for various antimicrobial classes and the relation between pharmacodynamics/pharmacokinetics and antechodynamics/antechokinetics. Full article

Firework-related injuries remain a serious public health issue in Germany, especially during New Year’s Eve. While many injuries are minor, the misuse of illegal or homemade fireworks can cause severe trauma resembling military combat injuries and can heavily burden emergency services. Notably, injury rates declined during the COVID-19 firework bans, underscoring the impact of preventive measures. We report two cases of young males with severe injuries from illicit fireworks. The first is a case of a 16-year-old that detonated an illegal Polish firework ball bomb, sustaining 9% total body surface area (TBSA) burns (second- to third-degree), hand fractures, compartment syndrome of the hand, and soft-tissue trauma. He underwent multiple surgeries, including fasciotomy, osteosynthesis, and skin grafting. The other case presented is a 19-year-old man who was injured by a homemade device made of bundled firecrackers, suffering deep facial and bilateral hand burns. He required prolonged ventilation, surgical debridement, and treatment with Kerecis^® fish skin and Epicite^® dressings. Both required intensive ICU care, interdisciplinary management, and lengthy rehabilitation. Total hospital costs amounted to €58,459.52 and €94,230.23, respectively, as calculated according to the standardized German DRG. These cases illustrate the devastating impact of illegal fireworks. The devastating consequences of explosive trauma are often difficult to treat and may lead to long-term functional and psychological impairments. Prevention through public education, stricter regulations, and preparedness is essential. Pandemic-era injury reductions support sustained policy efforts. Full article

Background: The pancreas develops from two independent buds that fuse to form the adult organ. Ontogeny has largely been neglected in pancreatic surgery. This study aims to demonstrate that the adult pancreas can still be divided into morphogenetic units based on its embryological compartments and connective tissue borders for potential therapeutic purposes. Methods: Ten donor bodies (four female, six male, aged 73–101 years) were used. Manual dissection, guided by the common bile duct to locate the embryological fusion plane, was performed to divide the pancreatic tissue. Immunohistochemical staining for pancreatic polypeptide differentiated the pancreatic tissue by embryological origin and was used to quantify dissection accuracy. Results: Landmark-guided dissection successfully separated the pancreas along a connective tissue plane in seven cases. The resulting compartments were distinctly divided along the dissection plane into an area rich in pancreatic polypeptide and an area with low accumulation. Two cases showed deviations from the dissection plane at the histological level. One case contained tumor tissue, interfering with the utilization of landmarks. Conclusions: Landmark-guided dissection of the pancreas based on its embryological fusion plane allows for reliable separation into morphogenetic compartments. Immunohistochemical staining for pancreatic polypeptide effectively differentiates tissue origins. This approach may enable more precise, differentiated pancreatic resections and tailored treatments, with potential for refinement in routine surgical practice. Approaching the pancreatic tissue with regard to its ontogenetic origin and its clearly distinguishable compartments might even enable tailored treatment beyond refined surgical procedures. Full article

Fontan circulation is a fragile system in which imperfections at any of multiple levels may compromise the quality of life, produce secondary pathophysiology, and shorten life span. Increased inferior vena caval pressure itself may play a role in “Fontan failure”. This study describes a mock flow loop model (MFL) designed to quantitatively estimate pulmonary flow entrainment induced by continuous and pulsed flow injections. A patient generic 3D-printed phantom model of the total cavopulmonary connection (TCPC) with average dimensions matching those of a 2–4-year-old patient was inserted in an MFL derived from a reduced lumped parameter model (LPM) representing cardiovascular circulation. The LPM comprises four 2-element Windkessel compartments (compliance and resistance), approximating the upper and lower systemic circulations and the right and left pulmonary circulations. The prescribed cardiac output is about 2.3 L/min for a body surface area of $0.675{ \mathrm{m}}^2$. The injections originate from an external pump through a 7–9 fr catheter, following a strict protocol suggested by the clinical team, featuring a variation in injection rate (flow rate), injection volume, and injection modality (continuous or pulsed). The key measurements in this study are the flow rates sampled at the distal pulmonary arteries, as well as at the upper and lower body boundaries. These measurements were then used to calculate effective entrainment as the difference between the measured and expected flow rates, as well as jet relaxation (rise and fall time of injection). The results show that for continuous or pulsed injections, varying the total volume injected has no significant influence on the entrainment rate across all injection rates. On the other hand, for both injection modalities, increasing the injection rate results in a reduction in entrainment that is consistent across all injected volumes. This study demonstrates the effectiveness of a high-speed injection jet entraining a slow co-flow while determining the potential for fluid buildup, which could ultimately cause an increase in caval pressure. To avoid the increase in caval pressure due to mass accumulation, we added a fenestration to our proposed injection jet shunt-assisted Fontan models. It was found that for a set of well-defined parameters, the jet not only can be beneficial to the local flow, but any adverse effect can be obviated by careful tuning. These results were also cross-validated with similar in silico findings. Full article