Search

Abstract Background Both interpregnancy intervals (IPI) and environmental factors might contribute to low birth weight (LBW). However, the extent to which air pollution influences the effect of IPIs on LBW remains unclear. We aimed to investigate whether IPI and air pollution jointly affect LBW. Methods A retrospective cohort study was designed in this study. The data of birth records was collected from the Jiangsu Maternal Child Information System, covering January 2020 to June 2021 in Nantong city, China. IPI was defined as the duration between the delivery date for last live birth and date of LMP for the subsequent birth. The maternal exposure to ambient air pollutants during pregnancy—including particulate matter (PM) with an aerodynamic diameter of ≤ 2.5 μm (PM2.5), PM10, ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2) and carbon monoxide (CO)—was estimated using a hybrid kriging-LUR-RF model. A novel air pollution score was proposed, assessing combined exposure to five pollutants (excluding CO) by summing their concentrations, weighted by LBW regression coefficients. Multivariate logistic regression models were used to estimate the effects of IPI, air pollution and their interactions on LBW. Relative excess risk due to interaction (RERI), attributable proportion of interaction (AP) and synergy index (S) were utilized to assess the additive interaction. Results Among 10, 512 singleton live births, the LBW rate was 3.7%. The IPI-LBW risk curve exhibited an L-shaped pattern. The odds ratios (ORs) for LBW for each interquartile range increase in PM2.5, PM10, O3 and the air pollution score were 1.16 (95% CI: 1.01–1.32), 1.30 (1.06–1.59), 1.22 (1.06–1.41), and 1.32 (1.10–1.60) during the entire pregnancy, respectively. An additive interaction between IPI and PM2.5 was noted during the first trimester. Compared to records with normal IPI and low PM2.5 exposure, those with short IPI and high PM2.5 exposure had the highest risk of LBW (relative risk = 3.53, 95% CI: 1.85–6.49, first trimester). Conclusion The study demonstrates a synergistic effect of interpregnancy interval and air pollution on LBW, indicating that rational birth spacing and air pollution control can jointly improve LBW outcomes.

Abstract To investigate the effect and safety of percutaneous endovascular angioplasty (PEA) with optional stenting for the treatment of severe stenosis or occlusion of subclavian artery, patients with severe stenosis ≥ 70% or occlusion of subclavian artery treated with PEA were retrospectively enrolled. The clinical data were analyzed. A total of 222 patients were retrospectively enrolled, including 151 males (68.0%) and 71 females (32.0%) aged 48–86 (mean 63.9 ± 9.0) years. Forty-seven (21.2%) patients had comorbidities. Subclavian artery stenosis ≥ 70% was present in 201 (90.5%) patients and complete subclavian occlusion in 21 (9.5%) cases. Angioplasty was successfully performed in all (100%) patients. Balloon-expandable stents were used in 190 (85.6%) cases, and self-expandable stents in 20 (9.0%) cases. Only 12 (5.4%) cases were treated with balloon dilation only. Among 210 patients treated with stent angioplasty, 71 (33.8% or 71/210) cases underwent balloon pre-dilation, 139 (66.2% or 139/210) had direct deployment of balloon-expandable stents, and 2 (1.0% or 2/210) experienced balloon post-dilation. Distal embolization protection devices were used in 5 (2.3% or 5/222) cases. Periprocedural complications occurred in 3 (1.4%) patients, including aortic dissection in 2 (0.9%) cases and right middle cerebral artery embolism in 1 (0.5%). No hemorrhage occurred. Among 182 (82.0%) patients with 6-month follow-up, restenosis > 70% occurred in 1 (0.5%) patient, and among 68 (30.6%) patients with 12-month follow-up, restenosis > 70% took place in 11 (16.2%) patients. Percutaneous endovascular angioplasty can be safely and efficiently performed for the treatment of severe stenosis ≥ 70% or occlusion of subclavian artery.

Abstract Background Pneumoconiosis, a chronic disease stemming from prolonged inhalation of dust particles, stands as a significant global burden of occupational diseases. This study aims to investigate the survival outcomes of pneumoconiosis patients in Huangshi city, China, while also evaluating the disease burden on afflicted patients. Methods Data for this study were sourced from the Huangshi Center for Disease Control and Prevention. Survival analyses of pneumoconiosis patients were conducted employing life tables and the Kaplan-Meier method. The Cox proportional hazards models were deployed to identify factors influencing pneumoconiosis patients’ survival duration. Competing risks models were employed to confirm the validity of the model outcomes. Additionally, in the disease burden assessment, disability-adjusted life years (DALYs) were computed for various demographic groups and time frames. Results A total of 5,641 pneumoconiosis cases, diagnosed in Huangshi City, Hubei Province between 1958 and 2021, were incorporated into the cohort analysis. The probability of mortality and the risk ratio increased with advancing age. Notably, the median survival time of stage III pneumoconiosis patients was significantly shorter compared with those in stages I and II. The Cox proportional hazards model and competing risks analyses underscored several significant factors influencing survival time, including dust exposure duration (HR = 1.197, 95% CI: 1.104–1.298), age at first diagnosis (HR = 3.149, 95% CI: 2.961–3.349), presence of silicosis (HR = 1.378, 95% CI: 1.254–1.515), and stage II-III pneumoconiosis (HR = 1.456, 95% CI: 1.148–1.848). Cumulatively, DALYs amounted to 7,974.35 person-years, with an average of 1.41 person-years. The period between 2000 and 2019 witnessed the highest disease burden. Conclusion Our findings highlight the urgent need for improved prevention, earlier detection, and more effective management strategies for the occupational pneumoconiosis population. This study not only underscores the persistent issue of pneumoconiosis in industrial environments but also serves as a crucial call to action for policymakers and healthcare providers.

Abstract To investigate the significance of atherosclerotic plaque location in hybrid surgery comprising both endovascular recanalization approaches and carotid endarterectomy for symptomatic atherosclerotic non-acute long-segment occlusion of the internal carotid artery (ICA), 162 patients were enrolled, including 120 (74.1%) patients in the proximal plaque group and 42 (25.9%) in the distal plaque group. Surgical recanalization was performed in all patients, with successful recanalization in 119 (99.2%) patients in the proximal and 39 (92.9%) in the distal plaque group. The total successful recanalization rate was 97.5% (158/162) with a failure rate of 2.5% (4/162). Periprocedural complications occurred in 5 (4.2% or 5/120) patients in the proximal plaque group, including neck infection in two (1.7%), recurrent nerve injury in 1 (0.8%), and laryngeal edema in 2 (1.7%), and 2 (4.8%) in the distal plaque group, including femoral puncture infection in 2 (4.8%). No severe complications occurred in either group. Univariate analysis showed plaque location was a significant (P = 0.018) risk factor for successful recanalization, and multivariate analysis indicated that the plaque location remained a significant independent risk factor for recanalization success (P = 0.017). In follow-up 6–48 months after the recanalization surgery, reocclusion occurred in two (2.8%) patients in the proximal plaque group and 4 (13.3%) in the distal plaque group. In conclusion, although hybrid surgery achieves similar outcomes in patients with ICA occlusion caused by either proximal or distal atherosclerotic plaques, plaque location may be a significant risk factor for successful recanalization of symptomatic non-acute long-segment ICA occlusion.

Purpose: The objective of this study is to develop a novel diagnostic tool using deep learning and radiomics to distinguish bone tumors on CT images as metastases from breast cancer. By providing a more accurate and reliable method for identifying metastatic bone tumors, this approach aims to significantly improve clinical decision-making and patient management in the context of breast cancer. Methods: This study utilized CT images of bone tumors from 178 patients, including 78 cases of breast cancer bone metastases and 100 cases of non-breast cancer bone metastases. The dataset was processed using the Medical Image Segmentation via Self-distilling TransUNet (MISSU) model for automated segmentation. Radiomics features were extracted from the segmented tumor regions using the Pyradiomics library, capturing various aspects of tumor phenotype. Feature selection was conducted using LASSO regression to identify the most predictive features. The model’s performance was evaluated using ten-fold cross-validation, with metrics including accuracy, sensitivity, specificity, and the Dice similarity coefficient. Results: The developed radiomics model using the SVM algorithm achieved high discriminatory power, with an AUC of 0.936 on the training set and 0.953 on the test set. The model’s performance metrics demonstrated strong accuracy, sensitivity, and specificity. Specifically, the accuracy was 0.864 for the training set and 0.853 for the test set. Sensitivity values were 0.838 and 0.789 for the training and test sets, respectively, while specificity values were 0.896 and 0.933 for the training and test sets, respectively. These results indicate that the SVM model effectively distinguishes between bone metastases originating from breast cancer and other origins. Additionally, the average Dice similarity coefficient for the automated segmentation was 0.915, demonstrating a high level of agreement with manual segmentations. Conclusion: This study demonstrates the potential of combining CT-based radiomics and deep learning for the accurate detection of bone metastases from breast cancer. The high-performance metrics indicate that this approach can significantly enhance diagnostic accuracy, aiding in early detection and improving patient outcomes. Future research should focus on validating these findings on larger datasets, integrating the model into clinical workflows, and exploring its use in personalized treatment planning.

Introduction Tuberculosis (TB) is a major global health issue, particularly, in India and South Africa. We aim to evaluate the potential of the new TB vaccine, Vaccae, to enhance TB control by integrating with active case finding (ACF) strategies in these regions.Methods Using age-structured dynamic models, we projected the epidemiological and economic outcomes of combining Vaccae vaccination with ACF over 27 years. In India, four age-targeted strategies were analysed: (1) adolescent (15 years), (2) adolescent and young adult (AYA, 15–34 years), (3) adult (18–55 years) and (4) elderly (60+ years). In South Africa, strategies were based on HIV status: (1) HIV-targeted, (2) non-HIV and (3) general population. The vaccine efficacy of Vaccae was set at 54.7%, priced at US$120 per course. Outcomes measured included reductions in TB incidence and mortality, prioritised based on budget, incremental cost-effectiveness ratios (ICER) and benefit-cost ratios (BCR).Results In India, the adult strategy could prevent 8.70 (95% UI: 6.86–11.13) million TB cases and 0.61 (0.39–0.91) million deaths, reducing incidence and mortality by 20.1% (18.7%–23.5%) and 19.0% (17.5%–22.5%), respectively. In South Africa, the general population strategy could avert 0.67 (0.45–0.99) million TB cases and 0.21 (0.15–0.28) million deaths, reducing incidence by 28.1% (26.1%–30.3%) and mortality by 27.0% (23.5%–30.0%). The vaccination budgets for the AYA strategy in India and the HIV-targeted strategy in South Africa were US$14.0 (10.14–23.29) billion and US$0.09 (0.06–0.15) billion, respectively. The ICERs were US$1082 (927–1426) and US$70 (53–123) per disability-adjusted life year averted, and the BCRs were 2.0 (1.6–2.4) and 176 (83.4–255.3), respectively. Thus, the AYA strategy in India and the HIV-targeted strategy in South Africa were the most favourable.Conclusion Integrating Vaccae vaccination with ACF could significantly enhance TB control in high-burden countries. Policymakers should consider these strategies, with further research needed to confirm the findings.

BackgroundDemonstrating the positive effects of Nigella sativa supplementation (Nigella spp) on Allergic Rhinitis (AR) treatment is challenging. To investigate the role of Nigella spp in managing AR, a comprehensive review through systematic reviews and meta-analyses was conducted.PurposeTo carry out a meta-analysis of clinical trials that used Nigella spp in treating AR based on current data.Study DesignA meta-analysis of randomized controlled trials (RCTs) was performed.MethodsVarious databases, including PubMed, Web of Science, Embase, Science Direct, Springer Link and the Cochrane Library, were searched until October 2023 to obtain RCTs assessing impact of Nigella spp in the control of AR. The current meta-analysis was carried out with a random-effects model.ResultsThere were 8 studies enrolled, and our meta-analysis findings revealed that, relative to the control group, observation group exhibited the markedly increased total effective rate for allergic rhinitis treatment (odds ratio [OR] = 4.24, 95% confidence interval [CI] (2.57, 7.27), and p < 0.00001); three studies showed that the effect of Nigella spp for nasal symptoms treatment among patients with allergic rhinitis was superior in observation group to control group [mean difference = −2.60, 95% CI (−2.82, −2.38), p < 0.00001]; adverse effects occurred in five studies, all of which were transient, did not require medical intervention, and were not statistically significant between the two groups [OR = 1.01, 95% CI (0.59, 1.73), p = 0.98].ConclusionThe observation group demonstrated relative safety and had an enhanced effect on allergic rhinitis treatment and total nasal symptom improvement than the control group. The inclusion of fewer studies and the lower quality of trial design might affect the stability of the results. However, the evidence-based findings that Nigella spp for allergic rhinitis treatment is more accurate should be validated in future large-scale, multicenter, and well-designed RCTs.

Objective: Continuous research on the structure and function of intestinal microecology has confirmed the association between gut microbiota and the occurrence, development, and outcome of allergic diseases. Here, we explored the genetic causality between gut microbiota and rhinitis. Methods: We conducted a two-sample Mendelian Randomization (MR) study to investigate the genetic causal relationship between gut microbiota and allergic rhinitis and vasomotor rhinitis. Genetic variations in the human gut microbiota were obtained from the summary statistics of the MiBioGen study. Genome-wide summary statistics of rhinitis were obtained from the FinnGen consortium. The causal effect between gut microbiota and rhinitis was assessed using the inverse variance weighted, MR-Egger regression, and weighted median methods. In addition, sensitivity analyses were conducted using different methods, including maximum likelihood, simple mode, and weighted model methods. Results: The IVW approach revealed a causal association of the genus Ruminococcus gauvreauii group with an increased risk of allergic rhinitis (IVW Odds Ratio [OR = 1.26] [1.04, 1.53], p-value = 0.01645). In addition, the genus Fusicatenibacter (IVW OR = 1.20 [1.02, 1.41], p-value = 0.02868) was causally associated with an increased risk of vasomotor rhinitis. Conclusion: Gut microbiota belonging to different genera exert different effects on allergic rhinitis and vasomotor rhinitis, including reducing the risk of rhinitis, and increasing the risk of rhinitis. New insights into the mechanisms of underlying gut microbiota-associated rhinitis are provided. Level of evidence: Level 5.

By reviewing the relevant literature in the field of T cell and allergic rhinitis, we determined the development status, study hotspots, and research frontiers viewpoints of this field to provide a reference for researchers and clinical workers. Methods: Web of Science Core Collection (WoSCC) was applied to obtain the studies related to T cells and allergic rhinitis (AR) from 2003 to 2023, and the information extracted from these studies was analyzed using CiteSpace 6.1.R6 and VOSviewer 1.6.18. Results: In total, 1585 articles were collected from WoSCC, with the time set between 2003 and 2023. Overall, a growing number of articles are being published annually. The countries and institutions with the maximum publications volume are China (370, 23.34 %) and Sun Yat-sen University (34, 2.15 %). The biggest contributor to the field was Durham, Stephen R. from the UK (22, 1.39 %). The Journal of Allergy and Clinical Immunology published the most related papers in the field (88, 5.54 %). Immunotherapy, Th cells, and inflammation were found to be the research hotspots in this area of T cells and allergic rhinitis in recent years. Pathway, model, Regulatory T cells (Treg cells), regulatory B cells, immunoglobulin E,and innate lymphoid cells were the current research hotspots in this field. Conclusion: The field of T cell and allergic rhinitis is developing rapidly, and many countries significantly contributed to this field. Most researchers in this field mainly focused on immunotherapy, Th cell, and inflammation. Pathway, model, Treg cell, regulatory B cell, immunoglobulin E,and innate lymphoid cells were the main subject of current research, and future development is expected to occur in this field.

Rice, a critical staple on a global scale, faces escalating challenges in yield preservation due to the rising prevalence of abiotic and biotic stressors, exacerbated by frequent climatic fluctuations in recent years. Moreover, the scorching climate prevalent in the rice-growing regions of South China poses obstacles to the cultivation of good-quality, heavy-grain varieties. Addressing this dilemma requires the development of resilient varieties capable of withstanding multiple stress factors. To achieve this objective, our study employed the broad-spectrum blast-resistant line Digu, the brown planthopper (BPH)-resistant line ASD7, and the heavy-grain backbone restorer lines Fuhui838 (FH838) and Shuhui527 (SH527) as parental materials for hybridization and multiple crossings. The incorporation of molecular markers facilitated the rapid pyramiding of six target genes (Pi5, Pita, Pid2, Pid3, Bph2, and Wxb). Through a comprehensive evaluation encompassing blast resistance, BPH resistance, cold tolerance, grain appearance, and quality, alongside agronomic trait selection, a promising restorer line, Guihui5501 (GH5501), was successfully developed. It demonstrated broad-spectrum resistance to blast, exhibiting a resistance frequency of 77.33% against 75 artificially inoculated isolates, moderate resistance to BPH (3.78 grade), strong cold tolerance during the seedling stage (1.80 grade), and characteristics of heavy grains (1,000-grain weight reaching 35.64 g) with good grain quality. The primary rice quality parameters for GH5501, with the exception of alkali spreading value, either met or exceeded the second-grade national standard for premium edible rice varieties, signifying a significant advancement in the production of good-quality heavy-grain varieties in the southern rice-growing regions. Utilizing GH5501, a hybrid combination named Nayou5501, characterized by high yield, good quality, and resistance to multiple stresses, was bred and received approval as a rice variety in Guangxi in 2021. Furthermore, genomic analysis with gene chips revealed that GH5501 possessed an additional 20 exceptional alleles, such as NRT1.1B for efficient nitrogen utilization, SKC1 for salt tolerance, and STV11 for resistance to rice stripe virus. Consequently, the restorer line GH5501 could serve as a valuable resource for the subsequent breeding of high-yielding, good-quality, and stress-tolerant hybrid rice varieties.

The undulating terrain in mountainous and hilly regions results in a greater variety and complexity of shadows. Efficient methods for shadow detection and reconstruction in high-resolution remote sensing images are particularly important in such hilly areas. The accurate detection of shadow masks is a prerequisite for shadow reconstruction. By utilizing the features of high hue and low intensity in shadow areas, an initial spectral ratio is constructed based on the CIELCh color space model. Simple linear iterative clustering is employed to perform superpixel segmentation on the image, and the segmented results are spatially constrained to reconstruct the initial spectral ratio. Afterward, an automatic multilevel global thresholding approach is applied to obtain the shadow mask and eliminate the influence of interfering objects. For shadow reconstruction, the segmented superpixels are treated as the smallest processing units. Similar neighboring objects have similar ambient light intensities. Based on this, we propose a shadow reconstruction method, which compensates shadow superpixels using adjacent nonshadow superpixels and determines compensation weights based on their similarity. Furthermore, the shadow boundaries are dilated to obtain penumbra, and mean filtering is performed to compensate for the illumination in the penumbra. Finally, the proposed method is qualitatively and quantitatively compared with existing shadow detection and reconstruction methods. Experimental results demonstrate that this method can accurately detect shadows in high-resolution remote sensing images in mountainous and hilly environments, and effectively reconstruct the spectral information of shadow areas. This has significant implications for subsequent feature extraction and further analysis in mountainous and hilly regions.

Abstract Background Right ventricle failure (RVF) is a progressive heart disease that has yet to be fully understood at the molecular level. Elevated M-type pyruvate kinase 2 (PKM2) tetramerization alleviates heart failure, but detailed molecular mechanisms remain unclear. Objective We observed changes in PKM2 tetramerization levels during the progression of right heart failure and in vitro cardiomyocyte hypertrophy and explored the causal relationship between altered PKM2 tetramerization and the imbalance of redox homeostasis in cardiomyocytes, as well as its underlying mechanisms. Ultimately, our goal was to propose rational intervention strategies for the treatment of RVF. Method We established RVF in Sprague Dawley (SD) rats by intraperitoneal injection of monocrotaline (MCT). The pulmonary artery pressure and right heart function of rats were assessed using transthoracic echocardiography combined with right heart catheterization. TEPP-46 was used both in vivo and in vitro to promote PKM2 tetramerization. Results We observed that oxidative stress and mitochondrial disorganization were associated with increased apoptosis in the right ventricular tissue of RVF rats. Quantitative proteomics revealed that PKM2 was upregulated during RVF and negatively correlated with the cardiac function. Facilitating PKM2 tetramerization promoted mitochondrial network formation and alleviated oxidative stress and apoptosis during cardiomyocyte hypertrophy. Moreover, enhancing PKM2 tetramer formation improved cardiac mitochondrial morphology, mitigated oxidative stress and alleviated heart failure. Conclusion Disruption of PKM2 tetramerization contributed to RVF by inducing mitochondrial fragmentation, accumulating ROS, and finally promoted the progression of cardiomyocyte apoptosis. Facilitating PKM2 tetramerization holds potential as a promising therapeutic approach for RVF.

Background/Aims: The involvement of long noncoding RNAs in the carcinogenesis of hepatocellular carcinoma (HCC) has been well documented by substantial evidence. However, whether cytoskeleton regulator RNA (CYTOR) could affect the progression of HCC remains unclear. Methods: The relative expression of CYTOR, miR-125a-5p and HS1-associated protein X-1 (HAX-1) mRNA in HCC cells were determined via quantitative real-time polymerase chain reaction. The viability of treated HCC cells was measured by Cell Counting Kit-8 assay. Cell apoptosis was estimated by flow cytometry analysis, assessment of caspase-9 activity and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, and Western blot of apoptosis-related proteins. The interplay between CYTOR or HAX-1 and miR-125a-5p was validated by dual-luciferase reporter assay. Results: CYTOR was upregulated and miR-125a-5p was downregulated in HCC cells. CYTOR silencing inhibited cell proliferation and promoted cell apoptosis in HepG2 and SMMC-7721 cells. miR-125a-5p was sponged and negatively regulated by CYTOR, and HAX-1 was directly targeted and negatively modulated by miR-125a-5p. Overexpression of miR-125a-5p enhanced the repressive effects of CYTOR knockdown on HCC cells, and knockdown of HAX-1 enhanced the inhibitory effects of miR-125a-5p mimics on HCC cells. Conclusions: CYTOR silencing facilitates HCC cell apoptosis in vitro via the miR-125a-5p/HAX-1 axis.

In order to investigate the microstructure evolution, tensile deformation mechanism and strengthening mechanism of Ni36Co30Fe11Cr11Al8Nb4 high entropy alloy (HEA), the alloy samples were prepared by directional solidification at different solidification rates (5, 10, 20, 50 and 100 μm/s). Results indicate that the microstructure of the directionally solidified Ni36Co30Fe11Cr11Al8Nb4 HEA is composed of primary bulky dendrites (FCC1 phase) and inter-dendritic lamellar structures which consist of the Laves phase and the Nb-enriched FCC2 phase. With the increase of solidification rate, the dendrites are refined, the volume fraction of inter-dendritic lamellar structure decreases, and Laves phase accumulates at the grain boundaries. Since FCC2 phase has lower nucleation barriers, the nucleation and growth of FCC2 phase are preferential to those of Laves phase in the inter-dendrite region. Tensile results indicate that the directionally solidified Ni36Co30Fe11Cr11Al8Nb4 HEA possesses the highest ultimate tensile strength and fracture strain at 5 μm/s, which are 740.15 MPa and 35.23 %, respectively. The microscopic deformation behavior shows that FCC1 phase yields first, followed by FCC2 and Laves phases in sequence during tensile deformation. The moderately strong FCC2 phase coordinates the large inherent strength gap between FCC1 and Laves phases to avoid stress concentration and maintain ductility. FCC2- Laves interface plays a significant role in hindering dislocation movement and increasing the strength, the overall interfacial strengthening stress is estimated to be 9.1 GPa.

Abstract Background Previous studies have suggested the potential association between air pollution and tuberculosis incidence, but this association remains inconclusive and evidence to assess causality is particularly lacking. We aimed to draw causal inference between fine particulate matter less than 2.5 μm in diameter (PM2.5) and tuberculosis in China. Methods Granger causality (GC) inference was performed within vector autoregressive models at levels and/or first-differences using annual national aggregated data during 1982–2019, annual provincial aggregated data during 1982–2019 and monthly provincial aggregated data during 2004–2018. Convergent cross-mapping (CCM) approach was used to determine the backbone nonlinear causal association based on the monthly provincial aggregated data during 2004–2018. Moreover, distributed lag nonlinear model (DLNM) was applied to quantify the causal effects. Results GC tests identified PM2.5 driving tuberculosis dynamics at national and provincial levels in Granger sense. Empirical dynamic modeling provided the CCM causal intensity of PM2.5 effect on tuberculosis at provincial level and demonstrated that PM2.5 had a positive effect on tuberculosis incidence. Then, DLNM estimation demonstrated that the PM2.5 exposure driven tuberculosis risk was concentration- and time-dependent in a nonlinear manner. This result still held in the multi-pollutant model. Conclusions Causal inference showed that PM2.5 exposure driving tuberculosis, which showing a concentration gradient change. Air pollutant control may have potential public health benefit of decreasing tuberculosis burden.

Abstract Introduction Dolutegravir (DTG)-based regimen was included in the expanded formulary of China's National Free Antiretroviral Treatment Program at the end of 2021. Yet high price of DTG and lack of health economic evaluation in China present barriers for implementation of the regimen. The study aims to investigate the lifetime cost-effectiveness of DTG-based regimen for treatment-naive HIV infection in China. Methods A decision-analytic Markov model was used to obtain the costs and effectiveness of four regimens: Arm A, efavirenz (EFV)-based regimen; Arm B, DTG-based regimen; Arm C, elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (EVG/c/FTC/TAF) regimen; Arm D, abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) regimen. The potential impact of national centralized drug procurement policy was assessed in scenario analysis. The results were further validated through sensitivity analysis. Results Compared with other three regimens, DTG-based regimen led to the fewest cumulative adverse reactions, opportunistic infections and deaths. Compared with EFV-based regimen, the base-case ICERs for DTG-based regimen were 13,357 (USD/QALY) and 13,424 (USD/QALY) from the healthcare system and societal perspective respectively. In the policy scenario analysis with the procurement price of DTG equal to that of LPV/r, DTG-based regimen would be dominant. The model results remained robust in sensitivity analyses. Conclusions DTG-based regimen for treatment-naive patients is likely to be cost-effective and deserve wider implementation in China. This study strongly suggests the centralized procurement of DTG to minimize cost and maximize cost-effectiveness.

Background While global newborn hearing screening programmes (NHSP) are far from the optimal level, the combined hearing and genetic screening has emerged as an innovative approach of early healthcare interventions. There is a clear need for economic evaluation to establish whether newborn deafness gene screening (NDGS), currently mandated by many cities in China, is a good investment.Methods A decision-tree model was constructed to simulate a hypothetical 10-million Chinese newborn cohort over a lifetime with three strategies: (1) no screening, (2) NHSP (standard screening) and (3) NHSP+NDGS (combined screening). The presence of permanent congenital hearing loss (PCHL) and genetic mutation were assigned at birth and held constant for all strategies. Input parameters were obtained from the Cohort of Deafness-gene Screening study and literature review. The government contract price for genetic screening was US$77/child. Outcomes of interest included the number of early diagnosed PCHL, prelingual deafness, total deafness, special education referral, incremental cost-effectiveness ratio (ICER) and benefit–cost ratio (BCR).Results Both standard and combined screening strategies were more effective and more costly than ‘no screening’. Compared with standard screening, combined screening led to 9112 (28.0%) more PCHL cases early detected, avoiding 4071 (66.9%) prelingual deafness cases and 3977 (15.6%) special education referrals. The ICER and BCR for combined screening were US$ 4995/disability-adjusted life-year (95% uncertainty interval, 2963 to 9265) and 1.78 (1.19 to 2.39), from healthcare sector perspective. Combined screening would dominate standard screening from societal perspective. Moreover, it remained cost-effective even in pessimistic scenarios.Conclusions Our findings have particular implication for the ‘scale-up’ of genetic screening at the national level in China. The model may serve as a feasible example for hearing screening strategies in other countries, as well as genetic screening for other diseases.

Abstract Electrochemical CO2 reduction in acidic electrolytes is a promising strategy to achieve high utilization efficiency of CO2. Although alkali cations in acidic electrolytes play a vital role in suppressing hydrogen evolution and promoting CO2 reduction, they also cause precipitation of bicarbonate on the gas diffusion electrode (GDE), flooding of electrolyte through the GDE, and drift of the electrolyte pH. In this work, we realize the electroreduction of CO2 in a metal cation-free acidic electrolyte by covering the catalyst with cross-linked poly-diallyldimethylammonium chloride. This polyelectrolyte provides a high density of cationic sites immobilized on the surface of the catalyst, which suppresses the mass transport of H+ and modulates the interfacial field strength. By adopting this strategy, the Faradaic efficiency (FE) of CO reaches 95 ± 3% with the Ag catalyst and the FE of formic acid reaches 76 ± 3% with the In catalyst in a 1.0 pH electrolyte in a flow cell. More importantly, with the metal cation-free acidic electrolyte the amount of electrolyte flooding through the GDE is decreased to 2.5 ± 0.6% of that with alkali cation-containing acidic electrolyte, and the FE of CO maintains above 80% over 36 h of operation at −200 mA·cm−2.

Abstract Background Interleukin (IL)-36 family cytokines have received increasing attention, especially in the fields of inflammation and immunity research. However, whether IL-36 family cytokine levels are correlated with the results of the assessment of allergic rhinitis (AR) and affect the severity of AR remains unknown. Therefore, this study aimed to investigate the correlations between IL-36 family cytokine levels and subjective and objective assessment results and to further analyze the possible mechanisms of IL-36 family cytokines in the development of AR. Methods An enzyme-linked immunosorbent assay (ELISA) was used to detect the concentrations of the IL-36 family cytokines IL-36α, IL-36β, IL-36γ, IL-36Ra, and IL-38 in the peripheral blood of patients with AR. The condition of patients with AR was assessed by 22-item sino-nasal outcome test (SNOT-22) score, visual analogue scale (VAS) scores for disease severity, and serum inhalant allergen immunoglobulin E (IgE) detection. Correlations between IL-36 family cytokine levels and subjective and objective assessment results in patients with AR were analyzed. Results The concentration of IL-36α in the peripheral blood of patients with AR was the highest, and the concentration of IL-36β was the lowest. The concentration of IL-36α was higher in juvenile patients than in adult patients, and there was a difference in the IL-36Ra level between the perennial allergen group and the seasonal allergen group. There was a positive correlation between IL-36α level and IL-36γ level, IL-36γ level and IL-36Ra level, and IL-36Ra level and IL-38 level, and IL-36β level was positively correlated with IL-36Ra and IL-38 levels, respectively. IL-36α level was positively correlated with VAS score for nasal congestion symptom. IL-36β level was positively correlated with the total VAS score for ocular symptoms and VAS scores for ocular itching and eye pain symptoms. However, there was no correlation between the levels of all cytokines in IL-36 family and SNOT-22 score, the number of positive inhaled allergens, or the highest positive intensity of allergen specific immunoglobulin E (sIgE). Conclusion Peripheral blood IL-36 family cytokines play an important role in AR, and the concentrations of IL-36α and IL-36β were related to the severity of symptoms in patients with AR.

Abstract Homeobox A13 (HOXA13) has been verified as an oncogen in some malignancies. However, its role in nasopharyngeal carcinoma (NPC) is still unclear. This study aims to explore the role of HOXA13 in NPC and its underlying mechanism. The mRNA expression of HOXA13 in NPC was obtained from the GSE53819 and GSE64634 datasets in the Gene Expression Omnibus (GEO) database. MTT, colony formation and transwell assays and xenograft tumour models were used to investigate the effects of HOXA13 on NPC HNE1 cells in vitro and in vivo. The expression of HOXA13, epithelial-mesenchymal transition-transcription factor (EMT-TF) Snail and matrix metalloproteinase 2 (MMP-2) was detected by immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The results showed that HOXA13 was upregulated in NPC. Silencing HOXA13 suppressed the proliferation, migration, and invasion of HNE1 cells, which inhibited tumour growth, while overexpression of HOXA13 induced the opposite effects. In addition, the expression of Snail and MMP-2 at the transcriptional and protein levels was associated with the expression of HOXA13. In summary, our results suggest that HOXA13 plays a role as a cancer-promoting gene in NPC. The underlying mechanism may be related to the upregulation of Snail and MMP-2.

Earthquake disasters are marked by their unpredictability and potential for extreme destructiveness. Accurate information on building damage, captured in post-earthquake remote sensing images, is critical for an effective post-disaster emergency response. The foundational features within these images are essential for the accurate extraction of building damage data following seismic events. Presently, the availability of publicly accessible datasets tailored specifically to earthquake-damaged buildings is limited, and existing collections of post-earthquake building damage characteristics are insufficient. To address this gap and foster research advancement in this domain, this paper introduces a new, large-scale, publicly available dataset named the Major Earthquake Damage Building Feature Set (MEDBFS). This dataset comprises image data sourced from five significant global earthquakes and captured by various optical remote sensing satellites, featuring diverse scale characteristics and multiple spatial resolutions. It includes over 7000 images of buildings pre- and post-disaster, each subjected to stringent quality control and expert validation. The images are categorized into three primary groups: intact/slightly damaged, severely damaged, and completely collapsed. This paper develops a comprehensive feature set encompassing five dimensions: spectral, texture, edge detection, building index, and temporal sequencing, resulting in 16 distinct classes of feature images. This dataset is poised to significantly enhance the capabilities for data-driven identification and analysis of earthquake-induced building damage, thereby supporting the advancement of scientific and technological efforts for emergency earthquake response.

A novel nano-laminated GdB2C2 material was successfully synthesized using GdH2, B4C, and C via an in situ solid-state reaction approach for the first time. The formation process of GdB2C2 was revealed based on the microstructure and phase evolution investigation. Purity of 96.4 wt.% GdB2C2 was obtained at a low temperature of 1500 °C, while a nearly fully pure GdB2C2 could be obtained at a temperature over 1700 °C. The as-obtained GdB2C2 presented excellent thermal stability at a high temperature of 2100 °C in Ar atmosphere due to the stable framework formed by the high-covalence four-member and eight-member B-C rings in GdB2C2. The GdB2C2 material synthesized at 1500 °C demonstrated a remarkably low minimum reflection loss (RLmin) of −47.01 dB (3.44 mm) and a broad effective absorption bandwidth (EAB) of 1.76 GHz. The possible electromagnetic wave absorption (EMWA) mechanism could be ascribed to the nano-laminated structure and appropriate electrical conductivity, which facilitated good impedance matching, remarkable conduction loss, and interfacial polarization, along with the reflection and scattering of electromagnetic waves at multiple interfaces. The GdB2C2, with excellent EMWA performance as well as remarkable ultra-high-temperature thermal stability, could be a promising candidate for the application of EMWA materials in extreme ultra-high temperatures.

Abstract Chronic hepatitis B is a significant public health problem and complex pathologic process, and unraveling the underlying mechanisms and pathophysiology is of great significance. Data independent acquisition mass spectrometry (DIA-MS) is a label-free quantitative proteomics method that has been successfully applied to the study of a wide range of diseases. The aim of this study was to apply DIA-MS for proteomic analysis of patients with chronic hepatitis B. We performed comprehensive proteomics analysis of protein expression in serum samples from HBV patients and healthy controls by using DIA-MS. Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and protein network analysis were performed on differentially expressed proteins and were further combined with literature analysis. We successfully identified a total of 3786 serum proteins with a high quantitative performance from serum samples in this study. We identified 310 differentially expressed proteins (DEPs) (fold change > 1.5 and P value

Objective To identify the clinical features and prognostic factors for sublingual gland carcinoma. Methods This was a case–control study. Patients with surgically treated sublingual gland carcinoma were retrospectively included in the Surveillance, Epidemiology and End Results database and divided into adenoid cystic carcinoma (ACC) and non-ACC groups. Primary outcome variables were disease-specific survival (DSS) and overall survival (OS). Prognostic factors for each group were analyzed using Cox models. Results We included 251 patients (115 men and 136 women). Compared with the non-ACC group, the ACC group had a larger average tumor size and received more adjuvant radiotherapy. In patients with ACC, the pathologic grade had an independent impact on DSS and OS, and patients who were undergoing adjuvant chemotherapy had worse DSS than those who were not receiving chemotherapy. In the non-ACC group, pathologic grade IV, lymph node metastasis, and adjuvant chemotherapy were associated with poor DSS and OS, and tumor extension predicted worsening DSS. Conclusions In sublingual gland carcinoma, the pathologic grade and adjuvant chemotherapy were the most important prognostic factors, whereas lymph node metastasis had a negative impact in non-ACC patients but not in ACC patients.

Aspergillus fumigatus is a common causative pathogen of aspergillosis. At present, triazole resistance of A. fumigatus poses an important challenge to human health globally. In this study, the biological characteristics and mechanisms of azole resistance of five A. fumigatus strains (AF1, AF2, AF4, AF5, and AF8) were explored. There were notable differences in the sporulation and biofilm formation abilities of the five test strains as compared to the standard strain AF293. The ability of strain AF1 to avoid phagocytosis by MH-S cells was significantly decreased as compared to strain AF293, while that of strains AF2, AF4, and AF5 were significantly increased. Fungal burden analysis with Galleria mellonella larvae revealed differences in pathogenicity among the five strains. Moreover, the broth microdilution and E-test assays confirmed that strains AF1 and AF2 were resistant to itraconazole and isaconazole, while strains AF4, AF5, and AF8 were resistant to voriconazole and isaconazole. Strains AF1 and AF2 carried the cyp51A mutations TR34/L98H/V242I/S297T/F495I combined with the hmg1 mutation S541G, whereas strains AF4 and AF8 carried the cyp51A mutation TR46/Y121F/V242I/T289A, while strain AF5 had no cyp51A mutation. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis revealed differences in the expression levels of genes associated with ergosterol synthesis and efflux pumps among the five strains. In addition, transcriptomics, RT-qPCR, and the NAD+/NADH ratio demonstrated that the mechanism of voriconazole resistance of strain AF5 was related to overexpression of genes associated with energy production and efflux pumps. These findings will help to further elucidate the triazole resistance mechanism in A. fumigatus.

Abstract Background Femoral neck fractures are associated with substantial morbidity and mortality for older adults. Multi-system medical diseases and complications can lead to long-term care needs, functional decline and death, so patients sustaining hip fractures usually have comorbid conditions that may benefit from application of multidisciplinary team(MDT). Methods This is a retrospective cohort study that incorporates medical record review with an outcomes management database. 199 patients were included who had surgery for a new unilateral femoral neck fracture from January 2018 to December 2021 (96 patients in usual care (UC) model and 103 patients in MDT model. High-energy, pathological, old and periprosthetic femoral neck fracture were excluded. Age, gender, comorbidity status, time to surgery, and postoperative complication, length of stay, in-hospital mortality, 30-day readmission rate, 90-day mortality data were collected and analyzed. Results Preoperative general data of sex, age, community dwelling and charlson comorbidity score of MDT group (n = 103) have no statistically significant difference with that of usual care (UC) group. Patients treated in the MDT model had significantly shorter times to surgery (38.5 vs. 73.4 h;P = 0.028) and lower lengths of stay (11.5 vs. 15.2 days;P = 0.031). There were no significant differences between two models in In-hospital mortality (1.0% vs. 2.1%; P = 0.273), 30-day readmission rate (7.8% vs. 11.5%; P = 0.352) and 90-day mortality (2.9% vs. 3.1%; P = 0.782). The MDT model had fewer complications overall (16.5% vs. 31.3%; P = 0.039), with significantly lower risks of delirium, postoperative infection, bleeding, cardiac complication, hypoxia, and thromboembolism. Conclusion Application of MDT can provide standardized protocols and a total quality management approach, leading to fewer complications for elderly patients with femoral neck fracture. Trial registration No.

Abstract Background Multimorbidity has become one of the main challenges in health care system. The association between prevalence, patterns of multimorbidity and health care utilization is less often discussed in China. The purpose of this study is to examine this association among Chinese middle-aged and older adults and take into account different sociodemographic, behavioral and health characteristics. Based on this, implications of current evidence and effective intervention on multimorbidity and health care utilization can be identified and put into practice. Methods The wave 4 in 2018 of the China Health and Retirement Longitudinal Study (CHARLS) was used in the study. Multimorbidity was defined as the co-occurrence of two or more chronic medical condition of a list of fourteen chronic diseases in one person. The presence of chronic diseases was assessed through self-report. Health care utilization include whether the respondents received outpatient service last month and inpatient service in the past year. Latent Class Analysis was conducted to identify the clustering pattern of chronic diseases. Logistic regressions were employed to explore the association between prevalence, patterns of multimorbidity and health care utilization. Analyses were weighted using individual sample weights, adjusted for non-response of individual and household. Results Among 19,559 participants aged 45 and older, 23.10% were aged above 70 years and 52.42% were female. The prevalence of multimorbidity was 56.73%. Four patterns were identified: relatively healthy class, respiratory class, stomach-arthritis class and vascular class. Multimorbid individuals used more outpatient services (OR = 1.89, 95%CI = 1.65–2.17) and more inpatient services (OR = 2.52, 95%CI = 2.22–2.86) compared to their no-multimorbid counterparts. Compared to relatively healthy class, the respondents classified into respiratory class, stomach-arthritis class and vascular class used more outpatient services (OR = 1.90, 95%CI = 1.57–2.30; OR = 2.39, 95%CI = 2.06–2.78; OR = 1.53, 95%CI = 1.32–1.79 respectively) and more inpatient services (OR = 2.19, 95%CI = 1.83–2.62; OR = 2.93, 95%CI = 2.53–3.40; OR = 1.90, 95%CI = 1.65–2.19 respectively). Conclusion Our study provided evidence that multimorbidity is high among Chinese older adults and is associated substantially higher health care utilization in China. Four multimorbidity patters were identified. Policy should prioritize improving the management of individuals with multimorbidity to increase healthcare efficiency. Further research is necessary with special emphasis on the trajectory of multimorbidity and the role of health system in satisfying needs of multimorbid individuals.

Abstract Objective We aimed to evaluate the efficacy and safety of anti-interleukin-1 therapeutics, including IL-1 antibodies, interleukin-1 receptor antagonists (IL-1 Ras) and IL-1 inhibitors, for knee osteoarthritis (KOA) treatment. Methods Databases (Medline, Embase, Web of Science and CENTRAL) and ClinicalTrials.gov were systematically searched for randomized controlled trials (RCTs) of anti-interleukin-1 therapeutics from inception to August 31, 2022. The outcomes were the mean change in pain and function scores and the risk of adverse effects (AEs). Results In the 12 studies included, anti-interleukin-1 therapeutics were superior to placebo in terms of pain relief (standardized mean difference [SMD] = − 0.38, 95% confidence interval [CI] = − 1.82 to − 0.40, p

Background: Research on post-infarction insomnia, particularly short sleep duration following myocardial infarction (MI), remains limited. Currently, there are no existing guidelines or risk prediction models to assist physicians in managing or preventing short sleep duration or insomnia following MI. This study aims to develop a nomogram for predicting the risk of short sleep duration after MI. Methods: We conducted a retrospective study on 1434 MI survivors aged 20 and above, utilizing data from the National Health and Nutrition Examination Survey (NHANES) database spanning from 2007 to 2018. Among them, 710 patients were assigned to the training group, while 707 patients were allocated to the testing group. We utilized logistic regression, least absolute shrinkage and selection operator (LASSO) regression, and the elastic network for variable selection. The stability and accuracy of the prediction model were assessed using receiver operator characteristics (ROCs) and calibration curves. Results: We included five variables in the nomogram: age, poverty income ratio (PIR), body mass index (BMI), race, and depression. The ROC curves yielded values of 0.636 for the training group and 0.657 for the testing group, demonstrating the model’s good prediction accuracy and robustness through a calibration curve test. Conclusions: Our nomogram can effectively predict the likelihood of short sleep duration in MI survivors, providing valuable support for clinicians in preventing and managing post-MI short sleep duration.

PurposeThis study aims to investigate the effect and feasibility of intra-aortic catheter looping via transradial access in angioplasty for symptomatic intracranial severe (>70%) atherosclerotic stenosis or occlusion of large arteries (SISOLAs).Materials and methodsPatients with SISOLAs who underwent transradial endovascular angioplasty using the catheter looping technique in the ascending aorta were retrospectively enrolled. The clinical data and treatment outcomes were analyzed.ResultsFifteen patients aged 48–71 years were enrolled in this study. Left vertebrobasilar artery occlusion was present in 1 (6.7%) patient, severe left middle cerebral artery stenosis in 7 (46.7%) patients, severe left internal carotid artery (ICA) stenosis of the ophthalmic segment in 4 (26.7%) patients, severe left ICA stenosis of the cavernous segment in 2 (13.3%) patients, and severe right middle cerebral artery stenosis in 2 (13.3%) patients. The arterial stenosis ranged from 70 to 92% (mean 86%) before stenting. The looping of a guiding catheter in the ascending aorta via transradial access for angioplasty was successful in all patients (100%). The vertebral artery intracranial segment occlusion was successfully recanalized, while severe stenosis in the remaining 14 patients was successfully eliminated. After endovascular recanalization, the residual stenosis was reduced by 12–26% (median 18%). No puncture-related complications or surgical-related neurological complications occurred in these patients. In the follow-up angiography conducted on 10 (66.7%) patients after 6–25 months, no in-stent restenosis was detected.ConclusionIntra-aortic guiding catheter looping via transradial access for endovascular angioplasty of SISOLAs is technically safe, feasible, and effective, especially when the transfemoral artery approach is difficult or impossible to undertake.

Background: To identify long non-coding RNAs (lncRNAs) that may be used as potential biomarkers of sensitivity to antiretroviral therapy (ART) against human immunodeficiency virus (HIV) infection. Method: A two-stage matched case-control study was conducted. First, in the screening stage, peripheral blood lymphocytes (PBLs) of six subjects receiving lamivudine-based ART (3 ART-resistant and 3 ART-sensitive subjects with matching durations of ART) were subjected to comprehensive microarray expression profiling in order to screen out lncRNAs associated with ART sensitivity. Secondly, during the validation stage, promising lncRNAs were evaluated via a 1:4 matched case-control study using 50 subjects (10 ART-resistant and 40 ART-sensitive subjects with matching durations of ART). Results: Seven lncRNAs were screened out (P

Abstract Background Previous studies have investigated the prognostic value of the systemic immune-inflammation index (SII) in nasopharyngeal carcinoma (NPC). However, the results have been inconsistent. Therefore, this study aims to investigate the prognostic significance of SII in NPC through a meta-analysis. Methods The PubMed, Web of Science, Embase, and Cochrane Library databases were thoroughly searched. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to evaluate the prognostic value of the SII for survival outcomes. Results A total of six studies comprising 2169 patients were included in the meta-analysis. Pooled analyses indicated that a high SII was significantly associated with worse overall survival (OS) (HR = 1.69, 95% CI = 1.36–2.09, P < 0.001) and progression-free survival (PFS) (HR = 1.60, 95% CI = 1.29–1.98, P < 0.001) in patients with NPC. Subgroup analysis showed that SII was a significant prognostic marker for PFS but not for OS in NPC. Conclusion Our meta-analysis demonstrated that a high SII could be an efficient prognostic indicator of OS and PFS in NPC. In our opinion, SII could be used to predict long-term and short-term outcomes in patients with NPC. Furthermore, we suggest that SII be applied to help individual patients with NPC assess the prognostic risk. Systematic review registration PROSPERO CRD42022321570

Background: Increasing evidence has shown that the risk of tuberculosis (TB) might be related to the exposure to air pollutants; however, the findings are inconsistent and studies on long-term air pollutant exposure and TB risk are scarce. This study aime to assess the relationship between monthly exposure to air pollution and TB risk in Nantong, China. Methods: We collected the time series data on the number of TB cases, as well as environmental and socioeconomic covariates from January 2005 to December 2020. The impact of air pollutant exposure on TB risk was evaluated using the distributed lag nonlinear model (DLNM). Stratified analyses were conducted to examine the effect modifications of sex and age on the association between air pollutants and TB risk. Sensitivity analyses were applied to test the stability of the model. Results: There were a total of 54,096 cases of TB in Nantong during the study period. In the single-pollutant model, for each 10 μg/m3 increase in concentration, the pooled relative risks (RRs) of TB reached the maximum to 1.10 (95% confidence interval (CI): 1.04–1.16, lag 10 months) for particulate matter with aerodynamic diameter less than 2.5 μm (PM2.5), 1.05 (95% CI: 1.01–1.10, lag 9 months) for particulate matter with aerodynamic diameter less than 10 μm (PM10), and 1.11 (95%CI: 1.04–1.19, lag 10 months) for nitrogen dioxide (NO2). Ozone (O3) did not show significant effect on TB risk. Effect modifications of sex and age on the association between air pollutants and TB risk were not observed. The multi-pollutant model results showed no significant variation compared with the single-pollutant model. Conclusions: Our study suggests that air pollutants pose a substantial threat to the TB risk. Reducing air pollution might be crucial for TB prevention and control.