Search

Introduction: Quinidine (QND) sulfate is an effective treatment for atrial fibrillation (AF) in horses, and several dosage regimens have been proposed to address its wide variability in response and potential adverse effects. The purpose of this study was to analyze the variability in plasma quinidine concentrations using population pharmacokinetics to determine an effective and safe dosage regimen for Thoroughbred horses. Methods: Six healthy Thoroughbred horses were treated with 20mg/kg quinidine sulfate dihydrate (16.58mg/kg QND base) administered PO or 5mg/kg quinidine hydrochloride monohydrate (4.28mg/kg QND base) administered IV (single administration), and blood samples were taken regularly. Four healthy horses were treated with 20mg/kg quinidine sulfate dihydrate administered twice (every 6h) via PO route. For the other 19 Thoroughbred racehorses that developed AF, blood samples were taken during quinidine therapy. Quinidine concentrations were measured in all plasma samples using liquid chromatography with tandem mass spectrometry, and the data from 29 horses were modeled using a nonlinear mixed-effects model, followed by Monte Carlo simulations (MCS). Results: The median quinidine concentration for successful sinus rhythm conversion was 2.0 µg/mL (range: 0.5-2.7 µg/mL) in AF horses, while a median concentration of 3.8 µg/mL (range: 1.6-5.1 µg/mL) showed adverse effects. MCS predicted that plasma quinidine concentrations for quinidine sulfate dihydrate PO administration (loading dose: 30 mg/kg, maintenance dose: 6.5 mg/kg q 2 h) reached 1.4, 2.0 and 2.7 µg/mL in 90, 50 and 10% of the horse populations, respectively. Increasing the loading dose to 45 mg/kg and the maintenance dose to 9 mg/kg q 2 h, the plasma concentrations achieved were 1.9, 2.8, and 3.8 µg/mL in 90, 50, and 10% of horse populations, respectively. Discussion: Using simulations, different empirical dosing regimens were proposed to achieve plasma quinidine concentrations immediately or progressively, representing a tradeoff between optimizing therapeutic effects and minimizing adverse effects. A combination of these dosing regimens is recommended to gradually increase the therapeutic concentration levels of quinidine for safe and effective treatment of AF in racehorses. [ABSTRACT FROM AUTHOR]

Background: Intra- and postoperative hemorrhage is a relevant problem in major abdominal surgery, leading to acute anemia and necessitating transfusion of packed red blood cells. It is estimated that in 30% of abdominal surgeries, intra- or postoperative transfusion is required. Transfusion potentially has detrimental health effects and poses a considerable socioeconomic burden. Tranexamic acid, a lysine analog inhibiting plasminogen activation and providing clot stability, has been used to reduce hemorrhage. While there is ample evidence in other surgical disciplines, it is almost completely lacking in abdominal surgery. Methods: This multicenter double-blind parallel group randomized superiority trial will compare tranexamic acid (loading dose 1000 mg over 10 min prior to skin incision, maintenance dose 125 mg/h continuously until skin closure or until 1000 mg have been administered) to placebo in patients ≥ 18 years undergoing elective esophagectomy, gastrectomy, colectomy, rectal resection, pancreatic resection, or hepatectomy. The primary efficacy endpoint is the intra- or postoperative transfusion of at least one unit of packed red blood cells. Key secondary endpoints are the number of transfused units per patient, estimated intraoperative blood loss, postoperative complications/mortality, length of hospital stay, operation/anesthesia time, D-dimer levels, and quality of life. Sample size calculation is based on the assumption that in the control group, 30% of patients require transfusion while the intervention achieves a risk reduction of 33%, reducing the probability to 20%. With a type one error of 5% and a power of 90%, using a two-sided χ2 test, this results in 412 patients per group. Accounting for non-compliance, 425 patients are to be randomized per group. The total trial duration will be 30 months with a recruitment period of 18 months. Discussion: If the proposed trial yielded positive results, the routine use of tranexamic acid in major abdominal surgery would be supported. This would avoid acute anemia with detrimental effects such as tissue hypoxia and organ injury, as well as the negative immediate and delayed effects of transfusions. Trial registration: EU CT Nr: 2023–509970-43–01, NCT06414031. Registered on 10 May 2024. [ABSTRACT FROM AUTHOR]

Aim Materials and Methods Results Conclusions ClinicalTrials.gov The aim was to investigate the effects of lotiglipron, a once‐daily, oral small‐molecule glucagon‐like peptide‐1 (GLP‐1) receptor agonist, in participants with type 2 diabetes (T2D) or obesity.A phase 2, randomized, double‐blind, placebo‐controlled, dose‐ranging study investigated the efficacy and safety of lotiglipron. The study was terminated early for safety reasons after routine data and monitoring review. The planned analyses for the end points were modified prior to unblinding the study.In total, 901 participants were treated with at least one dose of the study drug (T2D cohort: n = 512, obesity cohort: n = 389). Although the majority of participants who were randomly assigned to higher doses did not reach their target maintenance dose, statistically significant changes in HbA1c and body weight were observed. In the T2D cohort, reductions in HbA1c were observed across all lotiglipron doses at week 16 (p < 0.0001), with least squares mean decreases up to −1.44% (90% confidence interval [CI]: −1.63, −1.26) (lotiglipron 80 mg), versus placebo, −0.07% (90% CI: −0.25, 0.11). In the obesity cohort, decreases in body weight were observed across all lotiglipron doses at week 20 (p < 0.01), up to −7.47% (90% CI: −8.50, −6.43) (lotiglipron 200 mg, five‐step titration), versus placebo, −1.84% (90% CI: −2.85, −0.83). Across cohorts, the most frequently reported treatment‐emergent adverse events were gastrointestinal related (most mild to moderate severity), with nausea being the most common (ranging from 4% [placebo] to 28.8% [80 mg] in the T2D cohort and 12.5% [placebo] to 60.6% [200 mg, four‐step titration] in the obesity cohort). Transaminase elevations were observed in a subset of participants (6.6% and 6.0% of participants on lotiglipron in the T2D and obesity cohorts, respectively, compared with 1.6% on placebo in the obesity cohort).The efficacy (HbA1c and/or body weight) of a range of lotiglipron doses was demonstrated in T2D and obesity cohorts. The safety profile was largely consistent with what has been previously known about the mechanism of action. Our results are unique in reporting elevations in liver transaminases in a subset of participants treated with lotiglipron, with attempts to identify the at‐risk population unsuccessful and therefore clinical development of lotiglipron terminated.NCT05579977. [ABSTRACT FROM AUTHOR]

Background: Slow transit constipation (STC) is highly prevalent and has rising incidence. Shouhui Tongbian capsule (SHTB) is a traditional Chinese Medicine formula with extensive and highly efficacious usage in STC treatment, however, its mechanism of action, especially the regulation of microbiome and lipid metabolites, remains unclear. Methods: After quality control of SHTB using LC‒MS to obtain its material basis, we tried to elucidate the cohesive modulatory network of SHTB against STC using hyphenated methods from microbiomics, lipidomics, mass spectrometry imaging (MSI) and molecular methods. Results: SHTB could repair intestinal barrier damage, reduce systemic inflammation and increase intestinal motility in a diphenoxylate-induced STC rat model. Based on 16S rDNA sequencing results, SHTB rehabilitated the abnormal changes in Alloprevotella, Coprococcus, Marvinbryantia, etc., which were associated with STC symptoms. Meanwhile, microbial functional prediction showed that lipid metabolism was improved with SHTB administration. The differential lipids, including fatty acids, lysophosphatidylcholine, phosphatidylcholine, sphingomyelin triglyceride and ceramide, that are closely related to STC disease and SHTB efficacy. Furthermore, SHTB significantly reversed the abnormal expression of these key target enzymes in colon samples, including CTP-phosphocholine cytidylyltransferase, CTP-phosphoethanolamine cytidylyltransferase, phosphatidic acid phosphatase, acid sphingomyelinase etc. Conclusions: Combined analysis demonstrated that SHTB reducing lipid accumulation and recovery of intestinal microbial homeostasis was the critical mechanism by which SHTB treats STC. [ABSTRACT FROM AUTHOR]

Background: Astragali radix (AR) is one of the most widely used traditional Chinese herbal medicines. It exhibits diverse biological activities, including immunomodulatory and anti-inflammatory properties; however, some of its activities have only been demonstrated in vitro. Objective: To examine the effects of orally administered AR extract on immune cells and the intestine under physiological conditions, which bridges the gap between previously observed in vitro outcomes and in vivo results. Methods: AR extract was prepared by hot water extraction. Three separate animal experiments were conducted to isolate macrophages, splenocytes, and the small intestine epithelium. For the macrophage preparation experiment, an intraperitoneal injection of sterile thioglycolate was administered. The mice received oral AR extract at doses of 0.1, 0.5, or 2.5 g/kg for ten days. At the end of each experiment, cells or tissues were isolated. A portion of macrophages and splenocytes were analyzed for the phenotypic changes. The remaining cells were cultured and stimulated with lipopolysaccharide (LPS) or mitogen ex vivo to assess activation status, proliferation, and cytokine production. Samples of the intestine were subjected to real-time RT-PCR. Results: Peritoneal macrophages from AR-treated mice exhibited increased expression of scavenger receptors, including SRA and CD36. Stimulation of these macrophages ex vivo with LPS selectively modulated the inflammatory response, including reduced expression of the costimulatory molecules CD40 and CD86, which are important for T cell responses, without affecting TNF-α and IL-6 production. Splenocytes from AR-treated mice exhibited a dose-dependent increase in CD4 and CD8 T cells; however, stimulation with mitogen decreased T cell proliferation and reduced IFN-γ production, which is essential for macrophage activation. An analysis of the small intestinal epithelium revealed an attenuated antimicrobial response, including reduced IgA content in the lumen and decreased expression of mucin-2 and polymeric Ig receptor genes. Conclusion: The response of immune cells following oral treatment with AR extract did not replicate the previously documented in vitro findings. Immune cells and intestinal epithelium from mice administered oral AR extract exhibited a selective anti-inflammatory phenotype. The overall findings indicate that the systemic effects after oral administration of AR extract include reduced sensitivity to inflammatory insults. [ABSTRACT FROM AUTHOR]

Background: This study aims to investigate the short-term effects and safety of adjunct Suxiao Jiuxin Pills (SJPs) on conventional therapy in chronic coronary syndrome (CCS) patients who are intolerant to the adverse effects of long-acting nitrates. Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial. A total of 174 CCS participants from eight clinical study centers in China were included in the modified intention-to-treat analyses. Participants with CCS and intolerance to the adverse effects of long-acting nitrates were recruited and randomized to either the SJPs or the placebo group for a duration of 4 weeks. Results: Compared to the placebo group, the SJPs group showed a significant improvement in the efficacy rate after 4 weeks (OR = 2.43, 95% CI = 1.32 to 4.47, P = 0.004). Besides, individuals without a history of alcohol consumption showed a greater improvement in the SAQ summary score compared to those with a history of alcohol consumption. Conclusion: Adjunctive SJPs enhance the effectiveness of short-term conventional anti-angina treatment for patients with CCS who experience intolerance to long-acting nitrates, without significant adverse effects during application. Trial registration: Chinese Clinical Trials Registry Platform, ChiCTR2100050066. Registered 16 August 2021, https://www.chictr.org.cn/showproj.html?proj=131470. [ABSTRACT FROM AUTHOR]

Objectives: To determine the impact of intravenous Dexmedetomidine (Dex) administered perioperatively on stress response markers in patients undergoing ENT surgeries. Methods: This randomized interventional study was conducted at POFs Hospital and NUMS affiliated WMC, Wah Cantt, in collaboration with IIMC Rawalpindi, Pakistan, from October 2021 to April 2022. One hundred patients aged between 15-60 years, after satisfying the inclusion standards were randomly divided into two groups C and D. Group-C (n=50) received normal saline in addition to the standard anesthesia protocol. The intervention Group-D (n=50) was administered 1μg/kg dexmedetomidine hydrochloride intravenously over 10 minutes just before the induction followed 0.5μg/kg/hr as maintenance dose till the end of surgery. Serum inflammatory biomarkers (interleukins-6, TNF-α and cortisol) were measured in blood samples in both groups, taken at 0 (T0), 30 minutes(T1), and two hours (T2) time intervals and analyzed by using Enzyme-linked immunosorbent assay (ELISA). Data was statistically analyzed using SPSS 23. Results: The patients receiving Dex showed marked decrease in serum levels of cortisol, TNF-α and interleukins-6, from 139.73 to10.18, 99.51 to 0.96 and 85.09 to 0.96 respectively. Comparison between C and D groups revealed significant differences (p≤0.05) in these serum biomarkers. Conclusions: In the present study, intravenous Dex suppressed the intraoperative rise in levels of cytokine secretion and enhanced smooth recovery with no incidence of nausea and vomiting. These effects could be attributed to the anti-inflammatory effects of dexmedetomidine. [ABSTRACT FROM AUTHOR]

This article explores the emerging field of nanomedicine as a drug delivery system, aimed at enhancing the therapeutic efficacy of active pharmaceutical ingredients in medicinal plants. The traditional methods of applying medicinal plants present several limitations, such as low bioavailability, poor solubility, challenges in accurately controlling drug dosage, and inadequate targeting. Nanoformulations represent an innovative approach in drug preparation that employs nanotechnology to produce nanoscale particles or carriers, which are designed to overcome these limitations. Nanoformulations offer distinct advantages, significantly enhancing the solubility and bioavailability of drugs, particularly for the poorly soluble components of medicinal plants. These formulations effectively enhance solubility, thereby facilitating better absorption and utilization by the human body, which in turn improves drug efficacy. Furthermore, nanomedicine enables targeted drug delivery, ensuring precise administration to the lesion site and minimizing side effects on healthy tissues. Additionally, nanoformulations can regulate drug release rates, extend the duration of therapeutic action, and enhance the stability of treatment effects. However, nanoformulations present certain limitations and potential risks; their stability and safety require further investigation, particularly regarding the potential toxicity with long-term use. Nevertheless, nanomaterials demonstrate substantial potential in augmenting the efficacy of active pharmaceutical ingredients in medicinal plants, offering novel approaches and methodologies for their development and application. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are natural carriers of biomolecules that play a crucial role in cell-to-cell communication and tissue homeostasis under normal and pathological conditions, including inflammatory diseases and cancer. Since the discovery of the pro-regenerative and immune-modulating properties of EVs, EV-based therapeutics have entered clinical trials for conditions such as myocardial infarction and autoimmune diseases, among others. Due to their unique advantages—such as superior bioavailability, substantial packaging capacity, and the ability to traverse biological barriers—EVs are regarded as a promising platform for targeted drug delivery. However, achieving a sufficient accumulation of therapeutic agents at the target site necessitates a larger quantity of EVs per dose compared to using EVs as standalone drugs. This challenge can be addressed by administering larger doses of EVs, increasing the drug dosage per administration, or enhancing the selective accumulation of EVs at target cells. In this review, we will discuss methods to improve the isolation and purification of EVs, approaches to enhance cargo packaging—including proteins, RNAs, and small-molecule drugs—and technologies for displaying targeting ligands on the surface of EVs to facilitate improved targeting. Ultimately, this guide can be applied to the development of novel classes of EV-based therapeutics and to overcoming existing technological challenges. [ABSTRACT FROM AUTHOR]

OBJECTIVES: American Indian and Alaska Native (AI/AN) infants historically experienced a disproportionate burden of invasive Haemophilus influenzae type b (Hib) disease, especially early in life. PedvaxHIB vaccine is preferentially recommended for AI/AN infants because it elicits protective antibody levels postdose 1. Vaxelis, a hexavalent vaccine that contains the same Hib conjugate as PedvaxHIB but at lower concentration, is recommended for US children, but postdose 1 Hib immunogenicity data are needed to inform whether a preferential recommendation should be made for AI/AN infants. METHODS: We conducted a phase IV randomized, open-label, noninferiority trial comparing postdose 1 immunogenicity of Vaxelis to PedvaxHIB in AI/AN infants. Participants were randomized to receive a primary series of PedvaxHIB or Vaxelis. Serum samples collected 30 days postdose 1 were tested for anti-Hib immunoglobulin G antibody by enzyme-linked immunosorbent assay. The anti-Hib immunoglobulin G geometric mean concentration (GMC) ratio (Vaxelis/PedvaxHIB) was estimated by constrained longitudinal data analysis. Noninferiority was defined a priori as the lower bound of the 95% confidence interval (CI) of the GMC ratio ≥0.67. RESULTS: A total of 327 of the 333 infants enrolled in the study were included in the per-protocol analysis. The postdose 1 anti-Hib GMC was 0.41 µg/mL (95% CI 0.33-0.52) in the Vaxelis group (n = 152) and 0.39 µg/mL (95% CI 0.31-0.50) in the PedvaxHIB group (n = 146). The constrained longitudinal data analysis GMC ratio was 1.03 (95% CI 0.76-1.39). CONCLUSIONS: Postdose 1 immunogenicity of Vaxelis was noninferior to PedvaxHIB. Our findings support the use of Vaxelis in AI/AN children, a population with elevated risk of Hib disease. [ABSTRACT FROM AUTHOR]

Clinical outcomes after a first-episode of psychosis (FEP) are heterogeneous. Many patient-related factors such as gender and comorbidity have been studied to predict symptomatic outcomes. However, psychiatrist-related factors such as prescription behaviour and gender have received little attention. We assessed the relationship between patients' psychiatrists, psychosis severity and daily functioning in 201 patients remitted from an FEP for a duration of one year, treated by 18 different psychiatrists. We controlled for baseline severity, dose and type of antipsychotic medication, frequency of visits, and patients' education. Symptom severity, daily functioning, and antipsychotic drug use were assessed at baseline and at 3, 6, and, 12 months follow-up. We found that psychiatrists accounted for 9.1% of the explained variance in patients' symptom severity and 10.1% of the explained variance in daily functioning.These effects persisted even when controlling for factors such as baseline severity and the prescribed dose. The effect of prescribed dose on symptom severity and daily functioning differed between psychiatrists. Treatment centre, session frequency, and medication nonadherence were not related to symptom severity. Our results emphasize the importance of individual psychiatrist factors in symptomatic outcomes after an FEP. Further identification of psychiatrist-related factors such as the quality of therapeutic alliances and shared decision-making, may optimize psychiatrists' training with the goal of improving patient outcomes. [ABSTRACT FROM AUTHOR]

To present the final results of a phase I trial on stereotactic radiosurgery (SRS) delivered using volumetric modulated arc therapy (VMAT) in patients with primary or metastatic tumors in different extracranial sites. The DESTROY-2 trial, planned as a prospective dose escalation study in oligometastatic (one to five lesions) cancer patients relied on the delivery of a single high dose of radiation utilizing high-precision technology. The primary study endpoint was the definition of the maximum tolerated dose (MTD) of SRS-VMAT. The secondary objectives of the study were the evaluation of safety, efficacy, and long-term outcomes. All patients consecutively observed at our radiotherapy unit matching the inclusion criteria were enrolled. Each enrolled subject was included in a different phase I study arm, depending on the tumor site and the disease stage (lung, liver, bone, other), and sequentially assigned to a particular dose level. Two hundred twenty seven lesions in 164 consecutive patients (male/female: 97/67, median age: 68 years; range: 29–92) were treated. The main primary tumors were: prostate cancer (60 patients), colorectal cancer (47 patients), and breast cancer (39 patients). The maximum planned dose level was achieved in all study arms, and the MTD was not exceeded. 34 Gy, 32 Gy, 24 Gy, and 24 Gy were established as the single-fraction doses for treating lung, liver, bone, and other extracranial lesions, respectively. The prescribed BED 2Gy α/β:10 to the planning target volume ranged from 26.4 Gy to 149.6 Gy. Twenty-seven patients (16.5%) experienced grade 1–2 and only one grade 3 acute toxicity, which was a pulmonary one. In terms of late toxicity, we registered only 5 toxicity>G2: a G3 gastro-intestinal one, three G3 bone toxicity, and a G3 laryngeal toxicity. The overall response was available for 199 lesions: 107 complete response (53.8%), 50 partial response (25.1%), and 31 stable disease (15.6%), leading to an overall response rate of 94.5%. Progression was registered only in 11 cases (5.5%). The overall response rate in each arm ranged from 88.6% to 96.4%. The overall two-year local control, distant metastasis free survival, disease free survival, and overall survival were 81.7%, 33.0%, 25.4%, and 78.7% respectively. In conclusion, the planned doses of 34 Gy, 32 Gy, 24 Gy, and 24 Gy were successfully administered as single-fractions for the treatment of lung, liver, bone, and other extracranial lesions, respectively, in a prospective SRS dose-escalation trial. No dose-limiting toxicities were registered, and minimal acute and late toxicity were reported. New indications for SRS are currently being studied in oligoprogressive patients receiving targeted drugs or in combination with immunotherapy. The DESTROY-2 trial represents, in our opinion, a credible starting point for future modern radiosurgery trials. • One of the few prospective SRS studies exploring MTD across different clinical settings. • 34 Gy, 32 Gy, and 24 Gy single fraction were safely delivered to lung, liver, bone. • The highest dose level was reached in all the settings, not exceeding the MTD. • The toxicity profile was low with one acute and five late toxicities >G2. • High LC rates and encouraging long-term outcomes were observed. [ABSTRACT FROM AUTHOR]

Background and Purpose: The aim was to investigate whether neurofilament light chain (NfL) and profilin‐1 (PFN‐1) might qualify as surrogate disease and treatment‐response biomarkers by correlating their concentrations dynamic with clinical status in a cohort of 30 adult spinal muscular atrophy type 3 patients during nusinersen therapy up to 34 months. Methods: Neurofilament light chain was measured in cerebrospinal fluid at each drug administration with a commercial enzyme‐linked immunosorbent assay (ELISA); PFN‐1 concentrations were tested in serum sampled at the same time points with commercial ELISA assays. Functional motor scores were evaluated at baseline, at the end of the loading phase and at each maintenance dose and correlated to biomarker levels. The concurrent effect of age and clinical phenotype was studied. Results: Neurofilament light chain levels were included in the reference ranges at baseline; a significant increase was measured during loading phase until 1 month. PFN‐1 was higher at baseline than in controls and then decreased during therapy until reaching control levels. Age had an effect on NfL but not on PFN‐1. NfL was partially correlated to functional scores at baseline and at last time point, whilst no correlation was found for PFN‐1. Conclusion: Cerebrospinal fluid NfL levels did not qualify as an optimal surrogate treatment biomarker in adult spinal muscular atrophy patients with a long disease duration, whilst PFN‐1 might to a greater extent represent lower motor neuron pathological processes. The observed biomarker level variation during the first 2 months of nusinersen treatment might suggest a limited effect on axonal remodeling or rearrangement. [ABSTRACT FROM AUTHOR]

Purpose: Combined spinal-epidural analgesia (CSEA) is effective but not sufficient for labor pain. This study was conducted to assess the real-time analgesic efficacy, side effects of anesthetic drug dosage, and maternal satisfaction in labor to provide reference for the optimization of labor analgesia. Methods: This was a prospective, cohort, single-center study that included 3020 women who received CSEA for labor analgesia. The visual analogue scale (VAS) for labor pain, real-time anesthetic drug dosage, side effects, adverse labor outcomes, factors influencing average drug dosage, and maternal satisfaction with CSEA were assessed. Results: Overall, the VAS labor pain score was lowest at the first hour after the anesthesia was given. After 4 h for primiparas and 3 h for multiparas, the VAS score was greater than 3 but the anesthetic drug dosage did not reach the maximum allowed dosage at the same time. The average anesthetic drug dosage was positively correlated with fever, urinary retention, uterine atony, prolonged active phase, prolonged second stage, assisted vaginal delivery, and postpartum hemorrhage. The average anesthetic drug dosage was the highest in women ≤ 20 years old, those with a body mass index (BMI) ≥ 24.9 kg/m2, and those with a primary or secondary education level. Conclusion: Appropriate age guidance and emphasis on education of labor analgesia, weight management during pregnancy, and real-time anesthetic dosage adjustment during labor based on VAS pain score may have positive effects on the satisfaction of labor analgesia. Clinical trial number and registry: Clinicaltrials.gov (ChiCTR2100051809). [ABSTRACT FROM AUTHOR]

We aimed to investigate the factors associated with vitamin D deficiency and changes in 25 (OH)D levels, as well as the impact of those changes on disease activity and renal function among SLE patients. This retrospective cohort study was based on the medical records of SLE patients hospitalized between 2010 and 2021. We collected relevant information from this patient population. Logistic regression analysis was employed to determine the factors associated with vitamin D deficiency and increased 25 (OH)D levels, and we calculated the odds ratios (ORs) and 95% confidence intervals (CIs) accordingly. At baseline, among the 1257 SLE patients, the median and interquartile range of 25 (OH)D levels were 14 (9, 20) ng/ml, with 953 (75.8%) patients exhibiting 25 (OH)D deficiency (< 20 ng/ml). The presence of 25 (OH)D deficiency was found to be associated with renal involvement and a high glucocorticoid (GC) maintenance dose. Among the 383 patients who were followed up for an average of 18 months, an increase of at least 100% in 25 (OH)D levels was positively associated with a decreased GC maintenance dose and vitamin D3 supplementation, with adjusted odds ratios(OR) (95% confidence interval [CI]) of 2.16 (1.02, 4.59) and 1300 (70, 22300), respectively. Furthermore, an increased level of 25 (OH)D was significantly associated with a decrease in the Disease Activity Index 2000 score and the urinary protein/creatinine ratio. Patients with SLE have low vitamin D levels, especially those with impaired kidney function. Increased 25 (OH)D levels can be achieved through supplementation with high doses of vitamin D3 and are associated with improvements in disease activity and the urinary protein/creatinine ratio. [ABSTRACT FROM AUTHOR]

Childhood cancer survivors, in particular those treated with radiation therapy, are at high risk of long-term iatrogenic events. The prediction of risk of such events is mainly based on the knowledge of the radiation dose received to healthy organs and tissues during treatment of childhood cancer diagnosed decades ago. We aimed to set up a standardized organ dose table to help former patients and clinicians in charge of long-term follow-up clinics. We performed whole body dosimetric reconstruction for 2646 patients from 12 European countries treated between 1941 and 2006 (median, 1976). Most plannings were 2- or 3-dimensional. A total of 46% of patients were treated using Cobalt 60, and 41%, using a linear accelerator. The median prescribed dose was 27.2 Gy (IQ1-IQ3, 17.6-40.0 Gy). A patient-specific voxel-based anthropomorphic phantom with more than 200 anatomic structures or substructures delineated as a surrogate of each subject's anatomy was used. The radiation therapy was simulated with a treatment planning system based on available treatment information. The radiation dose received by any organ of the body was estimated by extending the treatment planning system dose calculation to the whole body, by type and localization of childhood cancer. The integral dose and normal tissue doses to most of the 23 considered organs increased between the 1950s and 1970s and decreased or plateaued thereafter. Whatever the organ considered, the type of childhood cancer explained most of the variability in organ dose. The country of treatment explained only a small part of the variability. The detailed dose estimates provide very useful information for former patients or clinicians who have only limited knowledge about radiation therapy protocols or techniques, but who know the type and site of childhood cancer, sex, age, and year of treatment. This will allow better prediction of the long-term risk of iatrogenic events and better referral to long-term follow-up clinics. [ABSTRACT FROM AUTHOR]

Postoperative adjuvant chemotherapy could improve the life quality of patients with breast cancer but also bring side effects and cause adverse reactions. Yiqi Yangyin decoction has been reported to possess anti-cancer activity and has been employed in the postoperative treatment of various cancers. A total of 128 patients with breast cancer who received surgical therapy were enrolled in this study and were randomly grouped as the control and the test group to receive different therapies. Patients in the control group received single chemotherapy of fluorouracil and hydrochloride, while the therapy of the test group patients supplemented Yiqi Yangyin decoction based on the control group. Both two therapeutic strategies improved life quality and TCM syndrome scores of enrolled patients, and the supplement of Yiqi Yangyin decoction significantly improved the therapeutic effect. Adverse reactions including nausea, vomiting, thrombocytopenia, diarrhea, leukopenia, and hemoglobinia occurred in both two groups, but the application of Yiqi Yangyin decoction significantly alleviated adverse reactions. Additionally, patients in the test group showed a better 1-year disease-free survival. The combination of adjuvant chemotherapy with Yiqi Yangyin decoction could improve postoperative life quality, improve therapeutic efficacy, and reduce adverse reactions in patients with breast cancer. [ABSTRACT FROM AUTHOR]

To enhance the anesthetic efficacy and reduce toxic side effects, a strategy is proposed involving the utilization of general anesthetics of Propofol (Pro) and Etomidate (Eto) to synergistic inhibition GABA receptors simultaneously. Four‐in‐one molecular aggregates were prepared to implement this strategy, which comprised of Pro and Eto with the bridging molecule monoglyceride monooleate (GMO) and surfactant F127 through intermolecular forces. The blood‐brain barrier (BBB) targeted lactoferrin (LF) is affixed to their surface, obtaining the final molecular aggregates. By employing lactoferrin enrich aggregates to the BBB, followed by ultrasound combine microbubbles to open the BBB, a remarkable 4.5‐fold enhancement in brain drug delivery was achieved. The molecular aggregates group maintained stable parameters of heart rate, diastolic blood pressure, and systolic blood pressure. A notable increase of more than twice therapeutic index (TI) value was observed, implying their higher anesthesia efficiency and reduced toxicity. Electroencephalogram (EEG) experiments demonstrate a significant elevation in the proportion of δ waves from 28% to 80% for aggregates, accompanied by a nearly fivefold reduction in the proportion of θ waves, meaning a significant improvement in synergistic anesthesia effectiveness (interaction index 0.289) with lower drug dosage. Furthermore, mouse immunofluorescence brain slice experiments suggest Pro and Eto enter the GABA receptor simultaneously, resulting in synergistic inhibition of GABA receptors. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study is to determine the effect of forcing and filling the electron density (ED) to 1.0 of the planning target volume (PTV) overdose distribution in lung SBRT treatment leading to shortening patient treatment time and increasing patient comfort by reducing MU/fraction due to ED manipulation effect. Methods: In this study, 36 lung SBRT plans of 12 suitable patients who prescribed a total dose of 50 Gy in five fractions were generated with Monaco v.5.10 TPS using the Monte Carlo (MC) algorithm and volumetric modulated arc therapy (VMAT) technique by PTV ED values forcing as well as filling to 1.0 and comparatively assessed. The first group of plans was created by using the patient's original ED, second and third groups of plans were reoptimized by forcing and filling the ED of PTV to 1.0, respectively, therefore acquiring a new dose distribution which lead to comparatively assessment the effects of changes in ED on PTV and OAR doses. Results: Assessment of treatment plans revealed that mean MU/fx numbers were decreased by 76% and 75.25% between Groups 1 and 2, Groups 1 and 3, respectively. The number of segments was also reduced in Group 1 by up to 15% compared with Groups 2 and 3. Maximum HI and CI differences for PTV between Groups 1 and 2 were less than 1% and Groups 1 and 3 were 1.5% which indicates all 3 group plans were comparable in terms of dose distribution within PTV. Conclusions: Forcing and filling the ED of PTV to 1.0 strategy has provided reduced a number of segments and MU/fx without a significant change in PTV mean and maximum doses, thereby decreasing treatment time and patient discomfort during treatment. This process should be considered in line of a potential number of patients as well as prescribed dose and MU/fx numbers. [ABSTRACT FROM AUTHOR]

Objectives: Dravet syndrome is a developmental and epileptic encephalopathy characterized by early onset epilepsy with multiple seizure types often intractable to treatment. Randomized clinical trials have demonstrated how treatment with fenfluramine significantly reduces seizure frequency in patients with Dravet syndrome. The study aims to (1) describe the efficacy and tolerability of fenfluramine in a Danish cohort of patients with Dravet syndrome; and (2) evaluate whether treatment with fenfluramine reduces epilepsy‐related hospital contacts administrated by pediatricians or epilepsy‐trained nurses. Methods: A retrospective registry‐based cohort study at the Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark, enrolled 30 pediatric patients with Dravet syndrome treated with fenfluramine between 2017 and 2023. Results: Thirty patients with Dravet syndrome (aged 3–21 years, 12 females) with a verified pathogenic SCN1A variant were included. They were treated with fenfluramine at a mean duration of 29 months with a mean maintenance dose of 0.5 mg/kg/day. The number of patient‐years on treatment was 75 years. At last follow‐up, 6 patients had discontinued treatment due to lack of efficacy or adverse effects. In the remaining 24 patients, generalized tonic–clonic seizures were reduced by ≥30% in 83%, by ≥50% in 67%, and by 100% in 25%. Additionally, 71% of the patients were reduced in concomitant anti‐seizure medication, and 75% experienced a reduction (mean reduction at 52%, range 11%–94%) in epilepsy‐related hospital contacts from baseline to the end of the treatment period. Significance: Treatment with fenfluramine effectively reduced seizure frequency and concomitant antiseizure medication in patients with Dravet syndrome. Furthermore, a decrease in epilepsy‐related contacts by 80% was observed over 6 years of treatment, which may indicate cost‐effective benefits. Plain Language Summary: Patients with Dravet syndrome suffer from severe epileptic seizures that are difficult to treat with medication. Earlier, treatment with fenfluramine (an anti‐seizure medication) has been documented to decrease the total number of seizures in patients with Dravet syndrome. This publication summarizes the experiences with fenfluramine in children with Dravet syndrome at the Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark. Our publication also illustrates that treatment with fenfluramine may reduce the patients' number of yearly contacts with doctors and nurses specialized in epilepsy treatment, which may indicate cost‐effectiveness. [ABSTRACT FROM AUTHOR]

Objective: Total cavo-pulmonary connection (TCPC) is a palliative treatment for single ventricular malformations. For high-risk patients (preoperative mean pulmonary arterial pressure, mPAP > 15 mmHg), between the inhaled and oral targeted medications, the application of intravenous treprostinil as a bridge therapy to achieve "seamless" management is core postoperative treatment. This study intends to explore the effect of different administration regimens on early postoperative recovery. Methods: This was a retrospective cohort study. High-risk pediatric patients (age ≤ 14 years) who underwent TCPC procedure in Fu Wai Hospital from 2015 to 2022 were included. Since the regimen of treprostinil was standardized in our center in 2021, the patients in 2020 and before were included in group 1, patients in 2021 and 2022 were included in group 2. The hemodynamic parameters were compared before and after the maintenance dose of treprostinil. The differences of demographic characteristics, surgical data and postoperative recovery were compared between the two groups. Results: A total of 51 pediatric patients were included. Group 1 included 35 patients who received treprostinil at 1–3 postoperative days and an average dose of 12 ± 4 ng/(kg·min). Group 2 included 16 patients who received treprostinil within postoperative 1 day and an average dose of 22 ± 7 ng/(kg·min). There were no significant differences between the two groups in terms of age, weight, preoperative percutaneous oxygen saturation and mPAP, heterotaxy syndrome, TCPC procedure type, other concurrent procedure, cardiopulmonary bypass time and aortic cross-clamp proportion (p > 0.05). After 24 h of treprostinil treatment, the mPAP in group 1 reduced from 17 ± 3 mmHg to 15 ± 2 mmHg (p < 0.001), and in group 2 from 17 ± 2 mmHg to 14 ± 2 mmHg (p < 0.001), with no difference between groups. In the postoperative recovery, patients in Group 2 exhibited a reduced duration of mechanical ventilation, 19 (11, 25) hours vs 69 (23, 189) hours, p = 0.001; a shorter stay in the ICU, 8 (6, 12) days vs 16 (9,26) days, p = 0.006; and a shorter postoperative length of stay, 27 (17,55) days vs 39 (29,58) days, p = 0.032. Patients in Group 2 also exhibited a lower incidence of thromboembolic events, 0 (0/26) vs 26% (9/35), p = 0.043; and the need for renal replacement therapy, 0 (0/26) vs 31% (11/35), p = 0.011. Conclusion: Treprostinil reduces pulmonary artery pressure after TCPC procedure. The standardized application of treprostinil may improve the postoperative recovery which should be proven by randomized controlled trials or matched cohort studies in the future. [ABSTRACT FROM AUTHOR]

Objective This study aimed to assess the beneficial effects of N-acetylcysteine (NAC) in the treatment of contrast-induced nephropathy (CIN). Materials and Methods A prospective study was conducted in the department of cardiology of a tertiary health care hospital. A sample of 100 patients who had developed CIN through coronary angioplasty were categorized into two groups: one group treated with intravenous fluids (IVF) monotherapy and the other group treated with the combination of IVF and NAC therapy. Statistical Analysis The data were analyzed using statistical software SPSS software version 26 and statistical significance was set at p < 0.05. Independent t -test and paired t -test were used to analyze the parameters. Results The rate of incidence of CIN was found to be 10%. We observed that the IVF + NAC combination therapy significantly decreases the serum creatinine compared to IVF monotherapy (p = 0.004). Both therapies show similar treatment outcomes with no significant difference (p = 0.556) in the case of estimated glomerular filtration rate (eGFR). Based on creatinine clearance, the results show adding NAC does not impact any additional benefits (p = 000). The duration of hospital stay of the NAC group was reduced significantly (p = 0.000). Conclusion At present, we found that the treatment outcomes which we analyzed based on factors such as serum creatinine, eGFR, and creatinine clearance, are too inconsistent to conclude the beneficial effect of NAC in the management of CIN. [ABSTRACT FROM AUTHOR]

Background: A dosimetric evaluation is still lacking in terms of clinical target volume (CTV) omission in stage III patients treated with 4D-CT Intensity-Modulated Radiation Therapy (IMRT). Methods: 49 stage III NSCLC patients received 4D-CT IMRT were reviewed. Target volumes and organs at risk (OARs) were re-delineated. Four IMRT plans were conducted retrospectively to deliver different prescribed dose (74 Gy–60 Gy), and with or without CTV implementation. Dose and volume histogram (DVH) parameters were collected and compared. Results: In the PTV-g 60 Gy plan (PTV-g refers to the PTV generated from the internal gross tumor volume), only 5 of 49 patients had the isodose ≥ 50 Gy line covering at least 95% of the PTV-c (PTV-c refers to the PTV generated from the internal CTV) volume. When the prescribed dose was elevated to 74 Gy to the PTV-g, 33 of 49 patients could have the isodose ≥ 50 Gy line covering at least 95% of the PTV-c volume. In terms of OARs protection, the SIB-IMRT plan showed the lowest value of V5, V20, and mean dose of lung, had the lowest V55 of esophagus, and the lowest estimated radiation doses to immune cells (EDIC). The V20, V30, and mean dose of heart was lower in the simultaneous integrated boost (SIB) IMRT (SIB-IMRT) plan than that of the PTV-c 60 Gy plan. Conclusions: CTV omission was not suitable for stage III patients when the prescribed dose to PTV-g was 60 Gy in the era of 4D-CT IMRT. CTV omission plus high dose to PTV-g (74 Gy for example) warranted further exploration. The SIB-IMRT plan had the best protection to normal tissue including lymphocytes, and might be the optimal choice. [ABSTRACT FROM AUTHOR]

Background: The presence of lymphovascular invasion (LVI) in cases with breast cancer is considered a bad prognostic sign. The purpose of this study is to compare the efficacy of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) versus unenhanced magnetic resonance imaging (UE-MRI + DBT) in predicting LVI in women with pathologically confirmed breast cancer. Methods: This prospective self-controlled study enrolled a total of 70 cases of pathologically proven breast cancer. All the patients underwent tomosynthesis, non-contrast, and post-contrast MRI. Depending on the broken halo sign seen in tomosynthesis, peritumoral edema, dark rim diffusion at diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) values evaluated in MRI. Results: The accuracy of LVI detection by tomosynthesis was 58%; unenhanced and enhanced MRI had the same results at 60%. The accuracy of detecting LVI was raised to 64% by combining the tomosynthesis results with unenhanced MRI. Conclusions: Tomosynthesis parameters are promising tools in detecting LVI in breast cancer with better diagnostic accuracy in combination with unenhanced MRI. [ABSTRACT FROM AUTHOR]

This randomized prospective clinical study aimed to compare the hemodynamic effects of propofol and alfaxalone for the induction of anesthesia in dogs. Thirty-one healthy dogs undergoing various procedures in a private referral center were premedicated with intramuscular acepromazine (0.015 mg/kg) and methadone (0.15 mg/kg). They then received 5 mg/kg of propofol over 30 s for induction, followed by a maintenance dose of 25 mg/kg/h (Group P), or 2 mg/kg of alfaxalone over 30 s for induction, followed by a continuous rate infusion of 10 mg/kg/h (Group A). Heart rate (HR), mean arterial pressure (MAP), and the velocity time integral (VTI) of the aortic blood flow using transthoracic echocardiography were measured before anesthetic induction and every 15 s for 180 s. Dogs not adequately anaesthetized for intubation were excluded from the hemodynamic evaluation. Events of hypotension (any MAP value lower than 60 mmHg) were also recorded. Statistical analyses utilized ANOVA for repeated measures, two-way repeated measures ANOVA, paired t-tests, or Wilcoxon signed rank-test as appropriate. Significance was set at p < 0.05. Two dogs in Group P (2/14) and 3 in Group A (3/17) were excluded from the study because the anesthesia plane was too light to allow intubation. Treatment P resulted in a significant decrease in MAP between 45 and 75 s during the induction period, with no significant variation in HR, VTI, and VTI*HR. In treatment A, HR increases between 60 and 105 s, VTI decreases at 150-180 s. Analysis between groups did not show any difference in MAP (p = 0.12), HR (p = 0.10), VTI (p = 0.22) and VTI*HR (p = 0.74). During induction, hypotension was detected in 3/12 (25%) dogs in Group P and 1/14 (8%) in Group A. In healthy premedicated dogs, propofol and alfaxalone induction produce similar hemodynamic variations. Propofol induction results in a short-term reduction in MAP, whereas alfaxalone induction preserves MAP and cardiac output by significantly increasing heart rate. [ABSTRACT FROM AUTHOR]

Background: Pharmacogenetics/pharmacogenomics (PGx) focuses on the genetic variation that causes the heterogeneity of pharmacokinetics and drug response among individuals and has the potential to predict individual efficacy and/or side effects. This study aims to investigate and understand the implementation of genetic testing for the personalized medication (GTPM) in children's hospitals in Mainland China. Methods: A survey was conducted on 50 children's hospitals from 31 provinces, municipalities, and autonomous regions across Mainland China, and statistical analysis and recommendations were made. Results: Questionnaire response was rate of 76.0% (38/50). Data from 15 hospitals conducting GTPM were included in this study, but only 6 hospitals had offered PGx tests for no less than five drug-related genes, and only 5 hospitals had covered more than ten drugs, which was a small scale overall. 20.0% of the laboratories did not conduct internal quality control, and 33.3% did not participate in inter-laboratory quality assessment. 46.7% of the practitioners did not receive external training. The primary goal for GTPM was to optimize drug dosage in the 15 hospitals, while the main challenge for GTPM was the implementation cost. Conclusion: Although GTPM in pediatrics has made major progress in Mainland China in recent years, there were still various problems in terms of software, hardware configuration, personnel allocation, business scale, quality control, and result interpretation. This requires joint efforts of health administration, medical insurance departments, researchers, and hospitals to promote and improve GTPM. [ABSTRACT FROM AUTHOR]

Background: Gegen Qinlian Decoction (GQD) is a classical traditional Chinese medicine (TCM) formula primarily utilized for treating gut disorders. GQD showed therapeutic effects on several diseases in clinical and animal studies by targeting gut microbes. Our recent studies also found that GQD efficiently alleviated anxiety in methamphetamine-withdrawn mice via regulating gut microbiome and metabolism. Given that various studies have indicated the link between the gut microbiome and the development of depression, here we endeavor to explore whether GQD can manage depression disorders by targeting the gut microbiome. Methods and materials: The depression-like model was induced in rats through chronic unpredictable mild stress (CUMS) and the depression levels were determined using the sucrose preference test (SPT). To address the depression-like behavior in rats, oral administration of GQD was employed. The colon microbiome and metabolite patterns were determined by 16s rRNA sequencing and untargeted metabolomics, respectively. Results: We found 6 weeks of CUMS can induce depression-like behavior in rats and 4 weeks of GQD treatment can significantly alleviate the depression-like behavior. GQD treatment can also ameliorate the histological lesions in the colon of CUMS rats. Then, CUMS increased the abundance of gut microbes, while GQD treatment can restore it to a lower level. We further discovered that the abundances of 19 bacteria at the genus level were changed with CUMS treatment, among which the abundances of Ruminococcus, Lachnoclostridium, Pygmaiobacter, Bacteroides, Pseudomonas, and Pseudomonas Family_XIII_AD3011_group were stored by GQD treatment. Besides, we identified the levels of 36 colon metabolites were changed with CUMS treatment, among which the levels of Fasciculic acid B, Spermine, Fludrocortisone acetate, alpha-Ketoglutaric acid, 2-Oxoglutaric acid, N'-(benzoyloxy)-2-(2,2-dichlorocyclopropyl) ethanimidamide, N6-Succinyl Adenosine Oleanolic acid, KQH, Ergosta-5,7,9(11),22-Tetraen-3-beta-Ol, Gentisic acid, 4-Hydroxyretinoic Acid, FAHFA (3:0/16:0), Leucine-enkephalin and N-lactoyl-phenylalanine can be restored by GQD treatment. Conclusion: Our findings provide evidence supporting the therapeutic efficacy of GQD in alleviating depression-like behavior in CUMS rats, potentially being targeted on colon bacteria (especially the abundance of Ruminococcus and Bacteroides) and metabolites (especially the level of Oleanolic acid). [ABSTRACT FROM AUTHOR]

Objective. This study simulated the potential of gold nanoparticles (GNPs) to improve the effectiveness of radiation therapy in pancreatic cancer cases. The purpose of this study was to assess the impact of GNPs on tumor control probability (TCP) and normal tissue complication probability (NTCP) in pancreatic cancer cases undergoing radiation therapy. The work aimed to compare treatment plans generated with a novel 2.5 MV beam using GNPs to conventional 6 MV plans and evaluate the dose-volume histogram (DVH), TCP, and NTCP. Approach. Treatment planning for five pancreatic computed tomography (CT) images was performed using the open-source MATLAB-based treatment planning program matRad. MATLAB codes were developed to calculate the relative biological effectiveness (RBE) of GNPs and apply the corresponding dose and RBE values to each voxel. TCP and NTCP were calculated based on the applied RBE values. Main results. Adding GNPs to the 2.5 MV treatment plan resulted in a significant increase in TCP, from around 59% to 93.5%, indicating that the inclusion of GNPs improved the effectiveness of the radiation treatment. The range in NTCP without GNPs was relatively larger compared to that with GNPs. Significance. The results indicated that the addition of GNPs to a 2.5 MV plan can increase TCP while maintaining a relatively low NTCP value (<1%). The use of GNPs may also reduce NTCP values by decreasing the dose to normal tissues while maintaining the same prescribed dose to the tumor. Hence, the addition of GNPs can improve the balance between TCP and NTCP. [ABSTRACT FROM AUTHOR]

An important aspect of improving care for people with hemophilia B (HB) is developing optimal treatment strategies. Here we aimed to provide in-silico evidence, comparing the estimated optimal posology of factor IX (FIX) products to support the patient-physician decision-making process. A population pharmacokinetic (popPK) model-based assessment comparing the performance of FIX products (rFIX, rIX-FP, rFIXFc, N9-GP) was developed. PopPK analyses were used to determine a product's optimal posology to target predefined steady-state FIX activity trough levels in a hypothetical population of 10,000 people with severe HB. Model-derived optimal posologies were compared across several parameters including trough levels, proportion of patients per regimen and consumption, considering 64 hypothetical patient scenarios of different FIX trough level targets and ages. Results indicated a marked difference between FIX products estimated to achieve target trough levels, consumption and dosing frequencies. rIX-FP was associated with higher trough levels than rFIX and rFIXFc, at a lower weekly dose and administration frequency, across all age groups. N9-GP use in adolescents and adults was associated with lower consumption compared with rIX-FP. Insights from this study may be utilized by clinicians to inform decision-making, by considering the model-generated estimated optimal posologies alongside multiple clinical factors and patient preferences. [ABSTRACT FROM AUTHOR]

Introduction: Chemotherapy-induced nausea and vomiting (CINV) is one of the adverse events that most affects oncologic patients' quality of life. Carboplatin AUC ≥ 4 belongs to agents with high emetic risk (moderate risk in ASCO guidelines). We aimed to compare the effectiveness of netupitant/palonosetron and dexamethasone triple combination (TC) therapy versus ondansetron and dexamethasone double combination (DC) therapy as antiemetic prophylaxis in patients with carboplatin AUC ≥ 4. As a secondary endpoint, in TC group we evaluated the effectiveness of changing NEPA administration timing from 1 h to 15 min before chemotherapy. Methods: Open-label prospective study conducted in a tertiary-care hospital in patients receiving carboplatin AUC ≥ 4. CINV was evaluated using MASCC antiemetic tool, in acute (<24 h) and delayed phase (24–120 h). Results were analyzed using χ2 test. Results: Two-hundred four completed questionnaires (CQ) were analyzed (76 in DC and 128 in TC). The proportion of patients who remained emesis-free was superior for TC-treated group compared to DC, either in acute (99.2% vs 92.1%, p = 0.0115) and delayed phase (97.6% vs 90.7%, p = 0.043). Likewise, a higher proportion of TC-treated patients compared to DC remained nausea-free for the first 24 h after treatment (90.6% vs 71%, p = 0.0004) and between 24 and 120 h (82.3% vs 62.7%, p = 0.0025). The change of NEPA administration time showed similar effectiveness in terms of CINV control (81.6% vs 74.5%, p = 0.70). Conclusions: TC showed superiority in early and delayed CINV control in carboplatin AUC ≥ 4 regimens, with no significant differences among cancer types. Change in NEPA administration timing has beneficial implications; it allows NEPA to be administered at hospitals before chemotherapy session. [ABSTRACT FROM AUTHOR]

Purpose: The National Comprehensive Cancer Network guidelines state that the oxaliplatin dose of 85 mg/m2 used in various gastrointestinal cancer regimens may be infused over a rapid rate of 85 min instead of the standard time of 120 min. We evaluated the safety outcomes of rapid administration of oxaliplatin compared to standard infusion. Methods: We performed a retrospective, cohort study by chart review. Adult patients who received oxaliplatin as part of a FOLFOX, FOLFOXIRI, or FOLRINOX chemotherapy regimen from January 1, 2018, through June 30, 2021, were included. Primary outcomes were the incidence of hypersensitivity reaction (HSR) and treatment modification of oxaliplatin due to adverse drug events. Secondary outcomes included peripheral neuropathy (PN), myelosuppressive signs, and oxaliplatin-related emergency department visit and/or hospital admission. Results: A total of 178 patients were included (90 and 88 in the rapid-rate and standard-rate groups, respectively). Rapid-rate oxaliplatin was not associated with increased HSR or difference in toxicity requiring dose reduction, delayed dose, or slowed infusion rate, but was associated with increased rate of permanent discontinuation of oxaliplatin, 7.8% and 1.1% in the rapid-rate group and standard-rate groups, respectively (p = 0.032). Peripheral neuropathy occurred in 72.2% and 42% of patients in the rapid-rate group and standard-rate groups, respectively (relative risk for PN, 2.09; 95%, CI: 1.43–3.04; p <.001). There were no differences in any other adverse drug event measured. Conclusion: Rapid-rate oxaliplatin was associated with minimal treatment modifications; however, there was an increase in PN incidence. A faster rate of oxaliplatin administration may not be worth the increased risk of PN. [ABSTRACT FROM AUTHOR]

This document provides information on the impact of menopause on urogenital health in women, specifically focusing on symptoms such as vaginal dryness, pain with intercourse, incontinence, and vulvovaginal irritation. It highlights the importance of healthcare providers initiating discussions about these symptoms and conducting examinations to provide appropriate treatment. Various treatment options, including lubricants, vaginal estrogen products, and hormone therapy, are available to alleviate genitourinary symptoms. The document also emphasizes the need for proper vulval care and offers practical tips for women. Overall, it emphasizes the role of primary care physicians in addressing these symptoms with their patients. [Extracted from the article]

Background: Insomnia is more common as people age. Several common hypnotics used to treat insomnia often do not adequately alleviate sleep issues in older adults and may be associated with negative residual effects such as an increased risk of falls, cognitive impairment, automobile accidents, and lack of response to auditory stimuli. The objective of these analyses of three clinical studies was to investigate the efficacy and safety of the dual orexin-receptor antagonist lemborexant (LEM) in older adults. Methods: Study E2006-G000-304 (Study 304; NCT02783729) was a randomized, double-blind, placebo (PBO)-controlled, active-comparator trial where subjects with insomnia disorder received LEM 5 mg (LEM5), LEM 10 mg (LEM10), zolpidem tartrate extended-release 6.25 mg (ZOL), or PBO for 30 days. In crossover Study E2006-E044-106 (Study 106; NCT02583451), healthy subjects (good sleepers) received LEM 2.5 mg, LEM5, LEM10, or PBO for eight nights or zopiclone on days 1 and 8 (and PBO on days 2–7). In crossover Study E2006-A001-108 (Study 108; NCT03008447), healthy subjects received a single dose of LEM5, LEM10, PBO, or ZOL. Sleep assessments included polysomnography-based latency to persistent sleep (LPS), wake after sleep onset (WASO), WASO in the second half of the night (WASO2H), sleep efficiency, postural stability, middle-of-the-night and next-day cognitive performance, middle-of-the-night auditory awakening threshold and return-to-sleep latency, and driving performance. Results: Overall, 453 of 1006 (45%; Study 304), 24 of 48 (50%; Study 106), and 28 of 56 (50%; Study 108) subjects were aged ≥ 65 years. In Study 304, LEM decreased (improved) LPS, WASO, and WASO2H from baseline more than ZOL and PBO; subjects treated with LEM had greater increases in sleep efficiency (improved) than with ZOL or PBO. In both Studies 304 and 108, postural stability was not impaired at waketime in subjects who received LEM compared with PBO. At waketime, LEM did not impair memory compared with PBO. In Study 108, following middle-of-the-night awakening, LEM and ZOL did not affect subjects' ability to awaken to auditory stimuli; LEM did not affect tests of memory and attention. In Study 106, LEM did not impair next-day driving performance in healthy elderly compared with PBO. LEM was well tolerated in subjects aged ≥ 65 years. Conclusions: LEM provided benefits on sleep variables without next-morning residual effects in subjects aged ≥ 65 years, supporting LEM as a treatment option for older adults with insomnia. Trial Registration Numbers and Dates of Registration: Study 304: ClinicalTrials.gov identifier, NCT02783729, date of registration, 26 May 2016. Study 106: ClinicalTrials.gov identifier, NCT02583451, date of registration, 22 October 2015. Study 108: ClinicalTrials.gov identifier, NCT03008447, date of registration, 2 January 2017. Plain Language Summary: The prevalence of insomnia increases with age; however, some hypnotics used for treating insomnia do not adequately resolve sleep problems in older adults and may be associated with adverse residual effects. Specifically, some hypnotics pose safety concerns in this population of patients who are generally more vulnerable to treatment-related effects, including increasing the risk of falls, risks of cognitive impairment, automobile accidents, and unresponsiveness to auditory stimuli. Safer and more effective insomnia medications are needed to reduce sleep problems with improved side-effect profiles. This analysis of lemborexant clinical studies conducted in adult subjects at least 65 years old found the drug to be effective without impairing memory, attention or balance the following day compared with placebo. These subjects were normal sleepers (for age) or had insomnia disorder. Furthermore, lemborexant was not associated with impaired ability to drive the next morning or awaken to loud middle-of-the-night sounds. Lemborexant was well tolerated in these older adults, similar to findings for adults aged at least 18 years. These findings indicate that lemborexant may be an appropriate treatment option for insomnia in older adults. [ABSTRACT FROM AUTHOR]

BACKGROUND: Preterm birth is the major cause of perinatal mortality both in developed and developing countries. The prevalence of preterm birth is increasing every year and it is nearly more than 15 million preterm births worldwide according to WHO, approximately one million may die and many more may suffer from neurodevelopmental impairment. Antenatal MgSO4 can prevent neonatal seizures and neonatal deaths in preterms. Aims and Objective of the study: To evaluate the use of antenatal Mgso4 for neuroprotection of preterm infants. MATERIAL AND METHODS- This study was conducted in Department of Obstetrics and Gynecology in Sree Mookambika Institute Of Medical Sciences. A total of 20 pregnant women between 28-32 weeks gestation presenting to the emergency department with abdominal pain associated with cervical dilatation (cervical dilatation > 4cm) at risk of imminent preterm delivery(delivery definitely planned within 24 hours) were given Mgso4 4gm iv for about 20-30 min followed by maintenance dose of 1gm/hr for a period of 24 hrs before delivery or upto delivery and all the preterm neonates born to the 20 women were followed up for 2 years for neonatal seizures, deaths and gross motor dysfunction. RESULTS: Antenatal MGSO4 has better role when given at 28-32 weeks of gestation as only 2 neonates (10% of total preterms) born at 32-34 weeks gestation developed neonatal seizures. CONCLUSION: When antenatal MgSO4 administered at an appropriate dose with proper monitoring, there is no evidence of harm to the fetus, neonate or mother and it helps in neuroprotection of the preterms. [ABSTRACT FROM AUTHOR]

Background: Cisatracurium and rocuronium are non-depolarizing neuromuscular blockers with an intermediate duration of action and are used safely in short and intermediateduration surgical procedures in the pediatric population. Aims and Objectives: A prospective randomized study is to assess the efficacy of cisatracurium compared to rocuronium in terms of intubating conditions, clinical duration of action, hemodynamic parameters, and side effects in pediatric patients undergoing surgeries under general anesthesia. Materials and Methods: In this study, 50 patients aged 2-12 years with the American Society of Anesthesiologists grades I and II were randomly allocated into two groups: Group I received injection cisatracurium 0.15 mg/kg IV and Group II received injection rocuronium 0.6 mg/kg IV for intubation. Intubating conditions by Cooper et al., score, TOF count, hemodynamic parameters, signs of histamine release, and complications if any were noted. Results: According to the Cooper et al., score, intubating conditions were excellent in 100% of patients in Group II and 84% of patients in Group I, which was statistically significant. The time required for the first maintenance dose was shorter in Group II (14.04±2.95 min) compared to Group I (20.08±3.68 min). Hemodynamic parameters and demographic profiles were comparable between the two groups. No associated signs of histamine release or any other complications were noted in either group. Conclusion: We concluded that rocuronium 0.6 mg/kg provides better intubating conditions and a shorter duration of action compared to cisatracurium 0.15 mg/kg without any signs of histamine release in pediatric patients. [ABSTRACT FROM AUTHOR]

Background and objectives: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired treatable autoimmune disorder. Due to limited availability and affordability of IV immunoglobulins and therapeutic plasma exchange in Pakistan, oral immunosuppressive drugs (ISDs) are used despite limited role in literature. The study aimed to determine the response to ISDs in CIDP patients by assessing the frequency of remission, reduction of disability using a neuropathy related disability score called Inflammatory Neuropathy Cause and Treatment score (or INCAT score), as well as reduction in steroid maintenance dose. Methods: The retrospective observational study of six months duration (May to October, 2020) was carried out in Aga Khan University Hospital, Karachi, Pakistan. Medical record of all the patients with idiopathic CIDP taking oral ISDs in last five years was selected which included bio-data, clinical signs and symptoms, medication details, and INCAT scores. Descriptive statistics were described i.e. frequency, percentages, mean/standard deviation using Microsoft Excel v.2021. Results: Out of thirteen patients, Azathioprine was used in nine, Mycophenolate mofetil in two and Cyclosporine in two, with remission (INCAT score improvement ≥ 1) achieved in eight, one and zero patients respectively. Duration of ISDs ranged from three to twenty-four months (average 15.8 months). Patients with monoclonal paraproteinemia and prior exposure to ISDs had a poor response to the introduction of subsequent ISDs. Conclusion: The study describes preliminary experience of the potential role of relatively cheaper and more convenient oral ISDs (especially Azathioprine) as an alternative or sparing agent to first line agents for CIDP and sets the stage for larger scale studies and randomized controlled trials. [ABSTRACT FROM AUTHOR]

Objective To recommend precision dosing and improve therapeutic efficacy against invasive fungal disease, a physiologically based pharmacokinetic model (PBPK) of oral isavuconazole (ISA) was established and used to explore its disposition across populations in different physiological and pathological states. Methods Twenty-five pharmacokinetic (PK) studies of oral ISA were identified through a systematic search of PubMed. Concentration–time data were extracted using WebPlotDigitizer. Physiochemical parameters were obtained from published literature and DrugBank. Model development and simulation used the Simcyp population-based simulator, and visual predictive check and predictive error were used for the model evaluation. Probability of target attainment and the cumulative fraction of response analyses were performed for dose optimization. Results The developed PBPK model was successfully validated in different populations. Most predicted concentration–time points aligned with the observed data, with acceptable predictive errors for the critical parameters. We predicted the PK profiles and parameters of ISA in a population with severe hepatic impairment (HI), a population with obesity and paediatric patients aged 1 to less than 6 years old. The probability of target attainment and cumulative fraction of response analyses indicated that the population with severe HI should have half the maintenance dose. The population with obesity and population with severe HI should have a loading dose of 300 mg every 8 h for 2 days. For paediatric patients aged 1 to less than 6 years old, a weight-based dosing regimen (5.38 mg/kg) of ISA was suggested. Conclusion The predicted value aligns with observations, suggesting ISA's potential predictability in PK profiles for other populations. The recommended dosing regimens increase our understanding of the use of ISA in special populations. [ABSTRACT FROM AUTHOR]

Introduction: Critically ill patients undergoing extracorporeal membrane oxygenation (ECMO) exhibit unique pharmacokinetics. This study aimed to assess the achievement of vancomycin therapeutic targets in these patients. Methods: This retrospective cohort study included patients on ECMO treated with vancomycin between January 2010 and December 2018. Ninety patients were analyzed based on ECMO connection modality, baseline creatinine levels, estimated glomerular filtration rate (eGFR), renal replacement therapy (RRT) requirements, and vancomycin loading dose administration. Results: Twenty-three percent of the patients achieved the therapeutic range defined by baseline levels. No significant differences in meeting the therapeutic goal were found in multivariate analysis considering ECMO cannulation modality, initial creatinine level, initial eGFR, RRT requirement, or loading dose use. All trough levels between 15 and 20 mcg/mL achieved an estimated area under the curve/minimum inhibitory concentration (AUC/MIC) between 400 and 600, almost all trough levels over 10 mcg/mL predicted an AUC/MIC >400. Discussion: Achieving therapeutic plasma levels in these patients remains challenging, potentially due to factors such as individual pharmacokinetics and pathophysiology. A trough plasma level between 12 and 20 estimated the therapeutic AUC/MIC for all models, proposing a possible lower target, maintaining exposure, and potentially avoiding adverse effects. Despite being one of the largest cohorts of vancomycin use in ECMO patients studied, its retrospective nature and single-center focus limits its broad applicability. [ABSTRACT FROM AUTHOR]

We conducted a multi-institutional dosimetric audit between FLASH and conventional dose rate (CONV) electron irradiations by using an anatomically realistic 3-dimensional (3D) printed mouse phantom. A computed tomography (CT) scan of a live mouse was used to create a 3D model of bony anatomy, lungs, and soft tissue. A dual-nozzle 3D printer was used to print the mouse phantom using acrylonitrile butadiene styrene (∼1.02 g/cm3) and polylactic acid (∼1.24 g/cm3) simultaneously to simulate soft tissue and bone densities, respectively. The lungs were printed separately using lightweight polylactic acid (∼0.64 g/cm3). Hounsfield units (HU), densities, and print-to-print stability of the phantoms were assessed. Three institutions were each provided a phantom and each institution performed 2 replicates of irradiations at selected anatomic regions. The average dose difference between FLASH and CONV dose distributions and deviation from the prescribed dose were measured with radiochromic film. Compared with the reference CT scan, CT scans of the phantom demonstrated mass density differences of 0.10 g/cm3 for bone, 0.12 g/cm3 for lung, and 0.03 g/cm3 for soft tissue regions. Differences in HU between phantoms were <10 HU for soft tissue and bone, with lung showing the most variation (54 HU), but with minimal effect on dose distribution (<0.5%). Mean differences between FLASH and CONV decreased from the first to the second replicate (4.3%-1.2%), and differences from the prescribed dose decreased for both CONV (3.6%-2.5%) and FLASH (6.4%-2.7%). Total dose accuracy suggests consistent pulse dose and pulse number, although these were not specifically assessed. Positioning variability was observed, likely due to the absence of robust positioning aids or image guidance. This study marks the first dosimetric audit for FLASH using a nonhomogeneous phantom, challenging conventional calibration practices reliant on homogeneous phantoms. The comparison protocol offers a framework for credentialing multi-institutional studies in FLASH preclinical research to enhance reproducibility of biologic findings. [ABSTRACT FROM AUTHOR]

Antivirals with proven effectiveness against the Omicron SARS-CoV-2 variant are required for COVID-19 treatment in hospitalized patients, particularly those with severe underlying conditions. Ensitrelvir, a 3C-like protease inhibitor, received emergency approval in Japan in November 2022, based on evidence of rapid symptom resolution in non-hospitalized patients, but confirmation of its effectiveness in hospitalized patients is lacking. This retrospective chart review reports outcomes for all patients who received ensitrelvir whilst hospitalized with SARS-CoV-2 infection at Rinku General Medical Center, Japan (November 2022–April 2023). Thirty-two hospitalized patients received 5 days of ensitrelvir treatment (375 mg loading dose, 125 mg as maintenance dose). Patients' mean age was 73.5 years and most had mild COVID-19. Patients exhibited various underlying diseases, most commonly hypertension (78.1%) and chronic kidney disease (25.0%). Seven (21.9%) patients were on hemodialysis. The most common concomitant medications were antihypertensives (59.4%) and corticosteroids (31.3%); 2 (6.3%) patients were being treated with rituximab; 28 (87.5%) patients had viral persistence following pre-treatment by remdesivir. Following ensitrelvir treatment, viral clearance was recorded in 18 (56.3%) patients by Day 6 and 25 (78.1%) patients at final measurement. All patients experienced clinical improvement as assessed by the investigator at Day 5. No intensive care unit admissions or deaths due to COVID-19 occurred. No new safety signals were observed. In conclusion, positive virological outcomes were observed following ensitrelvir treatment, in hospitalized patients with SARS-CoV-2 in a real-world setting, including high-risk patients, who failed previous antiviral therapy. These results require confirmation in more extensive studies. UMIN000051300. [ABSTRACT FROM AUTHOR]

[Display omitted] • Hydrogel containing viologen-based hyperbranched polyamide amines with dual drug loading capacity. • Wearable Patch (Patch-DT) uses hydrogel as the drug-carrying cathode and magnesium flakes as the anode. • Patch-DT enables release of two drugs simultaneously, overcoming the limitations of monotherapy. • Visible drug monitoring through wearable Patch's electrochromic properties. Wearable drug delivery systems (DDS) have made significant advancements in the field of precision medicine, offering precise regulation of drug dosage, location, and timing. The performance qualities that wearable DDS has always strived for are simplicity, efficiency, and intelligence. This paper proposes a wearable dual-drug synergistic release patch. The patch is powered by a built-in magnesium battery and utilizes a hydrogel containing viologen-based hyperbranched polyamidoamine as both a cathode material and an integrated drug reservoir. This design allows for the simultaneous release of both dexamethasone and tannic acid, overcoming the limitations of monotherapy and ensuring effective synergy for on-demand therapy. In a mouse model with praziquimod-induced psoriasis, the patch demonstrated therapeutic efficacy at a low voltage. The inflammatory skin returned to normal after 5 days with the on-demand release of dual drugs. This work provides a promising treatment option considering its straightforward construction and the therapeutic advantages of dual-drug synergy. [ABSTRACT FROM AUTHOR]

To compare the effects of propofol, ketamine–propofol and isoflurane, at similar anesthetic depth, on cardiopulmonary variables in unpremedictated chickens. Prospective, randomized, crossover experimental trial. A total of 10 male Leghorn domestic chickens, aged 3 months and body mass 1.4–2.0 kg. Birds were randomly assigned to each of three anesthetic protocols, 7 days apart: intravenous propofol, intravenous ketamine–propofol or isoflurane. Anesthesia was induced (indicated by loss of righting reflex and tracheal intubation) and maintained with propofol (10 mg kg–1 minute–1, then 1.1 mg kg–1 minute–1), ketamine–propofol (5 mg mL–1 ketamine and 5 mg mL–1 propofol combined; 10 mg kg–1 minute–1, then 1.1 mg kg–1 minute–1) or isoflurane [5% vaporizer setting initially, then end-tidal concentration (F e ′Iso) of 2%] for 65 minutes. Anesthesia was maintained at a similar anesthetic depth based upon positive or negative responses to toe pinch. Heart rate (HR), respiratory rate (f R), noninvasive arterial blood pressure and arterial blood gases were measured during anesthesia. Propofol or ketamine–propofol infusion rates and F e′ Iso required to prevent movement in response to a noxious stimulus and recovery times were recorded. Anesthesia induction dose was 9.0 ± 0.8 (mean ± SD) and 12.2 ± 0.3 mg kg–1 for propofol and ketamine–propofol, respectively. Propofol and ketamine–propofol infusion rates and F e′ Iso required to prevent movement in response to the noxious stimulus were 0.88 ± 0.14 mg kg–1 minute–1, 0.92 ± 0.14 mg kg–1 minute–1 and 1.45 ± 0.28%, respectively. Cardiopulmonary variables remained clinically acceptable, but ketamine–propofol was associated with a significantly higher HR (p = 0.0001) and lower f R (p = 0.0001). Time to extubation did not differ among treatments. Cardiovascular and respiratory variables were maintained within normal ranges in all treatments. Coadministration of ketamine with propofol significantly reduced the induction and maintenance dose of propofol. [ABSTRACT FROM AUTHOR]

Neonates with critical congenital heart disease of the ductal-dependent pulmonary circulation type (CCHD-DDPC) require prostaglandin E1 (PGE1) to maintain oxygen saturation until surgery. However, the factors contributing to the maintenance doses of PGE1 remain unclear. This study aimed to determine the predictors of high maintenance PGE1 doses in these neonates. This retrospective cohort study included neonates with CCHD-DDPC at Songklanagarind Hospital between January 1, 2006, and December 31, 2021. Factors associated with high maintenance PGE1 doses (> 0.01 mcg/kg/min) were analyzed to identify predictors. Odds ratios were calculated using tabulation and logistic regression analysis. A prediction score was developed for high maintenance PGE1 doses. Among 96 neonates with CCHD-DDPC, 55 % required high maintenance doses of PGE1. Three factors significantly associated with high maintenance PGE1 doses were patent ductus arteriosus (PDA) size-to-birthweight ratio ≤1.3 mm/kg, initial PGE1 dose >0.03 mcg/kg/min, and preoperative invasive mechanical ventilation. The area under the receiver operating characteristic curve for these three predictors was 0.7409. A predictive score of 0–3 was created based on these factors. The probabilities of receiving a high maintenance dose of PGE1 for patients with overall scores of 0, 1, 2, and 3 were 0.19 (95 % CI: 0.04–0.33), 0.42 (95 % CI: 0.30–0.54), 0.69 (95 % CI: 0.57–0.81), and 0.87 (95 % CI: 0.76–0.99), respectively. In neonates with CCHD-DDPC, a PDA size-to-birth weight ratio ≤1.3 mm/kg, an initial dose of PGE1 > 0.03 mcg/kg/min, and preoperative invasive mechanical ventilation were predictors of high maintenance PGE1 doses during the preoperative period. [ABSTRACT FROM AUTHOR]

Background: Coincidence of the treatment and imaging isocenter coordinates is required to safely perform small‐margin treatments, such as stereotactic radiosurgery of multiple brain metastases. A comprehensive and direct methodology for verifying concordance of kilovoltage cone‐beam computed tomography (kV‐CBCT) and treatment coordinates using an x‐ray CT‐based polymer gel dosimeter (dGEL) and onboard kV‐CBCT was previously reported. Using this methodology, we tested the ability of a new commercially available x‐ray CT‐based polymer dGEL with a rapid response to provide efficient quality assurance (QA). Purpose: The aim of this study was to evaluate the robustness of the three‐dimensional geometric QA methodology using dGEL. Methods: The dGEL were commercially manufactured. The prescribed dose for each field was determined by visually identifying the 5, 10, and 20 Gy isodose lines. A linear accelerator was used to irradiate the gels with seven non‐coplanar beams. An in‐house analysis program was used to identify the beam axes and treatment isocenter in kV‐CBCT coordinates by processing the pre‐ and post‐irradiation CBCT images. The impact of the radiation dose on the test reproducibility was examined, and the detectability of an intentional geometric error was assessed. Results: The treatment isocenter was within 0.4 mm of the imaging isocenter for all radiation doses. The residual error of the test with the intentional error was within 0.2 mm. The analysis and image quality variations for a single dGEL introduced displacement errors less than 0.3 mm. Conclusions: The test assessed the coincidence of treatment and kV‐CBCT isocenter coordinates and detected errors with high robustness. Even for a 10 Gy dose, the test yielded results comparable with those obtained using higher radiation doses owing to the rapid response of the dGEL dosimeter. [ABSTRACT FROM AUTHOR]

Purpose: A higher minimum monitor unit (minMU) for pencil‐beam scanning proton beams in intensity‐modulated proton therapy is preferred for more efficient delivery. However, plan quality may be compromised when the minMU is too large. This study aimed to identify the optimal minMU (OminMU) to improve plan delivery efficiency while maintaining high plan quality. Methods: We utilized clinical plans including six anatomic sites (brain, head and neck, breast, lung, abdomen, and prostate) from 23 patients previously treated with the Varian ProBeam system. The minMU of each plan was increased from the current clinical minMU of 1.1 to 3–24 MU depending on the daily prescribed dose (DPD). The dosimetric parameters of the plans were evaluated for consistency against a 1.1‐minMU plan for target coverage as well as organs‐at‐risk dose sparing. DPD/minMU was defined as the ratio of DPD to minMU (cGy/MU) to find the OminMU by ensuring that dosimetric parameters did not differ by >1% compared to those of the 1.1‐minMU plan. Results: All plans up to 5 minMU showed no significant dose differences compared to the 1.1‐minMU plan. Plan qualities remained acceptable when DPD/minMU ≥35 cGy/MU. This suggests that the 35 cGy/MU criterion can be used as the OminMU, which implies that 5 MU is the OminMU for a conventional fraction dose of 180 cGy. Treatment times were decreased by an average of 32% (max 56%, min 7%) and by an average of 1.6 min when the minMU was increased from 1.1 to OminMU. Conclusion: A clinical guideline for OminMU has been established. The minMU can be increased by 1 MU for every 35 cGy of DPD without compromising plan quality for most cases analyzed in this study. Significant treatment time reduction of up to 56% was observed when the suggested OminMU is used. [ABSTRACT FROM AUTHOR]

Background: Neurosurgical cranial titanium mesh and screws are commonly encountered in postoperative radiation therapy. However, only a limited number of reports are available in the context of proton therapy, resulting in a lack of consensus among the proton centers regarding the protocol for handling the hardware. Purpose: This study is to examine the impact of the hardware in proton plans. The results serve as evidence for proton centers to generate standard operating procedures to manage the hardware in proton treatment. Methods: Plans with different gantry angles and material overrides are generated on the CT images of a phantom made of the hardware. The dose distributions of the plans with and without material override, at different depths are compared. Films and ionization chambers are used to measure the plans and the measurements are compared to the treatment planning system (TPS) calculations by gamma analysis. Results: There are some overdose and underdose regions downstream of the hardware. The overdose and underdose values are within a few percent of the prescribed dose when multiple fields with large hinge angles are used. The gamma analysis results show that the measurements agree with the TPS calculations within limits that are clinically relevant. Conclusion: The study has demonstrated the influence of the hardware on proton plans. Based on the result of this study, a standard operating procedure of managing the hardware has been implemented in our clinic. [ABSTRACT FROM AUTHOR]

Background: The population pharmacokinetics of nirmatrelvir/ritonavir (NIR/RIT) has not yet been described for critically ill adult patient. Purpose: This was a prospective observational population pharmacokinetic study of nirmatrelvir/ritonavir (NIR/RIT) in critically ill adult patients and identify optimal dosing regimens. Patients and Methods: The prescription of NIR/RIT is determined by the attending physician and ranges from 150mg/100mg to 300mg/100mg twice a day. Two to three serial blood samples were collected for each patient after the second doses. We developed and validated PK model for plasma NIR and plasma RIT. Monte Carlo dosing simulations were performed to assess target attainment. Results: We analyzed 89 plasma samples from 31 adult patients. The data were best described by a one-compartment model. Among the covariates tested on pharmacokinetic parameters, creatinine clearance (CrCL) and area under curve (AUC) of RIT had a significant effect on apparent clearance (CL/F) of NIR. Mean (SD) parameters estimates for the absorption rate constant (Ka), apparent distribution (V/F) and CL/F were 0.42 (0.10) h− 1. 36.5 (8.5) L, 3.6 (0.26) L/h, respectively. Dosing simulations showed that the target in vitro 90% effective concentration (EC90) was more likely to be achieved twice a day than once a day at the same daily dose of NIR. High CrCL, low AUC of RIT were associated with a reduced likelihood of NIR reaching the target EC90. Conclusion: Based on our dosing simulations, the initial dosage of NIR/RIT was 300mg/100mg twice a day in critically ill patients with CrCL> 45 mL/min; When CrCL in critically ill patients is between 15 and 45 mL/min, NIR/RIT is 150mg/100mg twice a day. The maintenance dose is adjusted according to CrCL and AUC of RIT, with the dosages varying between 75mg/100mg and 300mg/100mg. [ABSTRACT FROM AUTHOR]

Cucumber (Cucumis sativus L.) is the world's most widely consumed salad vegetable, and it is frequently treated with pesticides to prevent pest and disease outbreaks. Pesticide residues in food commodities impede trade and pose a major health risk. Prior to residue estimation, the QuEChERS approach was validated utilising criteria such as limit of detection, limit of quantitation, linearity, accuracy, and precision. The residues of carbendazim, cypermethrin, ethion, profenofos, quinalphos, and triazophos were examined using a Gas Chromatograph equipped with an Electron Capture Detector or a Flame Photometric Detector and a high-performance liquid chromatography coupled to a photo diode array. The initial deposits of carbendazim, cypermethrin, ethion, profenofos, quinalphos, and triazophos at the prescribed dose were 1.235, 0.407, 0.817, 0.960, 0.628, and 0.985 mg/kg, respectively, with a pre-harvest interval of 5.58–11.30 days. According to the consumer risk evaluation data, the Hazard Quotient is less than one, and the Theoretical Maximum Dietary Intake is less than the Maximum Permissible Intake and Maximum Residue Limit, both of which are considered safe for human consumption at the authorised dose. [ABSTRACT FROM AUTHOR]