Identification of spinal circuits transmitting and gating mechanical pain.

Pain information processing in the spinal cord has been postulated to rely on nociceptive transmission (T) neurons receiving inputs from nociceptors and Aß mechanoreceptors, with Aß inputs gated through feed-forward activation of spinal inhibitory neurons (INs). Here, we used intersectional genetic manipulations to identify these critical components of pain transduction. Marking and ablating six populations of spinal excitatory and inhibitory neurons, coupled with behavioral and electrophysiological analysis, showed that excitatory neurons expressing somatostatin (SOM) include T-type cells, whose ablation causes loss of mechanical pain. Inhibitory neurons marked by the expression of dynorphin (Dyn) represent INs, which are necessary to gate Aß fibers from activating SOM(+) neurons to evoke pain. Therefore, peripheral mechanical nociceptors and Aß mechanoreceptors, together with spinal SOM(+) excitatory and Dyn(+) inhibitory neurons, form a microcircuit that transmits and gates mechanical pain. PAPERCLIP:

P2-Type Moisture-Stable and High-Voltage-Tolerable Cathodes for High-Energy and Long-Life Sodium-Ion Batteries.

P2-Na0.67Ni0.33Mn0.67O2 represents a promising cathode for Na-ion batteries, but it suffers from severe structural degradation upon storing in a humid atmosphere and cycling at a high cutoff voltage. Here we propose an in situ construction to achieve simultaneous material synthesis and Mg/Sn cosubstitution of Na0.67Ni0.33Mn0.67O2 via one-pot solid-state sintering. The materials exhibit superior structural reversibility and moisture insensitivity. In-operando XRD reveals an essential correlation between cycling stability and phase reversibility, whereas Mg substitution suppressed the P2-O2 phase transition by forming a new Z phase, and Mg/Sn cosubstitution enhanced the P2-Z transition reversibility benefiting from strong Sn-O bonds. DFT calculations disclosed high chemical tolerance to moisture, as the adsorption energy to H2O was lower than that of the pure Na0.67Ni0.33Mn0.67O2. A representative Na0.67Ni0.23Mg0.1Mn0.65Sn0.02O2 cathode exhibits high reversible capacities of 123 mAh g-1 (10 mA g-1), 110 mAh g-1 (200 mA g-1), and 100 mAh g-1 (500 mA g-1) and a high capacity retention of 80% (500 mA g-1, 500 cycles).

Ultrafast Charge-Discharge Capable and Long-Life Na3.9 Mn0.95 Zr0.05 V(PO4 )3 /C Cathode Material for Advanced Sodium-Ion Batteries.

Na4 MnV(PO4 )3 /C (NMVP) has been considered an attractive cathode for sodium-ion batteries with higher working voltage and lower cost than Na3 V2 (PO4 )3 /C. However, the poor intrinsic electronic conductivity and Jahn-Teller distortion caused by Mn3+ inhibit its practical application. In this work, the remarkable effects of Zr-substitution on prompting electronic and Na-ion conductivity and also structural stabilization are reported. The optimized Na3.9 Mn0.95 Zr0.05 V(PO4 )3 /C sample shows ultrafast charge-discharge capability with discharge capacities of 108.8, 103.1, 99.1, and 88.0 mAh g-1 at 0.2, 1, 20, and 50 C, respectively, which is the best result for cation substituted NMVP samples reported so far. This sample also shows excellent cycling stability with a capacity retention of 81.2% at 1 C after 500 cycles. XRD analyses confirm the introduction of Zr into the lattice structure which expands the lattice volume and facilitates the Na+ diffusion. First-principle calculation indicates that Zr modification reduces the band gap energy and leads to increased electronic conductivity. In situ XRD analyses confirm the same structure evolution mechanism of the Zr-modified sample as pristine NMVP, however the strong ZrO bond obviously stabilizes the structure framework that ensures long-term cycling stability.

Multiomics Sequencing and AlphaFold2 Analysis of the Stereoselective Behavior of Mefentrifluconazole for Bioactivity Improvement and Risk Reduction.

As the first isopropanol chiral triazole fungicide, mefentrifluconazole has broad prospects for application. In this study, the stereoselective stability, bioactivity, fate, and biotoxicity were systematically investigated. Our results indicated that the stability of mefentrifluconazole enantiomers differed between environmental media, and they were stable in water and sediment in the dark. The bactericidal activity of R-mefentrifluconazole against the four target pathogens was 4.6-43 times higher than that of S-mefentrifluconazole. In the water-sediment system, S-mefentrifluconazole dissipated faster than R-mefentrifluconazole in water; however, its accumulation capacity was higher than that of R-mefentrifluconazole in sediment and zebrafish. S-Mefentrifluconazole induced more differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in zebrafish than did R-mefentrifluconazole. Multiomics sequencing results showed that S-mefentrifluconazole enhanced the antioxidant, detoxification, immune, and metabolic functions of zebrafish by interacting with related proteins. Based on AlphaFold2 modeling and molecular docking, mefentrifluconazole enantiomers had different binding modes with key target proteins in pathogens and zebrafish, which may be the main reason for the stereoselective differences in bioactivity and biotoxicity. Based on its excellent bioactivity and low biotoxicity, the R-enantiomer can be developed to improve the bioactivity and reduce the risk of mefentrifluconazole.

Computational characterization of double reduction in autotetraploid natural populations.

Population genetic theory has been well developed for diploid species, but its extension to study genetic diversity, variation and evolution in autopolyploids, a class of polyploids derived from the genome doubling of a single ancestral species, requires the incorporation of multisomic inheritance. Double reduction, which is characteristic of autopolyploidy, has long been believed to shape the evolutionary consequence of organisms in changing environments. Here, we develop a computational model for testing and estimating double reduction and its genomic distribution in autotetraploids. The model is implemented with the expectation-maximization (EM) algorithm to dissect unobservable allelic recombinations among multiple chromosomes, enabling the simultaneous estimation of allele frequencies and double reduction in natural populations. The framework fills an important gap in the population genetic theory of autopolyploids.

Temporal modulation toward femtosecond laser-induced nonlinear ionization process.

The temporal chirp of single femtosecond (fs) pulses will affect the laser-induced ionization process. By comparing the ripples induced by negatively and positively chirped pulses (NCPs and PCPs), the growth rate showed a significant difference, resulting in a depth inhomogeneity of up to 144%. A carrier density model tailored with temporal characteristics showed that NCPs could excite a higher peak carrier density, contributing to a highly efficient generation of surface plasmon polaritons (SPPs) and overall advancement of the ionization rate. Such distinction originates from their contrary incident spectrum sequences. Current work reveals that temporal chirp modulation can control the carrier density in ultrafast laser-matter interaction, which possibly brings an unusual acceleration for surface structure processing.

Monkfish (Lophius litulon) Peptides Ameliorate High-Fat-Diet-Induced Nephrotoxicity by Reducing Oxidative Stress and Inflammation via Regulation of Intestinal Flora.

BACKGROUND: Renal damage and intestinal flora imbalance due to lipotoxicity are particularly significant in terms of oxidative stress and inflammation, which can be alleviated with bioactive peptides. The monkfish (Lophius litulon) is rich in proteins, which can be used as a source of quality bioactive peptides. This study aimed to examine the protective effect of monkfish peptides on renal injury and their potential role in regulating gut microbiota. METHODS: Monkfish meat was hydrolyzed using neutral protease and filtered, and the component with the highest elimination rate of 2,2-diphenyl-1-picrylhydrazyl was named lophius litulon peptides (LPs). Lipid nephrotoxicity was induced via high-fat diet (HFD) feeding for 8 weeks and then treated with LPs. Oxidative stress, inflammatory factors, and intestinal flora were evaluated. RESULTS: LP (200 mg/kg) therapy reduced serum creatinine, uric acid, and blood urea nitrogen levels by 49.5%, 31.6%, and 31.6%, respectively. Renal vesicles and tubules were considerably improved with this treatment. Moreover, the activities of superoxide dismutase, glutathione peroxidase, and total antioxidant capacity increased significantly by 198.7%, 167.9%, 61.5%, and 89.4%, respectively. LPs attenuated the upregulation of HFD-induced Toll-like receptor 4 and phospho-nuclear factor-kappa B and increased the protein levels of heme oxygenase 1, nicotinamide quinone oxidoreductase 1, and nuclear factor erythroid 2-related factor 2. The dysbiosis of intestinal microbiota improved after LP treatment. CONCLUSIONS: LPs significantly improve antioxidant activity, reduce inflammatory cytokine levels, and regulate intestinal dysbiosis. Thus, LPs are potential compounds that can alleviate HFD-induced renal lipotoxicity.

Concentrated Growth Factors Can Inhibit Photoaging Damage Induced by Ultraviolet A (UVA) on the Human Dermal Fibroblasts In Vitro.

BACKGROUND Photoaging is the main cause of extrinsic skin aging. Daily exposure to ultraviolet A (UVA) accelerates the process of photoaging. The present study aimed to understand the role of concentrated growth factors (CGF) on UVA irradiated human skin cells. MATERIAL AND METHODS We isolated and subcultured normal human dermal fibroblasts (NHDFs) from 6 different human dorsal skins and established photoaging models of NHDFs irradiated by UVA to detect the influence of CGF on fibroblasts in vitro. Three groups were examined: normal, cellular photoaging model (total dosages of 18J·cm--⁻²-), and cellular photoaging model plus CGF. In our study, we used the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay method to measure the cell viability. We also used reactive oxygen species (ROS) assay and superoxide dismutase (SOD) assay to measure respectively the amount of oxygen free radicals and antioxidative enzymes. We compared the migration rates among the photoaging model groups, the control groups, and the CGF-treated culture medium groups that were irradiated. RESULTS Our study results indicated that 5% CGF can reduce UVA-induced human skin fibroblasts damage significantly, improve the viability of NHDFs significantly, and largely decrease the UVA irradiation effect (P<0.05). The migration rates of the normal group and the UVA-irradiated NHDFs in the 5% CGF group had significantly increased migration rates (P<0.05), compared to the control medium group. The migration rates of the UVA-irradiated NHDFs in 5% CGF exceed those of the normal group. These results showed that 5% CGF could greatly promote cellular proliferation, migration, and SOD at the same time that the amounts of ROS were markedly decreased. CONCLUSIONS These experimental findings offer some important insights into CGF's capacity for scavenging ROS, improving SOD, and increasing migration rates in NHDFs irradiated by UVA.

A Coupled SD and CLUE-S Model for Exploring the Impact of Land Use Change on Ecosystem Service Value: A Case Study in Baoshan District, Shanghai, China.

Most of the cities in developing countries are experiencing rapid urbanization. Land use change driven by urban sprawl, population growth, and intensified socio-economic activities have led to a steep decline of ecosystem service value (ESV) in rapid urbanization areas, and decision-makers often ignore some valuable ecosystem service functions and values in land use planning. In this paper, we attempt to build a modeling framework which integrated System Dynamics model with Conversion of Land Use and its Effects at Small Extent model to simulate the dynamics of ESV of landscape and explore the potential impacts of land use change on ESV. We take Baoshan district of Shanghai as an example which is a fast urbanization area of metropolitan in China. The results of the study indicate that: (1) The integrated methodology can improve the characterization and presentation of the dynamics of ESV, which may give insight into understanding the possible impacts of land use change on ESV and provide information for land use planning. (2) Land use polices can affect the magnitude and location of ESV both directly and indirectly. Land use changes tend to weaken and simplify ecosystem service functions and values of landscape at urban rural fringe where land use change is more intensive. (3) The application of the methodology has proved that the integration of currently existing models within a single modeling framework could be a beneficial exploration, and should be encouraged and enhanced in the future research on the changing dynamics of ESV due to the complexity of ecosystem services and land use system.

Multilevel analysis of a riverscape under rapid urbanization in the Yangtze delta plain, China: 1965-2006.

River networks are the typical hydrological characteristic of the Yangtze delta plain. They have important ecological service functions and a unique landscape, which has been significantly degraded during the past 50 years. Qingpu District in Shanghai has been used as study area to develop an integrated method for riverscape assessment in floodplain areas with a dense river network. This integrated method bridges geomorgraphy, landscape, and regional planning. Indicators of sinuosity, connectivity, and circuitry have been integrated into a three-level framework, including river, intersection, and river network level. Furthermore, this method was integrated by the geographic information system method and stepwise regression to identify the riverscape response to the changes in the use of the land. The spatial and temporal changes of the riverscape and land use were calculated for each grid (3000 m×3000 m) from 1965 to 2006. The results indicated that the riverscape had been significantly degraded during the study period in terms of sinuosity, connectivity, and circuitry reducing. The land use changed significantly with more building areas and less water regions and agricultural land. Additionally, the regression results indicated that several specific land use conversion types had had strong effects on the change in the riverscape structure. Finally, according to the assessing method, we have proposed specific planning and management recommendations based on the pressure-state-response model to protect the riverscape from the impact of rapid urbanization.

Optimization of training for professional rugby union players: investigating the impact of different small-sided games models on GPS-derived performance metrics.

Introduction: Professional rugby union players can improve their performance by engaging in small-sided games (SSGs), which simulate the movement patterns of the game. This study collected metrics related to running performance and mechanical workload and their relative values from both forward and back positions, aiming to explore the impact of different SSGs factors on athlete workload, as well as the workload difference between official games (OGs) and SSGs. Methods: The monitored GPS data were collected from SSGs with different player numbers and pitch sizes (five sessions), SSG rules (5 weeks, four sessions per week), and OGs conducted throughout the year. Additionally, the study compared changes in players' sprinting performance before and after two SSG sessions. Results: Backs had greater workload than forwards. Less space and number of players SSG (4 vs. 4, 660 m2) was conducive to facilitating training for players in acceleration and deceleration. Conversely, larger spaces were associated with improved running performance. However, the introduction of a floater had no significant impact on performance improvement. Additionally, the 7 vs. 4 model (seven players engaged with four opponents) resulted in the greatest workload during medium-hard accelerations (F = 52.76-88.23, p < 0.001, ηp 2 = 0.19-0.28). Japan touch model allowed for more high-speed running training (F = 47.93-243.55, p < 0.001, ηp 2 = 1.52). The workload performed by SSGs can almost cover that of OGs (F = 23.36-454.21, p < 0.05, ηp 2 = 0.03-0.57). In the context of ηp 2, values around 0.01, 0.06 and 0.14 indicate small, medium and large effects respectively. Discussion: However, given the significantly higher workload of SSGs and the slight decrease in sprinting performance, further research is required to examine the training patterns of SSGs. This study provided insight into the impact of player numbers, pitch size, and rules on rugby-specific SSGs. Coaches should optimize SSG setups for enhanced training outcomes, ensuring the long-term development of physical capacity, technical and tactical skills.

Position-specific workload of professional rugby union players during tactical periodization training.

The positional workload characteristics in rugby union on three acquisition days (i.e. strength, endurance, and speed days) of tactical periodization are still relatively unknown. Therefore, the primary aim of this study was to shed light on the positional external workload variables (10 Hz Global Positioning System and accelerometer microtechnology) and internal workload indicators (the session rating of perceived exertion) of players in a professional rugby union team by utilizing and comparing two tactical periodization models. Twenty-six male players (15 forwards and 11 backs) were recruited from a French second-division rugby club. Data were obtained over 10 weeks of in-season home games: a total of 780 observations were analyzed. Student's t-test observed different external workload profiles between positions among acquisition days. Mean external workload values, except PlayerLoadslow, were significantly higher (p≤0.01; effect size: 0.41-1.93) for backs than forwards for all acquisition days. Moreover, forwards perceived a higher internal workload than backs on the strength day of both models. The findings demonstrate that applying these two tactical periodization models could result in effective rugby union training. Validating external and internal workload characteristics on tactical periodization acquisition days enables extensive analysis of training load monitoring data; these data can be utilized to discover the unique characteristics of each position and design position-specific acquisition days to improve performance.

Ni3 S2 -Ni Hybrid Nanospheres with Intra-Core Void Structure Encapsulated in N-Doped Carbon Shells for Efficient and Stable K-ion Storage.

Iron group metals chalcogenides, especially NiS, are promising candidates for K-ion battery anodes due to their high theoretical specific capacity and abundant reserves. However, the practical application of NiS-based anodes is hindered by slow electrochemical kinetics and unstable structure. Herein, a novel structure of Ni3 S2 -Ni hybrid nanosphere with intra-core voids encapsulated by N-doped carbon shells (Ni3 S2 -Ni@NC-AE) is constructed, based on the first electrodeposited NiS nanosphere particles, dopamine coating outer layer, oxygen-free annealing treatment to form Ni3 S2 -Ni core and N-doped carbon shell, and selective etching of the Ni phase to form intra-core void. The electron/K+ transport and K+ storage reaction kinetics are enhanced due to shortened diffusion pathways, increased active sites, generation of built-in electric field, high K+ adsorption energies, and large electronic density of states at Fermi energy level, resulting from the multi-structures synergistic effect of Ni3 S2 -Ni@NC-AE. Simultaneously, the volume expansion is alleviated due to the sufficient buffer space and strong chemical bonding provided by intra-core void and yolk-shell structure. Consequently, the Ni3 S2 -Ni@NC-AE exhibits excellent specific capacity (438 mAh g-1 at 0.1 A g-1 up to 150 cycles), outstanding rate performances, and ultra-stable long-cycle performance (176.4 mAh g-1 at 1 A g-1 up to 5000 cycles) for K-ion storage.

A systematic analysis of residue and risk of cyantraniliprole in the water-sediment system: Does metabolism reduce its environmental risk?

As a representative variety of diamide insecticides, cyantraniliprole has broad application prospects. In this study, the fate and risk of cyantraniliprole and its main metabolite J9Z38 in a water-sediment system were investigated. The present result showed that more J9Z38 was adsorbed in the sediment at the end of exposure. However, the bioaccumulation capacity of cyantraniliprole in zebrafish was higher than that of J9Z38. Cyantraniliprole had stronger influence on the antioxidant system and detoxification system of zebrafish than J9Z38. Moreover, cyantraniliprole induced more significant oxidative stress effect and more differentially expressed genes (DEGs) in zebrafish. Cyantraniliprole had significantly influence on the expression of RyR-receptor-related genes, which was confirmed by resolving their binding modes with key receptor proteins using AlphaFold2 and molecular docking techniques. In the sediment, both cyantraniliprole and J9Z38 had inhibitory effects on microbial community structure diversity and metabolic function, especially cyantraniliprole. The methane metabolism pathway, mediated by methanogens such as Methanolinea, Methanoregula, and Methanosaeta, may be the main pathway of degradation of cyantraniliprole and J9Z38 in sediments. The present results demonstrated that metabolism can reduce the environmental risk of cyantraniliprole in water-sediment system to a certain extent.

Effects of Nano-CeO2 on Microstructure and Properties of WC/FeCoNiCrMo0.2 Composite High Entropy Alloy Coatings by Laser Cladding.

FeCoNiCrMo0.2 high entropy alloy has many excellent properties, such as high strength, high wear resistance, high corrosion resistance, and high ductility. To further improve the properties of this coating, FeCoNiCrMo high entropy alloy (HEA) coatings, and two composite coatings, FeCoNiCrMo0.2 + WC and FeCoNiCrMo0.2 + WC + CeO2, were prepared on the surface of 316L stainless steel by laser cladding technology. After adding WC ceramic powder and CeO2 rare earth control, the microstructure, hardness, wear resistance, and corrosion resistance of the three coatings were carefully studied. The results show that WC powder significantly improved the hardness of the HEA coating and reduced the friction factor. The FeCoNiCrMo0.2 + 32%WC coating showed excellent mechanical properties, but the distribution of hard phase particles in the coating microstructure was uneven, resulting in unstable distribution of hardness and wear resistance in each region of the coating. After adding 2% nano-CeO2 rare earth oxide, although the hardness and friction factor decreased slightly compared with the FeCoNiCrMo0.2 + 32%WC coating, the coating grain structure was finer, which reduced the porosity and crack sensitivity of the coating, and the phase composition of the coating did not change; there was a uniform hardness distribution, a more stable friction coefficient, and the flattest wear morphology. In addition, under the same corrosive environment, the value of polarization impedance of the FeCoNiCrMo0.2 + 32%WC + 2%CeO2 coating was greater, the corrosion rate was relatively low, and the corrosion resistance was better. Therefore, based on various indexes, the FeCoNiCrMo0.2 + 32%WC + 2%CeO2 coating has the best comprehensive performance and can extend the service life of 316L workpieces.

The stereoselective toxicity of dinotefuran to Daphnia magna: A systematic assessment from reproduction, behavior, oxidative stress and digestive function.

Dinotefuran is a promising neonicotinoid insecticide with chiral structure. In the present study, the stereoselective toxicity of dinotefuran to Daphnia magna (D. magna) was studied. The present result showed that S-dinotefuran inhibited the reproduction of D. magna at 5.0 mg/L. However, both R-dinotefuran and S-dinotefuran had no genotoxicity to D. magna. Additionally, neither R-dinotefuran nor S-dinotefuran had negative influences on the motor behavior of D. magna. However, S-dinotefuran inhibited the feeding behavior of D. magna at 5.0 mg/L. Both R-dinotefuran and S-dinotefuran induced oxidative stress effect in D. magna after exposure. R-dinotefuran significantly activated the activities of superoxide dismutase (SOD) and glutathione S-transferase (GST), while S-dinotefuran showed the opposite effect. S-dinotefuran had more obvious activation effect on the acetylcholinesterase (AchE) activity and trypsin activity compared to R-dinotefuran. The transcriptome sequencing results showed that S-dinotefuran induced more DEGs in D. magna, and affected the normal function of ribosome. The DEGs were mainly related to the synthesis and metabolism of biomacromolecules, indicating the binding mode between dinotefuran enantiomer and biomacromolecules were different. Additionally, the present result indicated that the digestive enzyme activity and digestive gene expression levels in D. magna were greatly enhanced to cope with the inhibition of S-dinotefuran on the feeding.

Natural Wood-Derived Macroporous Cellulose for Highly Efficient and Ultrafast Elimination of Double-Stranded RNA from In Vitro-Transcribed mRNA.

Double-stranded RNA (dsRNA) is a major impurity that can induce innate immune responses and cause adverse drug reactions. Removing dsRNA is an essential and non-trivial process in manufacturing mRNA. Current methods for dsRNA elimination use either high-performance liquid chromatography or microcrystalline cellulose, rendering the process complex, expensive, toxic, and/or time-consuming. This study introduces a highly efficient and ultrafast method for dsRNA elimination using natural wood-derived macroporous cellulose (WMC). With a naturally formed large total pore area and low tortuosity, WMC removes up to 98% dsRNA within 5 min. This significantly shortens the time for mRNA purification and improves purification efficiency. WMC can also be filled into chromatographic columns of different sizes and integrates with fast-protein liquid chromatography for large-scale mRNA purification to meet the requirements of mRNA manufacture. This study further shows that WMC purification improves the enhanced green fluorescent protein mRNA expression efficiency by over 28% and significantly reduces cytokine secretion and innate immune responses in the cells. Successfully applying WMC provides an ultrafast and efficient platform for mRNA purification, enabling large-scale production with significant cost reduction.

Identification of an essential spinoparabrachial pathway for mechanical itch.

The sensation of itch is a protective response that is elicited by either mechanical or chemical stimuli. The neural pathways for itch transmission in the skin and spinal cord have been characterized previously, but the ascending pathways that transmit sensory information to the brain to evoke itch perception have not been identified. Here, we show that spinoparabrachial neurons co-expressing Calcrl and Lbx1 are essential for generating scratching responses to mechanical itch stimuli. Moreover, we find that mechanical and chemical itch are transmitted by separate ascending pathways to the parabrachial nucleus, where they engage separate populations of FoxP2PBN neurons to drive scratching behavior. In addition to revealing the architecture of the itch transmission circuitry required for protective scratching in healthy animals, we identify the cellular mechanisms underlying pathological itch by showing the ascending pathways for mechanical and chemical itch function cooperatively with the FoxP2PBN neurons to drive chronic itch and hyperknesis/alloknesis.

The efficacy and safety of different systemic combination therapies on advanced hepatocellular carcinoma: a systematic review and meta-analysis.

Background and aims: Systemic combinations have recently brought significant therapeutic benefits for advanced hepatocellular carcinoma (aHCC). To design the most effective combination regimens, a systematic review (PROSPERO ID: CRD42022321949) was conducted to evaluate the efficacy and safety of systemic combinations on aHCC. Methods: We retrieved all the studies from PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and China National Knowledge Infrastructure (CNKI) using the Medical Subject Headings (MeSH) terms until December 21, 2022. The effect indicators (hazard ratio [HR], relative risk [RR], and median) were pooled by a fixed- or random-effects model. A subgroup analysis was conducted according to types and specific therapies. Results: In total, 88 eligible studies were selected from 7249 potential records. Each kind of combination treatment (chemotherapy plus chemotherapy, targeted plus immune checkpoint inhibitor (ICI) therapy, targeted plus chemotherapy, and targeted plus targeted therapy) had a better objective response rate (ORR) in patients with aHCC, compared to the monotherapy mostly with sorafenib (RR: 1.57 [1.44-1.71]; I 2 = 30%). Of those, targeted plus ICI therapy showed better therapeutic efficiency in overall survival (median: 15.02 [12.67-17.38]), progression-free survival (median: 7.08 [6.42-7.74]), and ORR (RR: 1.81 [1.55-2.13]), compared to the monotherapy. Specifically, Atezo plus Beva showed all those benefits. Our pooled result showed all the combinations had increased ≥3 Grade treatment-related adverse events (TrAEs), with an RR of 1.25 [95% CI: 1.15-1.36], compared to the monotherapy. Conclusion: The systemic combinations, especially targeted plus ICI therapy, including Atezo plus Beva, significantly improve clinical outcomes but increase side effects in patients with aHCC. Future trials should concentrate on improvement in therapeutic efficiency and reduction of toxicity of targeted plus ICI therapy. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022321949.

Improvements in Maximum Bite Force with Gum-Chewing Training in Older Adults: A Randomized Controlled Trial.

No specific methods have been officially proposed for the prevention and improvement of oral hypofunction. Therefore, in this randomized controlled trial, we aimed to develop a gum-chewing training program and determine its effects in older adults. A total of 218 older adults, aged 65-85 years, were randomly allocated to the intervention or control groups. The intervention group chewed the experimental gum daily, whereas the control group consumed the experimental granular food daily. The outcome assessments measured the maximum bite force, occlusal contact areas, oral dryness, tongue pressure, tongue and lip functions, masticatory function, and gum-chewing time. The measured values for each outcome were compared between groups using the Mann-Whitney U test and within groups pre- and post-intervention using the Wilcoxon signed-rank test. A total of 211 participants completed the study. After 2 months, the intervention group had a significantly higher maximum bite force than the control group (p = 0.01), indicating that gum-chewing training improved maximum bite force in older adults. This was determined using one type of bite force measuring device. Therefore, it is suggested that gum-chewing training has a high potential to improve oral hypofunction.