Correction: Radiopharmaceutical-activated silicon naphthalocyanine nanoparticles towards tumor photodynamic therapy.

Correction for 'Radiopharmaceutical-activated silicon naphthalocyanine nanoparticles towards tumor photodynamic therapy' by Tingting Wang et al., Chem. Commun., 2024, https://doi.org/10.1039/d4cc03281k.

Radiopharmaceutical-activated silicon naphthalocyanine nanoparticles towards tumor photodynamic therapy.

Naphthalocyanine-based agents exhibit huge potential in photodynamic therapy, yet their photodynamic performance is restricted by the penetration depth of the external laser. Herein, we employed 18F-FDG as an internal light source to excite silicon naphthalocyanine nanoparticles to simultaneously circumvent radiative transition and boost 1O2 generation for tumor suppression.

KHK-A promotes fructose-dependent colorectal cancer liver metastasis by facilitating the phosphorylation and translocation of PKM2.

Excessive fructose diet is closely associated with colorectal cancer (CRC) progression. Nevertheless, fructose's specific function and precise mechanism in colorectal cancer liver metastasis (CRLM) is rarely known. Here, this study reported that the fructose absorbed by primary colorectal cancer could accelerate CRLM, and the expression of KHK-A, not KHK-C, in liver metastasis was higher than in paired primary tumors. Furthermore, KHK-A facilitated fructose-dependent CRLM in vitro and in vivo by phosphorylating PKM2 at Ser37. PKM2 phosphorylated by KHK-A inhibited its tetramer formation and pyruvic acid kinase activity but promoted the nuclear accumulation of PKM2. EMT and aerobic glycolysis activated by nuclear PKM2 enhance CRC cells' migration ability and anoikis resistance during CRLM progression. TEPP-46 treatment, targeting the phosphorylation of PKM2, inhibited the pro-metastatic effect of KHK-A. Besides, c-myc activated by nuclear PKM2 promotes alternative splicing of KHK-A, forming a positive feedback loop.

Spatial transcriptomics of gastric cancer brain metastasis reveals atypical vasculature strategies with supportive immune profiles.

Background: Gastric cancer brain metastasis (GCBM) represents a rare but highly aggressive malignancy. Metastatic cancer cells are highly heterogeneous and differentially remodels brain vasculature and immune microenvironments, which affects the treatment effectiveness and patient outcome. This study aimed to investigate the spatial interactions among different cell components, especially the vasculature system and the brain microenvironment of GCBM patients. Methods: We used digital spatial profiling to examine 140 regions composing tumor, immune, and brain tissues from three GCBM patients. Transcriptomic data with spatial information were analyzed for tissue areas related to different blood recruitment strategies. For validation, independent analysis of patient bulk transcriptomic data and in vivo single-cell transcriptomic data were performed. Results: Angiogenesis and blood vessel co-option co-existed within the same GCBM lesion. Tumors with high epithelial-mesenchymal transition and an enhanced transcriptomic gene signature composed of CTNNB1, SPARC, VIM, SMAD3, SMAD4, TGFB1, TGFB2, and TGFB3 were more prone to adopt blood vessel co-option than angiogenesis. Enriched macrophage infiltration, angiogenic chemokines, and NAMPT were found in angiogenic areas, while increased T cells, T cell activating cytokines, and reduced NAMPT were found in vessel co-option regions. Spatially, angiogenesis was enriched at the tumor edge, which showed higher DMBT1 expression than the tumor center. Conclusions: This study mapped the orchestrated spatial characteristics of tumor and immunological compositions that support the conventional and atypical vascularization strategies in GCBM. Our data provided molecular insights for more effective combinations of anti-vascular and immune therapies.

Impact of ultra-high-pressure treatment on microbial community composition and flavor quality of jujube juice: Insights from high-throughput sequencing technology, intelligent bionic sensory system, and metabolomics approach.

Ultra-high-pressure (UHP1) technology for cold pasteurization is a viable alternative to traditional heat sterilization for preserving food nutrients and flavor compounds during fruit juice processing. In this study, cutting-edge techniques, including high-throughput sequencing technology, intelligent bionic sensory systems, and metabolomics, were used to examine the impact of UHP treatment on microbial community composition, odor, and taste quality of jujube juice. The UHP treatment demonstrated its effect by inducing a reddish-yellow color in the jujube juice, thereby enhancing its brightness, overall color, and stability. The most significant enhancement was observed at 330 MPa. The microorganisms responsible for spoilage and deterioration of jujube juice during storage were categorized into three clusters: bacterial clusters at 0-330 MPa, 360-450 MPa, and 480-630 Mpa. The results showed no distinct distribution patterns for fungi based on the pressure strength. The dominant bacterial genera were Lactobacillus, Nocardia, Achromobacter, Enterobacter, Pseudomonas, Mesorhizobium, and Rhodococcus, whereas the dominant fungal genera were yeast and mold. Notably, Lactobacillus, Achromobacter, Enterobacter, and Pseudomonas were responsible for the significant differences between the 360 MPa to 450 MPa and 480 MPa to 630 MPa clusters in terms of bacterial spoilage, whereas Torulaspora, Lodderomyces, Wickerhamomyces, and Fusarium were the primary fungal spoilage genera. UHP treatment exerted no significant impact on the taste of jujube juice but influenced its sourness. Treatment at 330 MPa had the most pronounced effect on the presence of aromatic compounds and other odorants, which were substantially increased. Further analysis revealed the prevalence of organic acids, such as malic acid, succinic acid, and tartaric acid, in jujube juice and demonstrated a consistent relationship between changes in organic acids and sourness. In addition, nine distinct odorants with VIP values greater than 1 were identified in the jujube juice. Among these, methyl acetate and methyl caproate exhibited substantial increases following the UHP treatment at 330 MPa.

Inspection of defects in composite structures using long pulse thermography and shearography.

Long pulse thermography (LPT) and shearography have been developed as primary methods for detecting debonding or delamination defects in composites due to their full-field imaging, non-contact operation, and high detection efficiency. Both methods utilize halogen lamps as the excitation source for thermal loading. However, the defects detected by the two techniques differ due to their distinct inspection mechanisms. In this study, LPT and shearography are employed to evaluate internal damage in various composite structures. The experimental results demonstrate that LPT, when combined with thermal signal processing algorithms, can clearly detect debonding defects in rubber-to-metal bonded plates, whereas excessive adhesive defects can only be identified by shearography. Flat-bottom holes in the CFRP panel can only be detected by LPT, and shearography is particularly effective for detecting composite materials with a metal skin. For the quantitative measurement of defect sizes, the average errors of the rubber-to-metal bonded plate and CFRP panel using LPT are 4.9 % and 2.2 %, respectively, whereas the average errors of the rubber-to-metal bonded plate and aluminum honeycomb panel using shearography are 15.12 % and 95.4 %, respectively. This indicates that LPT is superior to shearography in quantitatively measuring defect sizes. These two nondestructive testing methods, based on different principles, each have their own advantages and disadvantages. Employing a multi-modal inspection method can leverage their complementary advantages, preventing misdetection and leakage of internal defects in composites.

Diagnostic value of fibrinogen in lower extremity deep vein thrombosis caused by rib fracture: A retrospective study.

Objectives: To investigate the diagnostic value of fibrinogen (FIB) in patients with rib fractures complicated by lower extremity deep venous thrombosis (DVT).Methods: Analyzing data from 493 patients at Shijiazhuang Third Hospital, FIB levels at 24, 48, and 72 h post-injury were compared between DVT and non-DVT groups.Results: DVT group had elevated FIB levels at all times (p < .001). FIB at 24 h showed highest AUC, particularly in patients with BMI <28.Conclusion: In conclusion, measuring FIB at 24 h post-injury enhances DVT detection in rib fracture patients, with potential BMI-related variations.

Dissimilarity of megabenthic community structure between deep-water seamounts with cobalt-rich crusts: Case study in the northwestern Pacific Ocean.

As anthropogenic disturbance on deep-sea seamount ecosystems grows, there is an urgent need for a better understanding of the biodiversity and community structure in benthic ecosystems, which can vary at local and regional scales. A survey of the benthic megafauna on two adjacent deep-water seamounts in the northwestern Pacific Ocean was conducted, which are covered by cobalt-rich crusts, to assess the biodiversity patterns and dissimilarity of assemblage composition. Based on a multidisciplinary dataset generated from video recordings, multibeam bathymetry data, and near-bottom currents, environmental and spatial factors impacting the megabenthic communities were explored. Results showed that these two deep-water seamounts were dominated by hexactinellids, crinoids, and octocorals. The seamounts were able to support diverse and moderately abundant megafauna, with a total of 6436 individuals classified into 94 morphospecies. The survey covered a distance of 52.2 km across a depth range of 1421-3335 m, revealing multiple distinct megabenthic assemblages. The megabenthic communities of the two deep-water seamounts, with comparable environmental conditions, exhibited similarities in overall density, richness, and faunal lists, while dissimilarities in the relative abundance of taxa and assemblage composition. No gradual depth-related change in terms of abundance, richness, or species turnover was observed across the two seamounts, despite the statistical significance of depth in structuring the overall communities. The spatial distribution of megabenthic communities displayed a discontinuous and patchy pattern throughout the two deep-water seamounts. This patchiness was driven by the interactive effects of multiple environmental factors. Near-bottom currents and microhabitat features were the primary drivers influencing their dissimilarities in megabenthic community structure. This case study on the megabenthic community structure of two adjacent seamounts with cobalt-rich crusts can serve as an environmental baseline, providing a reference status for the conservation and management of seamount ecosystems, particularly valuable for areas being considered for deep-sea mining.

Seamounts generate efficient active transport loops to nourish the twilight ecosystem.

Seamounts are ecological oases nurturing abundant fisheries resources and epibenthic megafauna in the vast oligotrophic ocean. Despite their significance, the formation mechanisms underlying these seamount ecological oases remain uncertain. To shed light on this phenomenon, this study conducted interdisciplinary in situ observations focusing on a shallow seamount in the oligotrophic ocean. The findings show that the seamount's topography interferes with the oceanic current to generate lee waves, effectively enhancing the nutrient supply to the euphotic layer downstream of the seamount. This continuous supply enhances phytoplankton biomass and subsequently the grazing and diurnal vertical migration of zooplankton, rapidly transporting the augmented phytoplankton biomass to the aphotic layer. Unlike the cyclonic eddies that move in the upper ocean, seamounts stand at fixed locations creating a more efficient and steady active transport loop. This active transport loop connects the euphotic and twilight zones, potentially conveying nourishment to benthic ecosystems to create stereoscopic oases in the oligotrophic ocean.

Roentgenoscopy of laser-induced projectile impact testing.

Laser-induced projectile impact testing (LIPIT) based on synchrotron imaging is proposed and validated. This emerging high-velocity, high-strain microscale dynamic loading technique offers a unique perspective on the strain and energy dissipation behavior of materials subjected to high-speed microscale single-particle impacts. When combined with synchrotron radiation imaging techniques, LIPIT allows for in situ observation of particle infiltration. Two validation experiments were carried out, demonstrating the potential of LIPIT in the roentgenoscopy of the dynamic properties of various materials. With a spatial resolution of 10 µm and a temporal resolution of 33.4 µs, the system was successfully realized at the Beijing Synchrotron Radiation Facility 3W1 beamline. This innovative approach opens up new avenues for studying the dynamic properties of materials in situ.

Exploring ALK fusion in colorectal cancer: a case series and comprehensive analysis.

Anaplastic lymphoma kinase (ALK) fusion-positive colorectal cancer (CRC) is a rare and chemotherapy-refractory subtype that lacks established and effective treatment strategies. Additionally, the efficacy and safety of ALK inhibitors (ALKi) in CRC remain undetermined. Herein, we examined a series of ALK-positive CRC patients who underwent various lines of ALKi treatment. Notably, we detected an ALK 1196M resistance mutation in a CRC patient who received multiple lines of chemotherapy and ALKi treatment. Importantly, we found that Brigatinib and Lorlatinib demonstrated some efficacy in managing this patient, although the observed effectiveness was not as pronounced as in non-small cell lung cancer cases. Furthermore, based on our preliminary analyses, we surmise that ALK-positive CRC patients are likely to exhibit inner resistance to Cetuximab. Taken together, our findings have important implications for the treatment of ALK-positive CRC patients.

Enhanced Co-Adsorption of Alcohols and Amines for Visible Light Driven Oxidative Condensation Using Iron-Based MOF.

Imines are essential intermediates in organic transformations, and is generally produced by dehydrogenative condensation of alcohols and amines with the assist of specialized catalysts and additives. Heterogeneous photocatalysis provides a sustainable platform for such process without the using of toxic oxidants, yet a functionalized photocatalyst with optimized co-adsorption of reactants needs to be developed to promote the stoichiometric oxidative condensation under ambient conditions. Here, we show that benzyl alcohol and aniline adsorb non-interferingly on the Fe node and the linker sites of the MIL-53(Fe) metal organic frameworks (MOFs), respectively. The co-adsorption of both reactants barely influences the reduction of molecular oxygen to generate oxygen radicals, resulting in efficient formation of benzaldehyde under visible light. Additionally, the weak adsorption of water together with surface acidity of the MIL-53(Fe) promote a rapid condensation of benzaldehyde with aniline and the depletion of generated water, achieving an efficient C-N bond creation for a wide range of substrates.

Three-dimensional printed personalised digital guide plate for greater palatine block in trigeminal neuralgia.

The nerve block is a safe and effective method to theat trigeminal neuralgia (TN). In terms of the V2 trigeminal neuralgia, the most difficult procedure in nerve block is accurate and fast greater palatine foramen (GPF) insertion. In this study, we developed a new technique using a personalised digital tooth-supported guide plate to increase insertion accuracy and success rates and reduce the pain of patients during injection. A total of 18 patients with TN (11 female and 7 male) were enrolled and treated between September 2020 and June 2022. Before injection, the guide plate was designed via Mimics three-dimensional (3D) reconstruction technology and printed via 3D printer. Then, all patients underwent maxillary nerve block with a guide plate for each injection. In this study, placement of all guide plates was completed within one minute and all punctures were successful the first time. The depth of the injection needle was over 2.5 cm in all cases and the guide plate was stability-supported by the maxillary teeth. The various pain scores had an obvious improvement. No patients presented symptoms of local anaesthetic toxicity or onset of new neurological sequelae. Using this new technology, we can significantly reduce the difficulty of GPF insertion and decrease patient pain during injection. The enhanced success rate of nerve block can achieve better therapeutic effect. For surgeons, personalised digital tooth-supported guide plates make the operation easier, especially for novice surgeons.

Enhancement of Astaxanthin Bioaccessibility by Encapsulation in Liposomes: An In Vitro Study.

Astaxanthin was encapsulated in liposomes by a thin layer dispersion and ultrasound method using soybean phospholipid. The digestion properties of liposomes for encapsulating astaxanthin were investigated in light of particle size, size distribution, zeta potential, and microstructure during in vitro digestion as a function of time. These results exhibited that the average particle size increased gradually with liposomal vesicles retained round shapes and a fairly uniform distribution after passage through the simulated gastric fluid digestion. The result revealed that astaxanthin-loaded liposomes were stable in low pH conditions. It was also found that the mixed micelles formed in a simulated intestinal fluid. The zeta potential of astaxanthin-loaded liposomes had a decrease in negativity after digestion. In comparison with free astaxanthin, there was an appreciable increase in the bioaccessibility of astaxanthin after encapsulation in liposomes. This enhancement can be attributed to more soluble astaxanthin in the mixed micelles for astaxanthin-loaded liposomes. It indicated that the barrier of the liposomal bilayer could inhibit astaxanthin fading and leaking after encapsulation in liposomes. These results provide useful information for designing more stable delivery systems in the gastrointestinal tract and improving the bioaccessibility of lipophilic nutraceuticals.

XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial.

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6-18.0) for the immunotherapy group compared with 9.9 months (8.0-11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40-0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3-32.8) for the control group (HR, 0.57 [95% CI, 0.33-0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

Patient-Controlled Subcutaneous Analgesia with Hydromorphone versus Oral Oxycontin for Opioid Titration of Cancer Pain: A Prospective Multicenter Randomized Trial.

Background: Studies have shown that oral oxycontin tablets can be used for opioid titration. The European Society for Medical Oncology (ESMO) guidelines for adult cancer pain recommend opioid titration through the parenteral route, usually the intravenous or subcutaneous route. Patient-controlled subcutaneous analgesia (PCSA) with hydromorphone needs further evaluation for opioid titration. This prospective multicenter study was designed to compare the efficacy and safety of hydromorphone PCSA with oral oxycontin tablets for opioid titration of cancer pain. Patients and Methods: Eligible patients with cancer pain were randomly assigned in a 1:1 ratio to the PCSA group or the oxycontin group for dose titration. Different titration methods were given in both groups depending on whether the patient had an opioid tolerance. The primary endpoint of this study was time to successful titration (TST). Results: A total of 256 patients completed this study. The PCSA group had a significantly lower TST compared with the oxycontin group (median [95% confidence interval (CI)], 5.5[95% CI:2.5-11.5] hours vs.16.0 [95% CI:11.5-22.5] hours; p<0.001). The frequency (median; interquartile) of breakthrough pain (Btp) over 24 hours was significantly lower in the PCSA group (2.5;2.0-3.5) than in the oxycontin group.(3.0; 2.5-4.5) (p=0.04). The pain was evaluated by numeric rating scale (NRS) score at 12 hours after the start of titration. The pain score (median; interquartile) was significantly lower in the PCSA versus the oxycontin group (2.5;1.5-3.0) vs 4.5;3.0-6.0) (p=0.02). The equivalent dose of oral morphine (EDOM) for a successful titration was similar in both groups (p=0.29), but there was a significant improvement in quality of life (QoL) in both groups (p=0.03). No between-group difference in the incidence of opioid-related adverse effects was observed (p=0.32). Conclusion: Compared with oral oxycontin tablet, the use of PCSA with hydromorphone achieved a shorter titration duration for patients with cancer pain (p<0.001), without significantly increasing adverse events (p=0.32).

Single-Cell and Spatial Transcriptome Profiling Identifies the Transcription Factor BHLHE40 as a Driver of EMT in Metastatic Colorectal Cancer.

Colorectal cancer is one of the most common malignant tumors in humans, with liver metastasis being the primary cause of mortality. The epithelial-mesenchymal transition (EMT) process endows cancer cells with enhanced metastatic potential. To elucidate the cellular mechanisms driving EMT in colorectal cancer, we analyzed single-cell RNA sequencing data from 11 nonmetastatic primary tumors (TnM) and 11 metastatic primary tumors (TM) from colorectal cancer patients. Compared with the TnM group, the TM samples showed elevated numbers of malignant epithelial cell and cancer-associated fibroblast (CAF) subsets that displayed enrichments of EMT, angiogenesis, and TGFß signaling pathways. One specific TM-enriched subgroup of malignant epithelial cells underwent EMT to transdifferentiate into CXCL1+ CAFs that subsequently differentiated into SFRP2+ CAFs, which was validated by spatial transcriptomic and pseudotime trajectory analyses. Furthermore, cell-cell communication analysis identified BHLHE40 as a probable key transcription factor driving EMT that was associated with poor prognosis. Finally, in vitro and in vivo experiments functionally substantiated that BHLHE40 promoted the proliferation, invasion, migration, EMT, and liver metastasis of colorectal cancer cells. In summary, this study identified BHLHE40 as a key transcription factor regulating EMT that promotes liver metastasis in colorectal cancer. Significance: Integrated analysis of single-cell RNA sequencing and spatial transcriptomics in metastatic colorectal cancer provides insights into the mechanisms underlying EMT and cancer-associated fibroblast differentiation, which could help improve patient diagnosis and treatment.

Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial.

Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P = 0.003), higher overall response rate (44.0% versus 13.0%, P = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+ T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239 .

Spatial distribution characteristics of carbazole and polyhalogenated carbazoles in water column and sediments in the open Western Pacific Ocean.

Polyhalogenated carbazoles (PHCZs), an emerging persistent halogenated organic pollutant, have been detected in the environment. However, our understanding of PHCZs in the ocean remains limited. In this study, 47 seawater samples (covering 50 - 4000 m) and sediment samples (49 surface and 3 cores) were collected to investigate the occurrence and spatial distribution patterns of carbazole and its halogenated derivants (CZDs) in the Western Pacific Ocean. In seawater, the detection frequencies of CZ (97.87%) and 3-CCZ (57.45%) were relatively high. In addition, the average concentration of ΣPHCZs in the upper water (< 150 m, 0.23 ± 0.21 ng/L) was significantly lower than that in the deep ocean (1000 - 4000 m, 0.65 ± 0.56 ng/L, P < 0.05), which may indicate the vertical transport of PHCZs in the marine environment. The concentration of ΣCZDs in surface sediment ranges from 0.46 to 6.48 ng/g (mean 1.54 ng/g), among which CZ and 36-CCZ were the predominant components. Results from sediment cores demonstrate a noteworthy negative correlation between the concentration of CZDs and depth, indicating the ongoing natural degradation process occurring in sediment cores over a long period. This study offers distinctive insights into the occurrence, composition, and vertical features of CZDs in oceanic environments.