Equivalent Dose Research Articles

Impact of corticosteroid doses on prognosis of severe and critical COVID-19 patients with Omicron variant infection: a propensity score matching study

BackgroundThere is lack of research on corticosteroid use for severe and critical COVID-19 patients with Omicron variant infection.MethodsThis multi-center retrospective cohort study involved 1167 patients from 59 ICUs across the mainland of China diagnosed with severe or critical SARS-CoV-2 Omicron variant infection between November 1, 2022, and February 11, 2023. Patients were segregated into two groups based on their corticosteroid treatment—usual dose (equivalent prednisone dose 30–50 mg/day) and higher dose (equivalent prednisone dose > 50 mg/day). The primary outcome was 28-day ICU mortality. Propensity score matching was used to compare outcomes between cohorts.ResultsAfter propensity score matching, 520 patients in the usual dose corticosteroid group and 260 patients in the higher dose corticosteroid group were included in the analysis, respectively. The mortality was significantly higher in the higher dose corticosteroid group (67.3%, 175/260) compared to the usual dose group (56.0%, 291/520). Logistic regression showed that higher doses of corticosteroids were significantly associated with increased mortality at 28-day (OR = 1.62,95% CI 1.19–2.21, p = 0.002) and mortality in ICU stay (OR = 1.66,95% CI 1.21–2.28, p = 0.002). Different types of corticosteroids did not affect the effect.ConclusionsThe study suggests that higher-dose corticosteroids may lead to a poorer prognosis for severe and critical COVID-19 patients with Omicron variant infection in the ICU. Further research is needed to determine the appropriate corticosteroid dosage for these patients.

Protocol for a randomised trial of a self-directed digital pain management intervention (Empowered Relief) tailored to adults with chronic pain and prescription opioid misuse/disorder: the MOBILE Relief study

IntroductionChronic pain increases the risk of prescription opioid misuse or opioid use disorder (OUD). Non-pharmacological treatments are needed to dually address pain and opioid risks. The purpose of the Mobile...

Dosimetric and radiobiological advantages from deep inspiration breath-hold and free breath technique for left-sided breast radiation using 3DCRT, IMRT and Rapid Arc methods-a complete assessment.

The verification and use of the best treatment approach using 3D conformal radiation therapy (3DCRT), intensity modulated radiation therapy (IMRT) and Rapid Arc methods for left breast radiation with dosimetric and radiobiological characteristics. The use of custom-built Python software for the estimation and comparison of volume, mean dose, maximum dose, monitor units and normal tissue integral dose along with radiobiological parameters such as NTCP, tumor control probability, equivalent uniform dose and LKB's effective volume from 3DCRT, IMRT and Rapid Arc planning with deep inspiration with breath holding (DIBH) and free breadth (FB) techniques. Volume growth of three-fourth in DIBH compared with FB causes a decrease in cardiac doses and complications because the left lung expands, pulling the heart away from the chest wall and the treatment area. A tiny area of the left lung was exposed during treatment, which reduced the mean dose. There was little difference in the treatment approaches because the spinal cord was immobile in both techniques. Rapid Arc is the unmatched modality for left-sided breast irradiation with significant patient breath-hold, as shown by the comparison of dosimetric and radiobiological parameters from treatment techniques with a deep inspiration breath-hold approach.

Cellulase-responsive hydroxypropyl cellulose-anchored hollow mesoporous silica carriers for pesticide delivery

In this study, a cellulase-responsive controlled-release formulation (FPR-HMS-HPC) was developed by grafting hydroxypropyl cellulose (HPC) onto fipronil (FPR) loaded hollow mesoporous silica (HMS) nanoparticles via ester linkage. The FPR-HMS-HPC formulation was characterized using scanning and transmission electron microscopies, Fourier transform infrared spectroscopy, and thermogravimetric analysis. The results indicated that FPR-HMS-HPC exhibited a high loading capacity of 10.0 % (w/w) and demonstrated favorable responsiveness to cellulase enzyme. Moreover, its insecticidal efficacy against Reticulitermes flaviceps surpassed that of an equivalent dose of FPR. Toxicology studies showed that the mortality and hatching rates of zebrafish exposed to FPR-HMS-HPC nanoparticles were reduced by >6.5 and 8.0 times, respectively. Thus, HPC-anchored HMS nanoparticles as insecticide delivery systems present a sustainable method for pest control significantly reducing harm to non-target organisms and the environment.

Drug Combination Nanoparticles Containing Gemcitabine and Paclitaxel Enable Orthotopic 4T1 Breast Tumor Regression.

Early diagnosis, intervention, and therapeutic advancements have extended the lives of breast cancer patients; however, even with molecularly targeted therapies, many patients eventually progress to metastatic cancer. Recent data suggest that residual breast cancer cells often reside in the lymphatic system before rapidly spreading through the bloodstream. To address this challenge, an effective drug combination composed of gemcitabine (G) and paclitaxel (T) is administered intravenously in sequence at the metastatic stage, but intravenous GT infusion may limit lymphatic GT drug accessibility and asynchronous drug exposure in cancer cells within the lymph. To determine whether co-localization of intracellular gemcitabine and paclitaxel (referred to as GT) could overcome these limitations and enhance the efficacy of GT, we have evaluated a previously reported GT drug-combination formulated in nanoparticle (referred to as GT-in-DcNP) evaluated in an orthotopic breast tumor model. Previously, with indocyanine green-labeled nanoparticles, we reported that GT-in-DcNP particles after subcutaneous dosing were taken up rapidly and preferentially into the lymph instead of blood vessels. The pharmacokinetic study showed enhanced co-localization of GT within the tumors and likely through lymphatic access, before drug apparency in the plasma leading to apparent long-acting plasma time-course. The mechanisms may be related to significantly greater inhibitions of tumor growth-by 100 to 140 times-in both sub-iliac and axillary regions compared to the equivalent dosing with free-and-soluble GT formulation. Furthermore, GT-in-DcNP exhibited dose-dependent effects with significant tumor regression. In contrast, even at the highest dose of free GT combination, only a modest tumor growth reduction was notable. Preliminary studies with MDA-231-HM human breast cancer in an orthotopic xenograft model indicated that GT-in-DcNP may be effective in suppressing human breast tumor growth. Taken together, the synchronized delivery of GT-in-DcNP to mammary tumors through the lymphatic system offers enhanced cellular retention and greater efficacy.

Population Pharmacokinetics of Naloxegol in Pediatric Subjects Receiving Opioids.

The pharmacokinetics (PK) of naloxegol were characterized in pediatric subjects, aged 6months or older to less than 18years who either have or are at risk of developing opioid-induced constipation following single dose administration. Subjects grouped as aged 12 years or older to less than 18years, 6 months or older to less than 12years, and 6months or older to less than 6years, received a single oral dose of naloxegol at doses that were estimated to achieve plasma exposures comparable to adult 12.5- or 25-mg doses. Intensive and sparse plasma naloxegol samples were collected to assess naloxegol concentrations. Data were combined with previously collected adult PK data and used to estimate PK parameters using population PK analyses. Naloxegol PK was described using a 2-compartment model with Weibull-type absorption. Neither age nor body weight was identified as a significant covariate indicating similar PK properties in adult and pediatric subjects. PK estimates in the youngest age group were approximately 80% less than those in adults (12.5-mg equivalent dose). Exposures in the other pediatric groups were similar to those in adult equivalent doses. The PK of naloxegol were characterized as linear over the dose range, with no clinically significant covariates and comparable PK characteristics in adults and pediatric subjects aged 6months or older.

Investigating the treatment shortening potential of a combination of bedaquiline, delamanid and moxifloxacin with and without sutezolid, in a murine tuberculosis model with confirmed drug exposures.

New and shorter regimens against multi-drug resistant tuberculosis (TB) remain urgently needed. To inform treatment duration in clinical trials, this study aimed to identify human pharmacokinetic equivalent doses, antimycobacterial and sterilizing activity of a novel regimen, containing bedaquiline, delamanid, moxifloxacin and sutezolid (BDMU), in the standard mouse model (BALB/c) of Mycobacterium tuberculosis (Mtb) infection. Treatment of mice with B25D0.6M200U200, B25D0.6M200, B25D0.6M200(U2003) or H10R10Z150E100 (isoniazid, rifampicin, pyrazinamide, ethambutol, HRZE), started 3 weeks after Mtb infection. Bactericidal activity was assessed after 1, 2, 3 and 4 months of treatment and relapse rates were assessed 3 months after completing treatment durations of 2, 3 and 4 months. B25D0.6M200U200 generated human equivalent exposures in uninfected BALB/c mice. After 1 month of treatment, a higher bactericidal activity was observed for the B25D0.6M200U200 and the B25D0.6M200 regimen compared to the standard H10R10Z150E100 regimen. Furthermore, 3 months of therapy with both BDM-based regimens resulted in negative lung cultures, whereas all H10R10Z150E100 treated mice were still culture positive. After 3 months of therapy 7% and 13% of mice relapsed receiving B25D0.6M200U200 and B25D0.6M200, respectively, compared to 40% for H10R10Z150E100 treatment showing an increased sterilizing activity of both BDM-based regimens. BDM-based regimens, with and without sutezolid, have a higher efficacy than the HRZE regimen in the BALB/c model of TB, with some improvement by adding sutezolid. By translating these results to TB patients, this novel BDMU regimen should be able to reduce treatment duration by 25% compared to HRZE therapy.

Kidney Blood Flow and Renin-Angiotensin-Aldosterone System Measurements Associated With Kidney and Cardiovascular Dysfunction in Pediatric Shock.

Pediatric acute kidney injury (AKI) is a prevalent and morbid complication of shock. Its pathogenesis and early identification remain elusive. We aim to determine whether renal blood flow (RBF) measurements by point-of-care ultrasound (POCUS) and renin-angiotensin-aldosterone system (RAAS) hormones in pediatric shock associate with vasoactive requirements and AKI. This is a single-center prospective, noninterventional observational cohort study in one tertiary PICU in North American from 2020 to 2022 that enrolled children younger than 18 years with shock without preexisting end-stage renal disease. RBF was measured by POCUS on hospital days 1 and 3 and plasma RAAS hormone levels were measured on day 1. The primary outcome was the presence of AKI by Kidney Disease Improving Global Outcomes criteria at first ultrasound with key secondary outcomes of creatinine, blood urea nitrogen (BUN), Vasoactive-Inotrope Score (VIS), and norepinephrine equivalent dosing (NED) 48 hours after first ultrasound. Fifty patients were recruited (20 with AKI, mean age 10.5 yr, 48% female). POCUS RBF showed lower qualitative blood flow (power Doppler ultrasound [PDU] score) and higher regional vascular resistance (renal resistive index [RRI]) in children with AKI (p = 0.017 and p = 0.0007). Renin and aldosterone levels were higher in the AKI cohort (p = 0.003 and p = 0.007). Admission RRI and PDU associated with higher day 3 VIS and NED after adjusting for age, day 1 VIS, and RAAS hormones. Admission renin associated with higher day 3 creatinine and BUN after adjusting for age, day 1 VIS, and the ultrasound parameters. In pediatric shock, kidney blood flow was abnormal and renin and aldosterone were elevated in those with AKI. Kidney blood flow abnormalities are independently associated with future cardiovascular dysfunction; renin elevations are independently associated with future kidney dysfunction. Kidney blood flow by POCUS may identify children who will have persistent as opposed to resolving AKI. RAAS perturbations may drive AKI in pediatric shock.

Utilizing Entropy of Cadence to Optimize Cycling Rehabilitation in Individuals With Parkinson’s Disease

Background Previous studies have established that increased Sample Entropy (SampEn) of cadence, a measure of non-linear variability, during dynamic cycling leads to greater improvements in motor function for individuals with Parkinson’s disease (PD). However, there is significant variability in responses among individuals with PD due to symptoms and disease progression. Objectives The aim of this study was to develop and test a paradigm for adapting a cycling exercise intervention using SampEn of cadence and rider effort to improve motor function. Methods Twenty-two participants were randomized into either patient-specific adaptive dynamic cycling (PSADC) or non-adaptive (NA) group. SampEn of cadence was calculated after each of the 12 sessions, and motor function was evaluated using the Kinesia test. Pearson’s correlation coefficient was used to analyze the relationship between SampEn of cadence and motor function improvement. Multiple linear regression (MLR) was used to identify the strongest predictors of motor function improvement. Results Pearson’s correlation coefficient revealed a significant correlation between SampEn of cadence and motor function improvements (R2 = −.545, P = .009), suggesting that higher SampEn of cadence led to greater motor function improvement. MLR demonstrated that SampEn of cadence was the strongest predictor of motor function improvement (β = −8.923, t = −2.632, P = .018) over the BMI, Levodopa equivalent daily dose, and effort. Conclusions The findings show that PSADC paradigm promoted a greater improvement in motor function than NA dynamic cycling. These data will be used to develop a predictive model to optimize motor function improvement after cycling in individuals with PD.

The reduction of LEDD leads to visual dysfunction in patients with PD after STN-DBS: a randomized clinical trial

Background: Medication adjustment after deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson’s disease (PD) may influence visual function. However, no clinical trials have been designed specifically to investigate this effect. Objectives: To compare the effects of levodopa equivalent daily dose (LEDD) reduction and non-reduction on visual function in patients with Parkinson’s disease (PD) following STN-DBS. Methods: This was a multi-center, prospective, randomized, double-blinded clinical trial. A total of 208 patients with Parkinson’s disease were referred for DBS between June 2019 and July 2021 and analyzed between June 2023 and July 2023. STN-DBS was performed, and the LEDD was reduced in one study arm but not in the other. The primary outcome measure was visual impairment in Parkinson’s disease questionnaire (VIPD-Q) with or without LEDD reduction 12 months postoperatively, and the secondary outcomes included retinal nerve fiber layer (RNFL) thickness, vessel density, eye-tracking system results, contrast sensitivity and visual field. Results: During the short-term follow-up, DBS implantation and stimulation did not significantly affect visual function (VIPD-Q, baseline vs. 1 month, 9.269±8.385 vs. 8.938±7.666, Mann–Whitney U tests; P=0.6746). In the long-term follow-up, the reduction group demonstrated a significant decline in visual function, RNFL thickness, and vessel density after STN-DBS compared with the control group without STN-DBS (P<0.001). Conclusions: Visual dysfunction, particularly a thinner RNFL and lower vessel density, is related to LEDD reduction after STN-DBS. Prolonged administration of dopamine-mimetic drugs prevents visual symptoms. Thus, physicians should consider LEDD adjustment when patients report visual dysfunction before surgery or severe visual symptoms after STN-DBS.

Probiotic Supplements For Depression In Parkinson’s Disease (Pro-Park): A Randomized, Triple-Blind, Placebo-Controlled, Phase IIb Trial Protocol

Introduction: Parkinson’s disease (PD) is the second most prevalent degenerative neurological disorder globally. Comorbid major depressive disorder (MDD) is a common occurrence which adds considerably to disease burden. This protocol presents a study designed to investigate the effect of add-on probiotic supplementation on MDD in patients with PD. Methods: We designed a phase IIb, randomized, triple-blind, placebo-controlled study to evaluate the efficacy and safety of probiotics as an adjuvant treatment to selective serotonin reuptake inhibitors (SSRI) for patients with mild to moderate PD and MDD. Participants will be randomized to probiotics (n=62) or placebo (n=62) arms using a permuted block randomization approach. Co-primary outcomes include changes in Montgomery-Åsberg Depression Rating Scale (MADRS)scores and SSRI equivalent doses, which will be compared between groups using a bivariate joint model. Secondary outcomes will include changes in both Beck Depression Inventory-II (BDI-II) score and levodopa dose, which will be analyzed using t-tests or Mann-Whitney tests as appropriate. Concurrent validity between MADRS and BDI-II will be assessed using Pearson’s or Spearman’s correlation tests. Safety will be evaluated by comparing discontinuation rates and adverse events between groups using chi-square. Data will be analyzed using intention-to-treat and per-protocol analyses, and missing data will be addressed using multiple imputation methods. Discussion: Probiotics represent a potential new approach to managing depression in patients with PD by targeting the gut-brain axis. The results will offer crucial information about the safety and efficacy of a low-cost and readily available supplement that may alleviate depression in this vulnerable population.

Decision Support and Behavioral Health for Reducing High-Dose Opioids in Comorbid Chronic Pain, Depression and Anxiety: Stepped-Wedge Cluster Randomized Trial.

High prevalence of depression or anxiety with opioid use for chronic pain complicates co-management and may influence prescribing behaviors. Compare clinical effectiveness of electronic medical record clinical decision support (EMR-CDS) versus additional behavioral health (BH) care management for reducing rates of high-dose opioid prescriptions. Type 2 effectiveness-implementation hybrid stepped-wedge cluster randomized trial in 35 primary care clinics within a health system in LA, USA. Patients aged 18+ receiving chronic opioid therapy for non-cancer pain with depression or anxiety and matched controls. EMR-CDS included opioid risk mitigation procedures. BH care included cognitive behavioral therapy; depression or anxiety medication adjustments; and case management. Outcomes of interest included difference-in-difference (DID) estimate of changes in probability for prescribing high-dose morphine equivalent daily dose (MEDD ≥50 mg/day and MEDD ≥90), average MEDD, and rates of hospitalization, emergency department use, and opioid risk mitigation. Most participants were female with 3+ pain syndromes. Data analysis included 632 patients. Absolute risk differences for MEDD≥50 and ≥90 decreased post-index compared to pre-index (DID of absolute risk difference [95%CI]: -0.036 [-0.089, 0.016] and -0.029 [-0.060, 0.002], respectively). However, these differences were not statistically significant. The average MEDD decreased at a higher rate for the BH group compared to EMR-CDS only (DID rate ratio [95%CI]: 0.85 [0.77, 0.93]). There were no changes in hospitalization and emergency department utilization. The BH group had higher probabilities of new specialty referrals and prescriptions for naloxone and antidepressants. Incorporation of a multidisciplinary behavioral health care team into primary care did not decrease high-dose prescribing; however, it improved adherence to clinical guideline recommendations for managing chronic opioid therapy for non-cancer pain. ClinicalTrials.gov ID NCT03889418.

Predictors of continuation for asenapine from real-world data in patients with schizophrenia

BackgroundThe continuation rates of pharmacotherapy in schizophrenia exhibit variability, a phenomenon influenced by the specific antipsychotic agent prescribed and patient-related factors such as age and duration of illness. In this context, our study aims to elucidate the predictors of medication continuation for asenapine sublingual tablets, characterized by unique formulation properties.MethodsOur investigation leveraged real-world data collected through post-marketing surveillance in Japan, comprising 3236 cases. Utilizing multivariate logistic regression analysis, we identified patient-related factors associated with medication continuation as the primary outcome measure, subsequently employing survival analysis for further evaluation. Additionally, adverse event occurrence was assessed as a secondary outcome measure.ResultsMultivariate logistic regression analysis unveiled significant predictors of asenapine continuation, notably including patient-related factors such as a chlorpromazine equivalent dose exceeding 600 mg/day and an illness duration of 25 years or more. While the overall continuation rate stood at 40.6%, patients exhibiting factors such as a chlorpromazine equivalent dose surpassing 600 mg/day or an illness duration exceeding 25 years demonstrated continuation rates of 46.3% and 47.9%, respectively. Remarkably, patients presenting both factors showcased the highest continuation rate at 52.5%.ConclusionsOur findings shed light on distinct patient-related predictors of asenapine continuation, deviating from those observed with other antipsychotic medications. This underscores the necessity of recognizing that predictive factors for antipsychotic medication continuation vary across different agents. Moving forward, elucidating these predictive factors for various antipsychotic medications holds paramount importance in schizophrenia treatment, facilitating the delivery of tailored therapeutic interventions for individual patients.

Capsaicin Modulates Hepatic and Intestinal Inflammation and Oxidative Stress by Regulating the Colon Microbiota.

We aimed to investigate the role of capsaicin (CAP) in modulating lipopolysaccharide (LPS)-induced hepatic and intestinal inflammation, oxidative stress, and its colonic microflora in mice. Thirty healthy male Kunming mice with similar body weights were randomly assigned to three groups: the control group (CON), the LPS group, and the CAP group, with ten mice in each group. The CON and the LPS groups received a daily dose of normal saline, respectively, while the CAP group received an equivalent dose of CAP. On the 28th day of the experiment, the LPS and the CAP groups were intraperitoneally injected with LPS, while the CON group was injected with an equal volume of normal saline. The results lead to the following conclusions. Compared to the LPS group, CAP improved the loss of hepatic lobular structure and significantly increased the duodenal villus length and ratio of villus length to crypt depth. CAP increased hepatic and colon interleukin-10 (IL-10) and decreased IL-6, IL-1β, and tumor necrosis factor (TNF-α) levels. CAP also increased hepatic catalase (CAT), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) expression, and decreased malondialdehyde (MDA) levels. CAP significantly increased the relative abundances of Mucispirillum, Helicobacter, Prevotellaceae-UCG-001, Colidextribacter, unclassified-f-Oscillospiraceae, and Odoribacter, some of which were closely related to hepatic and colonic immune and oxidative markers. CAP also decreased the overall content of short-chain fatty acids, except for propionic acid. Overall, CAP can regulate the colon microbiota and exert anti-inflammatory and antioxidant effects. Whether CAP exerts its anti-inflammatory and antioxidant effects by modulating the colonic microflora, mainly Mucispirillum spp. and Helicobacter spp., requires further investigation.

Comparative analysis of machine learning-based dose assessment algorithms for TL dosimetry

This paper explores the implementation of machine learning-based algorithms for TL dose assessment. It focuses on the radiation field classification, performance quotient evaluation, and shallow and deep dose equivalent assessment of ANN and LGBM, in comparison to the traditional method of DT. We evaluate these algorithms based on the element response data measured by TLD. A data set was built for training, and the base element responses of test categories were amplified, and normalized to 1 mSv Cs-137 within the range of ±3 %. Both algorithms consist of five subset models for classifying radiation fields and identifying ratios of mixed fields. The LGBM showed the best accuracy in classifying considered radiation fields and the lowest performance quotients. By comparing the tolerance levels of deep dose and shallow dose equivalents among the three algorithms, the LGBM yields the smallest difference between the predicted and true dose equivalents. This smaller difference implies the LGBM offers the least bias and standard deviation in the expected value, giving higher accuracy and precision in dose assessment over the traditional DT method. The findings from this study further contribute to the adoption of ML-based algorithms for TL dose assessment, underscoring its importance in the field.

Stable transduction of the neonatal mouse liver using a hybrid rAAV/sleeping beauty transposon gene delivery system.

Conventional adeno-associated viral (AAV) vectors, while highly effective in quiescent cells such as hepatocytes in the adult liver, confer less durable transgene expression in proliferating cells owing to episome loss. Sustained therapeutic success is therefore less likely in liver disorders requiring early intervention. We have previously developed a hybrid, dual virion approach, recombinant AAV (rAAV)/piggyBac transposon system capable of achieving stable gene transfer in proliferating hepatocytes at levels many fold above conventional AAV vectors. An alternative transposon system, Sleeping Beauty, has been widely used for ex vivo gene delivery; however liver-targeted delivery using a hybrid rAAV/Sleeping Beauty approach remains relatively unexplored. We investigated the capacity of a Sleeping Beauty (SB)-based dual rAAV virion approach to achieve stable and efficient gene transfer to the newborn murine liver using transposable therapeutic cassettes encoding coagulation factor IX or ornithine transcarbamylase (OTC). At equivalent doses, rAAV/SB100X transduced hepatocytes with high efficiency, achieving stable expression into adulthood. Compared with conventional AAV, the proportion of hepatocytes transduced, and factor IX and OTC activity levels, were both markedly increased. The proportion of hepatocytes stably transduced increased 4- to 8-fold from <5%, and activity levels increased correspondingly, with markedly increased survival and stable urinary orotate levels in the OTC-deficient Spfash mouse following elimination of residual endogenous murine OTC. The present study demonstrates the first in vivo utility of a hybrid rAAV/SB100X transposon system to achieve stable long-term therapeutic gene expression following delivery to the highly proliferative newborn mouse liver. These results have relevance to the treatment of genetic metabolic liver diseases with neonatal onset.

Improved therapeutic index of the liposomal docetaxel-glutathione prepared by active click loading

The clinical usage of docetaxel (DTX) is severely hindered by the dose-limiting neutropenia and peripheral neurotoxicity of polysorbate 80-solubilized DTX injection, and there are no alternative formulations until now. In this study, we developed a new liposomal formulation of DTX to reduce its toxicities, accompanying with the greatly improved antitumor activity. The DTX was encapsulated into liposomes in the form of hydrophilic glutathione (GSH)-conjugated prodrugs using a click drug loading method, which achieved a high encapsulation efficiency (∼95 %) and loading capacity (∼30 % wt). The resulting liposomal DTX-GSH provided a sustained and efficient DTX release (∼50 % within 48 h) in plasma, resulting in a greatly improved antitumor activities as compared with that of polysorbate 80-solubilized DTX injection in the subcutaneous and orthotopic 4T1 breast tumor bearing mice. Even large tumors > 500 mm3 could be effectively inhibited and shrunk after the administration of liposomal DTX-GSH. More importantly, the liposomal DTX-GSH significantly decreased the neutropenia and peripheral neurotoxicity as compared with that of polysorbate 80-solubilized DTX injection at the equivalent dose. These data suggested that the liposomal DTX-GSH might become a superior alternative formulation to the commercial DTX injection.

Safety and efficiency of deep brain stimulation in the elderly patients with Parkinson's disease.

Deep brain stimulation (DBS) is not routinely performed in elderly patients (≥75 years old) to date because of concerns about complications and decreased benefit. This study aimed to evaluate the safety and efficacy of DBS in elderly patients with Parkinson's disease. A retrospective analysis was performed using data from 40 elderly patients from four centers who were treated with neurosurgical robot-assisted DBS between September 2016 and December 2021. These patients were followed up for a minimum period of 2 years, with a subgroup of nine patients followed up for 5-7 years. Patient demographic characteristics, surgical information, pre- and postoperative motor scores, non-motor scores, activities of daily living, and complications were retrospectively analyzed. The mean surgical procedure duration was 1.65 ± 0.24 h, with a mean electrode implantation duration of 1.10 ± 0.23 h and a mean pulse generator implantation duration of 0.55 ± 0.07 h. The mean pneumocephalus volume, electrode fusion error, and Tao's DBS surgery scale were 16.23 ± 12.81 cm3, 0.81 ± 0.23 mm, and 77.63 ± 8.08, respectively. One patient developed a skin infection, and the device was removed. The Unified Parkinson's disease rating scale, Unified Parkinson's disease rating scale of Part III, tremor, rigidity, bradykinesia, axial, and Barthel index for activities of daily living (ADL-Barthel) scores significantly improved at the 2-year follow-up (p < 0.05). The levodopa equivalent daily dose (LEDD) was significantly reduced at the 2-year follow-up (p < 0.05). However, the Montreal cognitive assessment, Hamilton depression scale, and Hamilton anxiety scale scores did not significantly change during the 2-year follow-up (p > 0.05). Additionally, in the subgroup with a 5-year follow-up, the motor symptoms, ADL-Barthel score, and cognitive function worsened over time compared to baseline. However, there was still an improvement in motor symptoms and ADL with DBS on-stimulation compared with the off-stimulation state. The LEDD increased 5 years after surgery compared to that at baseline. Eleven patients had passed away during follow-up, the mean survival time was 38.3 ± 17.3 months after surgery, and the mean age at the time of death was 81.2 (range 75-87) years. Robot-assisted DBS surgery for the elderly patients with Parkinson's disease is accurate and safe. Motor symptoms and ADL significantly improve and patients can benefit from long-term neuromodulation, which may decrease the risk of death.

Awake versus asleep deep brain stimulation for Parkinson's disease: a comprehensive systematic review and meta-analysis.

Deep brain stimulation (DBS) has become an effective and safe treatment in patients with Parkinson's disease (PD) not responding to conventional treatments. With the growing body of literature regarding the use of DBS in different movement disorders, there remain controversies regarding performing awake or asleep DBS. This systematic review provides the most comprehensive review of the literature comparing the two techniques from various aspects in detail. A systematic review of the PubMed, Scopus, Web of Science, and Cochrane Library databases was conducted. All studies comparing any aspects of asleep and awake DBS were included. Risk of bias was assessed using the Risk of Bias in Non-Randomized Studies of Interventions tool. Meta-analysis was conducted with consideration of baseline characteristics. Thirty-one studies with 2563 PD patients were included. A total of 1423 patients underwent asleep DBS. The two groups were comparable regarding their baseline characteristics. The follow-up ranged from 3 to 60 months. The two DBS techniques were comparable in terms of motor symptom improvements and levodopa equivalent daily doses. However, the asleep technique showed slightly better improvements in Mattis Dementia Rating Scale and Parkinson's Disease Questionnaire scores. Moreover, the asleep technique was associated with more surgical adverse events, whereas pneumocephalus and psychological disorders such as mood, affect, and cognitive disorders were more common in the awake technique. Subgroup analyses revealed no significant differences in outcomes between asleep and awake DBS when categorized by targeted brain nuclei, use of intraoperative or preoperative imaging, and whether microelectrode recordings were used. These findings suggest comparable clinical outcomes between the two DBS approaches. The two methods had their salient differences in terms of lead passes and specific adverse events. The decision to perform awake or asleep DBS should be based on the patient's preference, the surgeon's experience, the availability of advanced intraoperative imaging, and the patient's tolerance for specific adverse events.

Price benchmarks of drugs selected for Medicare price negotiation and their therapeutic alternatives.

The Centers for Medicare and Medicaid Services (CMS) are currently negotiating prices with pharmaceutical manufacturers for the first 10 Part D drugs selected for Medicare drug price negotiation. Non-publicly available data, including the net prices of selected drugs and their therapeutic alternatives, will play a central role in the determination of the maximum fair prices (MFPs). To estimate price benchmarks involved in the derivation of the starting point of the CMS initial price offer for the 10 drugs selected for Medicare price negotiation. For the 10 drugs selected for negotiation, we reported (1) the list price, (2) the net price after manufacturer discounts, (3) the maximum negotiated price based on the minimum statutory discount, and (4) the ceiling of the MFP, estimated as the lowest of the latter 2. We also estimated net prices for therapeutic alternatives to the selected drugs. Net prices were estimated using peer-reviewed methodology that isolates commercial discounts negotiated between payers and manufacturers from mandatory discounts under government programs. All price benchmarks were estimated at the product level, for 30-day equivalent dosing, using 2021 data. 6 products (apixaban, rivaroxaban, empagliflozin, sacubitril/valsartan, etanercept, and insulin aspart) had therapeutic alternatives with lower net prices, which will be integrated with clinical benefit data in the derivation of initial price offers. The other 4 products (ustekinumab, ibrutinib, sitagliptin, and dapagliflozin) had therapeutic alternatives with higher net prices than the drugs selected for negotiation. For ibrutinib and ustekinumab, prices based on the minimum discounts were considerably lower than the estimated net prices and will likely set the starting point of the initial price offer. For dapagliflozin and sitagliptin, the starting point of the initial price offer will likely resemble their existing net prices. Our analyses identify different negotiation scenarios for the first 10 drugs selected for Medicare price negotiation, based on key elements involved in the derivation of the initial price offer. Our analyses can help improve transparency in the negotiation process, because the CMS is not required to reveal the information used in the derivation of price offers.