Predictive value of frailty assessment tools in patients undergoing surgery for gastrointestinal cancer: An observational cohort study.

BACKGROUND: Few studies have simultaneously compared the predictive value of various frailty assessment tools for outcome measures in patients undergoing gastrointestinal cancer surgery. Therefore, it is difficult to determine which assessment tool is most relevant to the prognosis of this population. AIM: To investigate the predictive value of three frailty assessment tools for patient prognosis in patients undergoing gastrointestinal cancer surgery. METHODS: This single-centre, observational, prospective cohort study was conducted at the Affiliated Lianyungang Hospital of Xuzhou Medical University from August 2021 to July 2022. A total of 229 patients aged ≥ 18 years who underwent surgery for gastrointestinal cancer were included in this study. We collected baseline data on the participants and administered three scales to assess frailty: The comprehensive geriatric assessment (CGA), Fried phenotype and FRAIL scale. The outcome measures were the postoperative severe complications and increased hospital costs. RESULTS: The prevalence of frailty when assessed with the CGA was 65.9%, 47.6% when assessed with the Fried phenotype, and 34.9% when assessed with the FRAIL scale. Using the CGA as a reference, kappa coefficients were 0.398 for the Fried phenotype and 0.291 for the FRAIL scale (both P < 0.001). Postoperative severe complications and increased hospital costs were observed in 29 (12.7%) and 57 (24.9%) patients, respectively. Multivariate logistic analysis confirmed that the CGA was independently associated with increased hospital costs (odds ratio = 2.298, 95% confidence interval: 1.044-5.057; P = 0.039). None of the frailty assessment tools were associated with postoperative severe complications. CONCLUSION: The CGA was an independent predictor of increased hospital costs in patients undergoing surgery for gastrointestinal cancer.

The gut microbiota from maintenance hemodialysis patients with sarcopenia influences muscle function in mice.

Background: Sarcopenia is a common complication in patients undergoing maintenance hemodialysis (MHD). Growing evidence suggests a close relationship between the gut microbiota and skeletal muscle. However, research on gut microbiota in patients with sarcopenia undergoing MHD (MS) remains scarce. To bridge this knowledge gap, we aimed to evaluate the pathogenic influence of gut microbiota in the skeletal muscle of patients with MS, to clarify the causal association between gut microbiota and skeletal muscle symptoms in patients with MS and identify the potential mechanisms underlying this causal association. Methods: Fecal samples were collected from 10 patients with MS and 10 patients without MS (MNS). Bacteria were extracted from these samples for transplantation. Mice (n=42) were randomly divided into three groups and, after antibiotic treatment, fecal microbiota transplantation (FMT) was performed once a day for 3 weeks. Skeletal muscle and fecal samples from the mice were collected for 16S rRNA gene sequencing and for histological, real-time PCR, and metabolomic analyses. Results: Mice colonized with gut microbiota from MS patients exhibited notable decreases in muscle function and muscle mass, compared with FMT from patients with MNS. Moreover, 16S rRNA sequencing revealed that the colonization of MS gut microbiota reduced the abundance of Akkermansia in the mouse intestines. Metabolome analysis revealed that seven metabolic pathways were notably disrupted in mice transplanted with MS microbiota. Conclusion: This study established a connection between skeletal muscle and the gut microbiota of patients with MS, implying that disruption of the gut microbiota may be a driving factor in the development of skeletal muscle disorders in patients undergoing MHD. This finding lays the foundation for understanding the pathogenesis and potential treatment methods for sarcopenia in patients undergoing MHD.

The relationship between triglyceride, cholesterol and lipoprotein levels, and immune responses to hepatitis B vaccine.

Cholesterol homeostasis disorder and hypertriglyceridemia, as common metabolic conditions, have rarely been reported to affect the immune responses to the hepatitis B vaccine. Our study found that higher high-density lipoprotein (HDL) level showed a significant relationship with positive anti-HBs results (cOR = 1.479, 95% CI: 1.150, 1.901, p = 0.002; aOR = 1.304, 95% CI: 1.006, 1.691, p = 0.045), especially in individuals aged 18- to 40-year-old, female, smoking more than 100 cigarettes in life, and drinking more than 12 times every year. Lower low-density lipoprotein (LDL) level was associated with a negative anti-HBs result among participants aged 18- to 40-year-old, and participants who were obese. Higher level of HDL and lower level of LDL may be protective factors of better immune effect of hepatitis B vaccine. More research should be conducted to investigate the influence of the cholesterol level on the immune responses to the hepatitis B vaccine, and more in-depth research should be performed to uncover the mechanism.

Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2.

S-217622 (Ensitrelvir) is a reversible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3-chymotrypsin-like protease (3CLpro) inhibitor which obtained emergency regulatory approval in Japan for the treatment of SARS-CoV-2 infection on Nov 22, 2022. Herein, analogs of S-271622 with deuterium-for-hydrogen replacement were synthesized for comparison of the antiviral activities and pharmacokinetic (PK) profiles. Compared to the parent compound, C11-d2-S-217622 compound YY-278 retained in vitro activity against 3CLpro and SARS-CoV-2. X-ray crystal structural studies showed similar interactions of SARS-CoV-2 3CLpro with YY-278 and S-271622. The PK profiling revealed the relatively favorable bioavailability and plasma exposure of YY-278. In addition, YY-278, as well as S-217622, displayed broadly anti-coronaviral activities against 6 other coronaviruses that infect humans and animals. These results laid the foundation for further research on the therapeutic potential of YY-278 against COVID-19 and other coronaviral diseases.

Using Wool Keratin as a Structural Biomaterial and Natural Mediator to Fabricate Biocompatible and Robust Bioelectronic Platforms.

The design and fabrication of biopolymer-incorporated flexible electronics have attracted immense interest in healthcare systems, degradable implants, and electronic skin. However, the application of these soft bioelectronic devices is often hampered by their intrinsic drawbacks, such as poor stability, inferior scalability, and unsatisfactory durability. Herein, for the first time, using wool keratin (WK) as a structural biomaterial and natural mediator to fabricate soft bioelectronics is presented. Both theoretical and experimental studies reveal that the unique features of WK can endow carbon nanotubes (CNTs) with excellent water dispersibility, stability, and biocompatibility. Therefore, well-dispersed and electroconductive bio-inks can be prepared via a straightforward mixing process of WK and CNTs. The as-obtained WK/CNTs inks can be directly exploited to design versatile and high-performance bioelectronics, such as flexible circuits and electrocardiogram electrodes. More impressively, WK can also be a natural mediator to connect CNTs and polyacrylamide chains to fabricate a strain sensor with enhanced mechanical and electrical properties. With conformable and soft architectures, these WK-derived sensing units can be further assembled into an integrated glove for real-time gesture recognition and dexterous robot manipulations, suggesting the great potential of the WK/CNT composites for wearable artificial intelligence.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and nucleotide analog GS-441524 conjugates with potent in vivo efficacy against coronaviruses.

Coronaviruses (CoVs) infect a broad range of hosts, including humans and various animals, with a tendency to cross the species barrier, causing severe harm to human society and fostering the need for effective anti-coronaviral drugs. GS-441524 is a broad-spectrum antiviral nucleoside with potent anti-CoVs activities. However, its application is limited by poor oral bioavailability. Herein, we designed and synthesized several conjugates via covalently binding NSAIDs to 5'-OH of GS-441524 through ester bonds. The ibuprofen conjugate, ATV041, exhibited potent in vitro anti-coronaviral efficacy against four zoonotic coronaviruses in the alpha- and beta-genera. Oral-dosed ATV041 resulted in favorable bioavailability and rapid tissue distribution of GS-441524 and ibuprofen. In MHV-A59 infected mice, ATV041 dose-dependently decreased viral RNA replication and significantly reduced the proinflammatory cytokines in the liver and the lung at 3 dpi. As a result, the MHV-A59-induced lung and liver inflammatory injury was significantly alleviated. Taken together, this work provides a novel drug conjugate strategy to improve oral PK and offers a potent anti-coronaviral lead compound for further studies.

The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus driving the ongoing coronavirus disease 2019 (COVID-19) pandemic, continues to rapidly evolve. Because of the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOCs), orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously, we showed that the parent nucleoside of remdesivir, GS-441524, has potent anti-SARS-CoV-2 activity. Here, we report that esterification of the 5'-hydroxyl moieties of GS-441524 markedly improved antiviral potency. This 5'-hydroxyl-isobutyryl prodrug, ATV006, demonstrated excellent oral bioavailability in rats and cynomolgus monkeys and exhibited potent antiviral efficacy against different SARS-CoV-2 VOCs in vitro and in three mouse models. Oral administration of ATV006 reduced viral loads and alleviated lung damage when administered prophylactically and therapeutically to K18-hACE2 mice challenged with the Delta variant of SARS-CoV-2. These data indicate that ATV006 represents a promising oral antiviral drug candidate for SARS-CoV-2.

Comparison of the prevalence and associated factors of cognitive frailty between elderly and middle-young patients receiving maintenance hemodialysis.

PURPOSE: This study aimed at comparing the prevalence of cognitive frailty and explore the differences in the influencing factors between elderly and middle-young patients receiving maintenance hemodialysis (MHD). METHODS: In this cross-sectional study, the frailty phenotype, mini-mental state examination, and clinical dementia rating were used to assess the current status of cognitive frailty in 852 patients receiving MHD from four hospitals in Lianyungang City and Xuzhou City, Jiangsu Province, China; the influencing factors were then analyzed for statistical significance. RESULTS: Of the total 852 patients receiving MHD, 340 were classified into an elderly group (≥ 60 years) and 512 into a middle-young group (< 60 years). The prevalence of cognitive frailty was 35.9% and 8.8%, respectively. The results of multivariate logistic regression analysis showed that the independent factors of cognitive frailty were age (P < 0.001), education level (P = 0.010), nutritional status (P = 0.001), serum albumin level (P = 0.010), calf circumference (P = 0.024), and social support level (P < 0.001) in the elderly group and comorbidity status (P = 0.037), education level (P < 0.001), nutritional status (P = 0.008), serum creatinine level (P = 0.001), waist circumference (P < 0.001), and depression (P = 0.006) in the middle-young group. CONCLUSION: The prevalence of cognitive frailty was significantly higher in the elderly group than in the middle-young group, and the influencing factors differed between the two populations.

Characterization of the gut microbiota in hemodialysis patients with sarcopenia.

PURPOSE: Maintenance hemodialysis (MHD) patients are at high risk of sarcopenia. Gut microbiota affects host metabolic and may act in the occurrence of sarcopenia importantly. This study aimed to study the characterization of the gut microbiota in MHD patients with sarcopenia, and to further reveal the complex pathophysiology of sarcopenia in MHD patients. METHODS: Fecal samples and clinical data were collected from 30 MHD patients with sarcopenia, and 30 age-and-sex-matched MHD patients without sarcopenia in 1 general hospital of Jiangsu Province from December 2020 to March 2021. 16S rRNA sequencing technology was used to analyze the genetic sequence of the gut microbiota for evaluation of the diversity, species composition, and differential microbiota of the two groups. RESULTS: Compared to MHD patients without sarcopenia, the ACE index of patients with sarcopenia was lower (P = 0.014), and there was a structural difference in the ß-diversity between the two groups (P = 0.001). At the genus level, the relative abundance of Tyzzerella_4 in the sarcopenia group was significantly higher than in the non-sarcopenia group (P = 0.039), and the relative abundance of Megamonas (P = 0.004), Coprococcus_2 (P = 0.038), and uncultured_bacterium_f_Muribaculaceae (P = 0.040) decreased significantly. CONCLUSION: The diversity and structure of the gut microbiota of MHD patients with sarcopenia were altered. The occurrence of sarcopenia in MHD patients may be influenced by gut microbiota.

Automatic Sensing Setup for Methamphetamine Based on the Reactional Wettability Variation Strategy.

An automatic setup for reactional wettability variation (RWV) was developed by interlinking liquid selection and transportation, object movement, and image recognition. In this way, the performance of the RWV strategy is updated to a nearly unmanned control manner with the example of methamphetamine and its aptamer. On the automatic RWV detection setup, the sensing surface acts similarly as before. The aptamer-based sensing surface resulted from the breakdown of the hydrophobic basis. The hydrophobicity is constructed on the metastable aptamer layer, which is responsive to the corresponding target. Methamphetamine interacts with its corresponding aptamer and destroys the basis of the hydrophobicity. A decrease in contact angle indicates the existence of methamphetamine. The RWV phenomenon is also affected by concentration and temperature. The development of an automatic detection ability would bring new possibilities to the surface reaction on smarter detection.

A Novel MEMS Gyroscope In-Self Calibration Approach.

This paper presents a novel approach for hand-held low-cost MEMS (micro-electro-mechanical system) gyroscope in-self calibration. This method does not need the support of external high-precision equipment compared with traditional calibration scheme and can be accomplished by user hand rotation. In this approach, Kalman filter is designed to perform the calibration procedure and estimate gyroscope bias error, scale factor error and non-orthogonal error. The system observability is analyzed and the dynamic rotating conditions under which the sensor errors become observable are derived. The design principles of optimal calibration procedure are provided as well. Both simulated and practical experiments are carried out to test the validation of the proposed calibration algorithm. The achieved results demonstrate that the introduced approach can provide promising calibration scheme for the low-cost MEMS gyroscope.

Association of maternal diabetes with attention deficit/hyperactivity disorder (ADHD) in offspring: A meta-analysis and review.

AIMS: Researches on the relationship between maternal pregestational or gestational diabetes and attention deficit/hyperactivity disorder (ADHD) in offspring provided inconsistent findings; therefore, we performed an updated and comprehensive literature review and meta-analysis to evaluate the available evidence. METHOLDS: Relevant articles in Pubmed, Web of Science, Cochrane, Embase, and Wanfang database published until January 2019 were searched without language restriction. We performed a meta-analysis about maternal pregestational and gestational diabetes and risk of ADHD in offspring using odds ratio (OR), relative risk (RR), hazard ratio (HR) and 95% confidence interval (95% CI) extracted from each study. RESULTS: Seven articles were included in this study and a total of 3,169,529 participants were accumulated. We found maternal pregestational diabetes increased the risk of ADHD in offspring by 44% (95% CI was 1.32-1.57). CONCLUSIONS: Maternal pregestational diabetes is a potential adverse risk of ADHD in offspring. Considering the limited amount of reliable information availabe. In the future, more in-depth and detailed researches, especially population-based prospective cohort studies, are needed to explore this topic more comprehensively.

5-Hydroxyindole-Based EZH2 Inhibitors Assembled via TCCA-Catalyzed Condensation and Nenitzescu Reactions.

5-Hydroxyindole derivatives have various demonstrated biological activities. Herein, we used 5-hydroxyindole as a synthetic starting point for structural alterations in a combinatorial process to synthesize 22 different compounds with EZH2 inhibitor pharmacophores. A series of 5-hydroxyindole-derived compounds were screened inhibitory activities against K562 cells. According to molecular modeling and in vitro biological activity assays, the preliminary structure-activity relationship was summarized. Compound L-04 improved both the H3K27Me3 reduction and antiproliferation parameters (IC50 = 52.6 µM). These findings revealed that compound L-04 is worthy of consideration as a lead compound to design more potent EZH2 inhibitors. During the preparation of compounds, we discovered that trichloroisocyanuric acid (TCCA) is a novel catalyst which demonstrates condensation-promoting effects. To gain insight into the reaction, in situ React IR technology was used to confirm the reactivity. Different amines were condensed in high yields with ß-diketones or ß-ketoesters in the presence of TCCA to afford the corresponding products in a short time (10~20 min), which displayed some advantages and provided an alternative condensation strategy.

Targeting cancer stem cells in drug discovery: Current state and future perspectives.

In recent decades, cancer stem cells (CSCs) have been increasingly identified in many malignancies. CSC-related signaling pathways and their functions provide new strategies for treating cancer. The aberrant activation of related signaling pathways (e.g., Wnt, Notch, and Hedgehog pathways) has been linked to multiple types of malignant tumors, which makes these pathways attractive targets for cancer therapy. CSCs display many characteristic features, such as self-renewal, differentiation, high tumorigenicity, and drug resistance. Therefore, there is an urgent need to develop new therapeutic strategies to target these pathways to control stem cell replication, survival, and differentiation. Notable crosstalk occurs among different signaling pathways and potentially leads to compensatory escape. Therefore, multitarget inhibitors will be one of the main methods to overcome the drug resistance of CSCs. Many small molecule inhibitors of components of signaling pathways in CSCs have entered clinical trials, and some inhibitors, such as vismodegib, sonidegib, and glasdegib, have been approved. Tumor cells are susceptible to sonidegib and vismodegib resistance due to mutations in the Smo protein. The signal transducers and activators of transcription 3 (STAT3) inhibitor BBI608 is being evaluated in a phase III trial for a variety of cancers. Structural derivatives of BBI608 are the main focus of STAT3 inhibitor development, which is another strategy for CSC therapy. In addition to the potential pharmacological inhibitors targeting CSC-related signaling pathways, other methods of targeting CSCs are available, such as nano-drug delivery systems, mitochondrion targeting, autophagy, hyperthermia, immunotherapy, and CSC microenvironment targeting. In addition, we summarize the latest advances in the clinical development of agents targeting CSC-related signaling pathways and other methods of targeting CSCs.

Is low body mass index a risk factor for semen quality? A PRISMA-compliant meta-analysis.

BACKGROUND: Male infertility has become a worldwide public health problem. However, the effect of low body mass index (BMI) is still controversial. METHODS: Relevant articles in Pubmed, Embase, Web of science, and Wanfang database published until September 2017 were searched without language restriction. We performed a meta-analysis about low BMI and semen parameters containing total sperm count, concentration, semen volume, and sperm motility (overall and progressive), including 709 men with low BMI and 14,622 men with normal BMI. RESULTS: Thirteen studies were included in this meta-analysis and a total of 15,331 individuals were accumulated. We pooled data from these articles and found standardized weighted mean differences in semen parameters (total sperm count and semen volume) showed significant difference between low BMI and normal BMI. CONCLUSIONS: This systematic review with meta-analysis has confirmed that there was a relationship between low BMI and semen quality, which suggesting low BMI may be a harmful factor of male infertility. Yet lacking of the raw data may influence the accuracy of the results. Further researches are needed to identify the role of underweight in male sterility.

l -( -) -Quebrachitol as a Ligand for Selective Copper(0)-Catalyzed N-Arylation of Nitrogen-Containing Heterocycles.

l-(-)-Quebrachitol (QCT) has been found as a ligand of copper powder for selective N-arylation of nitrogen-containing heterocycles with aryl halides. Furthermore, another potential catalytic system (copper powder/QCT/ t-BuOK) was successfully adapted to unactivated aryl chlorides.

A Low Power Cardiovascular Healthcare System With Cross-Layer Optimization From Sensing Patch to Cloud Platform.

Nowadays, cardiovascular disease is still one of the primary diseases that limit life expectation of humans. To address this challenge, this work reports an Internet of Medical Things (IoMT)-based cardiovascular healthcare system with cross-layer optimization from sensing patch to cloud platform. A wearable ECG patch with a custom System-on-Chip (SoC) features a miniaturized footprint, low power consumption, and embedded signal processing capability. The patch also integrates wireless connectivity with mobile devices and cloud platform for optimizing the complete system. On the big picture, a "wearable patch-mobile-cloud" hybrid computing framework is proposed with cross-layer optimization for performance-power trade-off in embedded-computing. The measurement results demonstrate that the on-patch compression ratio of the raw ECG signal can reach 12.07 yielding a percentage root mean square variation of 2.29%. In the test with the MIT-BIH database, the average improvement of signal to noise ratio and mean square error are 12.63 dB and 94.47%, respectively. The average accuracy of disease prediction operation executed in cloud platform is 97%.

Synthesis and biological evaluation of 2,2-dimethylbenzopyran derivatives as potent neuroprotection agents.

The development of novel neuroprotection agents is of great significance for the treatment of ischemic stroke. In this study, a series of compounds comprising 2,2-dimethylbenzopyran groups and cinnamic acid groups have been synthesized. Preferential combination principles and bioisostere that improved the neuroprotective effect of the compounds were identified for this series via biological activity assay in vitro. Meanwhile, a functional reversal group of the acrylamide amide resulted in the most active compounds. Among them, BN-07 significantly improved the morphology of neurons and obviously increased cell survival rate of primary neurons induced by oxygen glucose deprivation (OGD), superior to clinically used anti-ischemic stroke drug edaravone (Eda). Overall, our findings may provide an alternative strategy for the design of novel anti-ischemic stroke agents with more potency than Eda.

OAB-14, a bexarotene derivative, improves Alzheimer's disease-related pathologies and cognitive impairments by increasing ß-amyloid clearance in APP/PS1 mice.

The pathogenesis of Alzheimer's disease (AD) is complex, though the clinical failures of anti-AD candidates targeting Aß production (such as ß- and γ-secretase inhibitors) make people suspect the Aß hypothesis, in which the neurotoxicity of Aß is undoubtedly involved. According to studies, >95% of AD patients with sporadic AD are primarily associated with abnormal Aß clearance. Therefore, drugs that increase Aß clearance are becoming new prospects for the treatment of AD. Here, the novel small molecule OAB-14, designed using bexarotene as the lead compound, significantly alleviated cognitive impairments in amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice after administration for 15 days or 3 months. OAB-14 rapidly cleared 71% of Aß by promoting microglia phagocytosis and increasing IDE and NEP expression. This compound also attenuated the downstream pathological events of Aß accumulation, such as synaptic degeneration, neuronal loss, tau hyperphosphorylation and neuroinflammation in APP/PS1 mice. Moreover, OAB-14 had no significant effect on body weight or liver toxicity after acute and chronic treatment. OAB-14 was well tolerated and its maximum-tolerated dose in mice was >4.0 g/kg. Based on these findings, OAB-14 represents a promising new candidate for AD treatment.