Sustained High Concentrations Research Articles

A high-fat meal significantly impacts the bioavailability and biphasic absorption of cannabidiol (CBD) from a CBD-rich extract in men and women

Cannabidiol (CBD), a specialized metabolite (phytocannabinoid) abundant in Cannabis sativa, is attracting increasing attention for its alleged health-promoting properties. The present study aimed to investigate the pharmacokinetics of CBD and its primary metabolite, 7‐hydroxy‐cannabidiol (7-OH-CBD), following a single oral dose of a CBD-rich Cannabis sativa extract, equivalent to 70 mg CBD, in healthy male (n=5) and female (n=6) participants. Using a randomized crossover design, the study evaluated the impact of a standardized high-fat meal compared to fasting on the oral bioavailability of CBD. Consumption of a high-fat meal significantly increases the bioavailability of CBD. The geometric mean ratio (GMR) of CBD Cmax was 17.4 (90% CI 12.4–24.2 and of the AUC 9.7 (90% CI 7.7–12.3), demonstrating a substantial increase in peak concentration and total CBD exposure under fed conditions. A notable double peak phenomenon was observed after meal consumption, with a less pronounced effect in the fasted state. This contributes to sustained high plasma concentrations and may be (partially) attributed to lymphatic transport, enterohepatic recirculation, and/or a secondary meal effect.This trial was registered on October 19, 2020, with ClinicalTrials.gov under the identifier NCT04589455. The registration title is: Determination of Pharmacokinetics and Food-effect of CBD from a Hemp Extract in Healthy Human Volunteers.

Role of insulin in the management of diabetic foot

Despite insulin's well-documented benefits in wound healing over the last 70 years, challenges remain regarding the optimal method of administration. While systemic insulin therapy has significant side effects, topical insulin faces challenges with consistent delivery. This study aims to test the hypothesis that local insulin injections can provide sustained high concentrations in wounds, promoting healing with minimal systemic impact, combining the benefits of both systemic and topical insulin therapies.This study investigates the effect of local insulin injections on wound healing, focusing on enhancing the healing process in a non-healing diabetic foot ulcer. The objective is to determine whether insulin injections at the wound site can accelerate healing by promoting key processes like keratinocyte migration, differentiation, and angiogenesis.Conducted at a tertiary care center in South India, this study involved a 69-year-old male patient with a non-healing ulcer over the lateral aspect of the left foot due to Charcot's joint. The wound area was treated with a mixture of Insulin Isophane and Human Insulin (70/30) in a 4-unit to 10 ml saline ratio per 10 cm². The treatment was followed by a two-layer regenerative scaffold dressing and Negative Pressure Wound Therapy (NPWT) to support recovery.The insulin application significantly enhanced wound healing by promoting keratinocyte migration, differentiation, and angiogenesis. These effects led to a noticeable reduction in the time required for wound closure and improved tissue regeneration.The use of local insulin injections effectively improves wound healing by targeting key processes such as inflammation, re-epithelialization, and angiogenesis. This study underscores the potential of insulin as a promising therapeutic agent for chronic wound management. Further research is recommended to validate these findings and explore its application across diverse wound types.

Synovial vancomycin and meropenem concentrations in periprosthetic joint infection treated by single-stage revision combined with intra-articular infusion.

We aimed to determine the concentrations of synovial vancomycin and meropenem in patients treated by single-stage revision combined with intra-articular infusion following periprosthetic joint infection (PJI), thereby validating this drug delivery approach. We included 14 patients with PJI as noted in their medical records between November 2021 and August 2022, comprising eight hip and seven knee joint infections, with one patient experiencing bilateral knee infections. The patients underwent single-stage revision surgery, followed by intra-articular infusion of vancomycin and meropenem (50,000 µg/ml). Synovial fluid samples were collected to assess antibiotic concentrations using high-performance liquid chromatography. The peak concentrations of vancomycin and meropenem in the joint cavity were observed at one hour post-injection, with mean values of 14,933.9 µg/ml (SD 10,176.3) and 5,819.1 µg/ml (SD 6,029.8), respectively. The trough concentrations at 24 hours were 5,495.0 µg/ml (SD 2,360.5) for vancomycin and 186.4 µg/ml (SD 254.3) for meropenem. The half-life of vancomycin was 6 hours, while that of meropenem ranged between 2 and 3.5 hours. No significant adverse events related to the antibiotic administration were observed. This method can achieve sustained high antibiotic concentrations within the joint space, exceeding the reported minimum biofilm eradication concentration. Our study highlights the remarkable effectiveness of intra-articular antibiotic infusion in delivering high intra-articular concentrations of antibiotics. The method provided sustained high antibiotic concentrations within the joint cavity, and no severe side-effects were observed. These findings offer evidence to improve clinical treatment strategies. However, further validation is required through studies with larger sample sizes and higher levels of evidence.

Magic Touch sirolimus-coated balloon: animal and clinical evidence of a coronary sirolimus drug-coated balloon.

The Magic Touch sirolimus-coated balloon (SCB) was recently introduced in Europe and features robust clinical technology different from other devices on the market. This device is able to deliver a sufficient sirolimus dose to the target segment to reduce neointimal proliferation with very little exposure downstream and no apparent adverse effects at sustained high drug concentrations. The SCB represents a promising novelty within the drug-coated balloon arena due to its mid-term efficacy and safety in the treatment of coronary artery disease, especially in de novo and small-vessel coronary lesions. The purpose of this article is to provide an up-to-date overview of the currently available animal and clinical trial results, as well as to highlight ongoing trials on the Magic Touch SCB.

Potential Psychosis Induced by a Sustained High Plasma Levodopa Concentration Due to Continuous Subcutaneous Foslevodopa/Foscarbidopa Infusion in a Patient With Parkinson's Disease: A Case Report.

Potential Psychosis Induced by a Sustained High Plasma Levodopa Concentration Due to Continuous Subcutaneous Foslevodopa/Foscarbidopa Infusion in a Patient With Parkinson's Disease: A Case Report.

Exploration of the Effects of Cadmium Stress on Photosynthesis in Oenanthe javanica (Blume) DC.

Cadmium ion (Cd2+) stress is a major abiotic stressor affecting plant photosynthesis. However, the impact of sustained high-concentration Cd stress on the photosynthetic electron transport chain of aquatic plants is currently unclear. Here, prompt fluorescence (PF), delayed fluorescence (DF), and P700 signals were simultaneously measured to investigate the effect of Cd stress on photosynthesis in water dropwort [Oenanthe javanica (Blume) DC.]. We aimed to elucidate how Cd stress continuously affects the electron transport chain in this species. The PF analysis showed that with prolonged Cd stress, the FJ, FI and FP steadily decreased, accompanied by a positive shift in the K-band and L-band. Moreover, JIP-test parameters, including TRO/ABS, ABS/CSO, TRO/CSO and PIABS, were significantly reduced. The P700 signals showed that exposure to Cd stress hindered both the fast decrease and slow increase phases of the MR transient, ultimately resulting in a gradual reduction in both VPSI and VPSII-PSI. The DF analysis showed a gradual decrease in the I1 and I2 values as the duration of stress from Cd increased. The above results suggested that Cd stress affected the photosynthetic electron transport in water dropwort by influencing the amount of active PSII and PSI, primarily affecting PSII RCs in the early to mid-stages and PSI reductive activity in the later stage.

Formaldehyde Exposure of Aquaculture Workers in Korea

ABSTRACT Objectives Korea’s aquaculture sector primarily cultivates aquatic life, with fish seed production as a focus. Formalin, a parasiticide, consists of 37% formaldehyde mixed with yellow No. 4 dye. Formaldehyde vaporization poses cancer risks, classified as a carcinogen. Korea regulates formaldehyde as a hazardous substance, requiring workplace environment measurements. Few aquaculture farms have conducted these checks in recent years. In this study, we investigated actual formaldehyde exposure levels among Korean aquaculture workers, highlighting a critical safety concern. Methods A field survey was conducted to measure formaldehyde exposure at 10 aquaculture farms in areas where Korean aquaculture is concentrated. Short-term and long-term personal samples, local samples, and direct-reading measurements were conducted. Formaldehyde exposure levels were detected in short-term personal samples from six farms and in long-term personal samples from two farms, and formaldehyde was detected in all local samples. In direct-reading measurements, a high concentration of formaldehyde was sustained for short periods. Results Long-term (8-hour) personal samples were mostly non-detectable, except for farms A and D, which had levels of 0.0009 ppm and 0.0017 ppm, respectively. Short-term (15-minute) samples were non-detectable in four farms, with an average of 0.0158 (±0.0130) ppm in the remaining six farms. Local samples from all farms had an average of 0.0384 (±0.0957) ppm of formaldehyde. For farms A and D, where long-term sampling detected formaldehyde, real-time measurements showed a sustained high concentration in farm A for about 48 minutes before decreasing. Farm D had no detectable formaldehyde throughout the monitoring period. Conclusion According to the formaldehyde exposure level assessment, short term exposure to formaldehyde during and immediately after application of formalin nearly exceeded the ACGIH TLV STEL in one farm. However, concentration of long term samples appeared at 10% of ACGIH TLV TWA. Additional study is recommended to determine whether exposure to formaldehyde poses a health risk for aquaculture workers during application of formalin.

Correlation Between Lipoprotein(a) and Prognosis for Coronary Artery Disease in Patients Undergoing Percutaneous Coronary Intervention.

Elevated lipoprotein(a) (Lp[a]) is a risk factor for first atherosclerotic thrombosis events, but the role of elevated Lp(a) in secondary prevention is controversial. This study aimed to retrospectively investigate the influence of elevated Lp(a) levels on the prognosis of patients with coronary artery disease. The team collected and compared clinical information of patients hospitalized during percutaneous coronary intervention (PCI). This study used a multivariate logistic regression model to evaluate the relationships between Lp(a) levels, cardiovascular risk factors, and the prognosis of coronary artery disease in patients undergoing PCI. There were no statistically significant differences between patients grouped according to Lp(a) level in terms of sex; age; body mass index and obesity; hyperuricemia; smoking; cardiac insufficiency; acute myocardial infarction; multivessel lesion; in-stent restenosis; secondary PCI; apolipoprotein AI level; incidence of high total cholesterol or high low-density lipoprotein cholesterol; or family history of hypertension, diabetes, or coronary artery disease. The average Lp(a) concentration did not statistically significantly decrease after 1 year of statin treatment after PCI. One year after patients began statins, there were no significant differences between Lp(a) groups in the incidence of high triglycerides (P = .13), high total cholesterol (P = .52), or high low-density lipoprotein cholesterol (P = .051). Multivariate logistic regression analysis indicated that diabetes (P = .02) was associated with in-stent restenosis, whereas diabetes (P = .02) and multivessel lesions (P < .001) were associated with secondary PCI in patients who underwent coronary angiography 1 year after PCI. Compared with normal Lp(a) levels, high Lp(a) levels did not significantly increase the incidence of in-stent restenosis or secondary PCI in patients who underwent coronary angiography 1 year after PCI. Sustained high concentrations of Lp(a) did not significantly increase the incidence of in-stent restenosis or secondary PCI in patients who underwent coronary angiography 1 year after PCI.

Tumor oxygen microenvironment-tailored electron transfer-type photosensitizers for precise cancer therapy.

The oxygen level in a tumor typically exhibits complex characteristics, ranging from mild hypoxia to moderate and even severe hypoxia. This poses significant challenges for the efficacy of photodynamic therapy, where oxygen is an essential element. Herein, we propose a novel therapeutic strategy and develop a series of lipid droplet-targeting photosensitive dyes (Ser-TPAs), i.e., in situ synergistic activation of two different electron transfer-type reactions. Based on this strategy, Ser-TPAs can synergistically generate O2˙- and nitrogen radicals regardless of the oxygen content, which results in a sustained high concentration of strongly oxidizing substances in the lipid droplets of cancer cells. As such, Ser-TPAs exhibited inhibitory activity against tumor growth in vivo, resulting in a significant reduction in tumor volume (V experimental group : V control group ≈ 0.07). This strategy offers a conceptual framework for the design of innovative photosensitive dyes that are suitable for cancer therapy in complex oxygen environments.

Transcriptomic analysis revealed the dynamic response mechanism to acute ammonia exposure in the ivory shell, Babylonia areolata

The ivory shell (Babylonia areolata) is an economically important shellfish in tropical and subtropical regions, but its intensive culture and biological characteristic of hiding in the sandy substrate make it highly susceptible to ammonia stress. In this study, we investigated the dynamic changes in histopathology, oxidative stress, and transcriptome of the ivory shell at different time points under high concentration (60 mg/L) ammonia exposure. With prolonged exposure to stress, vacuoles appeared in the hepatopancreas while cell volume and intercellular space increased. The activities of superoxide dismutase (SOD) and catalase (CAT) decreased significantly under high concentrations of ammonia-induced stress while malondialdehyde (MDA) levels increased significantly. Integrated analysis of differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), and quantitative real-time polymerase chain reaction (qRT-PCR) revealed that lipid transport primarily contributed to maintaining cellular homeostasis during the early stage of stress (6 and 12 h). Subsequently, a significant upregulation of oxidation-reduction reactions occurred at the middle stage (24 h), leading to oxidative stress. Finally, during the later stage (48 h), metabolic decomposition provided energy for survival maintenance. Additionally, lysosome and apoptosis were identified as potential key pathways in response to acute ammonia toxicity. Overall, our findings suggest that ivory shells can respond to acute ammonia toxicity via immune and antioxidant defense mechanisms but sustained high concentrations may cause irreversible damage. This study provides valuable insights into the response mechanism of mollusks towards ammonia and serves as a data reference for breeding ammonia-tolerant varieties of ivory shells.

A programmed surface on dental implants sequentially initiates bacteriostasis and osseointegration.

Osteogenesis surrounding dental implants is initiated by a series of early physiological events, including the inflammatory response. However, the persistence of an anti-infection surface often results in compromised histocompatibility and osseointegration. Here, we presented a programmed surface containing both silver nanoparticles (AgNPs) and silver ions (Ag+) with a heterogeneous structure and time-dependent functionalities. The AgNPs were located at the surface of the heparin-chitosan polyelectrolyte coating (PEM), whereas Ag+ was distributed at both the surface and inside of the coating under optimized conditions (pH=4). The optimized coating (Ag-4) exhibited potent bactericidal activity at the early stage (12 and 24h after inoculation) and a sustained antibacterial efficacy in the subsequent stage (one or two weeks), as it gradually depleted. Furthermore, compared to coatings with sustained high silver concentrations in bacteria-cell coculture experiments, the degradable Ag-4 coating demonstrated improved cytocompatibility, better cell viability, and morphology over time. At a later stage (within one month), the in vivo test revealed that Ag-4-coated titanium had superior histocompatibility and osteogenesis outcomes compared to bare titanium in a bacteria-exposed environment. The programmed surface of dental implants presented in this study offers innovative ideas for sequential antibacterial effects and osseointegration.

Inducible Nitric Oxide Synthase Embedded in Alginate/Polyethyleneimine Hydrogel as a New Platform to Explore NO-Driven Modulation of Biological Function.

Nitric oxide (NO), a small free radical molecule, turned out to be pervasive in biology and was shown to have a substantial influence on a range of biological activities, including cell growth and apoptosis. This molecule is involved in signaling and affects a number of physiologic functions. In recent decades, several processes related to cancer, such as angiogenesis, programmed cell death, infiltration, cell cycle progression, and metastasis, have been linked with nitric oxide. In addition, other parallel work showed that NO also has the potential to operate as an anti-cancer agent. As a result, it has gained attention in cancer-related therapeutics. The nitric oxide synthase enzyme family (NOS) is required for the biosynthesis of nitric oxide. It is becoming increasingly popular to develop NO-releasing materials as strong tumoricidal therapies that can deliver sustained high concentrations of nitric oxide to tumor sites. In this paper, we developed NO-releasing materials based on sodium alginate hydrogel. In this regard, alginate hydrogel discs were modified by adsorbing layers of polyethyleneimine and iNOS-oxygenase. These NO-releasing hydrogel discs were prepared using the layer-by-layer film building technique. The iNOS-oxygenase is adsorbed on the positively charged polyethyleneimine (PEI) matrix layer, which was formed on a negatively charged sodium alginate hydrogel. We show that nitric oxide is produced by enzymes contained within the hydrogel material when it is exposed to a solution containing all the components necessary for the NOS reaction. The electrostatic chemical adsorption of the layer-by-layer process was confirmed by FTIR measurements as well as scanning electron microscopy. We then tested the biocompatibility of the resulting modified sodium alginate hydrogel discs. We showed that this NOS-PEI-modified hydrogel is overall compatible with cell growth. We characterized the NOS/hydrogel films and examined their functional features in terms of NO release profiles. However, during the first 24 h of activity, these films show an increase in NO release flux, followed by a gradual drop and then a period of stable NO release. These findings show the inherent potential of using this system as a platform for NO-driven modulation of biological functions, including carcinogenesis.

Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaques.

Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily or long-acting pre-exposure prophylaxis (PrEP). We performed dose ranging pharmacokinetics (PK) and efficacy studies of a vaginally applied insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) in macaques under PrEP or post-exposure prophylaxis (PEP) modalities. PK studies were performed in 3 groups of pigtailed macaques receiving inserts with different fixed-dose combinations of TAF and EVG (10/8, 20/16 and 40/24mg). PrEP and PEP efficacy of a selected insert was investigated in a repeat exposure vaginal SHIV transmission model. Inserts were administered 4 h before (n=6) or after (n=6) repeated weekly SHIV exposures. Infection outcome was compared with macaques receiving placebo inserts (n=12). Dose ranging studies showed rapid and sustained high drug concentrations in vaginal fluids and tissues across insert formulations with minimal dose proportionality. TAF/EVG (20/16mg) inserts were selected for efficacy evaluation. Five of the 6 animals receiving these inserts 4 h before and 6/6 animals receiving inserts 4 h after SHIV exposure were protected after 13 challenges (p=0.0088 and 0.0077 compared to placebo, respectively). The calculated PrEP and PEP efficacy was 91.0% (95% CI=32.2%-98.8%) and 100% (95% CI=undefined), respectively. Inserts containing TAF/EVG provided high protection against vaginal SHIV infection when administered within a 4 h window before or after SHIV exposure. Our results support the clinical development of TAF/EVG inserts for on-demand PrEP and PEP in women. Funded by CDC intramural funds, an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002), and by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development (USAID) under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School.

Multislice Computed Tomography Angiography Imaging Diagnosis of Lower Extremity Arteriosclerosis in Patients with Hypertension and Its Correlation with the Level of High-Sensitivity C-Reactive Protein.

The aim of this study was to investigate the relationship between multislice computed tomography (CT) angiography (MSCTA) imaging and high-sensitivity C-reactive protein (hs-CRP) in patients with hypertension and lower extremity arteriosclerosis. 68 hypertensive patients with lower extremity arteriosclerosis were selected as the observation group, and 68 healthy volunteers were selected as the control group to compare the differences in hs-CRP. According to the degree of stenosis, the patients were further divided into five grades: no obvious stenosis, mild stenosis, moderate stenosis, severe stenosis, and occlusion. The correlation between the degree of stenosis and the content of hs-CRP was compared. The changes of hs-CRP content before and after treatment were compared, and the difference of images before and after surgical treatment and the difference of hs-CRP expression in patients with occlusion were compared. Compared with the control group, the content of hs-CRP in the observation group was significantly higher (P < 0.05), and the degree of stenosis was positively correlated with the content of hs-CRP. After two weeks of treatment, the hs-CRP levels of patients with severe stenosis and occlusion were significantly lower than those before treatment (P < 0.01). The level of hs-CRP in patients with occlusion after arterial stent intervention was significantly lower than before, and the images also showed that the blood vessels were significantly expanded. The degree of stenosis in patients with lower extremity arteriosclerosis diagnosed by MSCTA imaging was closely related to the expression of hs-CRP in the patient, and a sustained high concentration of hs-CRP corresponded to a more severe degree of vascular occlusion. In conclusion, the hs-CRP can be used as one of the factors to predict and evaluate the occurrence of cardiovascular and cerebrovascular diseases.

Potential of Continuous Local Antibiotic Perfusion Therapy for Fracture-Related Infections

IntroductionFracture-related infections (FRIs) are challenging for orthopedic surgeons, as conventional surgical treatment and systemic antimicrobial therapy cannot completely control local infections. Continuous local antibiotic perfusion (CLAP) is a novel and innovative therapy for bone and soft-tissue infections, and is expected to eradicate biofilms by maintaining a sustained high concentration of antimicrobial agents at the infected site. If CLAP therapy can eradicate infection even in cases with implants while preserving the implants, it would be an ideal and effective treatment for local refractory infections. This study aimed to evaluate the usefulness of novel CLAP therapy for FRIs.MethodsNine patients treated with CLAP therapy were retrospectively analyzed. The mean age was 65.9 (43–82) years, and the mean follow-up period was 14.9 (6–45) months. In all cases, the infected sites were related to the lower extremities (tibia, n = 6; fibula, n = 1; hip joint, n = 1; foot, n = 1). All patients underwent similar procedures for this therapy combined with negative-pressure wound therapy after thorough irrigation and debridement of infected tissues.ResultsThe pathogens identified were Staphylococcus aureus (methicillin-resistant S. aureus, n = 5; methicillin-susceptible S. aureus, n = 1), Pseudomonas aeruginosa (n = 3), Enterococcus faecalis (n = 2), Corynebacterium (n = 1), and Enterobacter (n = 1); pathogens were not detected in one case. The mean duration of CLAP was 17.0 (7–35) days. In all cases, implants were preserved until bone union was achieved. Five cases relapsed; however, infection was finally suppressed in all cases by repeating this method. No side effects were observed.ConclusionThis novel case series presents treatment outcomes using CLAP therapy for FRIs. This method has the potential to control the infection without removing the implants, because of the sustained high concentration of antimicrobial agents at the infected site, and could be a valuable treatment option for refractory FRIs with implants, in which bone union has not been achieved.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00653-5.

Effect of sustained high buprenorphine plasma concentrations on fentanyl-induced respiratory depression: A placebo-controlled crossover study in healthy volunteers and opioid-tolerant patients.

BackgroundOpioid-induced respiratory depression driven by ligand binding to mu-opioid receptors is a leading cause of opioid-related fatalities. Buprenorphine, a partial agonist, binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects. The authors examined whether sustained buprenorphine plasma concentrations similar to those achieved with some extended-release injections used to treat opioid use disorder could reduce the frequency and magnitude of fentanyl-induced respiratory depression.MethodsIn this two-period crossover, single-centre study, 14 healthy volunteers (single-blind, randomized) and eight opioid-tolerant patients taking daily opioid doses ≥90 mg oral morphine equivalents (open-label) received continuous intravenous buprenorphine or placebo for 360 minutes, targeting buprenorphine plasma concentrations of 0.2 or 0.5 ng/mL in healthy volunteers and 1.0, 2.0 or 5.0 ng/mL in opioid-tolerant patients. Upon reaching target concentrations, participants received up to four escalating intravenous doses of fentanyl. The primary endpoint was change in isohypercapnic minute ventilation (VE). Additionally, occurrence of apnea was recorded.ResultsFentanyl-induced changes in VE were smaller at higher buprenorphine plasma concentrations. In healthy volunteers, at target buprenorphine concentration of 0.5 ng/mL, the first and second fentanyl boluses reduced VE by [LSmean (95% CI)] 26% (13–40%) and 47% (37–59%) compared to 51% (38–64%) and 79% (69–89%) during placebo infusion (p = 0.001 and < .001, respectively). Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection. In opioid-tolerant patients, fentanyl reduced VE up to 49% (21–76%) during buprenorphine infusion (all concentration groups combined) versus up to 100% (68–132%) during placebo infusion (p = 0.006). In opioid-tolerant patients, the risk of experiencing apnea requiring verbal stimulation following fentanyl boluses was lower with buprenorphine than with placebo (odds ratio: 0.07; 95% CI: 0.0 to 0.3; p = 0.001).InterpretationResults from this proof-of-principle study provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids like fentanyl.

Deriving hourly full-coverage PM2.5 concentrations across China's Sichuan Basin by fusing multisource satellite retrievals: A machine-learning approach

High ambient concentrations of fine particulate matter (PM2.5) increase the hazardousness of air pollution. Aerosol optical depth (AOD) retrieved by sun-synchronous or geostationary satellites is valuable for monitoring large-scale air quality. This study sought to combine the AOD of the Himawari-8 and the Visible Infrared Imaging Radiometer Suite (VIIRS) to derive the spatiotemporal distributions of hourly PM2.5 concentrations at ∼1 km resolution for China's Sichuan Basin by using a machine-learning approach. Two random forest submodels were developed to fill the daytime gaps in these two AOD datasets, which were then used as predictors in another random-forest submodel predicting the hourly PM2.5 concentrations in daytime. One more random-forest submodel was developed to predict the hourly PM2.5 in nighttime based on the auxiliary variables excluding the AOD data. Leveraging the complementary information of Himawari-8 and VIIRS, this approach demonstrated heightened predictive performance, with cross-validation R2 of 0.840 and RMSE of 15.9 μg/m3. The ability to predict nighttime PM2.5 (R2 from 0.826 to 0.858) was comparable to daytime PM2.5 (R2 from 0.831 to 0.853). In the Sichuan Basin, the sustained high concentrations of PM2.5 were mainly attributed to the stagnant meteorological conditions associated with the basin topography. Based on this full-coverage dataset, we characterized the spatiotemporal distributions of PM2.5 across the basin while demonstrating the regional diurnal patterns and the “weekend effect” for a central urban area. Provisioning comprehensive datasets of hourly PM2.5 as demonstrated in this study is essential for air quality management and environmental epidemiological analyses.

Intraperitoneal Chemotherapy for Peritoneal Metastasis from Gastric Cancer

The survival outcomes of gastric cancer patients with peritoneal metastases are still dismal, even with recentadvances in chemotherapy. Paclitaxel is an antineoplastic agent with high molecular weight and hydrophobic features. It has a pharmacokinetic advantage for the control of peritoneal lesions. After intraperitoneal delivery usingan implantable peritoneal access port, it slowly exits the peritoneal cavity, resulting in reduced systemic uptakeand toxicity, as well as sustained high concentrations in the peritoneal cavity. Intraperitoneal paclitaxel plus S-1and intravenous paclitaxel therapy was developed, and phase II trials were conducted to evaluate the efficacy forgastric cancer patients with peritoneal disease. Although two trials showed promising results, a subsequent phaseIII trial failed to show statistical superiority over S-1 plus cisplatin doublet systemic chemotherapy. I reviewed thehistorical background of this therapy and discussed its pros and cons.

Serum GP88 as a predictive biomarker for hepatocellular carcinoma in patients with viral hepatitis C after direct-acting antiviral agents.

Progranulin (GP88) is an 88-kDa glycoprotein growth factor with important biological effects in tumorigenesis and tumour survival. We investigated the usefulness of measuring serum GP88 concentrations as a predictive biomarker for hepatocellular carcinoma in patients with viral hepatitis C after treatment with direct-acting antiviral agents. We measured the serum GP88 concentrations by using a sandwich enzyme-linked immunoassay from 67 healthy control subjects and 29 patients (20 patients who did not develop hepatocellular carcinoma and 9 patients who developed hepatocellular carcinoma after treatment) with viral hepatitis C after treatment with asunaprevir and daclatasvir. The serum GP88 concentrations of patients with chronic hepatitis C prior to antiviral treatment were significantly higher than those of healthy control subjects. After antiviral treatment, the serum GP88 concentrations of patients who eventually developed hepatocellular carcinoma were significantly higher than those who did not develop hepatocellular carcinoma. The changes in the serum GP88 concentrations before and after treatment in patients who developed hepatocellular carcinoma were significantly lower than those in patients who did not develop hepatocellular carcinoma. The cumulative incidence of hepatocellular carcinoma was significantly higher in either patients with high serum GP88 concentrations after treatment or those with small changes of serum GP88 concentrations pre- and post-treatment. Sustained high concentrations of serum GP88 in patients treated with direct-acting antiviral agents are correlated with the risk of developing hepatocellular carcinoma.

Branched-Chain Amino Acids Associate Negatively With Postprandial Insulin Secretion in Recent-Onset Diabetes.

ContextIn addition to unfavorable effects on insulin sensitivity, elevated plasma branched-chain amino acids (BCAA) stimulate insulin secretion, which, over the long-term, could impair pancreatic β-cell function.ObjectiveTo investigate cross-sectional and prospective associations between circulating BCAA and postprandial β-cell function in recently diagnosed type 1 and type 2 diabetes.MethodsThe study included individuals with well-controlled type 1 and type 2 diabetes (known diabetes duration <12 months) and glucose-tolerant participants (controls) of similar age, sex, and body mass index (n = 10/group) who underwent mixed meal tolerance tests. Plasma BCAA levels were quantified by gas chromatography–mass spectrometry, postprandial β-cell function was assessed from serum C-peptide levels, and insulin sensitivity was determined from PREDIM index (PREDIcted M-value).ResultsIn type 1 diabetes, postprandial total BCAA, valine, and leucine levels were 25%, 18%, and 19% higher vs control, and total as well as individual postprandial BCAA were related inversely to C-peptide levels. In type 2 diabetes, postprandial isoleucine was 16% higher vs the respective controls, while neither total nor individual BCAA correlated with C-peptide levels. Whole-body insulin sensitivity was lower in both diabetes groups than in corresponding controls. ConclusionInsulin deficiency associates with sustained high BCAA concentrations, which could contribute to exhausting the insulin secretory reserve in early type 1 diabetes.