Correction: Establishment of a prediction model for prehospital return of spontaneous circulation in out-of-hospital patients with cardiac arrest.

[This corrects the article on p. 508 in vol. 15, PMID: 37900904.].

A combined model of serum neutrophil extracellular traps, CD8+ T cells, and tumor proportion score provides better prediction of PD-1 inhibitor efficacy in patients with NSCLC.

Immune checkpoint inhibitors provide a definite survival benefit for patients with driver-negative advanced non-small cell lung cancer (NSCLC), but predictors of efficacy are still lacking. There may be a relationship between immune inflammatory state and tumor immune response. We explored the relationship of serum neutrophil extracellular traps (NETs) with infiltrating cells in the tumor tissues of patients with NSCLC as well as their relationship with the therapeutic efficacy of programmed cell death protein 1 (PD-1) inhibitors. Serum myeloperoxidase (MPO)-double-stranded DNA (dsDNA) was detected as a marker of NET serum concentration. T cells were detected by immunohistochemical staining, and neutrophils were counted by MPO immunofluorescence staining. Of the 31 patients with NSCLC, a longer progression-free survival after PD-1 inhibitor treatment was associated with higher levels of CD3+ T cells, a lower neutrophil : CD3+-T-cell ratio (NEU/CD3+) and lower neutrophil : CD8+-T-cell ratio (NEU/CD8+) in tumor tissues. Patients with higher serum NETs were more likely to develop progressive disease after treatment (P = 0.003) and to have immune-related adverse events (IrAEs) as well as higher NEU/CD3+ and NEU/CD8+. The combined model of serum NETs, CD8+ T cells, and tumor proportion score (TPS) significantly improved the prediction of PD-1 inhibitor efficacy [P = 0.033; area under the curve (AUC) = 0.881]. Our results indicate that serum NETs are effective predictors of PD-1 inhibitor response and reflect the tissue neutrophil-to-lymphocyte ratio and IrAE levels. The combined model of serum NETs, CD8+ T cells, and TPS is a powerful tool for predicting the efficacy of PD-1 inhibitor treatment in patients with NSCLC.

Efficient dissolution of cellulose in slow-cooling alkaline systems and interacting modes between alkali and urea at the molecular level.

The dissolution of microcrystalline cellulose (MCC) in a urea-NaOH system is beneficial for its mechanical processing. The apparent MCC solubility was greatly improved to 14 wt% under a slow-cooling condition with a cooling rate of -0.3 °C/min. The cooling curve or thermal history played a crucial role in the dissolution process. An exotherm (-54.7 ± 3 J/g MCC) was detected by DSC only under the slow-cooling condition, and the cryogenic dissolution of MCC was attributed to the exothermic interaction between MCC and solvent. More importantly, the low cooling rate promoted the dissolution of MCC by providing enough time for the diffusion of OH- and urea into MCC granules at higher temperatures. The Raman spectral data showed that the intramolecularly and intermolecularly hydrogen bonds in cellulose were cleaved by NaOH and urea, respectively. XPS and solid-state 13C NMR results showed that hydrogen bonds were generated after dissolution, and a dual-hydrogen-bond binding mode between urea and cellulose was confirmed by DFT calculations. Both the decrease of enthalpy and increase of entropy dominated the spontaneity of MCC dissolution, and that is the reason for the indispensability of cryogenic environment. The high apparent solubility of MCC in the slow-cooling process and the dissolution mechanism are beneficial for the studies on cellulose modification and mechanical processing.

Non-linear relationship between pulse pressure and the risk of prediabetes: a 5-year cohort study in Chinese adults.

Previous research has established a strong link between pulse pressure (PP) and diabetes, but there is limited investigation into the connection between PP and prediabetes. This study aims to explore the potential association between PP and prediabetes. A retrospective cohort study encompassed 202,320 Chinese adults who underwent health check-ups between 2010 and 2016. Prediabetes was defined in accordance with the World Health Organization criteria, indicating impaired fasting glucose, with fasting blood glucose levels ranging from 6.1 to 6.9 mmol/L. To assess the PP-prediabetes relationship, we employed Cox regression analysis, sensitivity analysis, and subgroup analysis. Cox proportional hazards regression, coupled with cubic spline functions and smooth curve fitting, helped elucidate the non-linear PP-prediabetes relationship. Upon adjusting for confounding factors, we observed a positive association between PP and prediabetes (HR 1.15, 95% CI 1.11-1.18, P < 0.0001). Participants in the fourth quartile (PP ≥ 51 mmHg) had a 73% higher likelihood of developing prediabetes compared to those in the first quartile (PP < 36 mmHg) (HR 1.73, 95% CI 1.52-1.97, P < 0.0001). Moreover, the relationship between PP and prediabetes was non-linear. A two-piece Cox proportional hazards regression model identified an inflection point at 40 mmHg for PP (P for log-likelihood ratio test = 0.047). Sensitivity and subgroup analyses corroborated the robustness of our findings. Our study reveals a non-linear correlation between PP and prediabetes, signifying an increased risk of prediabetes when PP levels exceed 40 mmHg. This discovery has significant clinical implications for early prediabetes prevention and intervention, ultimately contributing to improved patient outcomes and quality of life.

Elevated platelet count is associated with decreased mortality from hemorrhagic stroke in hospital: a multi-center retrospective cohort study.

This study aimed to investigate the relationship between platelet count (PC) and mortality in patients with hemorrhagic stroke (HS). The research reviewed data from 10,466 patients hospitalized in 208 hospitals in the United States from January 1, 2014, to December 31, 2015. Of these, 3262 HS patients were included in the primary analysis for those admitted to the intensive care unit (ICU). The average age of these patients was 67.05 years, with 52.79% being male. The median PC was (221.67 ± 73.78) × 109/L. Multivariate logistic regression analysis revealed that PC was a protective factor for mortality in HS patients (OR = 0.98, 95% CI 0.97-1.00, P < 0.05). Additionally, a non-linear association between PC and mortality in HS patients was found using a generalized additive model (GAM) and smooth curve fitting (penalty spline method). For the first time, a recursive algorithm identified the inflection point of platelet count as 194 × 109/L. On the left side of the inflection point, for every increase of 10 units in platelet count, the mortality rate of HS patients decreases by 10%. The study demonstrates a non-linear relationship between PC and the risk of mortality in HS patients. A platelet counts higher than the inflection point (194 × 109/L) may be a significant intervention to reduce mortality in HS patients.

Learning From Human Educational Wisdom: A Student-Centered Knowledge Distillation Method.

Existing studies on knowledge distillation typically focus on teacher-centered methods, in which the teacher network is trained according to its own standards before transferring the learned knowledge to a student one. However, due to differences in network structure between the teacher and the student, the knowledge learned by the former may not be desired by the latter. Inspired by human educational wisdom, this paper proposes a Student-Centered Distillation (SCD) method that enables the teacher network to adjust its knowledge transfer according to the student network's needs. We implemented SCD based on various human educational wisdom, e.g., the teacher network identified and learned the knowledge desired by the student network on the validation set, and then transferred it to the latter through the training set. To address the problems of current deficiency knowledge, hard sample learning and knowledge forgetting faced by a student network in the learning process, we introduce and improve Proportional-Integral-Derivative (PID) algorithms from automation fields to make them effective in identifying the current knowledge required by the student network. Furthermore, we propose a curriculum learning-based fuzzy strategy and apply it to the proposed PID control algorithm, such that the student network in SCD can actively pay attention to the learning of challenging samples after with certain knowledge. The overall performance of SCD is verified in multiple tasks by comparing it with state-of-the-art ones. Experimental results show that our student-centered distillation method outperforms existing teacher-centered ones.

Serum calcium is associated with sudden cardiac arrest in stroke patients from ICU: a multicenter retrospective study based on the eICU collaborative research database.

This primary objective of our study was to investigate the relationship between serum calcium levels and the occurrence of sudden cardiac arrest (SCA) in stroke patients. We analyzed the clinical data of 10,423 acute stroke patients admitted to the intensive care unit. The association between serum calcium and SCA following an acute stroke was assessed through multivariate logistic regression. We explored the non-linear connection between serum calcium levels and SCA in stroke patients using a generalized additive model and smooth curve fitting. Our study uncovered that serum calcium serves as an independent risk factor for sudden cardiac arrest in stroke patients. Notably, we observed that the relationship between serum calcium levels upon admission and the occurrence of SCA in stroke patients within the hospital was non-linear. Furthermore, we identified inflection points in serum calcium levels at 8.2 and 10.4 mg/dL. These findings emphasize a non-linear relationship between serum calcium levels and the risk of SCA in stroke patients. Maintaining serum calcium within the range of 8.2-10.4 mg/dL could lead to a significant reduction in the incidence of cardiac arrest among stroke patients.

Defluorination of perfluorooctanoic acid and perfluorooctane sulfonic acid by heterogeneous catalytic system of Fe-Al2O3/O3: Synergistic oxidation effects and defluorination mechanism.

In this study, catalytic ozonation by Fe-Al2O3 was used to investigate the defluorination of PFOA and PFOS, assessing the effects of different experimental conditions on the defluorination efficiency of the system. The oxidation mechanism of the Fe-Al2O3/O3 system and the specific degradation and defluorination mechanisms for PFOA and PFOS were determined. Results showed that compared to the single O3 system, the defluorination rates of PFOA and PFOS increased by 2.32- and 5.92-fold using the Fe-Al2O3/O3 system under optimal experimental conditions. Mechanistic analysis indicated that in Fe-Al2O3, the variable valence iron (Fe) and functional groups containing C and O served as important reaction sites during the catalytic process. The co-existence of 1O2, OH, O2- and high-valence Fe(IV) constituted a synergistic oxidation system consisting of free radicals and non-radicals, promoting the degradation and defluorination of PFOA and PFOS. DFT theoretical calculations and the analysis of intermediate degradation products suggested that the degradation pathways of PFOA and PFOS involved Kolbe decarboxylation, desulfonation, alcoholization and intramolecular cyclization reactions. The degradation and defluorination pathways of PFOA and PFOS consisted of the stepwise removal of -CF2-, with PFOS exhibiting a higher defluorination rate than PFOA due to its susceptibility to electrophilic attack. This study provides a theoretical basis for the development of heterogeneous catalytic ozonation systems for PFOA and PFOS treatment.

Teacher-student complementary sample contrastive distillation.

Knowledge distillation (KD) is a widely adopted model compression technique for improving the performance of compact student models, by utilizing the "dark knowledge" of a large teacher model. However, previous studies have not adequately investigated the effectiveness of supervision from the teacher model, and overconfident predictions in the student model may degrade its performance. In this work, we propose a novel framework, Teacher-Student Complementary Sample Contrastive Distillation (TSCSCD), that alleviate these challenges. TSCSCD consists of three key components: Contrastive Sample Hardness (CSH), Supervision Signal Correction (SSC), and Student Self-Learning (SSL). Specifically, CSH evaluates the teacher's supervision for each sample by comparing the predictions of two compact models, one distilled from the teacher and the other trained from scratch. SSC corrects weak supervision according to CSH, while SSL employs integrated learning among multi-classifiers to regularize overconfident predictions. Extensive experiments on four real-world datasets demonstrate that TSCSCD outperforms recent state-of-the-art knowledge distillation techniques.

Feasibility of low-intensity ultrasound treatment with hydroxylamine to accelerate the initiation of partial nitrification and allow operation under intermittent aeration.

Partial nitrification is a key aspect of efficient nitrogen removal, although practically it suffers from long start-up cycles and unstable long-term operational performance. To address these drawbacks, this study investigated the effect of low intensity ultrasound treatment combined with hydroxylamine (NH2OH) on the performance of partial nitrification. Results show that compared with the control group, low-intensity ultrasound treatment (0.10 W/mL, 15 min) combined with NH2OH (5 mg/L) reduced the time required for partial nitrification initiation by 6 days, increasing the nitrite accumulation rate (NAR) and ammonia nitrogen removal rate (NRR) by 20.4% and 6.7%, respectively, achieving 96.48% NRR. Mechanistic analysis showed that NH2OH enhanced ammonia oxidation, inhibited nitrite-oxidizing bacteria (NOB) activity and shortened the time required for partial nitrification initiation. Furthermore, ultrasonication combined with NH2OH dosing stimulated EPS (extracellular polymeric substances) secretion, increased carbonyl, hydroxyl and amine functional group abundances and enhanced mass transfer. In addition, 16S rRNA gene sequencing results showed that ultrasonication-sensitive Nitrospira disappeared from the ultrasound + NH2OH system, while Nitrosomonas gradually became the dominant group. Collectively, the results of this study provide valuable insight into the enhancement of partial nitrification start-up during the process of wastewater nitrogen removal.

Effect of Stabilizers and Thermoplastic Polyurethane on the Properties of Three-Dimensional Printed Photochromic Wood Flour/Polylactic Acid Composites.

This study was aimed at investigating the photofatigue resistance and mechanical properties of photochromic wood-plastic composites using a stabilizer complex-AH (antioxidant 1010 and hindered amine light stabilizer HALS 770)-with different contents of thermoplastic polyurethane (TPU), which was prepared by the melt-blending extrusion process and three-dimensional (3D) printing. Photofatigue resistance, mechanical property, microtopography, and thermal analyses of 3D printed samples were performed. The results showed that the difference in surface color of composites improved by 26.7% with addition of AH after 10 days of accelerated aging, whereas the mechanical strength decreased. Upon adding TPU, composites' impact strength significantly increased by 25.48% and 87.87% with 10% and 20% addition, respectively. Meanwhile, the interface compatibilities between the components were enhanced. The differential scanning calorimetry and thermogravimetric analysis results indicated that 10% TPU could improve the thermal stability of composites.

Erratum: CXCL12-mediated monocyte transmigration into brain perivascular space leads to neuroinflammation and memory deficit in neuropathic pain: Erratum.

[This corrects the article DOI: 10.7150/thno.44364.].

Establishment of a prediction model for prehospital return of spontaneous circulation in out-of-hospital patients with cardiac arrest.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a leading cause of death worldwide. AIM: To explore factors influencing prehospital return of spontaneous circulation (P-ROSC) in patients with OHCA and develop a nomogram prediction model. METHODS: Clinical data of patients with OHCA in Shenzhen, China, from January 2012 to December 2019 were retrospectively analyzed. Least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression were applied to select the optimal factors predicting P-ROSC in patients with OHCA. A nomogram prediction model was established based on these influencing factors. Discrimination and calibration were assessed using receiver operating characteristic (ROC) and calibration curves. Decision curve analysis (DCA) was used to evaluate the model's clinical utility. RESULTS: Among the included 2685 patients with OHCA, the P-ROSC incidence was 5.8%. LASSO and multivariate logistic regression analyses showed that age, bystander cardiopulmonary resuscitation (CPR), initial rhythm, CPR duration, ventilation mode, and pathogenesis were independent factors influencing P-ROSC in these patients. The area under the ROC was 0.963. The calibration plot demonstrated that the predicted P-ROSC model was concordant with the actual P-ROSC. The good clinical usability of the prediction model was confirmed using DCA. CONCLUSION: The nomogram prediction model could effectively predict the probability of P-ROSC in patients with OHCA.

Farnesoid X receptor activation inhibits pancreatic carcinogenesis.

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily that controls bile acid (BA) homeostasis, has also been proposed as a tumor suppressor for breast and liver cancer. However, its role in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis remains controversial. We recently found that FXR attenuates acinar cell autophagy in chronic pancreatitis resulting in reduced autophagy and promotion of pancreatic carcinogenesis. Feeding Kras-p48-Cre (KC) mice with the BA chenodeoxycholic acid (CDCA), an FXR agonist, attenuated pancreatic intraepithelial neoplasia (PanIN) progression, reduced cell proliferation, neoplastic cells and autophagic activity, and increased acinar cells, elevated pro-inflammatory cytokines and chemokines, with a compensatory increase in the anti-inflammatory response. Surprisingly, FXR-deficient KC mice did not show any response to CDCA, suggesting that CDCA attenuates PanIN progression and decelerate tumorigenesis in KC mice through activating pancreatic FXR. FXR is activated in pancreatic cancer cell lines in response to CDCA in vitro. FXR levels were highly increased in adjuvant and neoadjuvant PDAC tissue compared to healthy pancreatic tissue, indicating that FXR is expressed and potentially activated in human PDAC. These results suggest that BA exposure activates inflammation and suppresses autophagy in KC mice, resulting in reduced PanIN lesion progression. These data suggest that activation of pancreatic FXR has a protective role by reducing the growth of pre-cancerous PDAC lesions in response to CDCA and possibly other FXR agonists.

Discovery of Novel Resistance Mechanisms of Vibrio parahaemolyticus Biofilm against Aminoglycoside Antibiotics.

Inappropriate use of antibiotics eventually leads to the emergence of antibiotic-resistant strains and invalidates the treatment of infectious diseases. Aminoglycoside antibiotics (AGAs) are a class of broad-spectrum cationic antibiotics widely used for the treatment of Gram-negative bacterial infections. Understanding the AGA resistance mechanism of bacteria would increase the efficacy of treating these infections. This study demonstrates a significant correlation between AGA resistance and the adaptation of biofilms by Vibrio parahaemolyticus (VP). These adaptations were the result of challenges against the aminoglycosides (amikacin and gentamicin). Confocal laser scanning microscope (CLSM) analysis revealed an enclosure type mechanism where the biological volume (BV) and average thickness (AT) of V. parahaemolyticus biofilm were significantly positively correlated with amikacin resistance (BIC) (p < 0.01). A neutralization type mechanism was mediated by anionic extracellular polymeric substances (EPSs). The biofilm minimum inhibitory concentrations of amikacin and gentamicin were reduced from 32 µg/mL to 16 µg/mL and from 16 µg/mL to 4 µg/mL, respectively, after anionic EPS treatment with DNase I and proteinase K. Here, anionic EPSs bind cationic AGAs to develop antibiotic resistance. Transcriptomic sequencing revealed a regulatory type mechanism, where antibiotic resistance associated genes were significantly upregulated in biofilm producing V. parahaemolyticus when compared with planktonic cells. The three mechanistic strategies of developing resistance demonstrate that selective and judicious use of new antibiotics are needed to win the battle against infectious disease.

Plasma ctDNA increases tissue NGS-based detection of therapeutically targetable mutations in lung cancers.

BACKGROUND: Circulating tumor DNA (ctDNA) has been becoming a novel convenient and noninvasive method for dynamically monitoring landscape of genomic information to guild personalized cancer treatment. In this study we comprehensively evaluated the additional value of plasma ctDNA to routine tissue next generation sequencing (NGS) of therapeutically targetable mutations in lung cancers. METHODS: The tumor tissues and peripheral blood samples from 423 cases of patients with lung cancer were subjected to NGS of mutations in oncodrivers (EGFR, ERBB2, ALK, ROS1, C-MET, KRAS, BRAF, RET, BRCA1 and BRCA2). RESULTS: One hundred and ninety-seven cases showed both plasma and tissue positive and 96 showed both negative. The concordance for tissue and blood detection was 69.27% (293/423). 83 (19.62%) cases showed positive by tissue NGS alone and 47 (11.11%) positive by plasma ctDNA alone. The sensitivity of tissue and plasma detection was 85.63%, and 74.62%, respectively. Plasma had lower detection and sensitivity than tissue, but plasma additionally detected some important mutations which were omitted by tissue NGS. Plasma plus tissue increased the detection rate of 66.19% by tissue alone to 77.30% as well as the sensitivity of 85.63-100%. Similar results were also observed when the cases were classified into subpopulations according to different stages (IV vs. III vs. I-II), grades (low vs. middle grade) and metastatic status (metastasis vs. no metastasis). CONCLUSION: Plasma ctDNA shares a high concordance with tissue NGS, and plasma plus tissue enhances the detection rate and sensitivity by tissue alone, implying that the tissue and plasma detection should be mutually complementary in the clinical application.

The Prognostic Model Established by the Differential Expression Genes Based on CD8+ T Cells to Evaluate the Prognosis and the Response to Immunotherapy in Osteosarcoma.

Osteosarcoma (OS) is a malignant tumor with an extremely poor prognosis, especially in progressive patients. Immunotherapy based on immune checkpoint inhibitors (ICIs) is considered to be a promising treatment option for OS. Due to tumor heterogeneity, only a minority of patients benefit from immunotherapy. Therefore, it is urgent to explore a model that can accurately assess the response of OS to immunotherapy. In this study, we obtained the single-cell RNA sequencing datasets of OS patients from public databases and defined 34 cell clusters by dimensional reduction and clustering analysis. PTPRC was applied to identify immune cell clusters and nonimmune cell clusters. Next, we performed clustering analysis on the immune cell clusters and obtained 25 immune cell subclusters. Immune cells were labeled with CD8A and CD8B to obtain CD8+ T cell clusters. Meanwhile, we extracted the differentially expressed genes (DEGs) of CD8+ T cell clusters and other immune cell clusters. Furthermore, we constructed a prognostic model (CD8-DEG model) based on the obtained DEGs of CD8+ T cells, and verified the excellent predictive ability of this model for the prognosis of OS. Moreover, we further investigated the value of the CD8-DEG model. The results indicated that the risk score of the CD8-DEG model was an independent risk factor for OS patients. Finally, we revealed that the risk score of the CD8-DEG model correlates with the immune profile of OS and can be used to evaluate the response of OS to immunotherapy. In conclusion, our study revealed the critical role of CD8 cells in OS. The risk score model based on CD8-DEGs can provide guidance for prognosis and immunotherapy of OS.

Antimicrobial resistomes in food chain microbiomes.

The safety and integrity of the global food system is in a constant state of flux with persistent chemical and microbial risks. While chemical risks are being managed systematically, microbial risks pose extra challenges. Antimicrobial resistant microorganism and persistence of related antibiotic resistance genes (ARGs) in the food chain adds an extra dimension to the management of microbial risks. Because the food chain microbiome is a key interface in the global health system, these microbes can affect health in many ways. In this review, we systematically summarize the distribution of ARGs in foods, describe the potential transmission pathway and transfer mechanism of ARGs from farm to fork, and discuss potential food safety problems and challenges. Modulating antimicrobial resistomes in the food chain facilitates a sustainable global food production system.

A self-gelling starch-based sponge for hemostasis.

Uncontrolled bleeding remains one of the direct causes of high mortality. There is an urgent need for developing emergency hemostats capable of coping with uncontrolled bleeding. The commercial starch-based hemostatic powder (PerClot®) requires compression during application, which limits its application in hemostasis of irregular and non-compressed wounds. Herein, a boronic acid-modified thiol starch sponge (St-SP sponge) with self-gelling properties was developed for hemorrhage control. The results show that the St-SP sponge could quickly absorb blood, self-gel and self-heal to seal the bleeding sites. In addition, the St-SP sponge can rapidly initiate the coagulation cascade and promote the adhesion and aggregation of erythrocytes and platelets. The St-SP sponge exhibited significantly improved in vitro and in vivo hemostatic abilities as compared with PerClot. Notably, the St-SP sponge attained complete hemostasis without any compression in 61.5 s and made a great difference compared to PerClot (169 s) for the irregular wound constructed on the rabbit liver. In addition, the St-SP sponge had good hemocompatibility and cytocompatibility. It turns out that the newly developed St-SP sponge is a promising material for first-aid hemostasis of irregular and non-compressed wounds.

Starch-based shape memory sponge for rapid hemostasis in penetrating wounds.

Death caused by excessive blood loss has always been a global concern. Timely control of bleeding in incompressible penetrated wounds remains a great challenge. Here, we developed a shape memory sponge (SQG) based on modified starch and gelatin (Gel) to control the hemorrhage of penetrating wounds. The porous structure of SQG greatly enhanced the absorption of blood, and the adhesion of erythrocytes and platelets. The water absorption rate of SQG reached 1178.72 ± 12.18% in 10 s. SQG quickly recovered its shape in water (∼3 s) and exhibited high mechanical strength (∼38 kPa), acting as a physically packed barrier to facilitate hemostasis. Furthermore, the positively charged sponges were conducive to activating platelets and promoting the release of coagulation factors. SQG sponges possessed the lowest blood coagulation index (BCI) of 21.32 ± 0.19%, and presented good biocompatibility and obvious inhibitory effect on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Moreover, SQG sponges controlled complete bleeding in 69 ± 20 s and a bleeding loss of 334 ± 138 mg was observed, nearly 50% lower than that of gelatin sponge in rabbit liver penetrating wounds. Overall, SQG possesses a combination of potent shape recovery, rapid hemostasis, and excellent antibacterial and degradation ability, enabling promising applications for hemostasis in non-compressible penetrating wounds.