Optimal Regimen Research Articles

A Comparison of Different Strategies for Optimizing the Selection of Empiric Antibiotic Therapy for Pneumonia Caused by Gram-Negative Bacteria in Intensive Care Units (ICUs): Unit-Specific Combination Antibiograms Versus Patient-Specific Risk Factors

Abstract Background Guidelines suggest dual anti-pseudomonal therapy for empiric treatment of pneumonia caused by Gram-negative bacteria in ICU patients. Additionally, consideration of local susceptibility data and patient-specific risk factors for resistance is recommended for selecting optimal empiric regimens. However, data assessing how to best do this are lacking, and it is unclear whether a local susceptibility data-based or a patient specific risk factor-based approach will better drive appropriate empiric treatment. This study aims to compare these two strategies. Methods This retrospective study was divided into two periods. In period I, Gram-negative respiratory cultures from ICU patients were used to develop unit-specific combination antibiograms, and individual patient charts were reviewed to assess the impact of risk factors on antimicrobial susceptibility to develop a risk-factor based treatment algorithm. Optimal empiric regimens based on these two strategies were then defined. In period II, these regimens were hypothetically applied to patients to compare rates of appropriate empiric therapy and overuse by the two methods. Results Risk factor-based regimens had a higher appropriateness rate compared to regimens derived from antibiograms (89.9% vs 83.7%). Additionally, applying antibiogram based regimens resulted in a higher prevalence of antibiotic overuse than a patient-specific risk factor based approach (69.8% vs. 40.3%), with excess overuse driven by a higher frequency of unnecessary use of combination therapy. Conclusion Both strategies provided high rates of appropriateness in empiric antibiotic selection. However, the patient-specific risk factor-based approach demonstrated a higher rate of appropriate therapy and offered advantages in reducing rates of unnecessary combination therapy.

Direct Oral Anticoagulants versus Vitamin K Antagonists for the management of left ventricular thrombus after myocardial infarction: A meta-analysis

Abstract Background/Introduction Left ventricular (LV) thrombus formation is not an uncommon complication after acute myocardial infarction (AMI) in the modern era of early reperfusion. The optimal anticoagulation regimen in this clinical scenario remains poorly-defined. Purpose The present meta-analysis sought to investigate the efficacy and safety profile of direct oral anticoagulants (DOACs) compared with Vitamin K antagonists (VKAs) for the management of LV thrombus following AMI. Methods A systematic literature review was conducted in electronic databases to identify studies reporting efficacy and safety outcome data regarding the use of DOACs versus VKAs for patients with LV thrombus after MI. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated and random-effects meta-analyses were conducted to synthesize pooled ORs. Results Eight studies comprising a total of 605 patients were included (Table). DOACs were associated with an almost 2-fold higher likelihood for achieving thrombus resolution compared to VKAs (pooled OR 1.95 [1.25-3.04]; p =0.003, I2 =0 %), while they achieved a 70% lower risk for systemic embolism (pooled OR 0.30 [0.12-0.75]; p =0.01, I2 =0%). The use of DOACs was associated with a 54% lower risk for bleeding compared to VKAs (pooled OR 0.46 [0.26-0.84]; p =0.01, I2 =0 %). Overall, patients receiving DOACs had a 63% lower risk to reach the composite outcome of any bleeding, systemic embolism, cardiovascular hospitalization, or all-cause death, compared with patients using VKAs (pooled OR 0.37 [0.23-0.60]; p <0.0001, I2 =0%) (Figure). Conclusion DOACs appear to have a more favorable efficacy and safety profile compared to VKAs for the management of LV thrombus following AMI.Graphical abstractTable

Mesoporous Biosilica Beads for Controlled Selenium Nanoparticle Delivery from Collagen‐Chitosan Scaffolds: Promoting Bone Formation and Suppressing Prostate Cancer Growth

The controlled delivery of selenium nanoparticles (Se‐NPs) is promising for bone cancer treatment due to their dual benefits in bone regeneration and tumor inhibition, yet achieving an optimal dosing regimen remains challenging. Natural mesoporous biosilica (BS) beads have shown promise for drug delivery due to their microporous structure. This study explores incorporating BS beads into collagen‐chitosan (Coll‐CS) scaffolds, known for bone repair, to control Se‐NP delivery. Two approaches are compared: loading Se‐NPs into BS beads before integrating them into Coll‐CS scaffolds versus directly loading Se‐NPs into Coll‐CS scaffolds. The scaffold properties, Se release kinetics, cytocompatibility, and effects on mesenchymal stem cells (MSCs) and prostate cancer cells (LNCaP) are evaluated. BS bead‐loaded scaffolds provide controlled Se‐NP release and enhanced mechanical properties compared to directly loaded scaffolds. Higher Se‐NP concentrations in BS‐loaded scaffolds effectively promote MSC osteogenic differentiation and mineralisation while inhibiting LNCaP cell viability. In contrast, low Se‐NP concentrations not only induce early osteogenic differentiation but also promote cancer cell proliferation, underscoring the need for optimal Se‐NP concentration and release. These findings suggest that BS bead‐loaded Coll‐CS scaffolds are a promising strategy for controlled Se‐NP delivery, addressing the dual challenges of bone formation and cancer recurrence prevention in bone cancer treatment.

Effect of Prednisone Dosing on Mineralocorticoid-Related Side Effects With Abiraterone in Prostate Cancer.

Abiraterone use for prostate cancer can cause mineralocorticoid excess syndrome (MES; eg, hypertension and hypokalemia). Prednisone mitigates these effects; however, the optimal dose level is unclear. This study examines MES effects from abiraterone with 5 mg of prednisone once daily versus 5 mg twice daily. Data for 1,410 abiraterone-treated patients from 2011 to 2022 were identified from a large academic/community hospital system. Three hundred and fifty-three patients were excluded for missing medication data and use of an alternative steroid; 1,057 patients remained (5 mg once daily, n = 550, 5 mg twice daily, n = 507). Prednisone dose was treated as a time-varying covariate. Hypokalemia and hypertension incidence over 24 weeks after abiraterone initiation was analyzed via Cox proportional hazard models using Common Terminology Criteria for Adverse Events (v5.0) grading via direct clinical measurements and International Classification of Diseases (ICD)-10 code outcomes. Patients receiving 5 mg of prednisone twice daily had a statistically significant decrease in cumulative hazard for experiencing at least one MES event (hypertension and/or hypokalemia) via direct clinical measurement (hazard ratio [HR], 0.79 [CI, 0.68 to 0.91]; P = .002) and by ICD-10 code (HR, 0.65 [CI, 0.54 to 0.79]; P < .001) analysis. This finding was durable with individual end point analysis of hypertension and hypokalemia. There were no changes to BMI or hyperglycemia (>140 mg/dL) between the cohorts. This retrospective analysis shows a decrease in risk for the development of at least one episode of hypertension or hypokalemia with abiraterone using 5 mg twice-daily prednisone in the study population. Assessments of metabolic impacts (BMI, hyperglycemia) did not show differences with prednisone dosing. These findings may merit consideration when determining an optimal prednisone dosing regimen.

Pharmacokinetics of Vancomycin in Healthy Korean Volunteers and Monte Carlo Simulations to Explore Optimal Dosage Regimens in Patients with Normal Renal Function.

Background/Objectives: To date, population pharmacokinetic (PK) studies of vancomycin on healthy Korean adults have not been conducted. This study aimed to investigate the PK properties of vancomycin in healthy volunteers and to identify optimal dosing regimens based on the area under the concentration-time curve (AUC) in adult patients with normal renal function. Methods: We conducted a prospective clinical study, analysing PK samples from 12 healthy participants using noncompartmental analysis and non-linear mixed-effects modelling. The population PK parameters derived were employed in Monte Carlo simulations to evaluate the adequacy of the current dosing regimen and to formulate dosing recommendations. Results: The PK profiles were optimally described by a two-compartment model, with body weight and age as significant covariates affecting total clearance. The simulations indicated that to achieve a therapeutic target-defined as an AUC at steady-state over 24 h of 400-600 mg·h/L-daily doses ranging from 60 to 70 mg/kg are necessary in adults with normal renal function. Conclusions: This study underscores the need to actively adjust dosage and administration based on a vancomycin PK model that adequately reflects the demographic characteristics of patients to meet both safety and efficacy standards.

Comparison of intravenous nalbuphine and dexmedetomidine in combination with lidocaine aerosol inhalation in awake direct laryngoscopy: a randomized, double-blind, placebo-controlled trial

BackgroundThe airway should be thoroughly and accurately evaluated before anesthesia induction and endotracheal intubation. Awake direct laryngoscopy (ADL) can provide rapid, accurate, and intuitive airway assessment, especially for suspected difficult airways, and sometimes eliminates the need for fiberoptic intubation in some suspicious difficult airway cases. However, an optimal regimen has not been determined.MethodsIn this double-blind, controlled study, prior to ADL, 60 patients scheduled for general anesthesia were randomly allocated to receive 0.75 μg/kg of dexmedetomidine (Dex group, n = 20), 0.15 mg/kg of nalbuphine (Nal group, n = 20), or a placebo (control group, n = 20) intravenously over 10 min. At the same time, all study subjects received nebulized lidocaine for 15 min. The primary outcome was patient tolerance as assessed by a 5-point ADL comfort score, while secondary outcomes included satisfaction, coughing, pain, nausea and vital signs.ResultsPatients undergoing ADL in the Nal group had higher tolerance scores than those in the control and Dex groups [4 (3,4) vs. 3 (2,2.75), P < 0.017, and 4 (3,4) vs. 2 (2,2,75), P < 0.001, respectively] and higher satisfaction [7 (6,8) vs. 4 (3,5.75), P < 0.017, and 7 (6,8) vs. 5.5 (5,6), P < 0.001, respectively]. Additionally, the Nal group had significantly fewer adverse events, such as pain and nausea than the control and Dex groups. The sedation score and peripheral oxygen and saturation were significantly higher in the Nal group than in the Dex group, with no difference between the Nal and control groups (P < 0.001, P = 0.159, respectively).ConclusionsIntravenous nalbuphine in combination with lidocaine aerosol inhalation significantly improved patient tolerance and satisfaction while reducing nausea, coughing, pain, sedation, and SpO2 levels during ADL.

Iron Deficiency Anaemia in Pregnancy: A Narrative Review from a Clinical Perspective.

Anaemia in pregnancy is a global problem of significance in all settings. The most common cause is iron deficiency. Large numbers of women are affected, ranging up to 25-30% antenatally and 20-40% postnatally. It is associated with serious adverse outcomes for both the mother and her baby. The risk of low birth weight, preterm birth, postpartum haemorrhage, stillbirth, and neonatal death are all increased in the presence of anaemia. For the infants of affected pregnancies, complications may include neurocognitive impairment. Making an accurate diagnosis during pregnancy has its challenges, which include the choice of thresholds of haemoglobin below which a diagnosis of anaemia in each trimester of pregnancy can be made and, aligned with this question, which are the most appropriate biomarkers to use to define iron deficiency. Treatment with oral iron supplements increases the haemoglobin concentration and corrects iron deficiency. But high numbers of women fail to respond, probably due to poor adherence to medication, resulting from side effects. This has resulted in an increased use of more expensive intravenous iron. Doubts remain about the optimal regimen to of oral iron for use (daily, alternate days, or some other frequency) and the cost-effectiveness of intravenous iron. There is interest in strategies for prevention but these have yet to be proven clinically safe and effective.

Oral corticosteroid dosage and taper duration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapse

BackgroundWe sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid...

Population Pharmacokinetic and Pharmacodynamic of Atorvastatin in Chinese Lung Transplant Recipients.

Atorvastatin is a widely prescribed cholesterol-lowering drug that inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase to reduce lipid levels. This study aimed to establish a population pharmacokinetic and pharmacodynamic model for atorvastatin in Chinese lung transplant recipients (LTRs), particularly those using voriconazole (VOR) and with different genotypes. It evaluated precise dosing regimens and analyzed the correlation between atorvastatin exposure and clinical outcomes. A nonlinear mixed-effects model was used for the population pharmacokinetic/pharmacodynamic (PK/PD) analysis. A one-compartment population PK model was developed, incorporating VOR, SLCO2A1 rs76906503, and SLC22A8 rs2187383 to assess apparent clearance and volume of distribution. LDL-C was modeled as a biomarker to evaluate atorvastatin efficacy. A Monte Carlo simulation was conducted to assess various dosing schemes and the effects of different covariates on achieving the target LDL concentration. The correlation between atorvastatin exposure and clinical outcomes was also evaluated. Results indicated that the average probability of target attainment for optimal dosing regimens across various covariate results exceeded 45.8%. Dosages of 10, 20, and 40 mg were deemed suitable for LTRs. A lower dose was recommended for LTRs taking VOR or with mutant-type genotypes to avoid overexposure and adverse reactions. The population PK/PD model offers valuable guidance for evaluating atorvastatin dosing regimens in clinical settings, particularly for LTRs using VOR and those with different genotypes.

ANTIBACTERIAL THERAPY IN SEPSIS PATIENTS

Today, sepsis, the cause of which is purulent-inflammatory processes of soft tissues, accounts for more than 45% of cases. In most multidisciplinary hospitals, the frequency of gram-positive and gram-negative sepsis is approximately the same. Antibacterial therapy (ABT) is the most important component of the complex therapy of sepsis, and early adequate empiric ABT leads to a decrease in mortality and the frequency of complications. ABT of sepsis at the beginning of treatment, in most cases, is empirical in nature, but it should be remembered that taking the material for microbiological research must be done before the start of antibacterial therapy! According to the principles adopted in the guideline "Sepsis - 3", the use of antibiotics for the treatment of sepsis is a necessary component, the effectiveness of which cannot be doubted. It should be remembered that a delay in the appointment of an antibacterial drug to patients with sepsis and septic shock for 1 hour leads to an increase in the risk of death of the patient by 7,6%. Empiric ABT should be initiated with a broad-spectrum regimen of one or more antibiotics in patients with sepsis or septic shock to cover all possible pathogens (including bacterial, possibly fungal, or viral). Empiric ABT should be narrowed after identification of the pathogen and determination of its sensitivity and/or when adequate clinical improvement is registered. There are no indications for long-term systemic antibacterial prophylaxis in patients with severe forms of inflammatory conditions of non-infectious origin (for example, severe pancreatitis, burns). Measurement of procalcitonin levels can be used to shorten the duration of antibacterial therapy in patients with sepsis. Rapid interpretation of the severity of the infectious process can be performed using ACCP/SCCM sepsis diagnostic criteria, organ dysfunction criteria (gSOFA, SOFA, MODS) or rapid procalcitonin test. Microbiological diagnosis of sepsis is the main factor in prescribing adequate ABT regimens. In the case when the same microorganism is released from the probable source of infection and from the peripheral blood, its etiological role in the development of sepsis should be considered as evidential. The standard for testing blood for sterility is the collection of material from two peripheral veins with an interval of up to 30 minutes, while blood from each vein must be collected in two vials. It is not permissible to take blood from the catheter! Building an ABT algorithm taking into account the etiology and characteristics of resistance of microorganisms to antibacterial drugs is the most optimal approach. Тoday, the optimal regimen of empiric ABT of sepsis with PON is carbapenems - as drugs that have the widest spectrum of action and to which the lowest level of resistance is observed among intra-hospital strains of gram(-) bacteria. In some cases, an alternative to carbapenems is cefepime, ceftaroline, protected by antipseudomonas β-lactams (cefaperazone/sulbactam, piperacillin/tazobactam) and "respiratory" fluoroquinolones. In cases of ineffectiveness of the indicated regimens of ABT, the feasibility of additional appointment of glycopeptides (vancomycin, teicoplanin or linezolid), as well as systemic antimycotics (fluconazole) should be evaluated. The latter should also be prescribed after 7-10 days after the start of ABT in a prophylactic dose of 150 mg per week.

Matched-pair analysis of mCRPC patients receiving 177Lu-labeled PSMA-targeted radioligand therapy in a 4-week versus 6-week treatment interval

BackgroundThe optimal regimen for 177Lu-labeled prostate-specific membrane antigen-targeted radioligand therapy, including treatment intervals, remains under study, with evidence suggesting shorter intervals could benefit patients with high disease volume and rapid progression. This retrospective analysis evaluated treatment toxicity, PSA response, PSA-progression-free survival (PSA-PFS), and overall survival (OS) in matched cohorts of mCRPC patients receiving 177Lu-PSMA-RLT at 4-week versus 6-week intervals.ResultsA PSA response (PSA decline ≥ 50%) was achieved in 47.8% and 21.7% of patients in the 4-week and 6-week treatment interval groups, respectively (p = 0.12). There was a trend towards longer PSA-PFS in the 4-week group compared to the 6-week group (median PSA-PFS, 26.0 weeks vs. 18.0 weeks; HR 0.6; p = 0.2). Although not statistically significant, there was a trend towards shorter OS in the 4-week group compared to the 6-week group (median OS, 15.1 months vs. 18.4 months; HR 1.3; p = 0.5). The 4-week group had a significantly greater decrease in leucocyte and platelet counts compared to the 6-week group (38.5% vs. 18.2% and 26.7% vs. 10.7%; p = 0.047 and p = 0.02). Severe adverse events were modest in both groups.ConclusionsIntensifying treatment intervals from 6 weeks to 4 weeks showed some improvements in PSA response and PSA-PFS for mCRPC patients, but did not significantly affect OS. Additionally, bone marrow reserve was significantly reduced with the intensified regimen. Therefore, the overall benefit remains uncertain, and further prospective studies are needed to compare 4-week and 6-week intervals regarding toxicity, treatment response, and outcome.

Pediatric pleuropulmonary blastoma: analysis of four cases

BackgroundPleuropulmonary Blastoma (PPB) is an extremely uncommon, highly aggressive tumor that arises from either the lungs or pleura. According to Dehner, PPB was classified into three groups: type I (cystic), type II (mixed), and type III (solid). Type I tends to occur more commonly in infants and has a more favorable prognosis compared to types II and III. This tumor is very rare in pediatric age group; hence, there is no consensus on the optimal treatment regimen for it to date. Type I tumors, which resemble congenital lung cysts, can eventually progress to more aggressive type II and type III tumors. This article aims to increase general awareness of this pathology, clinical presentation, and differential diagnosis in order to identify this rare entity early in its course. By presenting 4 such cases, we highlight that PPB can be missed early in diagnosis and it is important to be alert when putting this rare tumor in differential diagnosis of cystic lung lesions.MethodsA retrospective study was conducted between 2015 and 2020 involving patients who had a definitive diagnosis of PPB with emphasis on clinical presentation, preoperative imaging studies, intra-operative findings, pathological reports, ancillary treatment, and outcomes. All patients were followed up every 6 months to monitor local recurrence and distant metastasis by undergoing physical exam and non-contrast enhanced CT of the chest. The primary outcome is to identify the mortality and morbidity (recurrence and distant metastasis) of PPB for cases admitted in our institute.ResultsFour children were diagnosed with PPB during the study period. Clinically, patients presented with manifestations ranging from respiratory distress, fever to obstructive shock and radiologically, 2 cases were presented with mediastinal mass and the other 2 presented with pneumothorax. Regrettably, none of the cases were diagnosed pre-operatively. One lesion proved to be type I, 2 were type II and one was type III. All cases underwent chemotherapy using the combination of vincristine, Adriamycin and cyclophosphamide (VAC regimen). Recurrence was detected in a type II case, around 2 years after operation, and the other type II case developed brain metastasis that was discovered 3 years after operation. Type I case showed no local or distant metastasis.ConclusionA prompt preoperative diagnosis and workup of cases of PPB is crucial to enable optimal intervention intraoperatively and early postoperative treatment. Though it is uncommon, PPB should be considered in the differential diagnosis of cystic lung lesions.

Current National Treatment Trends for Gastric Adenocarcinoma in the United States.

The treatment of gastric adenocarcinoma (GA) continues to evolve. While neoadjuvant chemotherapy (NAC) has demonstrated emerging benefit, the optimal treatment regimen, and sequence remain to be firmly established. Patients with nonmetastatic GA who underwent resection were identified within the 2020 National Cancer Database. Patients were compared between the mutually exclusive treatment groups of NAC, neoadjuvant chemoradiotherapy (NCRT), adjuvant chemotherapy, adjuvant chemoradiotherapy (CRT), and surgery only. The primary endpoint was receipt of NAC or NCRT. Patients were 1-to-1 propensity score matched for receiving any neoadjuvant therapy. Multivariable logistic regression was used to identify predictors of receipt of any neoadjuvant therapy and receipt of any adjuvant therapy. Twenty-five thousand and seventy-three patients were included in the analysis. Patients were treated with NAC (25.0%), NCRT (31.4%), adjuvant chemotherapy (6.5%), adjuvant CRT (12.6%), and surgery only (24.5%). Compared to 2006-2011, patients diagnosed between 2012 and 2017 experienced the greatest increases in NAC (18.6% vs. 29.0%; p < 0.001) and NCRT (25.0% vs. 35.5%; p < 0.001). Median OS was 44.9 months. OS was longest for patients who received any neoadjuvant therapy compared to those receiving adjuvant or surgery only (51.0 vs. 42.4 vs. 38.0 months, respectively; p < 0.001). Patients who were Black, in the lowest income quartile or treated at lower volume facilities were less likely to receive NAT (all p < 0.001). There has been significant acceleration in the use of neoadjuvant therapy for GA. Currently, NCRT followed by surgery are the most common treatment sequences in the United States. Additional trials are needed to further define the optimal treatment sequence.

Therapeutic drug monitoring of linezolid in Chinese premature neonates: a population pharmacokinetic analysis and dosage optimization.

This study aimed to develop a pharmacokinetic model of linezolid in premature neonates and evaluate and optimize the administration regimen. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to detect the blood concentration data of 54 premature neonates after intravenous administration of linezolid, and the relevant clinical data were collected. The population pharmacokinetic (PPK) model was established by nonlinear mixed effects modeling. Based on the final model parameters, the optimal administration regimen of linezolid in premature neonates with different body surface areas (BSA) was simulated and evaluated. The pharmacokinetic properties of linezolid in premature neonates are best described by a single-compartment model with primary elimination. The population typical values for apparent volume of distribution and clearance were 0.783 L and 0.154 L/h, respectively. BSA was a statistically significant covariate with clearance (CL) and volume of distribution (Vd). Monte Carlo simulations showed that the optimal administration regimen for linezolid in premature neonates was 6 mg/kg q8h for BSA 0.11 m2, 7 mg/kg q8h for BSA 0.13 m2, and 9 mg/kg q8h for BSA 0.15 m2 with minimum inhibitory concentration (MIC) ≤1 mg/L, 7 mg/kg q8h for BSA 0.11 m2, 8 mg/kg q8h for BSA 0.13 m2, and 10 mg/kg q8h for BSA 0.15 m2 with MIC = 2 mg/L. A pharmacokinetic model was developed to predict the blood concentration on linezolid in premature neonates. Based on this model, the optimal administration regimen of linezolid in premature neonates needs to be individualized according to different BSA levels.

Optimized administration of human embryonic stem cell-derived immunity-and-matrix regulatory cells for mouse lung injury and fibrosis

BackgroundLung injury and pulmonary fibrosis (PF), frequently arising as sequelae of severe and acute lung disease, currently face a dearth of effective therapeutic potions. Mesenchymal stem cells (MSCs) with immunomodulatory and tissue repair functions have immense potential to treat lung injury and PF. However, the optimal route of administration, timing, and frequency of dosing remain elusive. Human embryonic stem cell-derived immunity-and-matrix-regulatory cells (IMRCs) have shown therapeutic potential for lung injury and PF.MethodsTo ascertain the optimal therapeutic regimen for IMRCs in PF, we conducted an experimental study. Utilizing a mouse model of PF induced by bleomycin (BLM), IMRCs were administered via either a single or double intravenous (IV) or intratracheal (IT) injection on the first and seventh days post-BLM induction.ResultsOur findings revealed that IV infusion of IMRCs surpassed IT infusion in enhancing survival rates, facilitating body weight recovery, and optimizing Ashcroft and Szapiel scores among the model mice. Notably, IV administration exhibited a more profound ability to mitigate lung inflammation and fibrosis. Moreover, earlier and more frequent administrations of IMRCs were found to be advantageous in enhancing their therapeutic effects. Specifically, early administration with two IV infusions significantly improved body weight, lung organ coefficient, pulmonary ventilation and diffusion functions, and PF. This was accompanied by an increase in alveolar type I and II epithelial cells and a suppression of macrophage infiltration via CD24.ConclusionCollectively, these results suggested that IMRCs infusion ameliorated lung injury by promoting lung regeneration and inhibiting macrophage infiltration in a route, time, and frequency-dependent manner.

Dried Blood Spots Sampling and Population Pharmacokinetic Modeling for Dosing Optimization of Piperacillin in Chinese Neonates.

Piperacillin is commonly used off-label in neonates for the treatment of bacterial infections. This study aimed to assess a dried blood spots (DBS)-based microsampling strategy for supporting population pharmacokinetics and treatment optimization of piperacillin in Chinese neonates. DBS samples from neonatal patients were collected at predefined intervals. Drug blood concentrations were quantified using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry method. A population pharmacokinetic model was developed using a nonlinear mixed-effects modeling approach. The pharmacokinetic/pharmacodynamics (PK/PD) target was 75% of the time with the unbound drug plasma concentration above the minimum inhibitory concentration (fT>MIC), with a toxicity threshold of unbound drug plasma trough concentration above 64 mg/L. A total of 45 piperacillin samples from 24 neonates were collected. The pharmacokinetics of piperacillin was described using a one-compartment model with postmenstrual age (PMA) as the most significant covariate on clearance. Simulations showed that dosing regimens achieving >90% PK/PD target attainment with <10% risk of possible toxicity were: PMA 33-35 weeks (50 mg/kg q12h), 35-37 weeks (50 mg/kg q8h), and 37-41 weeks (50 mg/kg q6h). In conclusion, Using DBS sampling, we developed a population pharmacokinetic model of piperacillin in Chinese neonates, incorporating PMA to determine optimal dosing regimens.

High-Dose TXA Is Associated with Less Blood Loss Than Low-Dose TXA without Increased Complications in Patients with Complex Adult Spinal Deformity.

Tranexamic acid (TXA) is commonly utilized to reduce blood loss in adult spinal deformity (ASD) surgery. Despite its widespread use, there is a lack of consensus regarding the optimal dosing regimen. The aim of this study was to assess differences in blood loss and complications between high, medium, and low-dose TXA regimens among patients undergoing surgery for complex ASD. A multicenter database was retrospectively analyzed to identify 265 patients with complex ASD. Patients were separated into 3 groups by TXA regimen: (1) low dose (<20-mg/kg loading dose with ≤2-mg/kg/hr maintenance dose), (2) medium dose (20 to 50-mg/kg loading dose with 2 to 5-mg/kg/hr maintenance dose), and (3) high dose (>50-mg/kg loading dose with ≥5-mg/kg/hr maintenance dose). The measured outcomes included blood loss, complications, and red blood cell (RBC) units transfused intraoperatively and perioperatively. The multivariable analysis controlled for TXA dosing regimen, levels fused, operating room time, preoperative hemoglobin, 3-column osteotomy, and posterior interbody fusion. The cohort was predominantly White (91.3%) and female (69.1%) and had a mean age of 61.6 years. Of the 265 patients, 54 (20.4%) received low-dose, 131 (49.4%) received medium-dose, and 80 (30.2%) received high-dose TXA. The median blood loss was 1,200 mL (interquartile range [IQR], 750 to 2,000). The median RBC units transfused intraoperatively was 1.0 (IQR, 0.0 to 2.0), and the median RBC units transfused perioperatively was 2.0 (IQR, 1.0 to 4.0). Compared with the high-dose group, the low-dose group had increased blood loss (by 513.0 mL; p = 0.022) as well as increased RBC units transfused intraoperatively (by 0.6 units; p < 0.001) and perioperatively (by 0.3 units; p = 0.024). The medium-dose group had increased blood loss (by 491.8 mL; p = 0.006) as well as increased RBC units transfused intraoperatively (by 0.7 units; p < 0.001) and perioperatively (by 0.5 units; p < 0.001) compared with the high-dose group. Patients with ASD who received high-dose intraoperative TXA had fewer RBC transfusions intraoperatively, fewer RBC transfusions perioperatively, and less blood loss than those who received low or medium-dose TXA, with no differences in the rates of seizure or thromboembolic complications. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Evaluation of Efficacy and Safety of Different Doses of Eladis® in the Therapy of Cough Against Acute Respiratory Viral Infection

Aim. Justification of the optimal dosage regimen regarding the efficacy and safety of Eladis®, film-coated tablets, 10 mg (Valenta Pharm JSC, Russia) in comparison with placebo in patients with non-productive cough due to acute respiratory viral infection (ARVI). Material and methods. A double-blind placebo-controlled randomized multicenter study was conducted in which 141 patients with non-productive cough on the background of acute respiratory viral infection took part. The study participants were randomized into 4 groups. Patients from the first group took 1 tablet of Eladis® 2 times a day (daily dose of 20 mg); patients from the second group took 2 tablets of Eladis® 2 times a day (daily dose of 40 mg); patients from the third group took 4 tablets of Eladis® 2 times a day (daily dose of 80 mg). Patients in the fourth group received placebo tablets in quantities corresponding to the first three groups. For this purpose, 3 subgroups of 12 people were allocated within group 4. The duration of therapy was 7–14 days. The effectiveness of therapy was assessed based on monitoring the frequency of cough attacks, changes in values on the day and night cough scales, a digital rating scale (DRS), and the time to achieve clinical cure of cough and ARVI symptoms was also taken into account. The safety of the studied drug was assessed based on monitoring of vital signs, laboratory parameters, and electrocardiogram (ECG) data. The number and severity of adverse events (AEs) and serious adverse events (SAEs) were assessed. Results. Analysis of data on the primary endpoint (reduction of cough attack frequency by ;)50% by the 5th day relative to the 1st visit) showed the superiority of Eladis® over placebo at a daily dose of 80 mg (P=0.00003). At the same time, the proportion of patients who reached the primary endpoint by day 5 when receiving Eladis® at a dose of 80 mg per day was 71.43%, while in the combined placebo group it was 22.22%. Conclusion. Evaluation of various dosage regimens of Eladis® has shown that a daily dose of 80 mg is optimal for the treatment of non-productive cough in patients with ARVIs, as it provides the greatest effectiveness with a safety profile comparable to other studied doses.

Survival Outcomes Associated With First-Line Procarbazine, CCNU, and Vincristine or Temozolomide in Combination With Radiotherapy in IDH-Mutant 1p/19q-Codeleted Grade 3 Oligodendroglioma.

Patients with IDH-mutant 1p/19q-codeleted grade 3 oligodendroglioma (O3IDHmt/Codel) benefit from adding alkylating agent chemotherapy to radiotherapy (RT). However, the optimal chemotherapy regimen between procarbazine, 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and vincristine (PCV) and temozolomide (TMZ) remains unclear given the lack of randomized trial data comparing both regimens. The objective was to assess the overall survival (OS) and progression-free survival (PFS) associated with first-line PCV/RT versus TMZ/RT in patients newly diagnosed with O3IDHmt/Codel. We included patients with histologically proven O3IDHmt/Codel (according to WHO criteria) from the French national prospective cohort Prise en charge des OLigodendrogliomes Anaplasiques (POLA). All tumors underwent central pathological review. OS and PFS from surgery were estimated using the Kaplan-Meier method and Cox regression model. 305 newly diagnosed patients with O3IDHmt/Codel treated with RT and chemotherapy between 2008 and 2022 were included, of which 67.9% of patients (n = 207) were treated with PCV/RT and 32.1% with TMZ/RT (n = 98). The median follow-up was 78.4 months (IQR, 44.3-102.7). The median OS was not reached (95% CI, Not reached [NR] to NR) in the PCV/RT group and was 140 months (95% CI, 110 to NR) in the TMZ/RT group (log-rank P = .0033). On univariable analysis, there was a significant difference in favor of PCV/RT in both 5-year (PCV/RT: 89%, 95% CI, 85 to 94; TMZ/RT: 75%, 95% CI, 66 to 84) and 10-year OS (PCV/RT: 72%, 95% CI, 61 to 85; TMZ/RT: 60%, 95% CI, 49 to 73), which was confirmed using the multivariable Cox model adjusted for age, type of surgery, gender, Eastern Cooperative Oncology Group performance status, and CDKN2A homozygous deletion (hazard ratio, 0.53 for PCV/RT, 95% CI, 0.30 to 0.92, P = .025). In patients with newly diagnosed O3IDHmt/Codel from the POLA cohort, first-line PCV/RT was associated with better OS outcomes compared with TMZ/RT. Our data suggest that the improved safety profile associated with TMZ comes at the cost of inferior efficacy in this population. Further investigation using prospective randomized studies is warranted.

Population pharmacokinetics of nirmatrelvir/ritonavir in critically ill Chinese COVID-19 patients and recommendations for medication use: a two-center retrospective study

ABSTRACT Background This study aimed to establish population pharmacokinetics (PPK) models of nirmatrelvir/ritonavir in critically ill Chinese patients with the coronavirus disease 2019 (COVID-19) infection, explore factors affecting the pharmacokinetics (PK) of nirmatrelvir/ritonavir. Methods A total of 285 serum samples and clinical data were collected from 152 patients. The PPK models of nirmatrelvir/ritonavir were analyzed using nonlinear mixed-effect modeling (NONMEM) approach. The optimal dosing regimen for patients with different renal function was determined using Monte Carlo simulations. Results The population typical values of apparent clearance (CL/F) and apparent volume of distribution (V/F) of nirmatrelvir were 2.26 L/h and 15.3 L, respectively. Notably, creatinine clearance (CrCL) significantly influenced the PK variation of nirmatrelvir. Monte Carlo simulations suggested that patients with mild-to-moderate renal impairment experienced a 22.0–59.9% increase in the area under the curve (AUC) when they were administered a standard dose of nirmatrelvir compared to those with normal renal function. The AUC in patients with severe renal impairment after administration of 150 mg q12h nirmatrelvir was similar to that in patients with normal renal function after administration of 300 mg q12h nirmatrelvir. Conclusions PPK modeling and simulation provided a reference for the rational clinical application of nirmatrelvir/ritonavir in critically ill Chinese patients.