Meta-analysis of the effects of bundle interventions on ICU-acquired weakness intervention.

BACKGROUND: Intensive care unit acquired weakness (ICU-AW) is a secondary neuromuscular complication in critically ill patients, characterized by profound weakness in all four limbs. Studies have shown that bundles of care are nursing strategies that combine a series of evidence-based interventions, which collectively optimize patients' clinical outcomes compared to individual interventions. OBJECTIVE: This study aims to conduct a meta-analysis of the effects of bundle interventions on ICU-AW deeply exploring the characteristics of bundle interventions, patient outcomes related to ICU-AW, and primarily investigating the effects of bundle interventions on ICU-AW. The main focus is to explore the clinical value of bundle interventions in treatment of ICU-acquired weakness in patients. METHODS: Computer and manual searches were conducted using keywords to retrieve relevant studies on the effects of bundle interventions on ICU-AW from databases such as PubMed, Web of Science, Cochrane Library and EMbase. The search period ranged from database inception to the present. The control group received standard ICU care, including basic nursing, while the intervention group received bundle nursing interventions. RESULTS: A total of 10 randomized controlled trials (RCTs) involving 1545 participants (790 in the intervention group and 755 in the control group) were included. Meta-analysis results showed that the intervention group had significantly higher muscle strength (MD = 7.41, 95% CI: 6.65-8.16, P< 0.00001) and daily living ability (MD = 34.01, 95% CI: 32.54-35.48, P< 0.00001) than the control group. Additionally, the incidence of ICU-AW (OR = 0.39, 95% CI: 0.26-0.59, P< 0.00001), mechanical ventilation time (MD =-3.71, 95% CI: -3.58∼-2.76, P< 0.0001), and ICU length of stay (MD =-2.73, 95% CI: -3.14∼-2.31, P< 0.00001) were significantly lower in the intervention group than in the control group. CONCLUSION: ICU-AW has a severe negative impact on the recovery and functional restoration of ICU patients, increasing the treatment complexity for healthcare providers and the mortality and disability rates for patients. The bundled care approach may help reduce the incidence of ICU-AW, promote the restoration of daily activity function, enhance muscle strength, and reduce ICU stay and mechanical ventilation time for ICU patients. However, the long-term effects of bundle interventions still require further in-depth research.

Thiol-containing hyperbranched polysiloxane for scavenging reactive oxygen species.

Unconventional luminescent polymers have attracted considerable attention in the biological field due to their intrinsic fluorescence properties and excellent biocompatibility. However, exploring the luminescent properties of thiol-containing polymers and the mechanism of their scavenging of ROS remains unclear. In this work, we synthesised three kinds of hyperbranched polysiloxanes (HE, HP, and HB) with terminal thiol groups containing different chain lengths by the polycondensation reaction. Surprisingly, HP exhibits longer-wavelength emission at 480 nm with a quantum yield of 12.23% compared to HE and HB. Experiments and density functional theory (DFT) calculations have revealed that the rigidity of the conformation is enhanced by substantial hydrogen bonds and through-space O⋯O interactions in the polymer structure. These interactions, combined with the rigid carbon chains, balance the flexibility of the Si-O-C chain segments, which emerges as a critical factor contributing to the superior fluorescence performance of HP. In addition, HP exhibits excellent biocompatibility and ROS scavenging ability with a scavenging capacity of up to 35.095%. This work provides a new fluorescent polymer for scavenging ROS for the treatment of ROS-related diseases.

Achieving Controllable Thermochromic Fluorescence via Synergistic Intramolecular Charge Transfer and Molecular Packing.

Thermochromic fluorescent materials (TFMs) have attracted significant attention due to their unique fluorescent colorimetric response to temperature. However, existing TFMs still suffer from weak stimulus responsiveness, broad temperature response ranges, uncontrollable emission color changes, and low quantum yields. In this study, we address these issues by designing and synthesizing three diketone-boron complexes with distinct emission wavelengths (NWPU-(2-4)). Utilizing a molecular engineering strategy to manipulate intramolecular charge transfer transitions and molecular packing modes, our synthesized complexes exhibit efficient fluorescence emission in both solution and solid states. Moreover, their emission wavelengths are highly sensitive to environmental polarity. By incorporating these compounds into thermosensitive matrices of long-chain alkanes, we produced TFMs with varied fluorescence emission peak variation ranges. Notably, the TFM based on NWPU-4, owing to its strong charge transfer transitions and dense J-aggregate packing configuration, not only exhibits intense fluorescence emission spanning the deep red to near-infrared spectrum but also displays a remarkable 90 nm broad range of thermochromic properties. Ultimately, it was successfully applied to programmable, thermally controlled, multi-level information encryption.

Recent Advances of Organic-Inorganic Hybrid Fluorescent Hyperbranched Polymer: Synthesis, Performance Regulation Strategies and Applications.

The organic-inorganic hybrid fluorescent hyperbranched polymer, including hyperbranched polysiloxane and hyperbranched polyborate, have attracted much attention due to their excellent optical properties and wide range of applications. Hyperbranched polysiloxane and polyborates, prepared by introducing Si or B elements into organic polymer chains at the molecular level through rational molecular design and novel synthesis methods, exhibit outstanding photophysical properties as an indispensable branch of organic-inorganic hybrid fluorescent materials. Herein, this review highlights the recent research progress on hyperbranched polysiloxanes and hyperbranched polyborates, including strategies for regulating their emission wavelengths, quantum yields, and fluorescence lifetimes, potential emission mechanisms, and various applications. Finally, some challenges and promising future directions in the field of organic-inorganic hybrid fluorescent polymers are summarized.

Si, B-containing dynamic covalent bonds enable excellent flame retardancy and reduced fire hazards for cyanate ester resin.

Cyanate ester (CE) resins are distinguished by excellent dielectric properties in electronic packaging materials but face significant fire risks, with existing strategies often compromising their processability or original properties. Herein, we propose an innovative strategy involving the exchange of dynamic covalent bonds under heat stimuli aimed at forming a continuous and compact char layer to enhance the fire safety of CE resin. Using a straightforward one-pot method, dynamic Si-O and B-O bonds were integrated into a novel hyperbranched polymer (HPSiB), ensuring good compatibility with CE resin while lowering its peak curing temperature by 185 °C for facile processability. The resulting material with 6 wt% HPSiB exhibits a LOI value of 32.8% and UL-94 V0 rating, especially a low total smoke production of 6.7 m2, demonstrating excellent flame retardancy and reduced fire hazards compared to reported Si or B-containing flame-retardant materials. Moreover, its glass transition temperature increased by 35 °C, along with enhanced mechanical properties and an ultra-low dielectric loss of 0.0031 at 10 GHz. These advancements highlight the significant potential of this work in developing high-performance fire-resistant materials.

Unconventional Luminescence Polymer with Color-Tunability based on Solvent-Induced Electrostatic Potential Distribution of Fluorophore.

Tuning full-color emission of polymers holds significant promise. However, preparing unconventional luminescence polymers with color-tunability in dilute solution and understanding the relationship between non-covalent interactions and luminescent behavior remains a great challenge. We report two emitters (P1 and P2) incorporating tetracoordinate boron. The P1 with non-conjugated D-π-A structure, exhibited red delayed fluorescence at 645 nm with quantum yield of 9.15 % in aggregates. Notably, the emission wavelength of P1 can be tuned from 418 to 588 nm at different solvent. Similarly, the emission wavelength of P2 can also be adjusted by manipulating the interactions between the solvent and fluorophore. Experimental characterization and theoretical calculations indicate that the B←N bond and electronic interactions between solvent and fluorophore significantly regulate the equilibrium the electrostatic potential (ESP) and the intramolecular O⋅⋅⋅O interactions of P1, thereby modulating its emission wavelength. Additionally, these polymers showed excellent potential in fluoride ions detection. This work provides new insights into the complex effects of intermolecular interactions on luminescent properties.

Cardiovascular comorbidities among patients with psoriasis: a national register-based study in China.

This study aims to illustrate epidemiology of comorbid CVD in the real-world clinical setting of patients with psoriasis in China. We used data of adult patients with psoriasis who were registered in the register of China National Clinical Center for Skin and Immune Diseases between August 2020 and September 2021. Psoriasis was clinically diagnosed following the national guidelines. Univariate and multivariate logistic regression models were used to examine the factors associated with comorbid CVD in patients with psoriasis. Of the 11,560 psoriasis patients (age ≥ 18 years, mean age 41.87 years, 64.88% males), 236 were ascertained with CVD, with the overall prevalence being 2.62%. Multivariate logistic regression analysis suggested that the odds ratio (95% confidence interval) of CVD in psoriasis patients was 2.27 (2.03-2.54) for older age (per 10-year increment), 0.65 (0.48-0.90) for female, 2.07 (1.39-3.06) for obesity (BMI ≥ 28 vs. < 24 kg/m2), 2.55 (1.85-2.52) for smoking, 7.63 (5.86-9.94) for hypertension, 4.27 (3.76-4.85) for diabetes, 1.14 (1.00-1.30) for having a history of drug allergy, 2.27 (1.61-3.20) for having family history of psoriasis, and 1.76 (1.16-2.67) for severe disease (severe vs. mild) with a dose-response relationship (Ptrend < 0.001). In patients with psoriasis, comorbid CVD was associated with smoking, obesity, hypertension, diabetes, history of drug allergy, family history of psoriasis, and the psoriasis severity.

Dual Infection of Different Clusters of HIV in People Living with HIV Worldwide: A Meta-Analysis Based on Next-Generation Sequencing Studies.

To understand the global dual HIV infection (DI) profiles comprehensively, the databases Cochrane Library, Embase, PubMed, and Web of Science were the data sources up to March 31, 2024 (PROSPERO: CRD42023388328). Stata and R-language software were used to analyze the extracted data. Publication bias was assessed using Egger's test. Sensitivity analysis was conducted to evaluate the stability of the combined effect values. Data from 17 eligible studies across four continents (Africa, Asia, Europe, and North America) with 1,475 subjects were used. The combined dual infection rate (DIR) was 10.47% (95% CI: 7.11%-14.38%) without a time trend (p = 0.105). The DIRs of target population groups differed significantly, with FSWs having the highest DIR (15.14%), followed by general population (12.08%), MSM (11.84%), and DUs (9.76%). The subtype profiles of 122 patients with dual infection were extracted, and the results showed that intrasubtype infections were predominant in coinfection (16/22, 72.73%) and superinfection (68/100, 68.00%) groups, with the subtype pattern B and B accounts for the largest proportion. The global dual infection rate may be underestimated, even though the data fluctuated around 10% and showed no time trend. The occurrence of DI indicated that individuals still do not acquire sufficient resistance to HIV even after primary infection, which could potentially compromise the patient's treatment effect and lead to the emergence of new subtypes, posing a significant challenge to HIV prevention, control, and treatment, suggesting that behavioral counseling and health education for all HIV-infected individuals are still crucial during the antiviral therapy.

Aliphatic hyperbranched polyphosphate: a novel multicolor RTP material with AIE character.

Long-lived photoluminescent probes are emerging as significant luminogens for biological imaging. However, currently, most long-lived luminescent materials contain expensive rare elements or cytotoxic bulky aromatic or conjugated units. Herein, a novel hyperbranched polyphosphate (HBPPE) was synthesized using triethyl phosphate (TEP) and ethylene glycol (EG) through a transesterification polycondensation reaction. The obtained HBPPE P1 can emit bright blue photoluminescence under UV light and show significant AIE character. Interestingly, the average photoluminescence lifetime of P1 is 12.82 µs. This suggests the first phosphorescent material without rare elements or aromatic structures attributed to the covalent-crystal-like structure. Besides, P1 shows an obvious red-shift along with the excitation wavelength, which emits blue, cyan, green, yellow and red photoluminescence, covering nearly all the visible light region. This study not only enriches the species of nonconventional multicolor AIE luminogens but also provides a concise method for the synthesis of HBPPE and demonstrates the possibility for phosphorescent materials without rare elements or bulky aromatic units.

The change of symptom clusters in gastric cancer patients during the perioperative period: a longitudinal study.

AIM AND OBJECTIVES: The purpose of this study was to describe the number, type and trajectory of symptom clusters during the perioperative period in patients with gastric cancer at four different time points. The study also aimed to identify the changes and consistency of these symptom clusters over time. DESIGN: This was a longitudinal study. METHODS: This study was conducted in a tertiary cancer hospital with 205 patients with gastric cancer. The M.D. Anderson Symptom Inventory Gastrointestinal Cancer Module was used to assess the incidence and severity of symptom clusters. Exploratory factor analysis was used to extract symptom clusters. RESULTS: The study identified four symptom clusters in patients with gastric cancer during the perioperative period: gastrointestinal symptom cluster, physical symptom cluster, psychological symptom cluster, and sleep disturbance symptom cluster. These clusters were observed across two to four time points. CONCLUSION: The findings of this study provide scientific evidence for medical staff and researchers to better understand the symptoms of patients with gastrointestinal cancer during the perioperative period. These findings can help develop individualized interventions for managing symptoms. RELEVANCE TO CLINICAL PRACTICE: Gastric cancer patients suffered from various symptom clusters, which lasted from one day before surgery to one month after surgery. They should be given careful consideration by clinical staff.

Regulation of Photophysical Behaviors in Hyperbranched Aggregation-Induced Emission Polymers for Reactive Oxygen Species Scavenging.

Developing nonconjugated materials with large Stokes shifts is highly desired. In this work, three kinds of hyperbranched aggregation-induced emission (AIE) polymers with tunable n/π electronic effects were synthesized. HBPSi-CBD contains alkenyl groups in the backbone and possesses a promoted n-π* transition and red-shifted emission wavelength with a large Stokes shift of 186 nm. Experiments and theoretical simulations confirmed that the planar π electrons in the backbone are responsible for the red-shifted emission due to the strong through-space n···π interactions and restricted backbone motions. Additionally, the designed HBPSi-CBD could be utilized as an ROS scavenger after coupling with l-methionine. The HBPSi-Met exhibits remarkable ROS scavenging properties with a scavenging capacity of 77%. This work not only gains further insight into the structure-property relationship of nonconjugated hyperbranched AIE polymers but also provides a promising ROS-scavenging biomaterial for the treatment of ROS-related diseases.

Rheumatoid Arthritis Patient With Neurofibromatosis Type 1: Case Report and Review of the Literature.

A 66-year-old neurofibromatosis type 1 (NF1) patient with polyarticular pain for nine years, aggravated for two days, was transferred from the Emergency Intensive Care Unit (EICU) to our rheumatology department. She was diagnosed with NF1 nine years ago by a gene mutation detection and coronary heart disease (CHD) three months ago. The patient was diagnosed with rheumatoid arthritis (RA) this time. After 24 days of treatment with appropriate medication, the patient was discharged with relieved joint pain. However, about four months later, the patient died of circulatory failure caused by myocardial infarction. We analyzed the possible reasons for her outcome and made a review of the literature. There are few clinical reports of NF1 complicated with RA. We found five cases reported in the literature up to date during our search and included them in our communication to compare with our case. NF1 combined with RA mainly affects adult women and usually starts with NF1 and is followed by RA after at least six years of NF1 symptom onset. Although the summarized characteristics of clinical and potential pathogenesis of NF1 combined with RA were limited with these six cases, we hope that this will help clinicians to increase their understanding of this rare complication, thus helping to guide clinical medication.

Involvement of GSTP1 in low dose radiation-induced apoptosis in GM12878 cells.

BACKGROUND: Low-dose ionizing radiation-induced protection and damage are of great significance among radiation workers. We aimed to study the role of glutathione S-transferase Pi (GSTP1) in low-dose ionizing radiation damage and clarify the impact of ionizing radiation on the biological activities of cells. RESULTS: In this study, we collected peripheral blood samples from healthy adults and workers engaged in radiation and radiotherapy and detected the expression of GSTP1 by qPCR. We utilized γ-rays emitted from uranium tailings as a radiation source, with a dose rate of 14 µGy/h. GM12878 cells subjected to this radiation for 7, 14, 21, and 28 days received total doses of 2.4, 4.7, 7.1, and 9.4 mGy, respectively. Subsequent analyses, including flow cytometry, MTS, and other assays, were performed to assess the ionizing radiation's effects on cellular biological functions. In peripheral blood samples collected from healthy adults and radiologic technologist working in a hospital, we observed a decreased expression of GSTP1 mRNA in radiation personnel compared to the healthy controls. In cultured GM12878 cells exposed to low-dose ionizing radiation from uranium tailings, we noted significant changes in cell morphology, suppression of proliferation, delay in cell cycle progression, and increased apoptosis. These effects were partially reversed by overexpression of GSTP1. Moreover, low-dose ionizing radiation increased GSTP1 gene methylation and downregulated GSTP1 expression. Furthermore, low-dose ionizing radiation affected the expression of GSTP1-related signaling molecules. CONCLUSIONS: This study shows that low-dose ionizing radiation damages GM12878 cells and affects their proliferation, cell cycle progression, and apoptosis. In addition, GSTP1 plays a modulating role under low-dose ionizing radiation damage conditions. Low-dose ionizing radiation affects the expression of Nrf2, JNK, and other signaling molecules through GSTP1.

The Effectiveness of Symptom Management Theory in Guiding Clinical Practice-A Systematic Review.

Objective: Symptom Management Theory has been extensively used in guiding clinical practice to reduce patients' symptom burden, improve their outcomes and quality of life. However, concerning various participants, settings and methods, the effectiveness of practice and research based on the theory was inconsistent, which hindered the further implementation of this theory in clinical practice. Thus, this study aims to systematically evaluate the effectiveness of the Symptom Management Theory in guiding clinical practice. Methods: Systematic review. An online search of Chinese and English databases, including SinoMed, CNKI, WanFang Library, VIP database, MEDLINE, PubMed, Embase, Web of Science database, and Cochrane Library up to December 2023. This systematic review was conducted in accordance with the Joanna Briggs Institute critical appraisal checklist for randomized controlled trials and controlled clinical trials. The literature appraisal and extraction were independently conducted by two researchers. The third person was consulted if there was any disagreement between the two researchers. Results: A total of 20 articles (15 randomized controlled trials and five controlled clinical trials) were finally included. The overall quality of the articles was high. Additionally, the results showed that symptom management measurements based on the Symptom Management Theory could reduce the severity of patient's symptoms, alleviate their distress, relieve patients' anxiety and depression and improve their quality of sleep and quality of life. Conclusion: The Symptom Management Theory positively influenced clinical symptom management. It could provide theory-based symptom management methods in clinical practice to reduce patients' severity and burden of symptoms, level of anxiety, depression and distress. More high-quality original research should be conducted to further explore the theory's influence in guiding clinical practice in the future.

Modulation of Deep-Red to Near-Infrared Room-Temperature Charge-Transfer Phosphorescence of Crystalline "Pyrene Box" Cages by Coupled Ion/Guest Structural Self-Assembly.

Organic cocrystals obtained from multicomponent self-assembly have garnered considerable attention due to their distinct phosphorescence properties and broad applications. Yet, there have been limited reports on cocrystal systems that showcase efficient deep-red to near-infrared (NIR) charge-transfer (CT) phosphorescence. Furthermore, effective strategies to modulate the emission pathways of both fluorescence and phosphorescence remain underexplored. In this work, we dedicated our work to four distinct self-assembled cocrystals called "pyrene box" cages using 1,3,6,8-pyrenetetrasulfonate anions (PTS4-), 4-iodoaniline (1), guanidinium (G+), diaminoguanidinium (A2G+), and hydrated K+ countercations. The binding of such cations to PTS4- platforms adaptively modulates their supramolecular stacking self-assembly with guest molecules 1, allowing to steer the fluorescence and phosphorescence pathways. Notably, the confinement of guest molecule 1 within "pyrene box" PTSK{1} and PTSG{1} cages leads to an efficient deep-red to NIR CT phosphorescence emission. The addition of fuming gases like triethylamine and HCl allows reversible pH modulations of guest binding, which in turn induce a reversible transition of the "pyrene box" cage between fluorescence and phosphorescence states. This capability was further illustrated through a proof-of-concept demonstration in shrimp freshness detection. Our findings not only lay a foundation for future supramolecular designs leveraging weak intermolecular host-guest interactions to engineer excited states in interacting chromophores but also broaden the prospective applications of room-temperature phosphorescence materials in food safety detection.

Phenotypic and proteomic characterization of the human erythroid progenitor continuum reveal dynamic changes in cell cycle and in metabolic pathways.

Human erythropoiesis is a complex process leading to the production of 2.5 million red blood cells per second. Following commitment of hematopoietic stem cells to the erythroid lineage, this process can be divided into three distinct stages: erythroid progenitor differentiation, terminal erythropoiesis, and reticulocyte maturation. We recently resolved the heterogeneity of erythroid progenitors into four different subpopulations termed EP1-EP4. Here, we characterized the growth factor(s) responsiveness of these four progenitor populations in terms of proliferation and differentiation. Using mass spectrometry-based proteomics on sorted erythroid progenitors, we quantified the absolute expression of ~5500 proteins from EP1 to EP4. Further functional analyses highlighted dynamic changes in cell cycle in these populations with an acceleration of the cell cycle during erythroid progenitor differentiation. The finding that E2F4 expression was increased from EP1 to EP4 is consistent with the noted changes in cell cycle. Finally, our proteomic data suggest that the protein machinery necessary for both oxidative phosphorylation and glycolysis is present in these progenitor cells. Together, our data provide comprehensive insights into growth factor-dependence of erythroid progenitor proliferation and the proteome of four distinct populations of human erythroid progenitors which will be a useful framework for the study of erythroid disorders.

Hyperbranched Dynamic Crosslinking Networks Enable Degradable, Reconfigurable, and Multifunctional Epoxy Vitrimer.

Degradation and reprocessing of thermoset polymers have long been intractable challenges to meet a sustainable future. Star strategies via dynamic cross-linking hydrogen bonds and/or covalent bonds can afford reprocessable thermosets, but often at the cost of properties or even their functions. Herein, a simple strategy coined as hyperbranched dynamic crosslinking networks (HDCNs) toward in-practice engineering a petroleum-based epoxy thermoset into degradable, reconfigurable, and multifunctional vitrimer is provided. The special characteristics of HDCNs involve spatially topological crosslinks for solvent adaption and multi-dynamic linkages for reversible behaviors. The resulting vitrimer displays mild room-temperature degradation to dimethylacetamide and can realize the cycling of carbon fiber and epoxy powder from composite. Besides, they have supra toughness and high flexural modulus, high transparency as well as fire-retardancy surpassing their original thermoset. Notably, it is noted in a chance-following that ethanol molecule can induce the reconstruction of vitrimer network by ester-exchange, converting a stiff vitrimer into elastomeric feature, and such material records an ultrahigh modulus (5.45 GPa) at -150 °C for their ultralow-temperature condition uses. This is shaping up to be a potentially sustainable advanced material to address the post-consumer thermoset waste, and also provide a newly crosslinked mode for the designs of high-performance polymer.

An ultra-sensitive ratiometric fluorescent thermometer based on monomer and excimer dual emission.

By leveraging natural saturated fatty acids with distinct melting points and swift reversible phase transitions, we correlated external thermal cues to monomer and excimer emissions of difluoroboron ß-diketonate fluorophores. This integration yielded a ratiometric fluorescent thermometer showcasing unparalleled sensitivity and thermochromism in the physiological temperature range.

Severe immediate hypersensitivity to gadolinium contrast agent after targeted treatment in a patient with alveolar soft part sarcoma: A case report and review of literature.

RATIONALE: Gadolinium-based contrast agents (GBCAs), benefiting from good tolerance and safety, become the priority contrast agents in magnetic resonance imaging. Serious hypersensitivity reactions caused by GBCAs are rare, but occur occasionally. The "immune surveillance" theory proposes that lowered immune function exists in patients with malignance, which decrease the occurrence of atopy. Natural immunosurveillance that enhanced by effective treatment of malignance may increase the risk of hypersensitivity. PATIENT CONCERNS: A 29-year-old female patient suffering from intensive pain with left leg mass was admitted in our hospital. DIAGNOSES: The patient was diagnosed with alveolar soft part sarcoma by histopathology and revealed destruction of the left fibula and lung metastasis by computed tomography scan, and treated with anlotinib hydrochloride, a multi-targeted tyrosine kinase inhibitor. After 4 cycles of effective targeted therapy, the patient developed severe immediate hypersensitivity due to gadopentetate dimeglumine-enhanced magnetic resonance imaging. INTERVENTIONS AND OUTCOMES: The vital signs of the patient returned to normal after rescue. Since then, the patient has not used gadolinium contrast agent again, and currently the condition is stable and still alive. LESSONS: Severe immediate hypersensitivity might be occurred by gadolinium contrast agent in patients with malignance after effective treatment. We explored the potential mechanism of GBCA-inducing hypersensitivity in detail, by especially focusing on the changes of immune environment. Furthermore, we propose new ideas for the safe use of GBCAs in patients with malignancies.