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Abstract Activated microglia play an important role in driving photoreceptor degeneration-associated neuroinflammation in the retina. Controlling pro-inflammatory activation of microglia holds promise for mitigating the progression of photoreceptor degeneration. Our previous study has demonstrated that pre-light damage treatment of hyperoside, a naturally occurring flavonol glycoside with antioxidant and anti-inflammatory activities, prevents photooxidative stress-induced photoreceptor degeneration and neuroinflammatory responses in the retina. However, the direct impact of hyperoside on microglia-mediated neuroinflammation during photoreceptor degeneration remains unknown. Upon verifying the anti-inflammatory effects of hyperoside in LPS-stimulated BV-2 cells, our results here further demonstrated that post-light damage hyperoside treatment mitigated the loss of photoreceptors and attenuated the functional decline of the retina. Meanwhile, post-light damage hyperoside treatment lowered neuroinflammatory responses and dampened microglial activation in the illuminated retinas. With respect to microglial activation, hyperoside mitigated the pro-inflammatory responses in DNA-stimulated BV-2 cells and lowered DNA-stimulated production of 2′3′-cGAMP in BV-2 cells. Moreover, hyperoside was shown to directly interact with cGAS and suppress the enzymatic activity of cGAS in a cell-free system. In conclusion, the current study suggests for the first time that the DNA sensor cGAS is a direct target of hyperoside. Hyperoside is effective at mitigating DNA-stimulated cGAS-mediated pro-inflammatory activation of microglia, which likely contributes to the therapeutic effects of hyperoside at curtailing neuroinflammation and alleviating neuroinflammation-instigated photoreceptor degeneration.

ObjectiveThe research aims to develop an advanced and precise lung cancer screening model based on Convolutional Neural Networks (CNN).MethodsBased on the health medical big data platform of Shandong University, we developed a VGG16-Based CNN lung cancer screening model. This model was trained using the Computed Tomography scans data of patients from Pingyi Traditional Chinese Medicine Hospital in Shandong Province, from January to February 2023. Data augmentation techniques, including random resizing, cropping, horizontal flipping, color jitter, random rotation and normalization, were applied to improve model generalization. We used five-fold cross-validation to robustly assess performance. The model was fine-tuned with an SGD optimizer (learning rate 0.001, momentum 0.9, and L2 regularization) and a learning rate scheduler. Dropout layers were added to prevent the model from relying too heavily on specific neurons, enhancing its ability to generalize. Early stopping was implemented when validation loss did not decrease over 10 epochs. In addition, we evaluated the model’s performance with Area Under the Curve (AUC), Classification accuracy, Positive Predictive Value (PPV), and Negative Predictive Value (NPV), Sensitivity, Specificity and F1 score. External validation used an independent dataset from the same hospital, covering January to February 2022.ResultsThe training and validation loss and accuracy over iterations show that both accuracy metrics peak at over 0.9 by iteration 15, prompting early stopping to prevent overfitting. Based on five-fold cross-validation, the ROC curves for the VGG16-Based CNN model, demonstrate an AUC of 0.963 ± 0.004, highlighting its excellent diagnostic capability. Confusion matrices provide average metrics with a classification accuracy of 0.917 ± 0.004, PPV of 0.868 ± 0.015, NPV of 0.931 ± 0.003, Sensitivity of 0.776 ± 0.01, Specificity of 0.962 ± 0.005 and F1 score of 0.819 ± 0.008, respectively. External validation confirmed the model’s robustness across different patient populations and imaging conditions.ConclusionThe VGG16-Based CNN lung screening model constructed in this study can effectively identify lung tumors, demonstrating reliability and effectiveness in real-world medical settings, and providing strong theoretical and empirical support for its use in lung cancer screening.

BackgroundAcute cadmium (Cd) exposure can cause damage to multiple tissues, with the kidney being the primary target organ. The development of Cd-induced acute kidney injury involves complex mechanisms, in which autophagy and oxidative stress play crucial roles.ObjectiveTo investigate the effect of 10-hydroxy-2-decenoic acid (10-HDA) on kidney injury in mice exposed to cadmium, and provide experimental basis for studying the pathogenesis and prevention of Cd poisoning.MethodsThirty-five male C57BL/6 mice were divided into 7 groups (each of 5 mice): control group (normal saline, intraperitoneal injection), CdCl2 group (4 mg·kg−1, intraperitoneal injection), intervention groups ( 4 mg·kg−1 CdCl2, intraperitoneal Injection + 50, 100, 150, or 200 mg·kg−1 10-HDA, oral gavage), and 10-HDA group (150 mg·kg−1, oral gavage). All treatments were given for 14 d. Twenty-four hours after the last infection, physiological indicators [blood urea nitrogen (BUN), creatinine (CRE), malondialdehyde (MDA), and superoxide dismutase (SOD)], histopathological indicators, autophagy-related proteins (Atg7, Atg5, Beclin-1, and LC3), and mitochondrial autophagy-related proteins (PINK1 and Parkin) were detected to examine the effect of 10-HDA on kidney injury caused by CdCl2.ResultsCompared with the control group, the body weight of mice in the CdCl2 group was significantly reduced (P

For the protection, restoration, and sustainable management of wetland ecosystems, precision in extracting high-quality wetland land cover information is crucial. This study focused on the National Nature Reserve of Liaohe Estuary in Panjin City, Liaoning Province, China. To enhance the classification accuracy of wetland land covers exhibiting similar spectral characteristics and alleviate the occurrence of the ‘salt-and-pepper’ effect, where certain land parcels are erroneously classified into multiple categories by pixel-based methods, an approach integrating object-oriented techniques and temporal features was employed for precise wetland land cover classification. The analysis utilized multi-temporal Sentinel-2 multispectral images. Initially, the images underwent segmentation using the SNIC method to generate uniform polygons, effectively mitigating misclassification issues. Subsequently, texture, geometry, band reflectance, and spectral deviation features were extracted for each segmented object. A total of 57 features, including vegetation and moisture components, were integrated to construct temporal characteristics. By applying the Random Forest (RF) algorithm in combination with Extreme Randomized Trees (ERT), 18 significant features influencing wetland extraction were identified. These selected features were then utilized to train a Random Forest (RF) model for classifying wetland land cover in the study area. The findings revealed that the integrated object-oriented and temporal feature classification approach achieved an impressive overall accuracy of 95.52% and a Kappa coefficient of 0.95 for the Liaohe Estuary wetland region. The accuracy for various land cover types reached 0.87 for both user and producer accuracy. Compared to alternative machine learning algorithms such as SegUnet++, SVM, and RF, the proposed method demonstrated a performance increase of 16.35%, 14.06%, and 6.14%, respectively. The incorporation of temporal features notably reduced land cover misclassifications, resulting in a 6.14% increase in overall accuracy and a 0.07 improvement in the Kappa coefficient compared to a method lacking temporal features. Particularly for categories like canals, aquaculture, rivers, and reservoirs, producer accuracy improved by over 7.5% and user accuracy by more than 2.9%. The effectiveness of the object-oriented approach was evident in addressing the “salt-and-pepper” effect, showcasing a rise of 2.81% in overall accuracy and 0.03 in Kappa coefficient compared to an approach not utilizing object-oriented techniques. In summary, the proposed classification method, integrating object-oriented methods and temporal features, offers superior accuracy in fine wetland land cover classification and mapping.

The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury. Ruxolitinib, a JAK-STAT inhibitor, exhibits effectiveness in autoimmune diseases, arthritis, and managing inflammatory cytokine storms. Although studies have shown the neuroprotective potential of ruxolitinib in neurological trauma, the exact mechanism by which it enhances functional recovery after spinal cord injury, particularly its effect on astrocytes, remains unclear. To address this gap, we established a mouse model of T10 spinal cord contusion and found that ruxolitinib effectively improved hindlimb motor function and reduced the area of spinal cord injury. Transcriptome sequencing analysis showed that ruxolitinib alleviated inflammation and immune response after spinal cord injury, restored EAAT2 expression, reduced glutamate levels, and alleviated excitatory toxicity. Furthermore, ruxolitinib inhibited the phosphorylation of JAK2 and STAT3 in the injured spinal cord and decreased the phosphorylation level of nuclear factor kappa-B and the expression of inflammatory factors interleukin-1β, interleukin-6, and tumor necrosis factor-α. Additionally, in glutamate-induced excitotoxicity astrocytes, ruxolitinib restored EAAT2 expression and increased glutamate uptake by inhibiting the activation of STAT3, thereby reducing glutamate-induced neurotoxicity, calcium influx, oxidative stress, and cell apoptosis, and increasing the complexity of dendritic branching. Collectively, these results indicate that ruxolitinib restores glutamate homeostasis by rescuing the expression of EAAT2 in astrocytes, reduces neurotoxicity, and effectively alleviates inflammatory and immune responses after spinal cord injury, thereby promoting functional recovery after spinal cord injury.

Abstract Introduction Ankylosing spondylitis(AS) is a chronic inflammatory rheumatic disease primarily affecting the spine and sacroiliac joints. While biologic disease-modifying antirheumatic drugs(bDMARDs) and targeted synthetic DMARDs(tsDMARDs) are popular treatments for AS, there is limited research on their combined use. This study examined a cohort of AS patients who demonstrated inadequate response to bDMARDs and subsequently initiated combination therapy with tofacitinib in conjunction with bDMARDs, assessing both the efficacy and safety profile of this therapeutic approach. Methods In this study, we retrospectively collected the electronic medical records (EMR) of 15 adult patients with AS who were admitted to the Fourth Affiliated Hospital Zhejiang University School of Medicine between January 2018 and June 2022. All patients had received at least one bDMARD treatment for more than three months and still exhibited moderate to high disease activity. Tofacitinib 5 mg bid was added to their original biological treatment. Treatment was continued for a minimum of 12 weeks following the initiation of combination therapy. Changes in ASDAS-CRP and BASDAI scores at week 12 were collected and analyzed from baseline, while changes in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) at weeks 4, 8, and 12 were also collected and analyzed. Results After 12 weeks of treatment, the overall ASDAS-CRP score decreased significantly from a baseline of 3.82 ± 1.47 (2.83 ~ 4.99) to 1.47 ± 0.48 (0.75 ~ 2.44), with remission achieved by 7 patients (46.7%) and low disease activity achieved by 5 patients (33.3%). The overall BASDAI score also showed significant improvement, decreasing from a baseline of 5.11 ± 1.42 (3.25 ~ 7 0.75) to 1.28 ± 0.70(0.20 ~ 2.55). Additionally, both ESR and CRP levels decreased significantly during the course of treatment without any reported adverse events leading to discontinuation. Conclusion To a certain extent, our findings provide some evidence supporting the efficacy and safety of the combination of bDMARD and JAK inhibitor tofacitinib in AS patients with inadequate response to bDMARD monotherapy. It effectively controls disease activity while maintaining a relatively low and manageable incidence of adverse events. Further prospective randomized controlled trials with large sample sizes are anticipated to provide evidence-based medical support.

Abstract Background Long-term exposure to air pollution has been found to contribute to the development of cognitive decline. Our study aimed to assess the association between various air pollutants and cognitive impairment and dementia. Additionally, explore the modification effects of lifestyle and genetic predisposition. Methods The exposure levels to various air pollutants, including particulate matter (PM) with diameters ≤ 2.5 (PM2.5), ≤ 10 (PM10), and between 2.5 and 10 μm (PM2.5−10) and nitrogen oxides (NO and NO2) were identified. An air pollution score (APS) was calculated to evaluate the combined exposure to these five air pollutants. A genetic risk estimate and healthy lifestyle score (HLS) were also generated. The Cox regression model adjusted by potential confounders was adopted to access the association between pollution exposure and cognitive decline, and several sensitivity analyses were additionally conducted to test the robustness. Results The combined exposure to air pollutants was associated with an increased risk of incident cognitive decline. Compared with the low exposure group, the hazard ratio (HR) and 95% confidence interval (CI) for all-cause dementia, Alzheimer’s dementia, vascular dementia, and mild cognitive impairment (MCI) in those exposed to the highest levels of air pollutants were respectively 1.07 (95% CI: 1.04 to 1.09), 1.08 (95% CI: 1.04 to 1.12), 1.07 (95% CI: 1.02 to 1.13), and 1.19 (95% CI: 1.12 to 1.27). However, the modification effects from genetic predisposition were not widely observed, while on the contrary for the healthy lifestyle. Our findings were proven to be reliable and robust based on the results of sensitivity analyses. Conclusions Exposure to air pollution was found to be a significant contributing factor to cognitive impairment and dementia, and this association was not easily modified by an individual’s genetic predisposition. However, adopting a healthy lifestyle may help to manage the risk of cognitive decline related to air pollution.

ObjectiveAnti-dipeptidyl-peptidase-like protein-6 (DPPX) encephalitis is a rare autoimmune encephalitis, and clinical and experimental information regarding this disease is limited. We conducted this study to comprehensively describe the clinical characteristics, ancillary test results, neuroimaging results, and treatment response in a group of Chinese patients with anti-DPPX encephalitis for better understanding this disease.MethodsWe recruited 14 patients who tested positive for anti-DPPX antibodies in the serum and/or cerebrospinal fluid from 11 medical centers between March 2021 and June 2023. This retrospective study evaluated data on symptoms, autoantibody test, auxiliary examinations, treatments, and outcomes.ResultsThe average age at diagnosis was 45.93 ± 4.62 years (range: 11–72 years), and 9 of the 14 patients were males. The main symptoms included cognitive impairment (50.0%, 7/14), central nervous system hyperexcitability (42.9%, 6/14), gastrointestinal dysfunction (35.7%, 5/14), and psychiatric disorders (35.7%, 5/14). Notably, we discovered specific findings on 18F-fluorodeoxyglucose positron-emission tomography (PET)/magnetic resonance imaging in two patients. Co-existing autoantibodies were identified in two patients. Parainfection was identified in four patients. One patient had other autoimmune diseases, and one had tumor. Eleven patients received immunotherapy and most patients improved at discharge. Surprisingly, three male patients but no female patients relapsed during the 6 months of follow-up.ConclusionThe development and outcome of anti-DPPX encephalitis are variable. Male patients were predominant in our cohort. The most common symptoms were the classical triad of prodromal gastrointestinal dysfunction, cognitive and mental disorders, and central nervous system hyperexcitability. Infections, immune dysregulation, and tumors may be important etiologies. Long-term monitoring of disease development should be done in male patients. Overall, our results highlight novel clinical characteristics of anti-DPPX encephalitis.

Several methods have been applied to measure healthcare accessibility, ie, the Euclidean distance, the network distance, and the transport time based on speed limits. However, these methods generally produce less accurate estimates than actual measurements. This research proposed a method to estimate historical healthcare accessibility more accurately by using taxi Global Positioning System (GPS) traces. The proposed method’s advantages were evaluated vis a case study using acute myocardial infarction (AMI) cases in Beijing in 2008. Comparative analyses of the new measure and three conventionally used measures suggested that the median estimated transport time to the closest hospital with percutaneous coronary intervention (PCI) capability for AMI patients was 5.72 minutes by the taxi GPS trace-based measure, 2.42 minutes by the network distance-based measure, 2.28 minutes by the speed limit-based measure, 1.73 minutes by the Euclidean distance-based measure; and the estimated proportion of patients who lived within 5 minutes of a PCI-capable hospital was 38.17%, 89.20%, 92.52%, 95.05%, respectively. The three conventionally used measures underestimated the travel time cost and overestimated the percentage of patients with timely access to healthcare facilities. In addition, the new measure more accurately identifies the areas with low or high access to healthcare facilities. The taxi GPS trace-based accessibility measure provides a promising start for more accurately estimating accessibility to healthcare facilities, increasing the use of medical records in studying the effects of historical healthcare accessibility on health outcomes, and evaluating how accessibility to healthcare changes over time.

Human interactions have led to the emergence of a higher complexity of urban metabolic networks; hence, traditional natural- or agriculture-oriented biogeochemical models might not be transferred well to urban environments. Increasingly serious environmental problems require the development of new concepts and models. Here, we propose a basic paradigm for urban–rural complex nitrogen (N) metabolic network reconstruction (NMNR) by introducing new concepts and methodologies from systems biology at the molecular scale, analyzing both local and global structural properties and exploring optimization and regulation methods. Using the Great Hangzhou Areas System (GHA) as a case study, we revealed that pathway fluxes follow a power law distribution, which indicates that human-dominated pathways constitute the principal part of the functions of the whole network. However, only 1.16% of the effective cycling pathways and an average hamming distance of only 5.23 between the main pathways indicate that the network lacks diverse pathways and feedback loops, which could lead to low robustness. Furthermore, more than half of the N fluxes did not pass through core metabolism, causing waste and pollution. We also provided strategies to design network structures and regulate system function: improving robustness and reducing pollution by referring to the characteristics of biochemical metabolic networks (e.g., the bow-tie structure). This method can be used to replace the trial-and-error method in system regulation and design. By decomposing the GHA N metabolic network into 4398 metabolic pathways and the corresponding fluxes with a power law distribution, NMNR helps us quantify the vulnerability in the current urban nitrogen cycle. The basic ideas and methodology in NMNR can be applied to coupled human and natural systems to advance global sustainable development studies, and they can also extend systems biology from the molecule to complex ecosystems and lead to the development of multi-scale unified theory in systems biology.

ObjectiveThe current study aimed to assess the relation between multi-dimension poverty, treatment-seeking behavior, and antibiotic misuse among urinary tract infection (UTI) patients.MethodA cross-sectional approach was utilized to recruit patients who had a history of UTI in the previous month from two provinces of Pakistan. The treatment-seeking behavior and antibiotic misuse data were collected on a self-developed questionnaire, whereas the poverty data were collected on a modified multi-dimension poverty index (MPI). Descriptive statistics were applied to summarize the data. The logistic regression analysis was carried out to assess the association of multi-dimension poverty with patient treatment-seeking behavior and antibiotic misuse.ResultsA total of 461 participants who had UTI symptoms in the previous month were recruited. Most of the participants in the severely deprived stage treated the UTI (p

BackgroundFreshwater snails are not only intermediate hosts for parasites but also an important part of the food chain as they convert plant biomass and humus into animal biomass. However, being widely distributed in freshwater environments, snails are highly affected by human activities, which makes their adaptation to altering environments challenging. The gut microbiome helps animals in their digestion, immune system, growth and adapting to changing environments. The effect of host species on intestinal microbial community has been poorly studied in snails.MethodsIn this study, single-molecule real-time sequencing technology (SMRT) was used to obtain full-length 16S rRNA genes to determine the intestinal microbiomes of three species of freshwater snails (SQ: Sinotaia quadrata, BU: Boreoelona ussuriensis, RP: Radix plicatula) with similar feeding habits in a same water environment.ResultsUnifrac PCoA (P

BackgroundPakistan is among top countries for antibiotic consumption around the globe and patients often receive antibiotics directly from community pharmacies. Thus, our aim was to assess the drug dispensing practices of pharmacies for presumed and confirmed tuberculosis by using standardized patients’ method in Pakistan.MethodsIn this cross-sectional study, we adopted two standardized patient cases in pharmacies of three cities of Punjab. The first case involved a presumed tuberculosis patient presenting with 2–3 weeks of cough and fever (Case-1), and the second case involved a confirmed tuberculosis patient carrying microbiologically confirmed tuberculosis results (Case-2). The ideal management for Cases-1 and Case-2 is referral of standardized patients to a healthcare provider without dispensing antibiotics or steroids, or both. The differences in antibiotic use, steroid use, and the number of medicines dispensed in referred and non-referred patients between Case-1 and Case-2 were analyzed using descriptive statistics.ResultsBetween April 1, 2020, and July 31, 2020, standardized patients completed 575 out of 598 interactions among community pharmacies in Lahore, Rawalpindi, and Sialkot. We recorded ideal management in 115 (37.7%) of the 305 Case-1 interactions and 130 (48.1%) of the 270 Case-2 interactions. Antibiotic dispensing was higher in Case-1, with 71 out of 305 instances (23.3%), than in Case-2 interactions, with 27 out of 270 instances (10.0%). Anti-tuberculosis drugs were dispensed to 1 patient in Case-1 (0.3%) and to 19 patients (7.0%) in Case-2.ConclusionSlightly more than one-third of pharmacies in Punjab, Pakistan, ideally managed patients with presumed tuberculosis, but almost half of them ideally managed cases of confirmed tuberculosis. The presence of confirmed diagnosis slightly changes the behavior in the correct management of patients.

Abstract Background Photoreceptor degeneration underpinned by oxidative stress-mediated mitochondrial dysfunction and cell death leads to progressive and irreversible vision impairment. Drug treatments that protect against photoreceptor degeneration are currently available in the clinical settings. It has been shown that hyperoside, a flavonol glycoside, protects against neuronal loss in part by suppressing oxidative stress and maintaining the functional integrity of mitochondria. However, whether hyperoside protects against photoreceptor degeneration remains unknown. Methods To address the pharmacological potentials of hyperoside against oxidative stress-mediated photoreceptor degeneration on molecular, cellular, structural and functional levels, multiple in vitro and in vivo methodologies were employed in the current study, including live-cell imaging, optical coherence tomography, electroretinography, histological/immunohistochemical examinations, transmission electron microscopy, RNA-sequencing and real-time qPCR. Results The in vitro results demonstrate that hyperoside suppresses oxidative stress-mediated photoreceptor cell death in part by mitigating mitochondrial dysfunction. The in vivo results reveal that hyperoside protects against photooxidative stress-induced photoreceptor morphological, functional and ultrastructural degeneration. Meanwhile, hyperoside treatment offsets the deleterious impact of photooxidative stress on multiple molecular pathways implicated in the pathogenesis of photoreceptor degeneration. Lastly, hyperoside attenuates photoreceptor degeneration-associated microglial inflammatory activation and reactive Müller cell gliosis. Conclusions All things considered, the present study demonstrates for the first time that hyperoside attenuates oxidative stress-induced photoreceptor mitochondrial dysfunction and cell death. The photoreceptor-intrinsic protective effects of hyperoside are corroborated by hyperoside-conferred protection against photooxidative stress-mediated photoreceptor degeneration and perturbation in retinal homeostasis, warranting further evaluation of hyperoside as a photoreceptor protective agent for the treatment of related photoreceptor degenerative diseases.

Abstract Background Primary headache disorders are a group of highly prevalent and disabling neurological diseases that mainly consist of migraine and tension-type headache (TTH). A previous study showed that the burden of headaches peaked at a working age that ranged from 15 to 49, particularly among females, affecting their productivity and severely damaging their social interactions. Methods The latest dataset was retrieved from the Global Burden of Disease (GBD) Study 2019. Three indicators, including prevalence, incidence, and years lived with disability (YLDs), were adopted for evaluation. The overall and specific headache burdens were fully compared and analysed at global, regional, and national levels. The ratio of female YLD rates to male YLD rates due to headaches was calculated to estimate the sex pattern. Finally, we utilized the two-tailed Spearman test to explore the potential association between socioeconomic background and headaches among young people. Results Globally, for overall headache disorders, a total of 2,049,979,883 prevalent cases (95% uncertainty interval (UI): 1,864,148,110 to 2,239,388,034), 601,229,802 incident cases (95% UI: 530,329,914 to 681,007,934), and 38,355,993 YLDs (95% UI: 7,259,286 to 83,634,503) were observed for those aged 10 to 54 in 2019. Sex differences were widely found for all headache types among adolescents and young adults, especially migraine. However, the most interesting finding was that the associations we tested between the socioeconomic environment and young headache patients were positive, regardless of region or specific country or territory. Conclusions Overall, the global burden of headaches in adolescents and young adults largely increased from 1990 to 2019. Although slight declines were observed in sex differences, they remained significant and challenging. The positive correlations between headache and socioeconomic background among young people were relatively inconsistent with previous investigations, and several related hypotheses were proposed for explanation. Interdisciplinary actions involving education, policy- and law-making, and basic medical practice are desperately needed to further fight against the headache burden, promote gender equality in headache care, and eliminate the stigmatization of headache patients in student and working groups.

Abstract Background The availability of physical activity (PA) facilities in neighborhoods is hypothesized to influence cardiovascular disease (CVD), but evidence from individual-level long-term cohort studies is limited. We aimed to assess the association between neighborhood exposure to PA facilities and CVD incidence. Methods A total of 4658 participants from the Chinese Multi-provincial Cohort Study without CVD at baseline (2007–2008) were followed for the incidence of CVD, coronary heart disease (CHD), and stroke. Availability of PA facilities was defined as both the presence and the density of PA facilities within a 500-m buffer zone around the participants’ residential addresses. Time-dependent Cox regression models were performed to estimate the associations between the availability of PA facilities and risks of incident CVD, CHD, and stroke. Results During a median follow-up of 12.1 years, there were 518 CVD events, 188 CHD events, and 355 stroke events. Analyses with the presence indicator revealed significantly lower risks of CVD (hazard ratio [HR] 0.80, 95% confidence interval ([CI] 0.65–0.99) and stroke (HR 0.76, 95% CI 0.60–0.97) in participants with PA facilities in the 500-m buffer zone compared with participants with no nearby facilities in fully adjusted models. In analyses with the density indicator, exposure to 2 and ≥ 3 PA facilities was associated with 35% (HR 0.65, 95% CI 0.47–0.91) and 28% (HR 0.72, 95% CI 0.56–0.92) lower risks of CVD and 40% (HR 0.60, 95% CI 0.40–0.90) and 38% (HR 0.62, 95% CI 0.46–0.84) lower risks of stroke compared with those without any PA facilities in 500-m buffer, respectively. Effect modifications between presence of PA facilities and a history of hypertension for incident stroke (P = 0.049), and a history of diabetes for incident CVD (P = 0.013) and stroke (P = 0.009) were noted. Conclusions Residing in neighborhoods with better availability of PA facilities was associated with a lower risk of incident CVD. Urban planning intervention policies that increase the availability of PA facilities could contribute to CVD prevention.

Abstract Drug development based on target proteins has been a successful approach in recent decades. However, the conventional structure-based drug design (SBDD) pipeline is a complex, human-engineered process with multiple independently optimized steps. Here, we propose a sequence-to-drug concept for computational drug design based on protein sequence information by end-to-end differentiable learning. We validate this concept in three stages. First, we design TransformerCPI2.0 as a core tool for the concept, which demonstrates generalization ability across proteins and compounds. Second, we interpret the binding knowledge that TransformerCPI2.0 learned. Finally, we use TransformerCPI2.0 to discover new hits for challenging drug targets, and identify new target for an existing drug based on an inverse application of the concept. Overall, this proof-of-concept study shows that the sequence-to-drug concept adds a perspective on drug design. It can serve as an alternative method to SBDD, particularly for proteins that do not yet have high-quality 3D structures available.

Spinal cord injury (SCI) is a severe disease of the nervous system that causes irreparable damage and loss of function, for which no effective treatments are available to date. Engineered extracellular vesicles (EVs) carrying therapeutic molecules hold promise as an alternative SCI therapy depending on the specific functionalized EVs and the appropriate engineering strategy. In this study, we demonstrated the design of a drug delivery system of peptide CAQK-modified, siRNA-loaded EVs (C-EVs-siRNA) for SCI-targeted therapy. The peptide CAQK was anchored through a chemical modification to the membranes of EVs isolated from induced neural stem cells (iNSCs). CCL2-siRNA was then loaded into the EVs through electroporation. The modified EVs still maintained the basic properties of EVs and showed favorable targeting and therapeutic effects in vitro and in vivo. C-EVs-siRNA specifically delivered siRNA to the SCI region and was taken up by target cells. C-EVs-siRNA used the inherent anti-inflammatory and neuroreparative functions of iNSCs-derived EVs in synergy with the loaded siRNA, thus enhancing the therapeutic effect against SCI. The combination of targeted modified EVs and siRNA effectively regulated the microenvironmental disturbance after SCI, promoted the transformation of microglia/macrophages from M1 to M2 and limited the negative effects of the inflammatory response and neuronal injury on functional recovery in mice after SCI. Thus, engineered EVs are a potentially feasible and efficacious treatment for SCI, and may also be used to develop targeted treatments for other diseases.

Abstract Background There are few studies that focus on the impact of online physical education teaching on college students during the coronavirus disease 2019 (COVID-19) pandemic. This research focuses on the impact of online physical education among medical school students in China by comparing physical fitness test results for three consecutive years from 2019 to 2021. Method This study is a longitudinal survey. The subjects of the experiments were students enrolled in a medical school who completed a physical fitness test for three consecutive years from 2019 to 2021. The student subjects were divided into two groups, namely, male and female. The test indices included body mass index (BMI), vital capacity (VC), 50-metre run, sit-and-reach, standing long jump, pull-up (male), 1000-metre run (male), sit-ups (female) and 800-metre run (female). Repeated measures ANOVA method was used in physical fitness test indices at three consecutive time points ranging from 2019 to 2021. The Greenhouse-Geisser correction was applied when Mauchly’s hypothesis test did not meet the assumption of sphericity, and the Bonferroni method was used for pairwise comparisons. Results A total of 3360 students (1490 males and 1870 females) completed physical fitness tests in three consecutive years from 2019 to 2021. The proportion of overweight and obesity in male students was significantly higher than that in female students (28.0% vs. 12.7%). For all subjects, in 2020, the BMI and VC indexes improved, while the 800-/1000-metre running indexes declined. In 2021, all indexes except sit-and-reach increased. Conclusion The pairwise comparisons of physical fitness test results from 2019 to 2021 show that online physical education is effective in improving all items except long-distance running. Future research needs to involve a larger and geographically more dispersed sample to further analyse the effectiveness of online physical education.

ABSTRACTGroup B streptococcus (GBS) is a major cause of neonatal death worldwide. A GBS vaccine for pregnant women is under development and is expected to be available in the near future. The perceptions and preferences of pregnant women in China of GBS vaccines has not been investigated, and this study aimed to investigate pregnant women‘s awareness of GBS and their potential preferences for the GBS vaccine. A discrete choice experiment was conducted among pregnant women in hospitals from Shaanxi, Hunan, and Zhejiang provinces located in Western, Central, and Eastern China, respectively. A conditional logit model was used to analyze the data and calculate willingness to pay values and choice probabilities of different GBS vaccine programs. A total of 354 pregnant women were included in the final analysis, 45.8% of whom were willing to receive a GBS vaccine if it were licensed. Vaccine safety was the most important attribute of a future vaccine, while cost was the least important attribute. Compared with no vaccination, pregnant women had a strong preference for future GBS vaccination (ASC = 1.267, p

Abstract Background The world faces severe challenges from migraine and tension-type headache (TTH), which cause grave disability to patients and place a heavy burden on their caregivers. However, headaches in specific individual regions have rarely been investigated. Therefore, we aimed to fully analyse and describe the current status and changing trends in migraine and TTH in non-high-income East and Southeast Asia to provide more detailed real-world information for policy-making. Methods The migraine and TTH data used for analysis were all extracted from the Global Burden of Disease (GBD) database. We adopted three major indicators of disease burden, including prevalence, incidence, and years lived with disability (YLD), and two major metrics, including the absolute number and the age-standardized rate, in our present study for further evaluation by age and sex. The results are presented in the form of mean values and 95% uncertainty intervals (UIs). In addition, the differences between non-high-income East and Southeast Asia and other regions, as well as the potential associations between headache burden and socioeconomic background, were explored. Results In 2019, approximately 195,702,169 migraine patients and 291,924,564 TTH patients lived in non-high-income East Asia, and 113,401,792 migraine patients and 179,938,449 TTH patients lived in non-high-income Southeast Asia. In terms of specific countries and regions, the highest age-standardized YLD rate (ASYR) of migraine was in Thailand [645 (95% UI: 64 to 1,554)]. The highest ASYR of TTH was in Indonesia [54 (95% UI: 15 to 197)]. Furthermore, people between the ages of 40 and 44, especially females, were identified as the main population that suffered from migraine and TTH. Unfortunately, we did not observe a significant association between headache burden and socioeconomic background. Conclusions To date, the threats from migraine and TTH in non-high-income East and Southeast Asia are still serious and ongoing, leading to prominently negative impacts on the daily life and work of local residents. Therefore, full attention and sound guidelines are urgently needed to obtain greater advantages in fighting against the burden of headache disorders in the future.

With the increasing demand for marine fish and cold-water predatory fish, to ensure its scale and industrialization in the process of breeding and to provide safe, high-quality, and healthy aquatic animal food for the society, the quality requirements of aquatic compound feed in the industry are increasing. Among the three nutrients, predatory fish have a poor ability to use sugar. Protein is the most expensive raw material, and the final product of its metabolism is ammonia, which can lead to the deterioration of water quality. Fat provides energy for fish growth, and essential fatty acids promotes the absorption of fat-soluble vitamins, and promotes protein deposition and utilization as a non-protein energy substance. Therefore, increasing the oil content in predatory fish feed and reducing the use of protein as energy can save feed protein and increase economic benefit. Different fish have different responses to nutrients and energy in feed. The fat metabolism of cultured fish has a certain species-specificity. It is generally believed that cold-water fish have a higher dietary fat requirement. The fat requirement of juvenile salmonids is 20%~30%, much higher than that of warm water fish. As a cold-water fish, Brachymystax lenok has successfully evolved key genotypic or phenotypic traits to adapt to growing at low temperatures, with fat requirements in the range of 17%~19%, slightly below the recommended fat requirements for regular Salmonidae fish.The high-fat feed has been widely used in carnivorous cold-water fish. As physiological conditions limit the demand and utilization capacity of fat, long-term intake of high-fat feed will easily cause fat metabolism disorder and meat quality decline during the breeding period, which seriously affects the health and quality of fish. Nutritional regulation of fat metabolism has become feasible means to reduce body fat deposition and improve meat quality. Therefore, it is particularly urgent to elucidate the fat metabolism mechanism and nutrition regulation of predatory fish. Lipase plays an essential role in lipid metabolism. As an enzyme with affinity at the oil-water interface, glycerol and fatty acids obtained after lipid hydrolysis can provide energy for the animal body and be utilized for its growth. Therefore, adding lipase in feed to regulate body fat nutrition has garnered considerable attention. Exogenous lipase has been well used in broilers and pigs to improve growth performance and physiological metabolism. It is also widely used in fish. However, it is rarely reported in the studies on cold water and freshwater fish nutrition. B. lenok is a rare and cold-water fish found in clear rivers and streams in China. The optimum temperature range for its growth is 18~20℃, and it has very high economic, edible, and research value.This study aims to, through adding different levels of lipase in different fat feed, use lipase in fat metabolism under the effect of high-fat feedstuff stress B. lenok to fat metabolism regulation, nutrition research on B. lenok growth performance, serum biochemical indices, and liver antioxidant effect, for lipase in B. lenok feeds for young fish provide a reference for the application. In this experiment, a 2×3 two-factor experimental design was used to prepare six experimental diets with two lipid levels (180 and 220 g/kg) and three lipase levels (0, 2500, and 5000 U/kg): C-0, C-2500, C-5000 and H-0, H-2500, H-5000. A total of 270 B. lenok with an initial body weight of (7.34±0.16) g were randomly divided into six groups with three replicates and 15 fish per replicate. Fish in each group were fed six different experimental diets for 63 days. The results show that different fat content and lipase level had extremely significant interaction on average body weight (P < 0.01) and significant interaction on weight gain rate and specific growth rate (P < 0.05). Both fat and lipase had an impact on the growth performance of the body. The body weight, weight gain rate, and specific growth rate of fish in the C-5000 group were the highest. Serum alanine aminotransferase (ALT) levels in H-0, H-2500, and H-5000 groups were lower than those in C-0, C-2500, and C-5000 groups, respectively. There were significant differences between H-0 and H-5000 groups and those in C-0 and C-5000 groups (P < 0.05). The low-density lipoprotein cholesterol (LDL-C) in H-0, H-2500, and H-5000 groups was higher than in C-0, C-2500, and C-5000 groups, respectively. There was a significant difference between H-0 and H-2500 groups, and the C-0 and C-2500 groups (P < 0.05). With the increase of lipase level, liver glutathione peroxidase (GPX) level increased. The GPX of the 220 g/kg group with the same lipase level was higher than that of the 180 g/kg group. In conclusion, the growth and antioxidant performance of juvenile B. lenok can be significantly improved at a lipid level of 183.7 g/kg, and the lipase level of 5000 U/kg.

Abstract Background Limited progress in terms of an effective treatment for spinal cord injury (SCI) emphasizes the urgent need for novel therapies. As a vital central nervous system component, the resident astrocytes play crucial roles in regulating recovery after SCI. In this study, recovery after SCI was compared following the transplantation of either A1 or A2 astrocytes. A1 astrocytes are harmful as they upregulate the neurotoxic classical complement cascade genes. Conversely, A2 astrocytes are characterized as neuroprotective as they upregulate the production of many neurotrophic factors. Methods We used different supernatant obtained from microglia stimulated with lipopolysaccharide or interleukin-4 to generate A1 and A2 astrocytes. We detected the influence of astrocytes on neurons by co-culturing A1 and A2 astrocytes with neurons. We transplanted astrocytes into the lesion site of the spinal cord and assessed lesion progression, neural restoration, glia formation and locomotor recovery. Results Astrocytes were polarized into A1 and A2 phenotypes following culture in the supernatant obtained from microglia stimulated with lipopolysaccharide or interleukin-4, respectively. Furthermore, co-culturing A2 astrocytes with neurons significantly suppressed glutamate-induced neuronal apoptosis and promoted the degree of neuron arborization. Transplantation of these A2 astrocytes into the lesion site of the spinal cord of mice significantly improved motor function recovery, preserved spared supraspinal pathways, decreased glia scar deposition, and increased neurofilament formation at the site of injury compared to the transplantation of A1 astrocytes. Additionally, enhanced A2 astrocytes with potentially beneficial A2-like genes were also detected in the A2 group. Moreover, luxol fast blue staining and electron microscopy indicated increased preservation of myelin with organized structure after transplantation of A2 astrocytes than of A1 astrocytes. Conclusions A2 astrocyte transplantation could be a promising potential therapy for SCI. Graphical Abstract Video abstract

Background Little is known about geographic variation in acute myocardial infarction (AMI) mortality within fast‐developing megacities and whether changes in health care accessibility correspond to changes in AMI mortality at the small‐area level. Methods and Results We included data of 94 106 AMI deaths during 2007 to 2018 from the Beijing Cardiovascular Disease Surveillance System in this ecological study. We estimated AMI mortality for 307 townships during consecutive 3‐year periods with a Bayesian spatial model. Township‐level health care accessibility was measured using an enhanced 2‐step floating catchment area method. Linear regression models were used to examine the association between health care accessibility and AMI mortality. During 2007 to 2018, median AMI mortality in townships declined from 86.3 (95% CI, 34.2–173.8) to 49.4 (95% CI, 30.5–73.7) per 100 000 population. The decrease in AMI mortality was larger in townships where health care accessibility increased more rapidly. Geographic inequality, defined as the ratio of the 90th to 10th percentile of mortality in townships, increased from 3.4 to 3.8. In total, 86.3% (265/307) of townships had an increase in health care accessibility. Each 10% increase in health care accessibility was associated with a −0.71% (95% CI, −1.08% to −0.33%) change in AMI mortality. Conclusions Geographic disparities in AMI mortality among Beijing townships are large and increasing. A relative increase in township‐level health care accessibility is associated with a relative decrease in AMI mortality. Targeted improvement of health care accessibility in areas with high AMI mortality may help reduce AMI burden and improve its geographic inequality in megacities.

Background: The study was designed to evaluate the impact of pharmacist-led clinical interventions on the health-related quality of life among tuberculosis patients in Pakistan.Methods: A randomized, controlled prospective study was carried out in a Pakistan Institute of Medical Sciences hospital tuberculosis (TB) control center. Participants who visited the TB center between September 2020 and December 2021 were randomly assigned to two clusters, the usual care group (UC group) vs. the intervention group (pharmaceutical care group), in a 1:1 ratio by a simple envelope technique. In the intervention group, a patient received centered care that encompassed informed decision-making, which can increase the quality of care and monitoring of adverse drug events. However, the control group received routine TB treatment at the hospital. The EuroQol-5D-3L instrument was used to assess the health-related quality of life (HRQoL) at the baseline and in the third and sixth months of the treatment time period.Results: A total of 503 patients were eligible, of which only 426 patients were included in this study. At the end of the study, n = 205 of the patients in the intervention group and n = 185 of those in the control group were analyzed. In the intervention group, the EQ-5D-3L health utility score improved significantly (p < 0.001) (from the baseline mean ± SD, 0.40 ± 0.36, to 6 months of treatment, 0.89 ± 0.09, while in the control group from 0.42 ± 0.35 to 0.78 ± 0.27). In multivariate regression analysis, the variables that remained statistically associated (p < 0.001) with the HRQoL (unstandardized β [95% confidence interval]) of the control group were as follows: gender, female vs. male (-0.039 [-0.076 to -0.003]); body weight, less than 40 kg vs. more than 40 kg (-0.109 [-0.195 to -0.024]); patients with any comorbidity vs. without comorbidity (-0.136 [-0.252 to -0.020]); and smokers vs. non-smokers (-0.204 [-0.291 to -0.118]). The study did not find any statistically significant associations between the intervention group’s variables and the HRQoL.Conclusion: Patient-centered care interventions led by pharmacists as part of care coordination enhanced the HRQoL for TB patients significantly. According to this study, clinical pharmacists should be included in the interdisciplinary clinical staff for TB patient management.

Excessive inflammation post-traumatic spinal cord injury (SCI) induces microglial activation, which leads to prolonged neurological dysfunction. However, the mechanism underlying microglial activation-induced neuroinflammation remains poorly understood. Ruxolitinib (RUX), a selective inhibitor of JAK1/2, was recently reported to inhibit inflammatory storms caused by SARS-CoV-2 in the lung. However, its role in disrupting inflammation post-SCI has not been confirmed. In this study, microglia were treated with RUX for 24 hours and then activated with interferon-γ for 6 hours. The results showed that interferon-γ-induced phosphorylation of JAK and STAT in microglia was inhibited, and the mRNA expression levels of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, interleukin-6, and cell proliferation marker Ki67 were reduced. In further in vivo experiments, a mouse model of spinal cord injury was treated intragastrically with RUX for 3 successive days, and the findings suggest that RUX can inhibit microglial proliferation by inhibiting the interferon-γ/JAK/STAT pathway. Moreover, microglia treated with RUX centripetally migrated toward injured foci, remaining limited and compacted within the glial scar, which resulted in axon preservation and less demyelination. Moreover, the protein expression levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 were reduced. The neuromotor function of SCI mice also recovered. These findings suggest that RUX can inhibit neuroinflammation through inhibiting the interferon-γ/JAK/STAT pathway, thereby reducing secondary injury after SCI and producing neuroprotective effects.

The composition of urban forests (UFs) exhibits homogenization among cities compared with rural forests (RFs) among different climate zones. However, the degree of homogenization in subtropical UFs and its difference from RFs remain unclear. In this study, we examined tree species composition and diversity in UFs in 19 cities in China’s subtropical zone with precipitation ranging from 458 to 1852 mm and compared them with RFs. We found that (1) the species composition similarity, Jaccard index (J~0.27), between UFs was significantly higher than that (J~0.15) of RFs, indicating biotic homogenization; (2) tree species richness, Simpson, Shannon–Wiener, and Pielou index of UFs converged along the precipitation gradient; (3) the similarity of tree composition between UFs increased as precipitation of the cities were more similar; (4) the UFs in the 19 cities contained a total of 932 tree species, among which the nonnative species were more prevalent than the native species, and the top 37 species with high frequency appeared in 80% of the cities; and (5) Salix babylonica, Ginkgo biloba, Platycladus orientalis, Juniperus chinensis, and other tree species were suitable for planting in UFs in subtropical zones, regardless of humidity. The findings contribute to the understanding of urban forest development and provide insights for implementing greening policies aimed at providing additional ecosystem services.

Alzheimer’s disease (AD) represents a significant public health concern in modern society. Metabolic syndrome (MetS), which includes diabetes mellitus (DM) and obesity, represents a modifiable risk factor for AD. MetS and AD are interconnected through various mechanisms, such as mitochondrial dysfunction, oxidative stress, insulin resistance (IR), vascular impairment, inflammation, and endoplasmic reticulum (ER) stress. Therefore, it is necessary to seek a multi-targeted and safer approach to intervention. Thus, 10-hydroxy-2-decenoic acid (10-HDA), a unique hydroxy fatty acid in royal jelly, has shown promising anti-neuroinflammatory, blood–brain barrier (BBB)-preserving, and neurogenesis-promoting properties. In this paper, we provide a summary of the relationship between MetS and AD, together with an introduction to 10-HDA as a potential intervention nutrient. In addition, molecular docking is performed to explore the metabolic tuning properties of 10-HDA with associated macromolecules such as GLP-1R, PPARs, GSK-3, and TREM2. In conclusion, there is a close relationship between AD and MetS, and 10-HDA shows potential as a beneficial nutritional intervention for both AD and MetS.

This paper proposes a deep learning-based model to predict stock price movements. The proposed model is composed of a deep belief network (DBN) to learn the latent feature representation from stock prices, and a long short-term memory (LSTM) network to exploit long-range relations within the trading history. The prediction target of the model is the stock close price direction on the next day. To predict the trend of one stock, the feature of recent trading information is generated from the raw intra-day data through a pre-trained DBN. Then the extracted features are fed into an LSTM classifier to produce the prediction result for the next day. The proposed model was tested on 36 companies in the Shanghai Stock Exchange (SSE) and the Shenzhen Stock Exchange (SZSE), which were selected based on their weights in Chinese A-shares. The experiments cover a span of 12 years, from 2005 to 2016, and the results show that the proposed model offers notable improvements in predicting performance comparing with other learning models. It is also observed that some companies are more predictable than others, which implies that the proposed model can be used for financial portfolio construction.

BackgroundVascular dementia (VaD) and carotid atherosclerotic plaques are common in the elderly population, conferring a heavy burden on families and society. Accumulating evidence indicates carotid atherosclerotic plaques to be a risk factor for VaD. However, the underlying mechanisms for this association are mainly unknown.Materials and methodsWe analyzed temporal cortex gene expression data of the GSE122063 dataset and gene expression data of the GSE163154 dataset to identify commonly differentially expressed genes (DEGs). Then we performed functional enrichment analysis, immune cell infiltration and evaluation, correlation analysis between differentially expressed immune-related genes (DEIRGs) and immune cells, receiver operating characteristic (ROC) analysis, and drug-gene analysis.ResultsWe identified 41 overlapped DEGs between the VaD and carotid atherosclerosis plaque datasets. Functional enrichment analyses revealed that these overlapped DEGs were mainly enriched in inflammatory and immune-related processes. Immunocyte infiltration and evaluation results showed that M0 macrophages, M2 macrophages, and T cells gamma delta had a dominant abundance in carotid atherosclerosis plaque samples, and M0 macrophages showed a significantly different infiltration percentage between the early and advanced stage plaques group. Resting CD4 memory T cells, M2 macrophages, and naive B cells were the top three highest infiltrating fractions in VaD. Furthermore, B cells and NK cells showed a different infiltration percentage between VaD and matched controls. We identified 12 DEIRGs, and the result of correlation analysis revealed that these DEIRGs were closely related to differentially expressed immune cells. We identified five key DEIRGs based on ROC analysis. The drug-gene interaction analysis showed that four drugs (avacopan, CCX354, BMS-817399, and ASK-8007) could be potential drugs for VaD and carotid atherosclerotic plaques treatment.ConclusionCollectively, these findings indicated that inflammatory and immune-related processes be a crucial common pathophysiological mechanism shared by VaD and carotid plaques. This study might provide new insights into common molecular mechanisms between VaD and carotid plaques and potential targets for the treatment.

Abstract Understanding the spatial distribution characteristics and formation mechanism of urban facilities (city functional components) constitutes the basis of urban layout optimization. Currently, research on the overall distribution of the various types of city functional components is lacking. In this study, by applying the gradient analysis method common in ecology, we considered 13 types of city functional components (80,214 individuals in total) in large, medium and small Chinese cities (9 cities in total) to carry out quantitative analysis of the distribution of components along urban–rural gradients through density distribution curves. The results indicated that: (1) a higher density of city functional components near the city centre revealed an obvious aggregated distribution; (2) the spatial distribution dynamics of city functional components were related to the city size, providing a reference for the rational distribution of components in cities of different sizes; (3) the distribution of city functional components was affected by their ecosystem services. This study offers a new perspective for the application of ecological methods in the examination of the distribution of city functional components.

BackgroundNeuroinflammation following spinal cord injury (SCI) results in prolonged neurological damage and locomotor dysfunction. Polarization of microglia is vital to regulation of neuroinflammation, although the underlying mechanisms have not yet been elucidated. Endocannabinoid receptor subtype 2 (CB2R) is reported to ameliorate neurodegeneration via immunomodulation activities. However, the underlying machinery in the context of SCI remains unclear.MethodsA lipopolysaccharide-induced microglia inflammation model and a mouse model of SCI were employed to investigate the regulatory role of CB2R in the polarization of microglia in response to excess neuroinflammation. Markers of inflammation and autophagy were measured by Western blot analysis, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent assays. Histological staining with hematoxylin and eosin, Nissl, and Luxol® fast blue was conducted using commercial kits. The locomotor function of the hindlimbs of the experimental mice was evaluated with the Basso Mouse Scale, Louisville Swim Scale, and footprint assay.ResultsThe results showed that CB2R promoted M2 differentiation, increased interleukin (IL)-10 expression, and inhibited M1 differentiation with decreased expression of IL-1β and IL-6. CB2R activation also increased ubiquitination of the NLRP3 inflammasome and interacted with the autophagy-related proteins p62 and microtubule-associated proteins 1B light chain 3. Treatment with the CB2R activator JWH-133 reduced loss of myelin, apoptosis of neurons, and glial scarring, leading to improved functional recovery of the hindlimbs, while the CB2R antagonist AM630 produced opposite results.ConclusionTaken together, these results suggested that CB2R activation attenuated neuroinflammation targeting microglial polarization by promoting NLRP3 clearance, thereby facilitating functional recovery post-SCI.

Introduction: The biomedical industry has grown significantly both globally and in China; however, there are still challenges. This study aimed at evaluating the biopharmaceutical sector of China, in terms of ability to innovate, current sales volume, investment, and R&D expenditure, as well as providing a case study detailing the progress and challenges of the industry in Shaanxi province.Method: A cross-sectional mixed-method study design was used to generate a comprehensive profile of the nature of biopharmaceutical innovation capacity and development in China by triangulating country-wide survey and interview data from Shaanxi province. Only biopharmaceutical companies that are currently marketing or conducting research and development were eligible for inclusion, and Shaanxi province was selected for conducting the interviews. Categorical and continuous variables were analyzed descriptively. Interviews were thematically analyzed by using NVivo version 12.Results: The analysis includes responses from 77 biopharmaceutical enterprises; the majority (36, 46.8%) are in Eastern China, followed by 26 (33.8%) in Central China. In 2018, the total sales of biological products amounted to 26.28 billion yuan, and in 2019, a slight increase was observed (30.34 billion); the amount doubled in 2020 to about 67.91 billion yuan. The top three biopharmaceutical products on sale in 2020 were Camrelizumab (5.14 billion yuan), human albumin (4.56 billion yuan), and human immunoglobulin for injection (3.78 billion yuan). Expenditure on R&D has also increased; it amounted to 1657.7 million yuan in 2018, which more than doubled in 2019 to 3572.1 million yuan and further increased to 5857.7 million yuan in 2020. Nonetheless, the progress is not uniform across all provinces, as shown from the results from Shaanxi province, because of lack of local government policies that will impact on the funding, incentives, and market share that motivate the producers.Conclusion: China’s biopharmaceutical industry has expand significantly. The increase in sales indicates that there is an increase in demand for biologicals; moreover, R&D funding is increasing. These are key indicators that influence innovation and development. However, the sector’s capacity to innovate and develop needs to be improved, particularly in the western region, where research and production are relatively weak.

ABSTRACT Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is a crucial disease for wheat worldwide and constantly threatens wheat production in southwestern and northwestern China, where the environment is a good fit for Pst oversummering and overwintering. However, the underlying genetic dynamics of spring epidemic Pst populations across large areas of continuous planting in the southwestern and northwestern regions are poorly understood. A total of 2,103 Pst isolates were sampled in the spring of 2019 from the two agroecosystems and grouped into three horizontal spatial scales (countywide, provincial, and regional subpopulations) and two vertical spatial scales that consisted of elevational and geomorphic subpopulations. A total of 776 multilocus genotypes were identified, with the highest genetic diversity found in the northern and Sichuan populations, particularly in the Ningxia and Sichuan Basins, while the lowest genetic diversity was found in the Yunnan and Guizhou populations. Multivariate discriminant analysis of principal components (DAPC) and STRUCTURE (STRUCTURE 2.3.4) analyses revealed variation in the genotypic compositions of the molecular groups on horizontal and vertical dimensions from north to south or vice versa and from low to high or vice versa, respectively. The regional neighbor-joining tree revealed three large spatial structures consisting of the southwestern, the northwestern, and the Xinjiang regions, while the Tibetan population connected the southwestern and northwestern regions. The isolates of the Sichuan Basin were scattered over the four quartiles by principal coordinate analysis, which indicated frequent genotype interchange with others. Greater genetic differentiation was observed between the southwestern and northwestern regions. Linkage equilibrium (P ≥ 0.05) was detected on different spatial scales, suggesting that Pst populations are using sexual reproduction or mixed reproduction (sexual and clonal reproduction) in southwestern and northwestern China. IMPORTANCE Understanding the epidemiology and population genetics of plant pathogens is crucial to formulate efficient predictions of disease outbreaks and achieve sustainable integrated disease management, especially for pathogens with migratory capability. Here, this study covers the genetic homogeneity and heterogeneity of different geographical Pst populations on broad to fine spatial scales from the key epidemic regions of the two agroecosystems in China, where wheat stripe rust occurs annually. We provide knowledge of the population genetics of Pst and reveal that, for instance, there is greater genetic diversity in northwestern China, there are close genetic relationships between Yunnan and Guizhou and between Gansu-Ningxia and Qinghai, and there are effects of altitude on genetic compositions, etc. All of these findings clarify the genetic relationships and expand the insights into the population dynamics and evolutionary mechanisms of Pst in southwestern and northwestern China, providing a theoretical basis for achieving sustainable control of wheat stripe rust in key epidemic regions.

Abstract Microglia activation post traumatic spinal cord injury (SCI) provokes accumulation of inflammatory metabolites, leading to increasing neurological disruption. Our previous studies demonstrated that blocking MAPKs pathway mitigated microglia inflammatory activation and prevented cords from neuroinflammation-induced secondary injury. Transforming growth factor-β-activated kinase 1 (TAK1) is an upstream gate regulating activation of MAPKs signaling. To validate the therapeutic effect of TAK1 inhibition in neuroinflammation post SCI, in the current study, cultures of microglia BV2 line was undergone lipopolysaccharide (LPS) stimulation in the presence of TAK1 inhibitor 5Z-7-Oxozeaenol (ZO), LPS, or control. LPS triggered inflammatory level, cell migration, and matrix metalloproteinase (MMP) 2/9 production, which was reduced in ZO-treated cultures. TAK1 inhibition by ZO also decreased activation of MAPKs pathway, indicating that ZO-mediated alleviation of neuroinflammation is likely modulated via TAK1/MAPKs axis. In vivo, neuroinflammatory level and tissue destruction were assessed in adult male mice that were undergone SCI by mechanical trauma, and treated with ZO by intraperitoneal injection. Compared with SCI mice, ZO-treated mice exhibited less microglia pro-inflammatory activation and accumulation adjacent to injured core linked to reduced MMP2/9 expression, leading to minor tissue damage and better locomotor recovery. To sum up, the obtained data proved that in the early phase post SCI, TAK1 inhibition impedes microglia biological activities including activation, enzymatic synthesis, and migration via downregulation of MAPKs pathway, and the effects may be accurately characterized as potent anti-inflammation.

Cuscuta chinensis Lam. (CCL) is a medicinal herb widely used in traditional Chinese medicine for the treatment of ophthalmic diseases, including age-dependent vision-threatening retinal degenerative disorders that involve irreversible loss of the first-order retinal neurons, photoreceptors. However, evidence is lacking if CCL is pharmacologically active at protecting against loss of photoreceptors and photoreceptor degeneration-associated retinal structural and functional impairment. The current study thus evaluates the potential photoreceptor protective effects of CCL to better support its clinical applications in the prevention and treatment of photoreceptor degenerative diseases. Non-invasive full-retinal optical coherence tomography, electroretinography, histological examination, immunohistochemistry and real-time qPCR analysis were performed to assess the retinal protective effects of CCL in light-exposed BALB/c mice characterized by photooxidative stress-mediated photoreceptor loss and associated retinal morphological and functional impairment. The results showed that CCL treatment protected against light-induced degeneration of the photoreceptor structure and deterioration of the retinal function. Furthermore, CCL treatment increased the retinal expression of rhodopsin, S-opsin and M-opsin, supporting the protective effects of CCL in both rod and cone photoreceptors. CCL treatment suppressed photoreceptor cell death in the light-exposed retinas. The morphological integrity of the second-order retinal neurons was also preserved as a result of CCL treatment. In addition, CCL treatment attenuated light-induced reactive müller gliosis, microglial activation and inflammation in the retina. In conclusion, the current work demonstrates for the first time that CCL protects against photooxidative stress-mediated degeneration of photoreceptors and associated disturbance of structural, functional and immune homeostasis of the retina. The findings here thus provide novel experimental evidence supporting the clinical application of CCL in the prevention and treatment photoreceptor degenerative diseases.

BackgroundIn China, the pharmacy departments of most hospitals have changed their main focus from drug procurement and distribution to providing pharmaceutical care services. Various regions of China have successively implemented the pilot Chief Pharmacist System (CPS) to help improve pharmaceutical care services and rational drug use in hospitals. This study was designed to explore the perspectives of pharmacists and government officials on CPS, including the advantages and barriers to the successful implementation of CPS.MethodsA qualitative study, based on semi-structured interviews, was conducted from October 1, 2018 to March 1, 2019. The interview data were gathered from 18 pharmacy staff and government representatives working in five distinct regions of China using purposive sampling. A thematic analysis approach and NVivo version 12 Plus was utilized to code and analysis of all interviews.ResultsFive broad themes were identified: the role of the chief pharmacist; their attitudes toward the CPS; the advantages and results of the CPS; the barriers toward CPS; and their suggestions toward CPS. Most of the participants believed that the chief pharmacist played a vital role in a hospital. Under CPS, the hospital pharmacy department pays more attention to prescription review, medication monitoring, and pharmaceutical consultation. However, an insufficient number of pharmacy personnel, unclear authority, and inadequate salaries were the main barriers to the implementation of the CPS.ConclusionThe attitudes of most of the participants were found to be positive toward CPS in China. The CPS can enhance the prestige of the hospital pharmacy department, improve the quality of hospital pharmaceutical care services, and promote rational drug use. Nevertheless, certain barriers highlighted in this study should be addressed promptly.

BackgroundFrailty is a state of cumulative degradation of physiological functions that leads to adverse outcomes such as disability or mortality. Currently, there is still little understanding of the prognosis of pre-stroke frailty status with acute cerebral infarction in the elderly.ObjectiveWe investigated the association between pre-stroke frailty status, 28-day and 1-year survival outcomes, and functional recovery after acute cerebral infarction.MethodsClinical data were collected from 314 patients with acute cerebral infarction aged 65–99 years. A total of 261 patients completed follow-up in the survival cohort analysis and 215 patients in the functional recovery cohort analysis. Pre-stroke frailty status was assessed using the FRAIL score, the prognosis was assessed using the modified Rankin Scale (mRS), and disease severity using the National Institutes of Health Stroke Scale (NIHSS).ResultsFrailty was independently associated with 28-day mortality in the survival analysis cohort [hazard ratio (HR) = 4.30, 95% CI 1.35–13.67, p = 0.014]. However, frailty had no independent effect on 1-year mortality (HR = 1.47, 95% CI 0.78–2.79, p = 0.237), but it was independently associated with advanced age, the severity of cerebral infarction, and combined infection during hospitalization. Logistic regression analysis after adjusting for potential confounders in the functional recovery cohort revealed frailty, and the NIHSS score was significantly associated with post-stroke severe disability (mRS > 2) at 28 days [pre-frailty adjusted odds ratio (aOR): 8.86, 95% CI 3.07–25.58, p < 0.001; frailty aOR: 7.68, 95% CI 2.03–29.12, p = 0.002] or 1 year (pre-frailty aOR: 8.86, 95% CI 3.07–25.58, p < 0.001; frailty aOR: 7.68, 95% CI 2.03–29.12, p = 0.003).ConclusionsPre-stroke frailty is an independent risk factor for 28-day mortality and 28-day or 1-year severe disability. Age, the NIHSS score, and co-infection are likewise independent risk factors for 1-year mortality.

Background: Multidrug-resistant tuberculosis (MDR-TB) is a growing public health problem. Treatment regimens used against MDR-TB are costly, prolonged, and associated with more side effects as compared with the drug-susceptible tuberculosis. This study was framed to determine the incidence of adverse drug events, risk factors, and their management in MDR-TB patients.Methods: This prospective follow-up cohort study was conducted at the site of programmatic management of drug-resistant TB located at the Pakistan Institute of Medical Sciences, Islamabad. All patients, irrespective of their age, gender, and ethnicity, were included in the study. Adverse drug events were observed in patients at different time points during the study. Patients enrolled for the treatment from January 2018 were prospectively followed till December 2020 up to their end treatment outcomes.Results: Out of 126 MDR-TB patients enrolled for treatment, 116 met the inclusion criteria and were included in the final analysis. Most patients (50.9%) were between 18 and 45 years of age. A minimum of one adverse event was experienced by (50.9%) patients. Of all the adverse events, gastrointestinal disorders were more frequent (47.4%), followed by arthralgia (28.4%) and psychiatric disturbance (20.6%). Furthermore, multivariate analysis showed a significant association with the incidence of adverse events in patients with age group above 60 years (odds ratio (OR) 4.50; 95% CI 1.05-19.2), active smokers (OR 4.20; 95% CI 1.31-13.4), delayed reporting to the TB center (OR 4.03; 95% CI 1.34-12.1), and treatment without bedaquiline regime (OR 3.54; 95% CI 1.23-10.1). Most of the patients (94.6%), counseled by the pharmacist, were found to be satisfied with the information provided and looked for more pharmacist counseling opportunities in the management of MDR-TB.Conclusion: Current findings recommend that ADEs might be well managed by timely identification and reporting. Bedaquiline coupled with other active medications lowered the chance of ADEs in MDR-TB patients. Elderly patients, active smoking behavior, and those who have a delay in the treatment initiation are more prone to ADEs. Clinical pharmacist’s contribution to TB control programs may help caregivers and patients concerning the rational use of medication, early detection, and management of ADEs.

Abstract The goal of the present study was to evaluate the effects of enzymes (cellulase combined with galactosidase) and their combination with Lactobacillus plantarum (LP) on bacterial diversity in alfalfa silages using high-throughput sequencing. Alfalfa forages were treated with or without cellulase + ɑ-galactosidase (CEGA), cellulase + LP (CELP), or ɑ-galactosidase + LP (GALP). After 56 days of ensiling, all treated silages exhibited improved fermentation quality, as reflected by decreased pH, ammonium-N and increased lactic acid levels compared to the control silage (P

Abstract Background Percutaneous kyphoplasty is the main method in the treatment of thoracolumbar osteoporotic compression fractures. However, much radiation exposure during the operation harms the health of surgeons and patients. In addition, the accuracy of this surgery still needs to be improved. This study aimed to assess the radiation exposure and clinical efficacy of Tirobot-assisted vertebroplasty in treating thoracolumbar osteoporotic compression fracture. Methods Included in this retrospective cohort study were 60 patients (60–90 years) who had undergone unilateral vertebroplasty for thoracolumbar osteoporotic compression fracture at our hospital between June 2019 and June 2020. All showed no systemic diseases and were assigned to Tirobot group (treated with Tirobot-assisted approach) and control group (treated with traditional approach). Fluoroscopic frequency, operative duration, length of stay (LOS), post-operative complications (cement leakage, infection, and thrombosis), and pre-operative and pre-discharge indexes (VAS score, JOA score, and Cobb’s angle) were compared. Results The fluoroscopic frequency (P < 0.001) and post-operative complications (P = 0.035) in Tirobot group were significantly lower than those in control group. The operative duration and LOS in the Tirobot group were shorter than those in the control group, but the differences were not statistically significant (P = 0.183). Pre-discharge VAS score and Cobb’s angle decreased, and JOA increased after surgeries in both groups. These three indexes showed a significant difference after surgery in each group (P < 0.001), but not between groups (P VAS = 0.175, P Cobb’s = 0.585, P JOA = 0.448). Conclusion The Tirobot-assisted vertebroplasty can reduce surgery-related trauma, post-operative complications, and patients’ and operators’ exposure to radiation. As a safe and effective strategy, this surgery can realize the quick recovery from thoracolumbar osteoporotic compression fracture.

Based on the known role of oxidative stress in the pathogenesis and progression of metabolic syndrome, we used two-dimensional gel electrophoresis with immunochemical detection of protein carbonyls (2D-Oxyblot) to characterize the carbonylated proteins induced by oxidative stress in spontaneously hypertensive rats/NDmcr-cp (CP), an animal model of metabolic syndrome. We also profiled the proteins that showed change of expression levels in their epididymal adipose tissue at the pre-symptomatic (6-week-old) and the symptomatic (25-week-old) stages of the metabolic syndrome. Two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF MS) was used to analyze proteins extracted from the epididymal adipose tissue. The up-regulated proteins identified at the pre-symptomatic stage were mainly associated with ATP production and redox reaction, while the down-regulated proteins found at the symptomatic stage were involved in antioxidant activity and the tricarboxylic acid (TCA) cycle. Further analysis using the 2D-Oxyblot showed significantly high carbonylation levels of gelsolin and glycerol-3-phosphate dehydrogenase [NAD+] at the symptomatic stage. These results suggest that reduced antioxidant capacity underlies the increased oxidative stress state in the metabolic syndrome. The identified carbonylated proteins, including gelsolin, are potential targets that may act as key regulators in the progression of the metabolic syndrome.

Background and Purpose: White matter hyperintensities (WMH) caused by chronic cerebral hypoperfusion are common in Moyamoya disease (MMD) patients, but WMH burden with comprehensive cognition in adult asymptomatic MMD remains unknown. This study tried to investigate the association between the WMH burden and cognitive function in adult asymptomatic MMD. Methods: Sixty-four adult asymptomatic MMD patients without surgical revascularization were enrolled in this study and underwent a 3T MRI scan and complete cognitive tests from 2021 to 2022. WMH volume was extracted with brain anatomical analysis using the diffeomorphic deformation (BAAD) toolbox, which works on SPM 12 software. Multivariable linear regression analysis was performed to assess the association between WMH burden and cognitive function in asymptomatic MMD. Results: Firstly, our data showed that lower education levels and higher WMH burden were strongly related to global cognitive impairment after adjusting for other variables. Secondly, WMH severity was significantly associated with several domains of neurocognitive function, including memory, semantic memory, and executive function. Finally, when stratified by sex, the female participants with WMH severity had lower cognitive performance in all areas than male participants. Conclusions: These results suggest that WMH burden was highly correlated with global cognition, memory, semantic memory, and executive function in asymptomatic MMD. Especially in female participants, the relationship became more evident.

In order to achieve efficient resource utilization of metal tailings, taking the roasted clinker of silver tailings (RCST) as the object, the dissolution behaviors of Si, Al and Fe in the water–acid two-stage leaching process and the water leaching kinetics of Si were investigated in this study. Single-factor experiments were performed to investigate the effects of the leaching parameters; the XRF, XRD and SEM-EDS methods were used to characterize the leaching residues with different leaching times, and the leaching kinetics models of Si were established. The results demonstrate that, in the water leaching stage, the sodium silicate and a small part of the structurally unstable sodium aluminosilicate in RCST are dissolved, while the nepheline, most of the sodium aluminosilicate and the mixed materials containing iron enter the water leaching residue. The first 5 min of water leaching is controlled by both interfacial transfer and diffusion across the product layer, with an apparent activation energy of 22.36 kJ/mol, and the dissolution reaction during 5–15 min is controlled by the unsteady diffusion of the liquid film, with an apparent activation energy of 14.22 kJ/mol. The structure of the materials in the clinker is completely destroyed, and a great number of fissures and pores are produced by the continued dissolving action of the water. Thus, in the acid leaching stage, the amorphous Si-, Al- and Fe-containing substances in the water leaching residue are rapidly dissolved in the sulfuric acid solution at a lower temperature.

Background: Antibiotic resistance (ABR) is one of the major issues around the globe. Timely education and awareness of pharmacy students regarding the appropriate use of antibiotics, ABR, and antimicrobial stewardships are required.Methods: The present study was first conducted in 12 (public and private sector) universities among undergraduate pharmacy students (UGPS) (n = 414) irrespective of their study year through a validated questionnaire, and the insights of pharmacy teachers were taken through in-depth semi-structured interviews in the second phase. For the quantitative data, different statistical methods were used, and data were presented in tabulated form, whereas inductive thematic interpretation was used to categorize themes and derive conclusions from qualitative evidence.Results: The majority of the students were males (n = 223, 54%) with the mean age group 19–23 years, and 20 faculty members were interviewed with a mean duration of 15 min. Students have good knowledge about antibiotics use and the majority purchased antibiotics through prescription (n = 277, 66.9%) during the last month and strongly agreed to stop unnecessary household storage (n = 183 44.2%). Most of the students have heard the terminologies related to antimicrobial resistance through social media while unaware (n = 104, 25.1%) of a Pakistan national action plan against AMR (antimicrobial resistance). Overall, respondents have a somewhat good understanding of the ABR. Regular use of antibiotics without consultation of a physician can lead to ABR and some wrong answers were observed (162, 39.1%; p > 0.05). The majority of the students (n = 198, 47.8%) and teachers believe that the current pharmacy syllabus must be swiftly updated with the new subjects related to ABR and AMS (antimicrobial stewardship) in Pakistan. The UGPS have emphasized (n = 220, 53.1%; Median = 1, IQR = 2) establishing a link between academia and hospitals. The ABR issue has been highlighted by pharmacy faculty members, who have urged students to take practical efforts toward ABR and AMS knowledge.Conclusion: The UGPS knowledge related to ABR and AMS must be updated. Students at the undergraduate level must get training in order to encourage the sensible use of antibiotics. Courses on ABR and AMS should be included in present pharmacy curricula.

Robot-assisted orthopedic surgery has great application prospects, and the accuracy of the robot is the key to its overall performance. The aim of this study was to develop a new orthopedic surgical robot to assist in spinal surgeries and to compare its feasibility and accuracy with the existing orthopedic robot. A new type of high-precision orthopedic surgical robot (Tuoshou) was developed. A multicenter, randomized controlled trial was carried out to compare the Tuoshou with the TiRobot (TINAVI Medical Technologies Co., Ltd., Beijing) to evaluate the accuracy and safety of their navigation and positioning. A total of 112 patients were randomized, and 108 patients completed the study. The position deviation of the Kirschner wire placement in the Tuoshou group was smaller than that in the TiRobot group (p = 0.014). The Tuoshou group was better than the TiRobot group in terms of the pedicle screw insertion accuracy (p = 0.016) and entry point deviation (p < 0.001). No differences were observed in endpoint deviation (p = 0.170), axial deviation (p = 0.170), sagittal deviation (p = 0.324), and spatial deviation (p = 0.299). There was no difference in security indicators. The new orthopedic surgical robot was highly accurate and optimized for clinical practice, making it suitable for clinical application.

Previous studies lacked attention to the spatial heterogeneity of the impact of urbanization on carbon emissions. To fill this knowledge gap, this study analyzed the spatio-temporal variations of carbon emissions (TCE), the per capita carbon intensity (PCI), and the economic carbon intensity (ECI) in the Chengdu-Chongqing urban agglomeration (CUA) based on the Open-Data Inventory for Anthropogenic Carbon dioxide (ODIAC) from 2000–2018. Bivariate spatial autocorrelation, and spatial Durbin models were combined to quantify the spatial correlation and driving mechanisms between carbon emission intensity and multi-dimensional urbanization (population, economic, and land urbanization). The following are the main results: (1) The TCE in CUA increased by 3.918 million tons at an average annual growth of 6.86%; CUA ranked last among China’s national strategic urban agglomerations in terms of TCE, PCI, and ECI. (2) High carbon emission values were concentrated in the Chengdu and Chongqing metropolitan areas, presenting a spatial feature of “Core-Periphery” gradient decay. (3) Nearly 30% of the agglomeration had carbon emission growth at low rates, with the growth cores concentrated in the main urban areas of Chengdu and Chongqing. (4) The “Low-Low” positive correlation was the main correlation type between multi-dimensional urbanization and carbon emissions and was distributed mainly in mountainous areas (e.g., Leshan and Ya’an). (5) Among the urbanization dimensions, the impacts on carbon emissions in local and adjacent areas exhibited varying levels of spatial heterogeneity. Economic urbanization was found to have the strongest positive direct and spillover effects; land urbanization inhibited the growth of carbon emissions in local and adjacent areas; population urbanization promoted carbon emission reduction in adjacent areas. Our findings provide support for CUA to carry out cross-city joint governance strategies of carbon emissions, also proving that regional carbon emission reduction should be an integration of various efforts including low-carbon living of residents, green transformation of economy and optimal land management.