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ObjectiveObservational studies suggest that the frailty index (FI) is closely related to delirium, but the relationship between them is still uncertain due to the influence of various confounding factors. Therefore, two-sample Mendelian randomization (MR) was used to explore the causal relationship between the FI and delirium risk.MethodsThis study obtained pooled statistics for the FI and delirium from two of the most extensive genome-wide association studies. To make the results more robust and reliable, supplementary analyses were performed using several robust analytical methods (inverse-variance weighting, MR-Egger regression, and weighted median). In addition, this study used the MR-Egger intercept test, Cochran’s Q test, funnel plots and the leave-one-out method to evaluate the pleiotropy and heterogeneity among the abovementioned genetic variation instrumental variables.ResultsFrailty might increase the relative risk of delirium, as shown by IVW (OR = 1.849, 95% CI 0.027∼2.067, P = 0.044), weighted median (OR = 1.726, 95% CI −0.178∼2.664, P = 0.083), MR-Egger regression (OR = 1.768, 95% CI −3.08∼6.171, P = 0.525) and leave-one-out sensitivity analysis (P = 0.058). Although the WME method and MR–Egger regression analysis showed no statistically significant causal relationship between the FI and the risk of delirium, the direction of the causal effect was consistent with the IVW method.ConclusionThere is a notable correlation between a higher FI and an elevated risk of delirium. This indicates that healthcare providers should take proactive measures to prevent delirium in hospitalized patients with a higher FI.

BackgroundOsteopenia and osteoporosis are posing a long-term influence on the aging population’s health contributing to a higher risk of mortality, loss of autonomy, hospitalization, and huge health system costs and social burden. Therefore, more pertinent data are needed to demonstrate the current state of osteoporosis. ObjectiveThis sampling survey seeks to assess the trends in the prevalence of osteopenia and osteoporosis in a Chinese Han population. MethodsA community-based cross-sectional study involving 16,377 participants used a multistage sampling method. Bone mineral density was measured using the quantitative ultrasonic densitometry. Student t test and Mann-Whitney U test were used to test the difference between normally and nonnormally distributed quantitative variables between male and female participants. A chi-square (χ2) test was used to compare categorized variables. Stratified analysis was conducted to describe the prevalence rates of osteoporosis (T score ≤–2.5) and osteopenia (T score –2.5 to –1.0) across age, sex, calcium intake, and menopause. A direct standardization method was used to calculate the age-standardized prevalence rates of osteoporosis and osteopenia. T-score was further categorized into quartiles (T1-T4) by age- and sex-specified groups. ResultsThe prevalence rates of osteopenia and osteoporosis were 40.5% (6633/16,377) and 7.93% (1299/16,377), respectively, and the age-standardized prevalence rates were 27.32% (287,877,129.4/1,053,861,940) and 3.51% (36,974,582.3/1,053,861,940), respectively. There was an increase in osteopenia and osteoporosis prevalence from 21.47% (120/559) to 56.23% (754/1341) and 0.89% (5/559) to 17.23% (231/1341), respectively, as age increased from 18 years to 75 years old. The prevalence rates of osteopenia and osteoporosis were significantly higher in female participants (4238/9645, 43.94% and 1130/9645, 11.72%) than in male participants (2395/6732, 35.58% and 169/6732, 2.51%; P

More than half of all cancers demonstrate aberrant c-Myc expression, making this arguably the most important human oncogene. Deregulated long non-coding RNAs (lncRNAs) are also commonly implicated in tumorigenesis, and some limited examples have been established where lncRNAs act as biological tuners of c-Myc expression and activity. Here, we demonstrate that the lncRNA denoted c-Myc Enhancing Factor (MEF) enjoys a cooperative relationship with c-Myc, both as a transcriptional target and driver of c-Myc expression. Mechanistically, MEF functions by binding to and stabilizing the expression of hnRNPK in colorectal cancer cells. The MEF-hnRNPK interaction serves to disrupt binding between hnRNPK and the E3 ubiquitin ligase TRIM25, which attenuates TRIM25-dependent hnRNPK ubiquitination and proteasomal destruction. In turn, the stabilization of hnRNPK through MEF enhances c-Myc expression by augmenting the translation c-Myc. Moreover, modulating the expression of MEF in shRNA-mediated knockdown and overexpression studies revealed that MEF expression is essential for colorectal cancer cell proliferation and survival, both in vitro and in vivo. From the clinical perspective, we show that MEF expression is differentially increased in colorectal cancer tissues compared to normal adjacent tissues. Further, correlations exist between MEF, c-Myc, and hnRNPK suggesting the MEF-c-Myc positive feedback loop is active in patients. Together these data demonstrate that MEF is a pivotal partner of the c-Myc network and propose MEF as a valuable therapeutic target for colorectal cancer.

Introduction: Virtual Synchronous Generators (VSGs) are used in Voltage Source Converter-based Multi-Terminal High-Voltage Direct Current (VSC-MTDC) systems to enhance power system stability. However, the MTDC framework can lead to instability due to reduced inertia in certain grid areas, especially during load switching at VSC stations. This instability is exacerbated by untimely adjustments of the VSG's power setpoint, leading to voltage and frequency oscillations.Methods: This study introduces a cooperative control approach for the DC voltage of the VSG, employing a consensus algorithm and Model Predictive Control (MPC). This method aims to achieve incremental power for the VSG and provide interactive power commands for both the grid side and the wind farm side. The consensus algorithm ensures coherent system adjustments, while the MPC algorithm tracks DC-side voltage changes in real time.Results: The application of this cooperative control approach significantly enhances DC voltage regulation performance. It effectively reduces the extent of frequency drops and mitigates secondary frequency drop (SFD) issues, particularly those arising from the use of wind farms for frequency regulation and the associated speed recovery in wind turbine units.Discussion: The increase in supplemental power effectively utilizes the energy stored in DC-side capacitors for power balance regulation and introduces additional inertial power into the system. Electromagnetic transient simulations have confirmed the effectiveness of the Consensus MPC-VSG method, demonstrating its ability to optimize the dynamic performance of VSC-MTDC systems and promote stability in DC voltage and frequency.Conclusion: The findings suggest that employing the Consensus MPC-VSG method offers a promising solution for enhancing the stability and operational efficiency of VSC-MTDC systems, addressing the challenges posed by the inherent segmentation of the grid and the integration of renewable energy sources like wind farms.

Traditional methods of garlic fertilization involve large amounts of balanced fertilizer with equal proportions of N, P, and K, leading to nutrient imbalances, reduced yield and nutritional quality, and elevated risk of environmental pollution. This study for the first time measured garlic nutrient absorption and mineral elements status in garlic fields. In addition, a garlic-specific fertilizer formula and recommended rate were designed and applied in multiple garlic fields during the 2019–21 growing season. We assessed the performance of garlic-specific fertilizer in terms of yield, quality, and nutrient utilization efficiency. We showed that garlic prefers to absorb N and K, and its absorption of P was much lower. Deficiencies in Cl, Mn, S, and Fe are found in 98.7%, 56.1%, 22.8%, and 11.9% of garlic fields. Compared with farmer fertilization, the garlic-specific fertilizers increased sprout yield by 12.9% to 30.5%, bulb yield by 11.0% to 33.5%, and net income by 18.2% to 45.6%. Furthermore, it improved the nutritional quality [vitamin C (Vc), soluble sugar (SS), and soluble protein] of the garlic and reduced the accumulation of nitrate. The formula of special fertilizer was more in line with the law of garlic nutrient absorption, increasing the nutrient utilization effect, reducing the environmental risks. Application of specific fertilizer increased N, P, and K partial productivity by 26.6% to 50.1%, 82.6% to 116.5%, and 54.6% to 83.3%, respectively. These results suggest that replacing balanced fertilizers in the garlic market with garlic-specific fertilizers can improve garlic farmers' incomes and soil health.

Abstract Urbanization is inevitable in both developing and developed countries. However, this growth and transformation of the urban area can pose a significant threat to urban cultural heritage, which is a sensitive component of the urban environment. As cities modernize and change, a risk of irreparable loss of cultural heritage exists. Therefore, taking steps to protect and preserve these sites for posterity is crucial. To better protect urban cultural heritage, decision-makers must rapidly assess the impact of urbanization on cultural heritage while maintaining a balance between cultural heritage preservation and urban growth. This study developed a risk-based cumulative impact assessment (CIA) method that integrates a set of quantifiable indicators to address these issues. This method generates standardized assessment results based on game theory and set pair analysis theory. In contrast to other CIA methods, this risk-based approach effectively manages scientific complexity and uncertainties, thus enhancing the quality of the assessment results. This method was applied to 21 classical gardens in Suzhou, China. The results show that Suzhou classical gardens are impacted by urbanization. This study confirmed that adopting a risk-based CIA method that considers the impact of adverse urbanization on cultural heritage sites is an efficient approach. Successful implementation of the proposed method can provide decision-making support for different types of cultural heritage in other areas.

Abstract Dysregulated fear reactions can result from maladaptive processing of trauma-related memories. In post-traumatic stress disorder (PTSD) and other psychiatric disorders, dysfunctional extinction learning prevents discretization of trauma-related memory engrams and generalizes fear responses. Although PTSD may be viewed as a memory-based disorder, no approved treatments target pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. Here, we show that closed-loop, SWR triggered neuromodulation of the medial forebrain bundle (MFB) can enhance fear extinction consolidation in male rats. The modified fear memories became resistant to induced recall (i.e., ‘renewal’ and ‘reinstatement’) and did not reemerge spontaneously. These effects were mediated by D2 receptor signaling-induced synaptic remodeling in the basolateral amygdala. Our results demonstrate that SWR-triggered closed-loop stimulation of the MFB reward system enhances extinction of fearful memories and reducing fear expression across different contexts and preventing excessive and persistent fear responses. These findings highlight the potential of neuromodulation to augment extinction learning and provide a new avenue to develop treatments for anxiety disorders.

This is a paper in the field of ceramic materials for metallurgy. Magnesia chrome refractory is widely used in copper industry due to its excellent high temperature strength, fine slag corrosion resistance and good performance. In this paper, the research status of corrosion mechanism of magnesia chrome refractories for copper metallurgy is summarized theoretically, and the effect and action mechanism of factors on the service life of metallurgical furnace was clarified, such as slag temperature, grade, Cr2O3 content and additives in magnesia chrome bricks. Finally, according to the research status, the main ways to improve the service life of magnesia chrome refractories are summarized, which will provide guidance and help for the structural design and performance control of magnesia chrome refractories in the future.

Plant organ biomass allocation and morphological characteristics are important functional traits. The responses of plant root, stem, and leaf traits to heterogeneous habitats in floodplain wetlands are highly important for understanding the ecological adaptation strategies of riparian plants. However, the patterns of these responses remain unclear. In a floodplain wetland in the middle reaches of the Heihe River, we studied the responses of the root, stem, and leaf morphological traits and biomass allocation of Leymus secalinus to varying habitat conditions. We measured these traits in three sample plots, delineated based on distance from the riverbank: plot I (near the riparian zone, 50–150 m from the riverbank), plot II (middle riparian zone, 200–300 m from the riverbank), and plot III (far riparian zone, 350–450 m from the riverbank). The results showed that in plot I, L. secalinus tended to have slender roots and stems and small leaves, with a biomass allocation strategy that maximized the root–shoot ratio (RSR). In plot II, L. secalinus had thick stems and moderate leaf and root patterns, and the RSR values were between those of plot I and plot III. In plot III, L. secalinus had thin and short stems and large leaves; furthermore, among the root morphological structures, plot III had the shortest Rhizome length (RL) and longest Rhizome diameter (RD), and the RSR was the lowest. Moreover, there was a significant correlation between organ biomass and leaf thickness, stem length, RD, and RL in the three habitats (p < 0.05). By balancing the biomass allocation among organs, wetland plants in floodplains balance changes in root, stem, and leaf morphological characteristics to improve their environmental adaptation.

In this study, a phase-generated carrier (PGC) demodulation algorithm combined with the extended Kalman filter (EKF) algorithm based on an electro-optic modulator (EOM) is proposed, which can achieve nonlinear distortion (such as modulation depth drift and carrier phase delay) suppression for high-frequency phase carrier modulation. The improved algorithm is implemented on a field-programmable gate array (FPGA) hardware platform. The experimental results by the PGC-EKF method show that total harmonic distortion (THD) decreases from −32.61 to −54.51 dB, and SINAD increases from 32.59 to 47.86 dB, compared to the traditional PGC-Arctan method. This indicates that the PGC-EKF demodulation algorithm proposed in this paper can be widely used in many important fields such as hydrophone, transformer, and ultrasound signal detection.

Background: The importance of N6-methyladenosine (m6A) modification in tumorigenesis and progression have been highlighted. This study aimed to investigate the modification of insulin receptor substrate 1 (IRS1) by m6A and its role in oral squamous cell carcinoma (OSCC). Methods: Bioinformatics was employed to predict differential genes related to epithelial-mesenchymal transition (EMT) in OSCC. Seventeen pairs of OSCC and paracancerous tissue samples were collected. The impact of IRS1 on OSCC cell growth and EMT was evaluated. The fluctuations in IRS1 enrichment and the involvement of p53/Line-1 were investigated. Results: IRS1 was highly expressed in OSCC. IRS1 silencing decreased OSCC cell proliferation and increased apoptosis. IRS1 silencing hindered EMT by regulating related markers. IRS1 silencing upregulated p53 and downregulated Line-1 ORF1p. The p53 inhibition reversed the effects of IRS1 silencing and induced EMT in OSCC cells. Furthermore, the m6A modification of IRS1 was increased in OSCC cells. IRS1 were positively regulated by the m6A regulators methyltransferase-like 14 (METTL14) and YTH domain-containing protein 1 (YTHDC1). IRS1 bound to YTHDC1, and YTHDC1 knockdown inhibited the IRS1 nuclear export. The obesity-associated protein (FTO) negatively regulated IRS1, and FTO overexpression reversed the IRS1-induced OSCC tumor growth. Conclusions: m6A methylation-mediated IRS1 regulated EMT in OSCC through p53/Line-1. These findings provide potential therapeutic strategies for managing OSCC.

Hexagonal boron nitride (h-BN) nanoparticles have attracted increasing attention due to their unique structure and properties. However, it is difficult to synthesize h-BN nanoparticles with uniform spherical morphology due to their crystal characteristic. The morphology control by tuning their precursor synthesis is a promising and effective strategy to solve this problem. Especially, the treatment temperature of precursors plays an important role in the morphology and surface area of h-BN nanoparticles. Herein, h-BN nanoparticles with different morphologies were synthesized via regulating the treatment temperature of precursors. The result shows that treatment temperature will affect the microstructure and state of precursor and further influence the morphology of h-BN products. Benefiting from the unique structure, the h-BN obtained using 250 °C precursors shows higher specific surface area (61.1 m2 g−1) than that of 85 °C (36.5 m2 g−1) and 145 °C (27.9 m2 g−1). h-BN products obtained using 250 °C precursors show higher specific surface area than that of 85 °C and 145 °C. The optimal condition for obtaining high-quality spherical h-BN is the pretreatment temperature of 250 °C and sintering temperature of 1300 °C. Importantly, compared with commercial h-BN nanoparticles, the synthesized h-BN nanoparticles show more uniform structure and larger specific surface area, indicating that sintering activity will be greatly improved. Furthermore, the reaction pathway and formation mechanism of h-BN was revealed by DFT calculations. The result shows that the five stationary states and five transition states exist in the reaction pathway, and the energy barrier can be overcome at high temperatures to form a ring h-BN. In view of its simplicity and efficiency, this work is promising for designing and guiding the synthesis of h-BN nanoparticles with uniform morphology.

Large-scale deep soil desiccation has occurred in the Loess Plateau caused by large-scale introduced vegetation rehabilitation over many years. Consequently, this occurrence has raised concerns among scholars regarding the obstacles to plant succession that may result from deep soil desiccation following large-scale artificial vegetation construction. In order to answer the question of whether vegetation can be replanted and water can be restored in the deep dry soil environment in this region, large soil columns in the field were used to simulate dry soil in the 0–1000 cm layer. Some soil columns were planted with Robinia pseudoacacia, Caragana korshinskii, alfalfa (Medicago sativa L.), jujube (Zizyphus jujuba Mill.), and Poa annua, while other columns were covered with stones, branches, ground cloth, and white plastic film. Bare soil columns were used as the control treatment (CK). Dynamic changes of soil water in the 0–1000 cm soil layer of the soil columns were regularly observed, and five years (2014–2018) of continuous observation data were analyzed. The results showed that: (1) Under the condition of severe desiccation of the deep soil layer in the semi-arid loess region of China, reintroducing plants can be successful, and the reintroduced plants can grow normally depending on the amount of local precipitation; (2) Due to the different water consumption amounts of reintroduced plants, a new soil water balance can emerge in the dry soil layer. Plants with high water consumption planted on dry soil can result in more severe soil desiccation, while plants with low water consumption planted on dry soil can alleviate soil desiccation. (3) The use of soil surface mulching had a strong effect on soil water restoration, with the order of effectiveness for soil desiccation remediation being white plastic film > ground cloth > branches ≈ stones > control (CK). In particular, the use of white plastic film can transform severely desiccated soil in the 0–640 cm layer into a non-desiccated state. These research findings directly address long-standing concerns of ecologists regarding plant succession and soil water restoration in deep desiccated soil, and can serve as a reference for the sustainable development of ecological construction in the Loess Plateau of China.

BackgroundIn Thailand, HIV transmission is well characterized in large urban centers such as Bangkok and Chiang Mai but less so outside of these areas. The main purpose of this study was to assess HIV incidence and associated risk factors in Nakhon Ratchasima and Ratchaburi.MethodsParticipants assigned male sex at birth were enrolled in this prospective observational cohort study between November 2017 and July 2018. HIV and syphilis testing and sociobehavioral questionnaires were administered over 18 months. HIV incidence rates and 95% confidence intervals (CIs) were estimated using a Poisson distribution. Cox proportional hazards models were used to estimate unadjusted and adjusted hazard ratios (aHRs) and 95% CIs for associations between potential risk factors and HIV seroconversion.ResultsA total of 1003 participants were enrolled. Overall HIV incidence was 1.56 per 100 person-years (95% CI:1.02-2.44) and similar at both sites. In the fully adjusted model, sex with a sex worker in the past six months was associated with reduced risk of seroconversion (aHR:0.10, 95% CI:0.01-0.77). In the reduced adjusted model, receptive anal sex (aHR:3.40, 95% CI:1.32-8.74) and STI diagnosis in the past six months (aHR:3.58, 95% CI:1.19-10.76) were associated with seroconversion, while sex with a sex worker in the past six months was associated with reduced risk of seroconversion (aHR:0.11, 95% CI:0.02-0.67). Additionally, 56% reported interest in taking PrEP and 82% reported willingness to participate in a hypothetical future vaccine trial.ConclusionsRecent receptive anal sex practices were associated with HIV acquisition in these populations, highlighting the continued need for interventions encouraging safer anal sex practices to reduce HIV incidence.

China's ‘dual carbon’ strategy is of strategic importance in leading global climate governance and promoting China's high-quality and green economic development. Cities are the centres of human activities. However, these are also places where high energy consumption and high carbon emissions are concentrated. This study selected data from 192 small and medium-sized cities in mainland China for the period 2000–2020. It classified these into seven categories using the K-means clustering method, calculated the decoupling status of different types of small and medium-sized cities based on the Tapio decoupling index, and analysed the relationship between carbon emissions and economic growth in various types of small and medium-sized cities based on the EKC curve theory. Finally, the backpropagation neural network (BPNN) model was used to classify and predict the time required to achieve carbon peaking for seven types of small and medium-sized cities. The following conclusions were drawn: (1) The development status of small and medium-sized cities shows a ‘geese echelon pattern’. New dynamic small and medium-sized urban areas may reach peak carbon emissions first, while resource-based small and medium-sized urban areas may be the last to do so. (2) The decoupling of carbon emissions from industrial development in small and medium-sized cities has not been completed. This manifests mainly through the states of declining decoupling, absolute decoupling, and strong negative decoupling. (3) A significant inverted U-shaped relationship exists between economic development and carbon emissions in these cities. (4) These cities may have the disadvantage of premature or excessive de-industrialisation. Additionally, these generally have an inefficient and expansionary economic development status. Therefore, this study contended for a more robust integration of a radical political economy and ecological economics to support the development of such cities in China. The paper proposes differentiated development paths and fundamental recommendations for small and medium-sized cities in the implementation of the ‘double carbon’ strategy. The intention is to provide theoretical guidance and implications for promoting green and low-carbon development in urban and rural areas and for the early achievement of the strategy in China.

Background: Immune checkpoint inhibitor therapy has demonstrated impressive clinical benefits in multiple tumor types. TQB2450, a novel monoclonal antibody targeting programmed cell death ligand 1, has shown safety and efficacy in preclinical studies. Objectives: This first-in-human study aimed to evaluate the safety/tolerability, pharmacokinetics (PK), immunogenicity, and preliminary antitumor activity of TQB2450 in patients with advanced malignant tumors. Design and methods: In this phase I study, eligible patients with advanced malignant tumors received intravenous TQB2450 once every 3 weeks. This study consisted of a 3 + 3 dose-escalation phase (1–30 mg/kg) and a specific dose-expansion phase (1200 mg). The primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety. The secondary endpoints were PK, immunogenicity, and investigator-assessed response rate. Results: Between April 2018 and February 2020, 40 patients were enrolled (22 in the dose-escalation phase and 18 in the dose-expansion phase). No DLT was reported and the MTD was not reached. Grade ⩾3 or worse treatment-related treatment-emergent adverse events (AEs) occurred in 11 (27.50%) patients, with the most frequent being aspartate aminotransferase increased (5.00%), leukopenia (5.00%), and anemia (5.00%). Treatment-related serious AEs were reported in six patients, the most common of which was decompensated liver function (5.00%). No treatment-related death was reported. The maximum serum concentration of TQB2450 increased in a dose-proportional manner. Treatment-induced anti-drug antibodies were detected in 31.58% (12/38) of patients. The investigator assessed the objective response rate as 5.00% and the disease control rate was 52.50%, including 2 partial responses and 19 stable diseases. The median progression-free survival was 2.69 (95% confidence interval, 2.07–6.14) months. Conclusion: TQB2450 has a manageable safety profile with favorable PK and immunogenicity and has shown early evidence of clinical activity in advanced malignant tumors. ClinicalTrials.gov identifier: NCT03460457.

ObjectiveThis study aimed to evaluate the clinical value of dynamic monitoring of neutrophil/lymphocyte ratio (NLR), APACHE II (Acute Physiology and Chronic Health Evaluation II) score, and Sequential Organ Failure Assessment (SOFA) score in predicting 28-day prognosis and drug resistance in patients with bloodstream infection with Acinetobacter baumannii–calcoaceticus complex (Abc complex).Patients and methodsIn this research, individuals admitted to Tianjin Medical University General Hospital from January 2017 to March 2023 with bloodstream infections and a minimum of one Abc complex positive blood culture were chosen. The risk factors for the 28-day prognosis and drug resistance were analyzed using logistic regression. The NLR, APACHE II score, and SOFA score were evaluated for predicting 28-day prognosis and drug resistance using an ROC curve analysis. The data were analyzed using R Studio to find correlations and conduct survival analysis with the Kaplan–Meier method.ResultsThe final statistical analysis included a total of 129 patients with bloodstream infections caused by Abc complex. Independent risk factors predicting mortality within 28 days were identified as follows: the SOFA score and APACHE II scores at 24 h, and APACHE II scores at 72 h after the onset of blood infection (p

Rivers are important habitats for wintering waterbirds. However, they are easily influenced by natural and human activities. An important approach for waterbirds to adapt to habitats is adjusting the activity time and energy expenditure allocation of diurnal behavior. The compensatory foraging hypothesis predicts that increased energy expenditure leads to longer foraging time, which in turn increases food intake and helps maintain a constant energy balance. However, it is unclear whether human-disturbed habitats result in increased energy expenditure related to safety or foraging. In this study, the scan sample method was used to observe the diurnal behavior of the wintering Spot-billed Duck (Anas poecilorhyncha) in two rivers in the Xin'an River Basin from October 2021 to March 2022. The allocation of time and energy expenditure for activity in both normal and disturbed environments was calculated. The results showed that foraging accounted for the highest percentage of time and energy expenditure. Additionally, foraging decreased in the disturbed environment than that in the normal environment. Resting behavior showed the opposite trend, while other behaviors were similar in both environments. The total diurnal energy expenditure of ducks in the disturbed environment was greater than that in the normal environment, with decreased foraging and resting time percentage and increased behaviors related to immediate safety (swimming and alert) and comfort. These results oppose the compensatory foraging hypothesis in favor of increased security. The optimal diurnal energy expenditure model included river width and water depth, which had a positive relationship; an increase in either of these two factors resulted in an increase in energy expenditure. This study provides a better understanding of energy allocation strategies underlying the superficial time allocation of wintering waterbirds according to environmental conditions. Exploring these changes can help understand the maximum fitness of wintering waterbirds in response to nature and human influences.

In order to explore the aging performance attenuation mechanism of 90# and SBS (styrene–butadiene–styrene block copolymer) modified asphalt under the large temperature difference and strong ultraviolet radiation in the Tibetan area, this paper adopts the outdoor natural exposure aging (NEA) condition in the Tibetan area. Scanning calorimetry and thermogravimetric analysis techniques were used to test and analyse the permanent deformation resistance and thermal stability of two asphalts with different aging times (0 month (0M), April (4M) and 8 months (8M)) to study the on-site aging mechanism of asphalt in Tibetan areas. The results show that with the prolongation of NEA time, the non-recoverable creep compliance, polymer area and glass transition temperature of the two asphalts decrease, while the average recovery rate and deformation temperature increase, and the aging degree gradually deepens. Under the special outdoor conditions in Tibetan areas, the permanent deformation resistance and thermal stability of SBS modified asphalt are better than 90# asphalt. The research results explored the aging and decay mechanism of the two asphalts from the macro and micro perspectives, which provided theoretical support for the research and development of anti-aging technology in Tibetan areas and guaranteeing the road performance of asphalt pavement in the whole life cycle.

BackgroundAntiretroviral Therapy (ART) in children remains challenging due to resource-constrained settings. We conducted a 13-year, prospective, multicenter cohort study on the effectiveness and safety of LPV/r-based regimens in ART-naive and ART-experienced children.MethodsFrom January 2008 to May 2021, children living with HIV-1 were recruited with LPV/r-based regimens from 8 clinical research sites in 6 provinces in China. Effectiveness outcomes were virologic failure (defined as at least two consecutive measurements of VL > 200 copies/mL after 6 months of ART) and immune response (defined as CD4% recovered to more than 25% after 12 months of treatment). The safety outcomes were treatment-related grade 2–4 adverse events and abnormal laboratory test results.ResultsA total of 345 ART-naïve children and 113 ART-experienced children were included in this cohort study. The median follow-up time was 7.3 (IQR 5.5–10.5) years. The incidence density of virologic failure was 4.1 (95% CI 3.3–4.9) per 100 person-years in ART-naïve children and 5.0 (95% CI 3.5–6.5) per 100 person-years in ART-experienced children. Kaplan Meyer (KM) curve analysis showed children with ART experience were at a higher risk of virologic failure (p 5 days of LPV intake (aHR = 1.889, 1.004–3.554); The risk factor of virologic failure in ART-experienced children was missed dose times >5 days (aHR = 2.689, 1.299–5.604) and mother as caregivers for ART administration (aHR = 0.475, 0.238–0.948). However, during long-term treatment, viral suppression rates between ART-naïve and ART-experienced children remained similar. No significant differences were observed in the immune response, treatment-related grade 2–4 events, and abnormal laboratory test results between ART-naïve children and ART-experienced children.ConclusionOur research underscores that with consistent, long-term treatment of LPV/r-based regimens, ART-experienced children can achieve therapeutic outcomes comparable to ART-naïve children. It provides crucial insights on LPV/r-based regimens in pediatric HIV treatment, especially in resource-limited settings where high-cost Integrase Strand Transfer Inhibitors (INSTs) are inaccessible. This evidence-based understanding provides an essential addition to the global therapeutic strategies for pediatric HIV treatment.

AbstractBackground Venous thromboembolism (VTE) is one of the most common and severe complications of multiple myeloma (MM). The aim of this study was to learn about the current awareness regarding MM-associated VTE among Chinese hematologists.Methods A nationwide, online, questionnaire-based survey was sent to the specialized hematologists in mainland China. The questionnaire investigated respondents’ demographic and occupational characteristics, their ability to identify VTE risk factors, and their thromboprophylaxis decisions for different anti-MM regimens. Six clinical vignettes were used to evaluate hematologists’ awareness of stratified thromboprophylaxis. The data were analyzed using SPSS software.Results A total of 518 valid questionnaires were received. Of the 518 hematologists investigated, only 23.7% of them could identify VTE-related risk factors correctly. Most hematologists could select appropriate thromboprophylaxis for common anti-MM regimens such as VCd (bortezomib, cyclophosphamide, and dexamethasone) and VRd (bortezomib, lenalidomide, and dexamethasone), but not for uncommon ones such as VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) and KRd (carfilzomib, lenalidomide, and dexamethasone). The results from the vignettes suggested that only 19.5% of the hematologists could be defined as the ‘stratified thromboprophylaxis’ group, and the awareness of stratified thromboprophylaxis depended significantly on physicians’ age and working seniority.Conclusion The results of our study showed that a large proportion of Chinese hematologists failed to recognize the VTE risk factors, most of them cannot select appropriate thromboprophylaxis for different MM therapeutic regimens and lack awareness of stratified thromboprophylaxis for MM-associated VTE. A standard VTE prevention guideline is urgently needed for the Chinese myeloma group. Continuous education for new professionals should be encouraged. A VTE collaborative group is supposed to be established in each hospital to enhance the overall medical care for VTE patients.

Abstract The inversion of remote sensing signatures of internal solitary waves (ISWs) can retrieve dynamic characteristics in the ocean interior. However, the presence of ubiquitous large‐amplitude ISWs poses challenges to the commonly used weakly nonlinear methods for parameter retrieval. Through laboratory experiments, we establish a relationship between surface features and internal characteristics of ISWs by the remote sensing imaging mechanism. The results demonstrate that strong nonlinearity significantly influences the retrieval of ISWs, primarily manifested in the calculation of wave‐induced velocities and the applicability of ISW solutions. A fully nonlinear model Dubreil–Jacotin–Long equation is used in the retrieval and has been tested under different conditions. Mooring observations indicate that the determination of ISW parameters from satellite images is affected by the complexity of in situ stratification, but additional remote sensing information such as surface velocities enables us to perform retrievals even if the real‐time measurement of pycnocline depth is not available.

Abstract Background Oocyte maturation arrest and early embryonic arrest are important reproductive phenotypes resulting in female infertility and cause the recurrent failure of assisted reproductive technology (ART). However, the genetic etiologies of these female infertility-related phenotypes are poorly understood. Previous studies have mainly focused on inherited mutations based on large pedigrees or consanguineous patients. However, the role of de novo mutations (DNMs) in these phenotypes remains to be elucidated. Results To decipher the role of DNMs in ART failure and female infertility with oocyte and embryo defects, we explore the landscape of DNMs in 473 infertile parent–child trios and identify a set of 481 confident DNMs distributed in 474 genes. Gene ontology analysis reveals that the identified genes with DNMs are enriched in signaling pathways associated with female reproductive processes such as meiosis, embryonic development, and reproductive structure development. We perform functional assays on the effects of DNMs in a representative gene Tubulin Alpha 4a (TUBA4A), which shows the most significant enrichment of DNMs in the infertile parent–child trios. DNMs in TUBA4A disrupt the normal assembly of the microtubule network in HeLa cells, and microinjection of DNM TUBA4A cRNAs causes abnormalities in mouse oocyte maturation or embryo development, suggesting the pathogenic role of these DNMs in TUBA4A. Conclusions Our findings suggest novel genetic insights that DNMs contribute to female infertility with oocyte and embryo defects. This study also provides potential genetic markers and facilitates the genetic diagnosis of recurrent ART failure and female infertility.

Abstract Dermal fibroblasts and cutaneous nerves are important players in skin diseases, while their reciprocal roles during skin inflammation have not been characterized. Here we identify an inflammation-induced subset of papillary fibroblasts that promotes aberrant neurite outgrowth and psoriasiform skin inflammation by secreting the extracellular matrix protein tenascin-C (TNC). Single-cell analysis of fibroblast lineages reveals a Tnc + papillary fibroblast subset with pro-axonogenesis and neuro-regulation transcriptomic hallmarks. TNC overexpression in fibroblasts boosts neurite outgrowth in co-cultured neurons, while fibroblast-specific TNC ablation suppresses hyperinnervation and alleviates skin inflammation in male mice modeling psoriasis. Dermal γδT cells, the main producers of type 17 pathogenic cytokines, frequently contact nerve fibers in mouse psoriasiform lesions and are likely modulated by postsynaptic signals. Overall, our results highlight the role of an inflammation-responsive fibroblast subset in facilitating neuro-immune synapse formation and suggest potential avenues for future therapeutic research.

Abstract Oocyte maturation arrest is one of the important causes of female infertility, but the genetic factors remain largely unknown. PABPC1L, a predominant poly(A)‐binding protein in Xenopus, mouse, and human oocytes and early embryos prior to zygotic genome activation, plays a key role in translational activation of maternal mRNAs. Here, we identified compound heterozygous and homozygous variants in PABPC1L that are responsible for female infertility mainly characterized by oocyte maturation arrest in five individuals. In vitro studies demonstrated that these variants resulted in truncated proteins, reduced protein abundance, altered cytoplasmic localization, and reduced mRNA translational activation by affecting the binding of PABPC1L to mRNA. In vivo, three strains of Pabpc1l knock‐in (KI) female mice were infertile. RNA‐sequencing analysis showed abnormal activation of the Mos‐MAPK pathway in the zygotes of KI mice. Finally, we activated this pathway in mouse zygotes by injecting human MOS mRNA, and this mimicked the phenotype of KI mice. Our findings reveal the important roles of PABPC1L in human oocyte maturation and add a genetic potential candidate gene to be screened for causes of infertility.

Abstract Due to pressure gain characteristics, the rotating detonation combustor (RDC) can be integrated into gas turbines by further improving the system's performance. The matching of unsteady flows in the RDC and turbine is a key challenge. Here, interactions in an RDC and planar turbine cascade are investigated using the unsteady Reynolds time‐averaged Navier‐Stokes method. The effects of the blade profiles on interactions between the oblique shock wave (OSW) and turbine cascade are analyzed, and the suppression effect of the turbine cascade on high‐frequency pressure oscillations is evaluated. The results show that the OSW interacts with the leading edge, pressure side, suction side, and trailing edge of the turbine stator and rotor blades, which generates complex wave systems in the cascade passage. The opposite propagation direction causes the OSW to be aligned or misaligned with the stator blade. The position of the OSW that operates on the turbine cascade changes, and two different wave system structures appear. The various pitches of the turbine cascade at different blade heights cause differing intensities and propagation directions in the reflected wave as generated by the action of the OSW and turbine cascade and the variable flow fields at different blade heights. The turbine cascade can significantly suppress the high‐frequency pressure oscillations, while the pressure amplitude attenuation rate can reach over 80% when the OSW propagates through the turbine cascade. These findings expound on the interaction mechanism between the rotating detonation wave complex and the turbine stator and rotor blades.

Nasopharyngeal carcinoma (NPC) is a prevalent malignant tumor worldwide. FKBP3 has been reported to participate in tumorigenesis. Nevertheless, the role and mechanism of FKBP3 in NPC remains unclear. In this study, FKBP3 expression was observed to upregulate in NPC patients and cells. Moreover, knockdown of FKBP3 suppressed cell growth, invasion, and migration in HK1 and C666-1 cells. Mechanically, FKBP3 could enhance the p-p65 expression and activated p65 signaling pathway and increased interleukin-6 (IL-6) expression through enhancing histone deacetylase 2 (HDAC2) expression. In rescued experiment, the overexpression of HDAC2 restored diminished cell growth, invasion, and migration caused by FKBP3 depletion. In summary, the knockdown of FKBP3 suppressed NPC cell growth, invasion and migration, deactivated nuclear factor-κB/IL-6 signaling pathway through inhibiting HDAC2 expression, providing a potential therapeutic strategy for NPC treatment.

IntroductionPostoperative delirium (POD) is an acute, transient brain disorder associated with decreased postoperative quality of life, dementia, neurocognitive changes, and mortality. A small number of trials have explored the role of S-ketamine in the treatment of POD due to its neuroprotective effects. Surprisingly, these trials have failed to yield supportive results. However, heterogeneity in delirium assessment methodologies, sample sizes, and outcome settings as well as deficiencies in S-ketamine use methods make the evidence provided by these studies less persuasive. Given the severe impact of POD on the health of elderly patients and the potential for S-ketamine to prevent it, we believe that designing a large sample size, and rigorous randomized controlled trial for further evaluation is necessary.MethodsThis is a single-center, randomized, double-blind, placebo-controlled, pragmatic study. Subjects undergoing total hip or knee arthroplasty will be randomized in a 1:1 ratio to intervention (n = 186) and placebo (n = 186) groups. This trial aims to explore the potential role of S-ketamine in the prevention of POD. Its primary outcome is the incidence of POD within 3 postoperative days. Secondary outcomes include the number of POD episodes, the onset and duration of POD, the severity and subtype of POD, pain scores and opioid consumption, sleep quality, clinical outcomes, and safety outcomes.DiscussionTo our knowledge, this is the first pragmatic study that proposes to use S-ketamine to prevent POD. We reviewed a large body of literature to identify potential preoperative confounding variables that may bias associations between the intervention and primary outcome. We will use advanced statistical methods to correct potential confounding variables, improving the test’s power and external validity of test results. Of note, the patient population included in this trial will undergo intraspinal anesthesia. Although large, multicenter, randomized controlled studies have found no considerable difference in the effects of regional and general anesthesia on POD, patients receiving intraspinal anesthesia have less exposure to at-risk drugs, such as sevoflurane, propofol, and benzodiazepines, than patients receiving general anesthesia. At-risk drugs have been shown to negatively interfere with the neuroprotective effects of S-ketamine, which may be the reason for the failure of a large number of previous studies. There is currently a lack of randomized controlled studies evaluating S-ketamine for POD prevention, and our trial helps to fill a gap in this area.Trial registration: http://www.chictr.org.cn, identifier ChiCTR2300075796.

Allergy is an autoimmune disorder described as an undesirable response of the immune system to typically innocuous substance in the environment. Studies have shown that the ability of proteins to trigger allergic reactions in susceptible individuals can be evaluated by bioinformatics tools. However, developing computational methods to accurately identify new allergenic proteins remains a vital challenge. This work aims to propose a machine learning model based on multi-feature fusion for predicting allergenic proteins efficiently. Firstly, we prepared a benchmark dataset of allergenic and non-allergenic protein sequences and pretested on it with a machine-learning platform. Then, three preferable feature extraction methods, including amino acid composition (AAC), dipeptide composition (DPC) and composition of k-spaced amino acid pairs (CKSAAP) were chosen to extract protein sequence features. Subsequently, these features were fused and optimized by Pearson correlation coefficient (PCC) and principal component analysis (PCA). Finally, the most representative features were picked out to build the optimal predictor based on random forest (RF) algorithm. Performance evaluation results via 5-fold cross-validation showed that the final model, called iAller (https://github.com/laihongyan/iAller), could precisely distinguish allergenic proteins from non-allergenic proteins. The prediction accuracy and AUC value for validation dataset achieved 91.4% and 0.97%, respectively. This model will provide guide for users to identify more allergenic proteins.

BackgroundThis study aimed to identify potential biomarkers in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) and further probe the prognostic implications of CDKN2A mutations, particularly within a subset receiving immunotherapy.MethodsIn this retrospective single-center study, we evaluated the next-generation sequencing (NGS) data from Foundation Medicine (FM) for patients with recurrent or metastatic HNSCC between January 1, 2019, and December 31, 2021. Patients were stratified based on CDKN2A loss-of-function (LOF) versus wild-type (WT) categorizations, with a focused subgroup analysis on those administered immunotherapy.ResultsThe study encompassed 77 patients, of which 62 had undergone immunotherapy. The median duration of follow-up was 22.6 months. For the CDKN2A LOF group, the median overall survival (OS) was 16.5 months, contrasted with 30.0 months in the CDKN2A WT group (P=0.014). Notably, female gender (hazard ratio [HR]=4.526, 95% confidence interval [CI]: 1.934-10.180, P=0.0003) and CDKN2A LOF (HR=2.311, 95% CI: 1.156-4.748, P=0.019) emerged as independent risk factors for mortality in patients with recurrent or metastatic HNSCC. Within the immunotherapy subset, the median OS was 11.7 months for the CDKN2A LOF group, and 22.5 months for the CDKN2A WT group (P=0.017). Further, the female gender (HR=4.022, 95% CI: 1.417-10.710, P=0.006), CDKN2A LOF (HR=4.389, 95% CI: 1.782-11.460, P=0.002), and a combined positive score below 1 (HR=17.20, 95% CI: 4.134-79.550, P

Cross-border activities are possibly associated with the use of amphetamine-type stimulants (ATS), this study was to explore poly-substance of ATS use and influencing factors among ATS use populations in southwest China. A cross-sectional study was conducted by response driven and continuous samplings from January to July 2021. Descriptive, univariate and logistic regression were carried out. ATS users accounted for 95.6% of the target population, of whom one-third had cross-border experiences with 4.1% of the cross-border purchase of drugs. ATS users were mainly over 31 years old (53.9%), male (98.7%), minority (79.1%), and unmarried (72.7%). Cross-border users consumed more ketamine (8%) and methamphetamine (40%) ( P

Among the semiconductor photocatalytic materials, zinc oxide (ZnO)-based composites show promising research prospects in the field of environmental and biomedical materials due to their simple preparation, low cost, high photocatalytic performance, excellent physical stability and biocompatibility. Therefore, this review summarizes the preparation and application of ZnO-based composites with high catalytic performance. Firstly, the modification strategies of ZnO by researchers in recent years are reviewed, including non-metal doping, metal doping, noble metal deposition, compounding with semiconductors and other surface modification methods. Subsequently, the applications of photocatalytic ZnO-based composites in biomedicine (antibacterial, anticancer, biosensing, etc.), environmental pollution and other fields in the last five years are presented. Finally, the challenges faced by the future development of ZnO-based composites in various fields are discussed. We hope that this review will provide ideas for the design and development of efficient photocatalysts based on ZnO-based composites in further applications.

Background: Neointimal hyperplasia (NIH) is the pathological basis of vascular injury disease. Vascular cells are the dominant cells in the process of NIH, but the extent of heterogeneity amongst them is still unclear. Methods: A mouse model of NIH was constructed by inducing carotid artery ligation. Single-cell sequencing was then used to analyze the transcriptional profile of vascular cells. Cluster features were determined by functional enrichment analysis, gene set scoring, pseudo-time analysis, and cell-cell communication analysis. Additionally, immunofluorescence staining was conducted on vascular tissues from fibroblast lineage-traced (PdgfraDreER-tdTomato) mice to validate the presence of Pecam1+Pdgfra+tdTomato+ cells. Results: The left carotid arteries (ligation) were compared to right carotid arteries (sham) from ligation-induced NIH C57BL/6 mice. Integrative analyses revealed a high level of heterogeneity amongst vascular cells, including fourteen clusters and seven cell types. We focused on three dominant cell types: endothelial cells (ECs), vascular smooth muscle cells (vSMCs), and fibroblasts. The major findings were: (1) four subpopulations of ECs, including ECs4, mesenchymal-like ECs (ECs1 and ECs2), and fibro-like ECs (ECs3); (2) four subpopulations of fibroblasts, including pro-inflammatory Fibs-1, Sca1+ Fibs-2, collagen-producing Fibs-3, and mesenchymal-like Fibs-4; (3) four subpopulations of vSMCs, including vSMCs-1, vSMCs-2, vSMCs-3, and vSMCs-3-derived vSMCs; (4) ECs3 express genes related to extracellular matrix (ECM) remodeling and cell migration, and fibro-like vSMCs showed strong chemokine secretion and relatively high levels of proteases; (5) fibro-like vSMCs that secrete Vegfa interact with ECs mainly through vascular endothelial growth factor receptor 2 (Vegfr2). Conclusions: This study presents the dynamic cellular landscape within NIH arteries and reveals potential relationships between several clusters, with a specific focus on ECs3 and fibro-like vSMCs. These two subpopulations may represent potential target cells for the treatment of NIH.

Quinone imines are important derivatives of quinones with a wide range of applications in organic synthesis and the pharmaceutical industry. The attack of nucleophilic reagents on quinone imines tends to lead to aromatization of the quinone skeleton, resulting in both the high reactivity and the unique reactivity of quinone imines. The extreme value of quinone imines in the construction of nitrogen- or oxygen-containing heterocycles has attracted widespread attention, and remarkable advances have been reported recently. This review provides an overview of the application of quinone imines in the synthesis of cyclic compounds via the domino annulation reaction.

Abstract Proton exchange membrane fuel cells (PEMFCs) have become a major component of current clean energy technologies. Accounting for nearly half the cost of a commercial fuel cell stack, Pt‐based catalysts are the main choices for both anode and cathode in PEMFCs. However, catalytical activity and operating life of Pt‐based catalysts are still unsatisfactory. High cost and scarcity of Pt further hinder the development of PEMFCs. Constructing core‐shell structure for Pt‐based catalysts is a promising strategy to enhance the catalytic activity and reduce the cost. In this review, we overview recent advances in Pt‐based core‐shell catalysts according to catalytic reaction types involved in PEMFCs. Furthermore, we discuss the working principle of core‐shell catalysts from the perspective of coupling between core and shell. In the end, we conclude the recent progress and discuss the future developments and facing challenges.

Background KN046 is a novel bispecific antibody targeting programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). This multicenter phase I trial investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of KN046 in patients with advanced solid tumors.Methods Patients who failed standard treatment were included. KN046 was administered at doses of 1, 3, and 5 mg/kg every 2 weeks (Q2W), 5 mg/kg every 3 weeks (Q3W), and 300 mg Q3W based on the modified toxicity probability interval method in the dose-escalation phase; the recommended dose was used in the expansion phase. Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose (RP2D) in escalation and preliminary efficacy in expansion. Secondary objectives included PK, pharmacodynamics, safety, and tolerability of KN046. We also explored biomarkers based on PD-L1 expression, multiplex immunofluorescence (mIF) staining, and RNAseq-derived nCounter platform.Results Totally, 100 eligible patients were enrolled, including 59 with nasopharyngeal carcinoma (NPC), 36 with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), and those with other advanced solid tumors. The most common treatment-related adverse events (TRAEs) were rash (33.0%), pruritus (31.0%), and fatigue (20.0%). Grade ≥3 TRAEs were observed in 14.0% of participants. No dose-limiting toxicity occurred in the dose-escalation phase, and the MTD was not reached. The RP2D was determined as 5 mg/kg Q2W according to the pharmacokinetic–pharmacodynamic model, the preliminary exposure–response analysis, and the overall safety profile. Among 88 efficacy-evaluable participants, the objective response rate (ORR) was 12.5%, and the median duration of response was 16.6 months. In the NPC subgroup, the ORR was 15.4%, and the median overall survival (OS) was 24.7 (95% CI 16.3 to not estimable) months. In the EGFR-mutant NSCLC subgroup, the ORR was 6.3%. mIF analysis results showed patients with high CD8 expression showed longer median OS (27.1 vs 9.2 months, p=0.02); better prognosis was observed in patients with high CD8 and PD-L1 expression.Conclusions KN046 was well tolerated and showed promising antitumor efficacy in advanced solid tumors, especially in patients with NPC. The combination of both CD8 and PD-L1 expression improved the prediction of KN046 response.Trial registration numbers NCT03733951 .

Abstract Background CXC chemokine receptor gene family consists of seven well-established members which are broadly involved in biological functions of various cancers. Currently, limited studies have shed light on the expression profile of CXCR family members (CXCRs), as well as their prognostic value, in head and neck squamous cells carcinoma (HNSCC). Methods The data for this study were retrieved from the Cancer Genome Atlas database and other publicly available databases, including gene expression, methylation profiles, clinical information, immunological features, and prognoses. The expression pattern and prognostic values of CXCRs were identified, and the potential mechanism underlying CXCRs function in HNSCC was investigated by gene set enrichment analysis (GSEA). Results CXCRs were differentially expressed in HNSCC. As shown by Kaplan–Meier analysis, high CXCR3-6 expression was significantly associated with better prognostic outcomes of HNSCC patients, including overall survival and progression-free survival. According to the results of univariate and multivariate Cox proportional risk regression analysis, it was demonstrated that upregulation of CXCR3-6 was an independent factor for better prognosis, while the two other clinical features, age and stage, were factors for worse prognosis. A significant positive correlation between CXCR3-6 and tumor-infiltrated immune cells was revealed by results from Tumor Immune Estimation Resource and CIBERSORT analysis database. The main involvement of CXCRs in immune and inflammatory responses was further confirmed by GSEA. Conclusions Overall, this study provided a rationale for targeting CXCRs as a promising therapeutic strategy of HNSCC.

Abstract The Yermak Plateau (YP) is located across the Arctic–Atlantic gateway in the northwest of the Svalbard archipelago. In this region, internal waves are believed to cause intense turbulent mixing and hence influence the heat budget in the Arctic Ocean. Based on year-long observations from three moorings, the characteristics and energetics of diurnal and semidiurnal internal waves on the southern slope of the YP are investigated in this study. Diurnal internal waves induce large isothermal displacements exceeding 100 m, which are nearly one order of magnitude greater than those of semidiurnal internal waves. In addition, diurnal internal waves are strong in winter but weak in summer, while the semidiurnal internal waves exhibit complicated temporal variation. For the diurnal internal waves, their available potential energy is greater than the horizontal kinetic energy; whereas the situation is opposite for the semidiurnal ones. This feature is further clarified with two-dimensional numerical simulations. Due to the larger tidal excursion, diurnal tidal forcing yields the generation of stronger higher harmonics, i.e., the semidiurnal internal waves. In contrast, higher harmonics are rather weak under the semidiurnal forcing. Moreover, a large proportion of energy for both diurnal and semidiurnal internal waves is dissipated locally. Results of this study can provide useful insight on the dynamics of internal waves in the Arctic Ocean.

Abstract Background Routine screening for HIV and other sexually transmitted infections (STIs) facilitates early diagnosis and treatment, thereby preventing morbidity and onward transmission. We estimated the prevalence of prior HIV/STI testing among men who have sex with men (MSM) and transgender women (TGW) in Bangkok, Thailand, and identified factors associated with prior testing. Methods Cross-sectional analyses were performed using data collected at enrollment into an HIV incidence cohort. From April to October 2017, MSM and TGW were enrolled if they were aged 18–35 years, reported anal intercourse with a male or TGW partner, and reported behavioral vulnerability to HIV. Participants answered questions about demographics, sexual behaviors, and lifetime HIV/STI testing history. Multivariable robust Poisson regression was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) for factors potentially associated with prior testing. Results Among 1,014 participants, 348 (34.3%) were TGW and the median age was 21.6 (interquartile range 20.0-24.8) years. Prior testing for HIV was reported by 421 (41.5%) and for other STIs by 268 (26.4%). HIV testing was more common among participants aged ≥ 22 years (RR 1.37 [95% CI 1.13–1.67]), with college education as compared to secondary or less (RR 1.37 [95% CI 1.08–1.72]), and who met male sexual partners online (RR 1.52 [95% CI 1.24–1.85]), but lower among participants attracted to both men and women as compared to men only (RR 0.64 [95% CI 0.51–0.81]) and who met male sexual partners in bars (RR 0.83 [95% CI 0.72–0.97]). Similar associations were observed with prior testing for other STIs, including increased testing among participants with college education (RR 1.52 [95% CI 1.11–2.09]) and who met male sexual partners online (RR 1.73 [95% CI 1.30–2.31]), but lower among participants attracted to both men and women (RR 0.70 [95% CI 0.51–0.96]) and who met male sexual partners in bars (RR 0.67 [95% CI 0.54–0.83]). Conclusions Despite behavioral vulnerability, prior testing for HIV and other STIs was uncommon. Online engagement strategies may be effectively reaching Thai MSM and TGW who meet sexual partners online, but new interventions are needed to encourage testing among younger, less educated, and bisexual MSM and TGW.

Objective: Mumps is a seasonal infectious disease, always occurring in winter and spring. In this study, we aim to analyze its epidemiological characteristics, transmissibility, and its correlation with meteorological variables. Method: A seasonal Susceptible–Exposed–Infectious/Asymptomatic–Recovered model and a next-generation matrix method were applied to estimate the time-dependent reproduction number (Rt). Results: The seasonal double peak of annual incidence was mainly in May to July and November to December. There was high transmission at the median of Rt = 1.091 (ranged: 0 to 4.393). Rt was seasonally distributed mainly from February to April and from September to November. Correlations were found between temperature (Pearson correlation coefficient [r] ranged: from 0.101 to 0.115), average relative humidity (r = 0.070), average local pressure (r = -0.066), and the number of new cases. In addition, average local pressure (r = 0.188), average wind speed (r = 0.111), air temperature (r ranged: -0.128 to -0.150), average relative humidity (r = -0.203) and sunshine duration (r = -0.075) were all correlated with Rt. Conclusion: A relatively high level of transmissibility has been found in Xiamen City, leading to a continuous epidemic of mumps. Meteorological factors, especially air temperature and relative humidity, may be more closely associated with mumps than other factors.

The nano-delivery system with a dual biomimetic effect can penetrate deeper in tumor microenvironments (TMEs) and release sufficient antitumor drugs, which has attracted much attention. In this study, we synthesized erythrocyte-like mesoporous silica nanoparticles (EMSNs) as the core loaded with doxorubicin (DOX) and coated them with calcium phosphate (CaP) and erythrocyte membrane (EM) to obtain DOX/EsPMs. The transmission electron microscopy (TEM), fluorescent co-localization and protein bands of SDS-PAGE were used to confirm the complete fabrication of EsPMs. The EsPMs with erythrocyte-like shape exhibited superior penetration ability in in vitro diffusion and tumor-sphere penetration experiments. Intracellular Ca2+ and ROS detection experiments showed that the CaP membranes of EsPMs with pH-sensitivity could provide Ca2+ continuously to induce reactive oxide species’ (ROS) generation in the TME. The EM as a perfect “camouflaged clothing” which could confuse macrophagocytes into prolonging blood circulation. Hemolysis and non-specific protein adsorption tests proved the desirable biocompatibility of EsPMs. An in vivo pharmacodynamics evaluation showed that the DOX/EsPMs group had a satisfactory tumor-inhibition effect. These advantages of the nano-erythrocytes suggest that by modifying the existing materials to construct a nano-delivery system, nanoparticles will achieve a biomimetic effect from both their structure and function with a facilitated and sufficient drug release profile, which is of great significance for antitumor therapy.

Stem cell therapy offers a promising avenue for advanced liver disease cases as an alternative to liver transplantation. Clinical studies are underway to explore the potential of stem cells from various sources in treating different liver diseases. However, due to the variability among current studies, further validation is needed to ensure the safety and effectiveness of stem cell therapy. To establish a strong foundation for optimal stem cell therapy applications, selection of suitable stem cell sources, standardization of transplantation protocols, and patient criteria are vital. This review comprehensively examines existing literature on stem cell sources, transplantation methods, and patient selection. Additionally, we discuss novel strategies, including stem cell preconditioning, cell-free therapy, genetic modification of stem cells, and the use of liver organoids, addressing the limitations of current stem cell therapies. Nevertheless, these innovative approaches require further validation.

Abstract Background The COVID-19 pandemic has exerted an unprecedented and universal impact on global health system, resulting in noticeable challenges in traditional chronic disease care, of which diabetes was reported to be most influenced by the reduction in healthcare resources in the pandemic. China has the world’s largest diabetes population, and current diabetes management in China is unsatisfactory, particularly in rural areas. Studies in developed countries have demonstrated that physician-pharmacist collaborative clinics are efficient and cost-effective for diabetes management, but little is known if this mode could be adapted in primary hospitals in China. The aim of this proposed study is to develop and evaluate physician-pharmacist collaborative clinics to manage type 2 diabetes mellitus (T2DM) in primary hospitals in Hunan province. Methods A multi-site randomized controlled trial will be conducted to evaluate the effectiveness and cost-effectiveness of the physician-pharmacist collaborative clinics compared with usual care for Chinese patients with T2DM. Six primary hospitals will participate in the study, which will recruit 600 eligible patients. Patients in the intervention group will receive services from both physicians and pharmacists in the collaborative clinics, while the control group will receive usual care from physicians. Patients will be followed up at the 3rd, 6th, 9th and 12th month. Comparison between the two groups will be conducted by assessing the clinical parameters, process indicators and costs on diabetes. A satisfaction survey will also be carried out at the end of the study. Discussion If effective, the physician-pharmacist collaborative clinics can be adapted and used in primary hospitals of China to improve glycemic control, enhance medication adherence, decrease incidence of complications and reduce patients’ dependence on physicians. Findings from the present study are meaningful for developing evidence-based diabetes care policy in rural China, especially in the COVID-19 pandemic era. Trial registration Chinese Clinical Trial Registry, ChiCTR2000031839 , Registered 12 April 2020.

Abstract Background The GNAS gene on chromosome 20q13.3, encodes the alpha-subunit of the stimulatory G protein, which is expressed in most tissues and regulated through reciprocal genomic imprinting. Disorders of GNAS inactivation produce several different clinical phenotypes including pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). The clinical and biochemical characteristics overlap of PHP subtypes and other related disorders presents challenges for differential diagnosis. Methods We enrolled a total of 11 Chinese children with PHP in our study and analyzed their clinical characteristics, laboratory results, and genetic mutations. Results Among these 11 patients, nine of them (9/11) presented with resistance to parathyroid hormone (PTH); and nine (9/11) presented with an Albright′s hereditary osteodystrophy (AHO) phenotype. GNAS abnormalities were detected in all 11 patients, including nine cases with GNAS gene variations and two cases with GNAS methylation defects. These GNAS variations included an intronic mutation (c.212 + 3_212 + 6delAAGT), three missense mutations (c.314C > T, c.308 T > C, c.1123G > T), two deletion mutations (c.565_568delGACT*2, c.74delA), and two splicing mutations (c.721 + 1G > A, c.432 + 1G > A). Three of these mutations, namely, c.314C > T, c.1123G > T, and c.721 + 1G > A, were found to be novel. This data was then used to assign a GNAS subtype to each of these patients with six cases diagnosed as PHP1a, two cases as PHP1b, one as PPHP, and two as POH. Conclusions Evaluating patients with PTH resistance and AHO phenotype improved the genetic diagnosis of GNAS mutations significantly. In addition, our results suggest that when GNAS gene sequencing is negative, GNAS methylation study should be performed. Early genetic detection is required for the differential diagnosis of GNAS disorders and is critical to the clinician’s ability to distinguish between heterotopic ossification in the POH and AHO phenotype.

Regulatory T (Treg) cells constitute a dynamic population that is critical in autoimmunity. Treg cell therapies for autoimmune diseases are mainly focused on enhancing their suppressive activities. However, recent studies demonstrated that certain inflammatory conditions induce Treg cell instability with diminished FoxP3 expression and convert them into pathogenic effector cells. Therefore, the identification of novel targets crucial to both Treg cell function and plasticity is of vital importance to the development of therapeutic approaches in autoimmunity. In this study, we found that conditional Pp6 knockout (cKO) in Treg cells led to spontaneous autoinflammation, immune cell activation, and diminished levels of FoxP3 in CD4+ T cells in mice. Loss of Pp6 in Treg cells exacerbated two classical mouse models of Treg-related autoinflammation. Mechanistically, Pp6 deficiency increased CpG motif methylation of the FoxP3 locus by dephosphorylating Dnmt1 and enhancing Akt phosphorylation at Ser473/Thr308, leading to impaired FoxP3 expression in Treg cells. In summary, our study proposes Pp6 as a critical positive regulator of FoxP3 that acts by decreasing DNA methylation of the FoxP3 gene enhancer and inhibiting Akt signaling, thus maintaining Treg cell stability and preventing autoimmune diseases.

IntroductionRebound pain, transient and acute postoperative pain after the disappearance of regional block anesthesia, has been a concern in recent years. Insufficient preemptive analgesia and hyperalgesia induced by regional block are the main mechanisms. At present, the evidence for the treatment of rebound pain is limited. The esketamine, as an antagonist of the N-methyl-D-aspartate receptor, has been proven to prevent hyperalgesia. Therefore, this trial aims to evaluate the impact of esketamine on postoperative rebound pain in patients undergoing total knee arthroplasty.Methods/designThis study is a single-center, prospective, double-blind, randomized, placebo-controlled trial. Participants who plan to undergo total knee arthroplasty will be randomly assigned to the esketamine group (N = 178) and placebo group (N = 178) in a ratio of 1:1. This trial aims to evaluate the impact of esketamine on postoperative rebound pain in patients undergoing total knee arthroplasty. The primary outcome of this trial is the incidence of rebound pain within 12 h after the operation in the esketamine group and the placebo group. The secondary outcome will be to compare (1) the incidence of rebound pain 24 h after the operation; (2) the time to enter the pain cycle for the first time within 24 h after the procedure; (3) the first time of rebound pain occurred within 24 h after surgery; (4) the modified rebound pain score; (5) NRS score under rest and exercise at different time points; (6) the cumulative opioid consumption at different time points; (7) patient’s prognosis and knee joint function evaluation; (8) blood glucose and cortisol concentration; (9) patient’s satisfaction score; (10) adverse reactions and adverse events.DiscussionThe effect of ketamine on preventing postoperative rebound pain is contradictory and uncertain. The affinity of esketamine to the N-methyl-D-aspartate receptor is about four times higher than levo-ketamine, the analgesic effect is 3 times higher than levo-ketamine, and there are fewer adverse mental reactions. To our knowledge, there is no randomized controlled trial to verify the impact of esketamine on postoperative rebound pain in patients undergoing total knee arthroplasty. Therefore, this trial is expected to fill an important gap in relevant fields and provide novel evidence for individualized pain management.Clinical Trial Registrationhttp://www.chictr.org.cn, identifier ChiCTR2300069044.