Meropenem for the Pharmacological Treatment of Severe Infections in Critically Ill Pediatric Patients: Breakthrough Standard Treatment Strategies Based on PK/PD.

Meropenem, as a carbapenem antibiotic, is commonly used in critically ill pediatric patients with severe infection because of its broad antimicrobial spectrum, high penetration into tissues, and favorable safety profile. Due to pathophysiological changes in critically ill children, the available evidence has demonstrated that the standard dosage regimens of meropenem could not meet an appropriate pharmacodynamic (PD) target attainment in severely infected children. Therefore, we reviewed the pharmacokinetic (PK) profile of meropenem in critically ill children, therapeutic drug monitoring (TDM), and dose optimization based on PK/PD. Meropenem kills bacteria in a timedependent manner and its efficacy is positively correlated with the percentage of the time of dosing interval during which the free serum concentration of meropenem remains above the minimum inhibitory concentration (MIC) of the pathogen (%fT>MIC), which is related to PK/PD targets. For critically ill children, TDM-based dosage optimization and setting even higher PK/PD targets seem necessary to be considered. The currently available studies have revealed that increasing the dose and the application of the extended or continuous infusion of meropenem were able to achieve better PK/PD targets. According to limited clinical data on efficacy and safety, these treatment measures cannot yet be adopted as routine regimens only when serious infections caused by drug-resistant bacteria or strains with high values of MIC are suspected. Further high-quality randomized controlled trials (RCTs) or observational studies with sufficient sample sizes are required to confirm the efficacy and safety of these modes of administration.

Recent progress in the mechanisms, preparations and applications of polymeric antifogging coatings.

Fog on a solid surface is prejudicial to its optical properties and will even cause hygienic and safety concerns in some exceptional cases. Thus, antifogging coatings have attracted great interest in fundamental research and industry applications. Superhydrophilic and superhydrophobic coatings have been mainly explored and described in the antifogging field. In recent years, hygroscopic antifogging coatings of hydrophilic and hydrophobic parties have been introduced due to their unique properties. In this review, three antifogging mechanisms are reviewed to provide design strategies for antifogging surfaces. The current techniques for fabricating polymeric antifogging coatings are discussed in depth. The recent progress in materials and structures for antifogging surfaces is briefly summarize. Finally, the practical applications and outlooks related to multifunctional antifogging coatings are mentioned.

Relationship of arterial tonometry and exercise in patients with chronic heart failure: a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Arterial stiffness is a common characteristic in patients with chronic heart failure (CHF), and arterial tonometric technologies related to arterial stiffness are novel and effective methods and have an important value in the diagnosis and prognosis of CHF. In terms of ameliorating arterial stiffness in patients with CHF, exercise training is considered an adjuvant treatment and also an effective means in the diagnosis and judgment of prognosis. However, there are huge controversies and inconsistencies in these aspects. The objective of this meta-analysis was to systematically test the connection of arterial tonometry and exercise in patients with CHF. METHODS: Databases, including MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, were accessed from inception to 7 March 2022. The meta-analysis was then conducted, and trial sequential analysis (TSA) was performed jointly to further verify our tests and reach more convincing conclusions by using RevMan version 5.4 software, STATA version 16.0 software, and TSA version 0.9.5.10 Beta software. RESULTS: Eighteen articles were included, with a total of 876 participants satisfying the inclusion criteria. The pooling revealed that flow-mediated dilation (FMD) was lower in basal condition [standardized mean difference (SMD): - 2.28%, 95% confidence interval (CI) - 3.47 to - 1.08, P < 0.001] and improved significantly after exercise (SMD: 5.96%, 95% CI 2.81 to 9.05, P < 0.001) in patients with heart failure with reduced ejection fraction (HFrEF) compared with healthy participants. The high-intensity training exercise was more beneficial (SMD: 2.88%, 95% CI 1.78 to 3.97, P < 0.001) than the moderate-intensity training exercise to improve FMD in patients with CHF. For augmentation index (AIx), our study indicated no significant differences (SMD: 0.50%, 95% CI - 0.05 to 1.05, P = 0.074) in patients with heart failure with preserved ejection fraction (HFpEF) compared with healthy participants. However, other outcomes of our study were not identified after further verification using TSA, and more high-quality studies are needed to reach definitive conclusions in the future. CONCLUSIONS: This review shows that FMD is lower in basal condition and improves significantly after exercise in patients with HFrEF compared with healthy population; high-intensity training exercise is more beneficial than moderate-intensity training exercise to improve FMD in patients with CHF; besides, there are no significant differences in AIx in patients with HFpEF compared with the healthy population. More high-quality studies on this topic are warranted.

Malignant hyperthermia when dantrolene is not readily available.

BACKGROUND: Malignant hyperthermia is a rare but life-threatening pharmacogenetic muscle disorder characterized by abnormal hypermetabolic reactions and commonly triggered in susceptible individuals by volatile anesthetics or succinylcholine, or both. Unfortunately, the specific medicine dantrolene is not readily available in many countries including China. The aim of this study was to find the characteristics of malignant hyperthermia under the situation that dantrolene is not readily available. METHODS: The cases of malignant hyperthermia reported on the most commonly used databases in China from 1985 to 2020 were analyzed. The inclusion criteria were the MH episodes only related to anesthesia. The exclusion criteria were dubious MH episodes only caused by Ketamine administration or MH episodes irrelevant to anesthesia. Independent samples t-test and Pearson's chi-squared test were applied to assess the difference between the survived and death cases. RESULTS: Ninety-two cases of malignant hyperthermia reported on the most commonly used databases in China from 1985 to 2020 were analyzed. Median (IQR [range]) age was 18.5 (11.8-37.0 [0-70.0]) years. Compared with the survived cases, the death cases had higher maximum end-tidal partial pressure of CO2 (P = 0.033), the maximum arterial partial pressure of CO2 (P = 0.006), temperature first measured when the patient was first discovered abnormal (P = 0.012), and maximum temperature (P < 0.001). Besides, the death cases had less minimum pH (P < 0.001) and higher potassium (P < 0.001) and were more likely to have coagulation disorders (p = 0.018). Concerning treatment, cases used furosemide (P = 0.024), mannitol (P = 0.029), blood purification treatment (P = 0.017) had the advantage on the outcome. Creatine phosphokinase, myoglobin, and MB isoenzyme of creatine phosphokinase differed greatly among cases during the first week. 43 (46.7%) cases had congenital diseases. 12 (13.0%) cases were reported with abnormal laboratory test results or abnormal signs that are possibly relevant before anesthesia. CONCLUSIONS: In countries that dantrolene is not readily available, early warning, diagnosis, and prompt effective therapies are crucial for MH patients to survive.

Multicolor and Multistage Response Electrochromic Color-Memory Wearable Smart Textile and Flexible Display.

Electrochromic materials have great application in soft displays and devices, but the application of ideal electrochromic textiles still faces challenges owing to the inconvenience of a continuous power supply. Here, electrochromic color-memory microcapsules (ECM-Ms-red, -yellow, and -blue) with a low drive voltage (2.0 V), coloration efficiency (921.6 cm2 C-1), a practical response rate (34.4 s-1), multistage response discoloration, and good color-memory performance (>72 h) and reversibility (≥1000 cycles) are developed. The color-memory performance is controlled by the energy difference of oxidation-reduction reactions. A multicolor and multistage response electrochromic color-memory wearable smart textile and flexible display are developed that are convenient and energy-efficient for application. The design philosophy of color-memory based on controllable energy difference of reactions has great potential application in sensors and smart textiles.

Suppression of mitochondrial respiration with local anesthetic ropivacaine targets breast cancer cells.

BACKGROUND: Retrospective studies on cancer patients who have received local anesthesia show a favorable decrease in tumor metastasis and recurrence. However, the mechanisms underlying the benefits of local anesthesia on cancer recurrence are not well understood. METHODS: In this study, we investigated the biological effects of ropivacaine on breast cancer cells and the mechanisms of its action with emphasis on mitochondrial respiration. RESULTS: Ropivacaine significantly inhibited growth, survival, and anchorage-independent colony formation in two human breast cancer cell lines. It also acted synergistically with a 5-FU in breast cancer cells. Mechanistically, ropivacaine was found to inhibit mitochondrial respiration by suppressing mitochondrial respiratory complex I and II activities, leading to energy depletion, and oxidative stress and damage. The inhibitory effects of ropivacaine in breast cancer cells were abolished in mitochondrial respiration-deficient ρ0 cells, indicating that mitochondrial respiration is essential for the mechanism of action of ropivacaine. Ropivacaine inhibited phosphorylation of Akt, mTOR, rS6, and EBP1 in breast cancer cells, suggesting the association between Akt/mTOR signaling pathway and mitochondrial functions in breast cancer. CONCLUSIONS: Our work clearly demonstrates the inhibitory effects of ropivacaine in breast cancer by disrupting mitochondrial function. Our findings provide a proper understanding of how local anesthetics reduce the risk of tumor recurrence, and thus, support the use of ropivacaine for surgery and to control pain in patients with breast cancer.

Inhibition of gastric cancer by local anesthetic bupivacaine through multiple mechanisms independent of sodium channel blockade.

BACKGROUND: Retrospective studies of patients undergoing cancer surgery suggest the use of local anesthesia may decrease tumor recurrence and improve survival. The mechanisms on the benefits of local anesthesia on cancer recurrence are complex and remain to be elucidated. METHODS: This study investigated the effects of bupivacaine on various cellular activities of gastric cancer using proliferation, migration, apoptosis assay. The underlying mechanism was analyzed focusing on mitochondrial functions and the activities of Rho family members. RESULTS: We show that bupivacaine at low concentrations (eg, 0.01 and 0.05 mM) inhibits migration whereas only at high concentrations (1 and 5 mM) inhibits growth and survival in two human gastric cancer cell lines. Bupivacaine also significantly augments 5-Fluorouracil in inhibiting growth and survival but not migration in gastric cancer cells. In addition, the mechanisms of bupivacaine's action on the growth and survival are different from those on the migration. We demonstrate that bupivacaine inhibits gastric cancer cell growth and survival through inhibiting mitochondrial respiratory complex I and II, leading to decreased mitochondrial oxidation and ATP production. In contrast, bupivacaine inhibits gastric cancer cell migration through decreasing RhoA and Rac1 activities without affecting their expression. Particularly, we demonstrate that bupivacaine inhibits gastric cancer cell migration via inhibiting RhoA/ROCK/MLC pathway. We further show that the action of bupivacaine on mitochondrial functions, RhoA, and Rac1 activities are independent of sodium channel blockade. CONCLUSIONS: Our work demonstrates that bupivacaine has direct anti-cancer activities with the dominant inhibitory effects on gastric cancer migration rather than growth and survival. Our findings also guide a proper understanding and provide underlying mechanisms on how local aesthesis could affect cancer patients.

ML-7 attenuates airway inflammation and remodeling via inhibiting the secretion of Th2 cytokines in mice model of asthma.

Previous studies have indicated that smooth muscle myosin light chain kinase (MLCK) has a prominent role in the regulation of smooth muscle contraction, which tends to be upregulated in asthma. In recent years, numerous studies have reported that MLCK is intimately connected with the immunoregulatory mechanism of T cells. The imbalance of T helper type 1 cells (Th1)/Th2 constitutes the immune­associated pathological basis of chronic asthma. Th2­associated cytokines, including interleukin­4, ­5, ­13, ­25 and ­33, are involved in airway inflammation, hyperresponsiveness and remodeling, which leads to a progressive decline in lung function. The purpose of the present study was to verify whether inhibition of bronchial MLCK attenuated the expression Th2­associated cytokines in asthmatic mice, including the above­mentioned ones. Female BALB/c mice were used to establish an ovalbumin (OVA)­induced model of asthma, of which one group was treated with the MLCK inhibitor (5-iodonaphthalene-1-sulfonyl) homopiperazine (ML­7). The inhibitor of MLCK, ML­7 attenuated airway inflammation and remodeling by reducing inflammatory cell infiltration and the secretion of Th2 cytokines in mice model of asthma, which may represent a promising therapeutic strategy for asthma.