Omeprazole is associated with voriconazole-associated hepatotoxicity: PPI-stratified analysis and a clinically actionable nomogram from an 848-patient cohort.

Evaluating the dose-response relationship between drop-jump height and bone adaptation: A randomized controlled trial.

Comparative efficacy of lithium carbonate loading dose versus standard dosing, each combined with quetiapine, in acute mania of bipolar I disorder: a randomized single-blind controlled trial.

Although patients with acute coronary syndrome supported by veno-arterial extracorporeal membrane oxygenation (VA-ECMO) have a high risk of thrombosis and bleeding, antiplatelet pharmacology in this setting is not well defined. This prospective observational study investigated the population pharmacokinetics of ticagrelor and its active metabolite AR-C124910XX and explored model-informed dosing strategies among this population. Paired pharmacokinetic sampling was performed at predefined time points during ON- and OFF-ECMO periods. Plasma concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay and analyzed with NONMEM to develop a joint parent-metabolite model and evaluate the effects of VA-ECMO status and flow rate on ticagrelor disposition. Monte Carlo simulations of various ECMO flow-rate scenarios examined alternative loading and maintenance regimens using prespecified trough concentrations of 180-360 ng/mL, as derived from previous exposure-response and exposure-bleeding analyses in non-ECMO populations. A total of 225 ticagrelor and 225 metabolite concentrations (127 ON-ECMO and 98 OFF-ECMO) from 20 patients were analyzed. VA-ECMO support was associated with reduced ticagrelor clearance and increased volume of distribution, while higher flow rates were associated with decreased volumes of distribution. In simulations, an initial loading dose of 120-135 mg followed by a 60 mg maintenance dose once daily most consistently maintained predicted trough concentrations within the target range during VA-ECMO, whereas 90 mg once daily frequently exceeded the upper bound. These findings indicate that VA-ECMO substantially altered ticagrelor pharmacokinetics and provided quantitative, model-informed support for reduced once daily dosing strategies; however, further pharmacokinetic-pharmacodynamic and outcome studies are needed to confirm these findings.

Extracorporeal membrane oxygenation (ECMO) serves as a critical life-support modality for patients with severe cardiac or respiratory failure, yet the large surface area of the circuit introduces significant variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of essential medications. This systematic review evaluates clinical evidence from 2015 to 2025 regarding drug dosing alterations in adult ECMO patients, focusing on anticoagulants, antibacterials, antifungals, and antivirals. Our analysis identifies drug sequestration as a primary determinant of therapeutic failure, particularly for highly lipophilic agents like voriconazole and fentanyl, which exhibit circuit losses exceeding 70% within hours of administration. Conversely, hydrophilic antibiotics such as beta-lactams and glycopeptides are primarily impacted by an increased volume of distribution (Vd) and augmented renal clearance, often necessitating loading dose increases of 20–50% or the use of extended infusions to maintain therapeutic levels. Regarding anticoagulation, evidence supports the superiority of anti-Xa (target 0.3–0.7 IU/mL) and viscoelastic assays over activated clotting time (ACT) for minimizing hemorrhagic risks. Current dosing guidelines remain fragmented; thus, clinicians must adopt individualized strategies involving aggressive therapeutic drug monitoring (TDM) and multimodal anticoagulation assessment to ensure efficacy and safety in this high-risk population.

Intravenous dexmedetomidine is a safe and effective adjunct in propofol-based sedation. Dexmedetomidine is typically administered as a loading dose, followed by continuous infusion or not. Whether the addition of a maintenance infusion of dexmedetomidine after a loading dose in propofol-based sedation for pediatric magnetic resonance imaging (MRI) can be beneficial in terms of propofol consumption or adverse events is not clear. We aimed to study whether maintaining dexmedetomidine infusion after loading dose can help reduce propofol consumption and minimize airway and cardiovascular interventions during sedation. We retrospectively reviewed 884 medical records of pediatric sedation for MRI using both propofol and dexmedetomidine, performed at a single tertiary hospital between May 2021 and January 2023. We compared patients who received dexmedetomidine loading + maintenance (group LM) and dexmedetomidine loading only (group L) as an adjunct to propofol-based sedation. The consumption of propofol and time to recovery were measured. We also compared the incidence of airway rescue maneuver and hypotension requiring intervention during sedation. Overall, 695 patients were included in the analysis (group LM, n = 351, group L, n = 344). The total sedation duration was similar between the two groups (52 vs. 50 min, p = 0.255). Group LM showed significantly less total propofol consumption (6.62 vs. 7.63 mg·kg-1·h-1, p = 0.001). The incidence of airway rescue maneuver did not differ significantly between the two groups (0.9 vs. 1.5%, p = 0.501); however, the incidence of hypotension requiring intervention was lower in group LM than in group L (4.3 vs. 8.1%, p = 0.040). The recovery time did not differ significantly between the two groups (34 vs. 34 min, p = 0.932). In propofol-based sedation for pediatric MRI, maintenance infusion of dexmedetomidine after a loading dose reduces total propofol consumption and hemodynamic instability requiring intervention without prolonging recovery time, compared with dexmedetomidine bolus without maintenance.

Cefepime is a key carbapenem-sparing agent due to its stability against AmpC β-lactamases. However, high plasma concentrations are associated with cefepime-induced neurotoxicity (CIN). Following 2019 EUCAST reclassification of 'intermediate' as 'susceptible, increased exposure', higher doses (6 g/day) are often recommended. Pharmacokinetic/pharmacodynamic (PK/PD) simulations suggest that a reduced daily dose of cefepime 4 g/day administered by continuous infusion may achieve adequate target attainment while limiting toxicity, but real-world clinical data are scarce. We conducted a prospective, single-centre observational study including adult inpatients treated with cefepime administered as a 2 g loading dose followed by continuous infusion of 4 g/day. Therapeutic drug monitoring was performed to assess steady-state free cefepime concentrations (ƒCss). The primary endpoint was pharmacodynamic target attainment (100% ƒT > MIC) for EUCAST 'susceptible, increased exposure' breakpoints. Among 46 included patients, median ƒCss was 26.2 mg/L (IQR 18.4-33.2). Pharmacodynamic targets were achieved in 96% of patients for Enterobacterales (MIC 4 mg/L) and 93% for Pseudomonas aeruginosa (MIC 8 mg/L). Clinical efficacy was observed in 96% of cases. Signs consistent with CIN occurred in three patients (6.5%), mainly in the context of renal function deterioration or pre-existing neurological vulnerability. A reduced-dose cefepime regimen consisting of 4 g/day administered by continuous infusion achieves high pharmacodynamic target attainment with a favourable efficacy-toxicity balance in real-life clinical practice. This strategy represents a promising alternative to higher-dose regimens and supports individualized dosing guided by renal function and therapeutic drug monitoring.

ObjectivesTo characterize the population pharmacokinetics of unbound cloxacillin in patients undergoing total arthroplasty of the hip (THA) or knee (TKA), and to explore alternative dosing regimens for cloxacillin prophylaxis.MethodsPlasma concentrations of total and unbound cloxacillin from 200 patients undergoing primary elective THA (n & 95) or TKA (n & 105) were analysed. Intravenous cloxacillin doses of 2 g were administered pre-surgery, and repeated after 2 and 6 hours. Samples (n & 496) were analysed using HPLC-MS/MS. Non-linear mixed-effects modelling was performed to develop a population pharmacokinetic model describing unbound cloxacillin exposure. Using this model, alternative prophylaxis regimens were explored with Monte Carlo simulations.ResultsA two-compartment model with non-linear protein binding adequately described the data. Estimated glomerular filtration rate (eGFR) and body weight (kg) were significant covariates on unbound cloxacillin clearance. In 13% of patients sampled at the end of surgery (n & 25/187), unbound cloxacillin <2 mg/L was observed. A model-predicted 18–22% (n & 36–43/200) of patients failed to sustain plasma levels ≥2 mg/L throughout the two-hour dosing interval with the current regimen. In contrast, a continuous 1 g/h infusion after a 1 g loading dose would ensure target attainment in >99% of patients, according to the model predictions.ConclusionsFor many THA and TKA patients, the current cloxacillin prophylaxis regimen may fail to provide adequate target site concentrations during the entire surgical procedure. Transitioning to a prolonged infusion protocol could increase attainment of PK/PD targets without exceeding the currently recommended total perioperative dose amounts.

Meropenem dosing regimens in critically ill patients undergoing prolonged intermittent renal replacement therapy (PIRRT) are limited. This study aimed to evaluate the probability of target attainment (PTA) of various meropenem regimens in these patients receiving PIRRT, using Monte Carlo simulations (MCS). Mathematical models were developed using published pharmacokinetic (PK) data from critically ill patients. Simulations incorporated PIRRT modalities (haemodialysis [HD] and hemofiltration [HF]) with an effluent rate of 300 mL/min and various durations of 4, 6, 8, or 10 h. MCS assessed drug exposure over 48 h in 10 000 virtual patients per regimen. The pharmacodynamic (PD) targets were free drug concentrations that remained above 4 times the minimum inhibitory concentration (MIC) of 2 mg/L. Optimal regimens were those achieving ≥ 90% PTA in each PIRRT setting. In alternate-day PIRRT, most session durations use a 1000 mg loading dose followed by 500 mg every 8 h, except for 10-h HD, which requires 1000 mg every 12 h. In daily PIRRT, HD requires 750 mg every 8 h for 4-8-h sessions and 1000 mg every 8 h for 10-h sessions. For HF, recommended regimens range from a 1000 mg loading dose followed by 500 mg every 8 h for 4-h sessions to 1000 mg every 12 h for 6-8-h sessions and 750 mg every 8 h for 10-h sessions. Optimized daily meropenem doses of 2000-3000 mg for PIRRT are recommended to ensure safe and effective outcomes, though further clinical validation is needed before widespread use.

This post hoc analysis of the CHAMPION-NMOSD trial evaluated the safety and efficacy of ravulizumab in patients with aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) previously exposed or naïve to rituximab (RTX). Patients received weight-based intravenous ravulizumab with a loading dose followed by maintenance dosing every 8 weeks. Patients were stratified by prior RTX exposure: no RTX exposure (RTX-naïve) vs RTX exposure > 3 months before initiating ravulizumab (RTX-exposed). Key outcomes included treatment-emergent adverse events (TEAEs), serious TEAEs (TESAEs), relapse rates, and vaccination timing from the last RTX dose. Of the 58 patients enrolled, 89.7% were female, with a mean age of 47.4 years, and 21/58 (36.2%) were RTX-exposed. Relapses occurred in 12/21 (57.1%) RTX-exposed patients between their first RTX dose and study entry. The safety profile of ravulizumab was generally similar between RTX-exposed and RTX-naïve groups. Common TEAEs included COVID-19, headache, urinary tract infection, and upper respiratory tract infection. UTIs were more frequent in RTX-exposed individuals. One patient in each group experienced a meningococcal infection. No adjudicated on-trial relapses were reported while on ravulizumab. Following initiation of ravulizumab, RTX-exposed and RTX-naïve patients with AQP4-Ab+ NMOSD achieved sustained disease control and demonstrated a manageable safety profile. The CHAMPION-NMOSD Trial; ClinicalTrials.gov identifier: NCT04201262 (registered October 06, 2020).

A Randomized Trial of Vitamin D Supplementation and COVID-19 Clinical Outcomes and Long COVID: The Vitamin D for COVID-19 Trial.

ABSTRACT Progressive hip displacement is a common problem in children with neurodevelopmental conditions, often leading to painful dislocation and impaired function. Hip reconstruction may be necessary to maintain containment but these reconstructions are major surgery in this vulnerable population. Effective pain management during and after hip reconstruction is crucial but challenging due to comorbidities and communication difficulties. Current practices vary widely, risking inadequate pain control. Epidural analgesia shows superior outcomes compared to local anesthesia, though optimal regimens remain unclear. This study aims to evaluate pain protocols used during and after hip reconstruction and propose a uniform protocol. This retrospective study analyzed records of children with neurodevelopmental conditions who underwent hip surgery at Erasmus MC from 2017 to 2021. Data included surgical details, pain management during and after the operations and pain scores using various validated tools. Pain assessments considered developmental level, using observational scales for non‐verbal children and self‐reports for others. Ninety‐one patients were included. Epidural analgesia was the main method of analgesia in 81 patients (89.0%). The group of patients who received intermittent epidural boluses after the loading dose had a higher number of high pain scores on the day of surgery, compared to those receiving continuous epidural infusion ( p = 0.045). Patients who had undergone previous surgery had significantly higher median pain scores on the day of surgery compared to patients undergoing their first operation ( p = 0.020). This study shows a wide variety in perioperative pain management. Patients who received intermittent epidural boluses instead of continuous epidural infusion during anesthesia experienced higher pain scores on the day of surgery. Next to that, patients who had undergone previous surgery experienced higher pain scores on the day of surgery, suggesting pain sensitization. This study has led to the development of a new uniform protocol.

Abstract Background The optimal timing of P2Y12 inhibitor administration remains a subject of debate. While P2Y12 pretreatment may enhance early platelet inhibition, its impact on thrombus burden (TB) in patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) remains unclear. Purpose This study aims to assess the impact of P2Y12 inhibitor pretreatment compared to cath-lab treatment on angiographic and clinical outcomes in STEMI patients undergoing PCI. Methods We prospectively enrolled STEMI patients undergoing PCI who received the P2Y12 inhibitor loading dose either at first medical contact (FMC) (pretreatment group) or after the initial angiographic assessment (cath-lab group). The primary outcome was intracoronary TB, classified as small (STB: grade 0-3) or large (LTB: grade 4-5), after guidewire crossing or small-diameter balloon inflation. Secondary outcomes included thrombolysis in myocardial infarction (TIMI) flow before and after PCI and 30-day clinical outcomes such as all-cause mortality and major adverse cardiovascular events (MACE), defined as all-cause death, myocardial infarction, stroke and heart failure hospitalization. Time-to-event analyses for clinical outcomes were performed using Kaplan–Meier estimates and compared with the log-rank test. Results A total of 112 consecutive STEMI patients were included in the present analysis, with 43 patients in the pretreatment and 69 patients in the cath-lab group. The mean age was 65 ± 13 years and 77.7% of the patients were males. The median time from FMC to coronary angiography was 54 (33 – 90) minutes. There was no significant difference in the incidence of LTB in the initial angiography between the two groups (pretreatment: 60.5% versus cath-lab: 73.9%, p=0.135). Initial TIMI 0 flow, indicating no perfusion, was significantly less frequent in the pretreatment group (41.9% versus 62.3%. p=0.034). Additionally, final TIMI III flow, suggesting better reperfusion, was more frequent in the pretreatment group (97.7% versus 81.2%, p=0.01). During the 30-day follow-up, there was no significant difference in all-cause mortality between the two groups (p=0.07). However, patients in the cath-lab group experienced higher rates of MACE compared to those in the pretreatment group (p=0.02). Conclusions The findings of the present study demonstrate that pretreatment with P2Y12 at FMC in STEMI patients undergoing PCI is associated with better coronary flow before and after PCI, in addition to more favorable 30-day clinical outcomes. There was no significant difference regarding the intracoronary thrombus burden between the two strategies.Table of baseline patient characteristicFor image description, please refer to the figure legend and surrounding text. Periprocedural and 30-day outcomesFor image description, please refer to the figure legend and surrounding text.

This study aimed to measure meropenem trough concentrations, assess their association with outcomes, and develop a clinical prediction score for optimal drug levels. In this retrospective single centre cohort study, we analysed 543 meropenem concentrations from 331 patients. Targets were defined as 100% fT>MIC (duration of time the drug concentration remains above the minimum inhibitory concentration) and 100% fT>4×MIC. A predictive scoring system was developed using logistic regression and validated via receiver operating characteristic (ROC) analysis. Propensity score matching (PSM) and inverse probability treatment weighting were applied. The target was reached in 73.8% of measurements for 100% fT>MIC and 48.8% for 100% fT>4×MIC. While the clinical cure rates were not different in patients with pharmacokinetic/pharmacodynamic (PK/PD) target attainment, microbiological cure rates were higher in case of achieving 100% fT>MIC and 100% fT>4×MIC (p<0.001). According to the multivariate logistic regression analysis, the best predictors of achieving the meropenem PK/PD target of 100% fT>MIC and >4×MIC were 6 g/24 hour loading dose, estimated glomerular filtration rate (eGFR) and age. While a 6 g/24 hour loading dose and older age were associated with higher target attainment, elevated eGFR correlated with lower serum levels. The prediction score derived by using these parameters had a sensitivity of 71.2%, specificity of 67.6%, positive predictive value of 86.1%, negative predictive value of 45.5% and accuracy of 70.2%. There is a trend towards clinical cure and target attainment according to PSM analysis. Three-quarters of the measurements achieved the PK/PD target of 100% fT>MIC, while half achieved the more stringent target of 100% fT>4×MIC, highlighting the need for optimised dosing strategies. Target achievement rates can be improved with therapeutic drug monitoring and personalised dosing approaches are needed.

A 57-year-old female with well-controlled bronchial asthma underwent percutaneous coronary intervention (PCI). Three hours after administration of a ticagrelor 180 mg loading dose, she developed severe bronchospasm, with oxygen saturation decreasing from 100% to below 90%. The patient received nasal mask oxygen, repeated nebulization with budesonide suspension, salbutamol, and ipratropium bromide, along with concurrent intravenous methylprednisolone. She was discharged from the ICU within 48 hours; clopidogrel 75 mg was substituted, and there was no recurrence. Severe acute asthma attacks, though rare, possibly induced by ticagrelor, require prompt recognition and aggressive management to prevent respiratory failure during PCI.

PRESERVE-003 is a two-stage phase 3 trial evaluating gotistobart (BNT316/ONC-392), a novel pH-sensitive anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody that selectively depletes regulatory T cells within the tumor microenvironment, in patients with metastatic squamous non-small cell lung cancer (sqNSCLC) without actionable genomic alterations who progressed on programmed cell death protein/programmed death ligand 1 inhibitor/platinum-based chemotherapy-a population with a poor prognosis. Here we report on stage 1, which aimed to confirm the dose and assess the preliminary efficacy (primary outcome: overall survival; secondary outcomes: progression‑free survival, objective response rate and duration of response) and safety of gotistobart compared to docetaxel. Patients with sqNSCLC were randomized (1:1) to gotistobart (6 mg kg-1 with two 10 mg kg-1 loading doses every 3 weeks (N = 45)) or docetaxel (75 mg m-2 every 3 weeks (N = 42)). After a median follow-up of 14.5 months, median overall survival was not reached with gotistobart (95% confidence interval (CI) 9.3 to not evaluable) versus 10.0 months (95% CI 6.2 to 11.9 months) with docetaxel (hazard ratio 0.46, 95% CI 0.25 to 0.84, nominal two-sided P = 0.0102). Safety was manageable, with grade ≥3 treatment-related adverse events in 42% and 49% of patients receiving gotistobart and docetaxel, respectively. Stage 1 results suggest that gotistobart monotherapy can provide clinically meaningful benefit for patients with programmed cell death protein/programmed death ligand 1-resistant and chemotherapy-resistant metastatic sqNSCLC. ClinicalTrials.gov identifier: NCT05671510 .

PurposeTo evaluate anatomical, functional, and treatment burden outcomes of Faricimab in neovascular age-related macular degeneration (nAMD) patients with persistent disease activity despite prior anti-VEGF therapy.Patients and MethodsSingle-centre retrospective study of 67 eyes switched to Faricimab (November 2022–December 2024). This cohort was unable to be extended beyond 4–6-week intervals on existing anti-VEGF therapy. All patients received three monthly loading doses followed by treat-and-extend regimen. Primary outcomes: central macular thickness (CMT), best-corrected visual acuity (BCVA), macular dryness over eight injections, and treatment interval extension.ResultsThe cohort had received mean 33 (range 10–78) prior anti-VEGF. Baseline mean BCVA was 0.42 logMAR (SD ± 0.28) and mean CMT was 244.5 μm (SD ± 62.2). Statistically significant CMT reduction occurred by injection 8 (−16.9 μm, p=0.0084). Complete macular dryness peaked by the time of third injection (43.3%) then declined to 32.8% at injection 8 (p=0.0089). Visual acuity remained unchanged (p=0.6043) with no correlation to CMT change (p=0.172). Treatment interval extension was achieved in 46.3% of patients (p=0.002). Dryness at injection 3 after switching to Faricimab did not predict treatment extension (p=0.217). Two patients (0.36% of total injections, 2/548) developed sterile intraocular inflammation requiring discontinuation.ConclusionFaricimab switching achieves statistically significant but modest anatomical improvement in heavily pretreated nAMD with meaningful treatment burden reduction in 46.3% of eyes. Our analysis revealed treatment burden did not indicate the potential for treatment interval extension.

To evaluate an initial intravenous loading dose of ketorolac 60 mg compared with 30 mg immediately after cesarean delivery and postoperative opioid requirements. This was a randomized, controlled, single-blind trial of pregnant individuals undergoing cesarean delivery under regional anesthesia at a large academic medical center between June 2022 and October 2023. Enrolled participants were randomized to receive an initial loading dose of 60 mg (intervention) or 30 mg (control) of intravenous ketorolac in the operating room at the end of surgery. Demographics, pregnancy, and surgical characteristics were collected. The primary outcome was morphine milligram equivalents (MMEs) in the first 24 hours after delivery. Secondary outcomes included MMEs postoperatively during the delivery admission, postpartum pain scores (scored 0-10) assessed with the Defense and Veterans Pain Rating Scale, and time from the end of cesarean delivery to first opioid administration. Summary statistics and bivariate analysis were performed. Outcomes were compared between the two study groups with the two-sample t test or the Wilcoxon rank-sum test as appropriate. Of 418 patients screened for eligibility, 92 were enrolled and randomized to receive a 60-mg (n=46) or 30-mg (n=46) loading dose of intravenous ketorolac. Baseline characteristics were similar between the two groups. The median opioid consumption in the first 24 hours postoperatively was 7.5 MMEs (interquartile range 0-15 MMEs) in the intervention group and 7.5 MMEs (interquartile range 0-22.5 MMEs) in the control group (P=.02). Participants receiving a 60-mg ketorolac load used an average of 15 MMEs (interquartile range 0-37.5 MMEs) postoperatively during the delivery admission compared with 30 MMEs (interquartile range 7.5-54.5 MMEs) in the 30-mg dose group (P=.043). The intervention group had a longer time interval between the end of surgery to first opioid administration (15 [3-25] vs 2.75 [2-5] hours, P=.002), as well as lower pain scores on admission to the postpartum unit (3 [0-5] vs 5 [3-6], P<.001). No treatment-related adverse effects were observed in either group. An initial loading dose of 60 mg compared with 30 mg of intravenous ketorolac after cesarean delivery resulted in lower postoperative opioid use without an increase in treatment-related adverse events. However, the effect size was small, and future studies may better address the clinical utility of ketorolac loading dose. ClinicalTrials.gov, NCT05248984.

Replicating the endogenous electromechanical microenvironment of bone remains a significant challenge in regenerative medicine. This study aims to develop a promising scaffold by integrating piezoelectric K0.5Na0.5NbO3/poly (KNN) nanoparticles into poly (L-lactic acid) (PLLA) nanofibers to promote bone healing. KNN/PLLA nanofibers were electrospun and verified via X-ray diffraction (XRD). Scanning Electron Microscope (SEM) was used to characterize morphology and assess biocompatibility on 9 wt% KNN/PLLA. The distribution of KNN was analyzed via energy dispersive spectroscopy (EDS). The mechanical properties were evaluated through Universal Testing Machine (UTM). Piezoelectric properties were quantified using an electrostatic voltmeter and Piezoresponse Force Microscopy (PFM), while Niobium (Nb) ion release was measured via inductively coupled plasma (ICP) analysis. Osteogenic differentiation was evaluated through cell proliferation, quantitative real-time PCR (qRT-PCR) for osteogenic markers osteocalcin (OCN) and runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP) and Alizarin Red S (ARS) assays for osteogenesis, and tube formation for angiogenesis. XRD confirmed successful KNN loading. Tensile tests showed that KNN incorporation enhanced mechanical properties. ICP analysis detected Nb release, reflecting the degradation. Increasing KNN content reduced fiber diameter and enhanced piezoelectricity. SEM verified biocompatibility via cell growth on 9 wt% KNN. Notably, KNN loading dose dependently upregulated OCN and RUNX2 expression, enhanced ALP activity and ARS staining, and promoted angiogenesis. The 9 wt% KNN/PLLA nanofibers exhibited superior physicochemical and mechanical properties, a sevenfold increase in piezoelectric output. The nanofibers significantly enhanced bone regeneration, evidenced by upregulated osteogenic markers (OCN/RUNX2) and markedly improved ALP activity (60%) and ARS mineralization (70%). Coupled with favorable degradation and enhanced angiogenesis, the nanofibers demonstrate high potential for functional bone tissue engineering.

Objectives: Acute coronary syndromes (ACS) are life-threatening manifestations of cardiovascular disease caused by thrombus after endothelial injury. Clopidogrel, a P2Y12 inhibitor, is widely used in ACS, but its antiplatelet response may reduce by drug interactions, inadequate dosing, and CYP2C19 polymorphisms, causes clopidogrel resistance (CR). Mean platelet volume (MPV), an indicator of platelet size and activation, has also been associated with adverse cardiovascular outcomes. This study evaluated to show temporal changes in CR and MPV, the relationship between them in ACS patients.Materials and Methods: This single-center prospective study included 90 ACS patients aged 18–80 years treated with clopidogrel (600 mg loading dose followed by 75 mg/day). Blood samples for MPV and CR were obtained within 24 hours of admission and after one month defined as first and second analyses. Platelet aggregation analysed by Multiplate aggregometry. Cut off values were ≥460 AU(aggregation unit) for CR and ≥9.3 fL for MPV.Results: Most patients were male (83.3%), the mean age was 57.4±10.2 years and hypertension was the most common risk factor (49%). While MPV values didn’t differ between both analyses (8.58±0.75 vs 8.59±0.71 fL, p=0.89), CR significantly increased over time (254.76±180.9 vs 348.2±175.2 AU, p=0.0001). CR observed in 27 patients (32.35%) and MPV values were similar in these patients at both analyses. Among patients prescribed lipid-lowering therapy firstly, AU values increased significantly (251.08±170.34 AU vs 344.3 ±167.8 AU p=0.0001).Conclusions: Clopidogrel resistance increased over time without parallel changes in MPV, suggested different mechanisms underlying clopidogrel response. So routine CR test should be limited to selected high-risk patients.