Objective:To observe the clinical effect of urokinase along the pipeline under offline status to dissolve dialyzer microthrombus in patients undergoing continuous renal replacement therapy (CRRT).Methods:A prospective research method was adopted. A total of 248 CRRT patients with dialyzer microthrombus in Sinopharm-Gezhouba Central Hospital from January 2017 to December 2021 were selected. The patients were divided into experimental group (continued CRRT treatment after urokinase along the pipeline under offline status to dissolve dialyzer microthrombus) and control group (continued CRRT treatment after dialyzer replacement) by random number table method with 124 cases in each group. The baseline data were recorded, including gender, age, primary disease, hemoglobin, platelet count, hematocrit, plasma albumin, D-dimer, fibrinogen, anticoagulant method and symptoms associated with dialyzer microthrombus. The blood indexes were detected before and after treatment of microthrombus, and the symptom scores were performed. The blood indexes included creatinine, urea nitrogen, β 2 microglobulin (β 2-MG), international normalized ratio (INR), hypersensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α); and the symptom scores included acute physiology and chronic health status score Ⅱ (APACHE Ⅱ) and (APACHE Ⅱ) and sequential organ failure score. The initial transmembrane pressure, transmembrane pressure before disembarkation, CRRT treatment extension time and coagulation classification were recorded. In experimental group, the blood coagulation function indexes before and after treatment were detected, including prothrombin time (PT), activated partial prothrombin time (APTT), thrombin time (TT) and fibrinogen (Fib). The adverse reactions were recorded, including black stools, arrhythmias and wound bleeding. Results:There were no statistical differences in baseline data, initial transmembrane pressure, transmembrane pressure before disembarkation, CRRT treatment extension time and coagulation classification between two groups ( P>0.05). There were no statistical differences in creatinine, urea nitrogen, β 2-MG, INR, hs-CRP, IL-6, TNF-α, APACHE Ⅱ and SOFA before treatment between two groups ( P>0.05); after treatment, the indexes in both groups were significantly lower than before treatment, and the indexes in experimental group were significantly lower than those in control group: (179.1 ± 41.2) μmol/L vs. (187.1 ± 53.9) μmol/L, (7.3 ± 2.8) mmol/L vs. (9.3 ± 2.5) mmol/L, (2.5 ± 0.6) mg/L vs. (4.2 ± 0.7) mg/L, 1.0 ± 0.3 vs. 1.8 ± 0.5, (8.7 ± 1.1) mg/L vs. (10.6 ± 2.4) mg/L, (21.5 ± 12.7) ng/L vs. (29.5 ± 10.3) ng/L, (20.2 ± 6.1) ng/L vs. (26.6 ± 7.2) ng/L, (12.1 ± 6.9) scores vs. (17.2 ± 5.2) scores and (5.9 ± 1.8) scores vs. (6.8 ± 1.9) scores, and there were statistical differences ( P<0.05). In experimental group, there were no statistical differences in PT, APTT, TT and Fib between before treatment and after treatment ( P>0.05). The incidence of adverse reactions in experimental group was significantly lower than that in control group: 4.03%(5/124) vs. 12.90%(16/124), and there was statistical difference ( χ2 = 6.30, P<0.05). Conclusions:The urokinase along the pipeline under offline status to dissolve dialyzer microthrombus in patients undergoing CRRT is safer, cheaper and more efficient. It can improve the biocompatibility of tissue with dialyzer and pipe, prolong the use time of the dialyzer, and complete renal replacement therapy.

Objective:To investigate the clinical efficacy of botulinum toxin type A（BTX-A）bladder injection in the treatment of neurogenic detrusor overactivity（NDO）with autonomic dysreflexia（AD）.Methods:The patients with spinal cord injury at or above T6，who were treated at Guangdong Provincial Work Injury Rehabilitation Hospital from January 2018 to December 2022，were included in this study prospectively. Inclusion criteria：①chronic spinal cord injury patients over 18 years old（with no progression of neurological symptoms within 3 months）；② presence of NDO and AD；③ inadequate response or intolerance to oral antimuscarinic agent（M-receptor antagonists or β 3-receptor agonists）④ perform clean intermittent catheterization to empty the bladder. Exclusion criteria：① primary disease in the acute or progressive phase；② previous surgeries that would affect lower urinary tract function，such as transurethral sphincterotomy，bladder neck resection，prostatectomy，or bladder surgery；③ allergy to BTX-A or its adjuvants，or those with allergic predisposition ④ patients who were pregnant，breastfeeding，or planning for pregnancy in the near future；⑤ patients did not accept or were unable to perform intermittent catheterization. Before treatment，all patients were required to maintain 3-5 day urine diary，along with urodynamic studies（UDS），incontinence specific quality of life instrument（I-QOL）and AD symptom severity assessment，and blood pressure monitored. Key UDS parameters recorded included maximum bladder capacity，maximum detrusor pressure during filling phase，changes in maximum systolic blood pressure（SBP）relative to baseline（ΔSBP）during UDS examination，and the frequency of 24-hour blood pressure exceeding baseline by 20 mmHg. After general anesthesia or epidural anesthesia，BTX-A（200 U）was injected into the bladder at 30 points（including the triangle）under the cystoscope using a special injection needle，6.7 U per injection，and then the catheter was kept for 3-5 days after treatment. Three months later，relevant indicators were collected and compared with pre-treatment data. Results:A total of 43 patients were included in this study，including 34 males and 9 females. The age was（39.23±13.17）years old and the disease course was（2.69±3.27）years old. There were 33 cervical and 10 thoracic cases. The American Spinal Injury Association Injury Scale score distribution was as follows：26（60%）A，4（9%）B，9（21%）C，and 4（9%）D. The presence of AD was confirmed in all patients during urodynamic examination（UDS），that was the systolic blood pressure（SBP）suddenly increased and exceeded 20 mmHg（1 mmHg = 0.133 kPa）. Before treatment，The AD symptoms severity score（consist of headache，sweating，goose bumps，anxiety and palpitation）were（14.53±2.51），Bladder-related AD frequency was 10.67 episodes/day. Baseline SBP was（103.51±9.64）mmHg，the maximum SBP was（150.40±22.75）mmHg，and the change in SBP（ΔSBP）from maximum to baseline SBP during UDS examination was（43.83±21.01）mmHg. The UDS indicated that the maximum detrusor pressure during storage phase was（54.95±24.68）cmH 2O，and the bladder capacity was（131.70±75.29）ml. Bladder diary showed the volume of catheterization each time from was（181.16±49.86）ml，and The I-QOL score was（44.07±8.60）. Three months after treatment，the AD symptoms severity score（consist of headache，sweating，goose bumps，anxiety and palpitation）were（11.37±2.39）. The frequency of bladder-related AD episodes was（7.51±2.37）episodes/day，showing statistically significant differences compared to pre-treatment（ P<0.05）.The SBP before UDS examination was（102.12±10.28）mmHg，with no statistically significant difference from baseline（ P = 0.518）. The maximum SBP in perfusion phase and the ΔSBP were（132.84±16.30）mmHg and（28.72 ± 14.02）mmHg，respectively，both demonstrating statistically significant differences（ P < 0.05）. The UDS examination revealed that the maximum detrusor pressure during the storage phase was（29.77±13.72）cmH 2O，showed a significant decrease，and the bladder capacity was（272.63±79.75）ml，which were both statistically different before and after surgery. Bladder diary showed the volume of catheterization each time was（326.74±63.71）ml；I-QOL score was（71.86±11.45），both were significant different after treatment（ P < 0.01）. Conclusion:BTX-A intravesical injection in the treatment of NDO can also alleviate the severity and frequency of bladder related AD.

Objective:To observe the clinical effect of urokinase along the pipeline under offline status to dissolve dialyzer microthrombus in patients undergoing continuous renal replacement therapy (CRRT).Methods:A prospective research method was adopted. A total of 248 CRRT patients with dialyzer microthrombus in Sinopharm-Gezhouba Central Hospital from January 2017 to December 2021 were selected. The patients were divided into experimental group (continued CRRT treatment after urokinase along the pipeline under offline status to dissolve dialyzer microthrombus) and control group (continued CRRT treatment after dialyzer replacement) by random number table method with 124 cases in each group. The baseline data were recorded, including gender, age, primary disease, hemoglobin, platelet count, hematocrit, plasma albumin, D-dimer, fibrinogen, anticoagulant method and symptoms associated with dialyzer microthrombus. The blood indexes were detected before and after treatment of microthrombus, and the symptom scores were performed. The blood indexes included creatinine, urea nitrogen, β 2 microglobulin (β 2-MG), international normalized ratio (INR), hypersensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α); and the symptom scores included acute physiology and chronic health status score Ⅱ (APACHE Ⅱ) and (APACHE Ⅱ) and sequential organ failure score. The initial transmembrane pressure, transmembrane pressure before disembarkation, CRRT treatment extension time and coagulation classification were recorded. In experimental group, the blood coagulation function indexes before and after treatment were detected, including prothrombin time (PT), activated partial prothrombin time (APTT), thrombin time (TT) and fibrinogen (Fib). The adverse reactions were recorded, including black stools, arrhythmias and wound bleeding. Results:There were no statistical differences in baseline data, initial transmembrane pressure, transmembrane pressure before disembarkation, CRRT treatment extension time and coagulation classification between two groups ( P>0.05). There were no statistical differences in creatinine, urea nitrogen, β 2-MG, INR, hs-CRP, IL-6, TNF-α, APACHE Ⅱ and SOFA before treatment between two groups ( P>0.05); after treatment, the indexes in both groups were significantly lower than before treatment, and the indexes in experimental group were significantly lower than those in control group: (179.1 ± 41.2) μmol/L vs. (187.1 ± 53.9) μmol/L, (7.3 ± 2.8) mmol/L vs. (9.3 ± 2.5) mmol/L, (2.5 ± 0.6) mg/L vs. (4.2 ± 0.7) mg/L, 1.0 ± 0.3 vs. 1.8 ± 0.5, (8.7 ± 1.1) mg/L vs. (10.6 ± 2.4) mg/L, (21.5 ± 12.7) ng/L vs. (29.5 ± 10.3) ng/L, (20.2 ± 6.1) ng/L vs. (26.6 ± 7.2) ng/L, (12.1 ± 6.9) scores vs. (17.2 ± 5.2) scores and (5.9 ± 1.8) scores vs. (6.8 ± 1.9) scores, and there were statistical differences ( P<0.05). In experimental group, there were no statistical differences in PT, APTT, TT and Fib between before treatment and after treatment ( P>0.05). The incidence of adverse reactions in experimental group was significantly lower than that in control group: 4.03%(5/124) vs. 12.90%(16/124), and there was statistical difference ( χ2 = 6.30, P<0.05). Conclusions:The urokinase along the pipeline under offline status to dissolve dialyzer microthrombus in patients undergoing CRRT is safer, cheaper and more efficient. It can improve the biocompatibility of tissue with dialyzer and pipe, prolong the use time of the dialyzer, and complete renal replacement therapy.

Objective:To investigate the clinical efficacy of botulinum toxin type A（BTX-A）bladder injection in the treatment of neurogenic detrusor overactivity（NDO）with autonomic dysreflexia（AD）.Methods:The patients with spinal cord injury at or above T6，who were treated at Guangdong Provincial Work Injury Rehabilitation Hospital from January 2018 to December 2022，were included in this study prospectively. Inclusion criteria：①chronic spinal cord injury patients over 18 years old（with no progression of neurological symptoms within 3 months）；② presence of NDO and AD；③ inadequate response or intolerance to oral antimuscarinic agent（M-receptor antagonists or β 3-receptor agonists）④ perform clean intermittent catheterization to empty the bladder. Exclusion criteria：① primary disease in the acute or progressive phase；② previous surgeries that would affect lower urinary tract function，such as transurethral sphincterotomy，bladder neck resection，prostatectomy，or bladder surgery；③ allergy to BTX-A or its adjuvants，or those with allergic predisposition ④ patients who were pregnant，breastfeeding，or planning for pregnancy in the near future；⑤ patients did not accept or were unable to perform intermittent catheterization. Before treatment，all patients were required to maintain 3-5 day urine diary，along with urodynamic studies（UDS），incontinence specific quality of life instrument（I-QOL）and AD symptom severity assessment，and blood pressure monitored. Key UDS parameters recorded included maximum bladder capacity，maximum detrusor pressure during filling phase，changes in maximum systolic blood pressure（SBP）relative to baseline（ΔSBP）during UDS examination，and the frequency of 24-hour blood pressure exceeding baseline by 20 mmHg. After general anesthesia or epidural anesthesia，BTX-A（200 U）was injected into the bladder at 30 points（including the triangle）under the cystoscope using a special injection needle，6.7 U per injection，and then the catheter was kept for 3-5 days after treatment. Three months later，relevant indicators were collected and compared with pre-treatment data. Results:A total of 43 patients were included in this study，including 34 males and 9 females. The age was（39.23±13.17）years old and the disease course was（2.69±3.27）years old. There were 33 cervical and 10 thoracic cases. The American Spinal Injury Association Injury Scale score distribution was as follows：26（60%）A，4（9%）B，9（21%）C，and 4（9%）D. The presence of AD was confirmed in all patients during urodynamic examination（UDS），that was the systolic blood pressure（SBP）suddenly increased and exceeded 20 mmHg（1 mmHg = 0.133 kPa）. Before treatment，The AD symptoms severity score（consist of headache，sweating，goose bumps，anxiety and palpitation）were（14.53±2.51），Bladder-related AD frequency was 10.67 episodes/day. Baseline SBP was（103.51±9.64）mmHg，the maximum SBP was（150.40±22.75）mmHg，and the change in SBP（ΔSBP）from maximum to baseline SBP during UDS examination was（43.83±21.01）mmHg. The UDS indicated that the maximum detrusor pressure during storage phase was（54.95±24.68）cmH 2O，and the bladder capacity was（131.70±75.29）ml. Bladder diary showed the volume of catheterization each time from was（181.16±49.86）ml，and The I-QOL score was（44.07±8.60）. Three months after treatment，the AD symptoms severity score（consist of headache，sweating，goose bumps，anxiety and palpitation）were（11.37±2.39）. The frequency of bladder-related AD episodes was（7.51±2.37）episodes/day，showing statistically significant differences compared to pre-treatment（ P<0.05）.The SBP before UDS examination was（102.12±10.28）mmHg，with no statistically significant difference from baseline（ P = 0.518）. The maximum SBP in perfusion phase and the ΔSBP were（132.84±16.30）mmHg and（28.72 ± 14.02）mmHg，respectively，both demonstrating statistically significant differences（ P < 0.05）. The UDS examination revealed that the maximum detrusor pressure during the storage phase was（29.77±13.72）cmH 2O，showed a significant decrease，and the bladder capacity was（272.63±79.75）ml，which were both statistically different before and after surgery. Bladder diary showed the volume of catheterization each time was（326.74±63.71）ml；I-QOL score was（71.86±11.45），both were significant different after treatment（ P < 0.01）. Conclusion:BTX-A intravesical injection in the treatment of NDO can also alleviate the severity and frequency of bladder related AD.

Health insurance fund regulation (HIFR) is a vital issue in the modernization of healthcare security governance, with its importance as a primary task of the healthcare security department continually reinforced in policy practice. This study focused on the 22 specialized policies issued by the National Healthcare Security Administration from its establishment in 2018 to March 2024, deeply analyzed their issue characteristics, and summarized the evolutionary trends of policy changes, as well as the knowledge production patterns that existed in the series of policy formulation, implementation, and feedback processes. Our analysis revealed that the diverse issue characteristics had led to heterogeneous directions in HIFR policies. The policy development process presented distinct composite evolutionary trends, mainly manifested in four aspects: the integration of regulatory system and content, the convergence of professional and societal forces, the parallelism of special governance and regular supervision, and the complementarity of conventional and emerging methods. Additionally, the study demonstrated that the knowledge production embedded in policy evolution encompassed four different dimensions: problem rectification, norm setting, pilot experience, and technical absorption. Together with issue characteristics and policy evolution, they formed an integrated, dynamic, and open system of knowledge production, continuously promoting the renewal and iteration of regulation policies.

Objective:This study aimed to analyze the homology between carbapenem-resistant organisms (CRO) intestinal colonization strains and bloodstream infection (BSI) strains in patients undergoing hematopoietic stem cell transplantation (HSCT), confirming the clinical use of the real-time rectal swab Xpert Carba-R assay, and investigate its feasibility in early warning of BSI.Methods:Drug-resistant strains obtained from rectal swabs and blood culture samples of patients undergoing the same HSCT from January 2021 to December 2021 were collected and analyzed. The homology of the CRO intestinal colonization and BSI strains was confirmed using strain identification, antimicrobial resistance phenotyping, whole genome sequencing (WGS), multilocus sequence typing (MLST), and carbapenemase type identification. Rectal swab cultures and the real-time rectal swab Xpert Carba-R assay were conducted concurrently on patients with HSCT from August 2021 to August 2022. The accuracy of the real-time rectal swab Xpert Carba-R assay was confirmed with the sequencing results of polymerase chain reaction amplification products of the carbapenemase gene from purified colonies as a reference standard.Results:This study included 24 CRO strains from 10 patients undergoing HSCT, including 14 intestinal colonizers and 10 CRO-BSI strains. The results revealed that the CRO intestinal colonization strains and CRO-BSI strains from the same patient and their carbapenemase genes were almost identical. Additionally, WGS revealed that CRO intestinal colonization and CRO-BSI strains from the same patient were more closely related than strains from different patients. Additionally, this study included 488 rectal swab specimens from 184 patients undergoing HSCT, with CRO detection rates of 16.4% for rectal swab culture and 18.4% for the real-time rectal swab Xpert Carba-R assay. The overall sensitivity, specificity, and positive and negative predictive values of the real-time rectal swab Xpert Carba-R assay were 96.6%, 72.8%, 90.6%, and 88.9%, respectively.Conclusions:A high degree of homology was found between the CRO intestinal colonization strains and the CRO-BSI strains in patients undergoing HSCT. The real-time rectal swab Xpert Carba-R assay is a reliable and convenient method for detecting common carbapenemase genes, serving as an alternative to rectal swab culture for early warning of CRO-BSI.

Objective:This study aimed to analyze the homology between carbapenem-resistant organisms (CRO) intestinal colonization strains and bloodstream infection (BSI) strains in patients undergoing hematopoietic stem cell transplantation (HSCT), confirming the clinical use of the real-time rectal swab Xpert Carba-R assay, and investigate its feasibility in early warning of BSI.Methods:Drug-resistant strains obtained from rectal swabs and blood culture samples of patients undergoing the same HSCT from January 2021 to December 2021 were collected and analyzed. The homology of the CRO intestinal colonization and BSI strains was confirmed using strain identification, antimicrobial resistance phenotyping, whole genome sequencing (WGS), multilocus sequence typing (MLST), and carbapenemase type identification. Rectal swab cultures and the real-time rectal swab Xpert Carba-R assay were conducted concurrently on patients with HSCT from August 2021 to August 2022. The accuracy of the real-time rectal swab Xpert Carba-R assay was confirmed with the sequencing results of polymerase chain reaction amplification products of the carbapenemase gene from purified colonies as a reference standard.Results:This study included 24 CRO strains from 10 patients undergoing HSCT, including 14 intestinal colonizers and 10 CRO-BSI strains. The results revealed that the CRO intestinal colonization strains and CRO-BSI strains from the same patient and their carbapenemase genes were almost identical. Additionally, WGS revealed that CRO intestinal colonization and CRO-BSI strains from the same patient were more closely related than strains from different patients. Additionally, this study included 488 rectal swab specimens from 184 patients undergoing HSCT, with CRO detection rates of 16.4% for rectal swab culture and 18.4% for the real-time rectal swab Xpert Carba-R assay. The overall sensitivity, specificity, and positive and negative predictive values of the real-time rectal swab Xpert Carba-R assay were 96.6%, 72.8%, 90.6%, and 88.9%, respectively.Conclusions:A high degree of homology was found between the CRO intestinal colonization strains and the CRO-BSI strains in patients undergoing HSCT. The real-time rectal swab Xpert Carba-R assay is a reliable and convenient method for detecting common carbapenemase genes, serving as an alternative to rectal swab culture for early warning of CRO-BSI.

Ischemic preconditioning (IPC) is a potential intervention known to protect the heart against ischemia/reperfusion injury, but its role in the no-reflow phenomenon that follows reperfusion is unclear. Dihydrotanshinone I (DT) is a natural compound and this study illustrates its role in cardiac ischemic injury from the aspect of IPC. Pretreatment with DT induced modest ROS production and protected cardiomyocytes against oxygen and glucose deprivation (OGD), but the protection was prevented by a ROS scavenger. In addition, DT administration protected the heart against isoprenaline challenge. Mechanistically, PKM2 reacted to transient ROS via oxidization at Cys423/Cys424, leading to glutathionylation and nuclear translocation in dimer form. In the nucleus, PKM2 served as a co-factor to promote HIF-1α-dependent gene induction, contributing to adaptive responses. In mice subjected to permanent coronary ligation, cardiac-specific knockdown of Pkm2 blocked DT-mediated preconditioning protection, which was rescued by overexpression of wild-type Pkm2, rather than Cys423/424-mutated Pkm2. In conclusion, PKM2 is sensitive to oxidation, and subsequent glutathionylation promotes its nuclear translocation. Although IPC has been viewed as a protective means against reperfusion injury, our study reveals its potential role in protection of the heart from no-reflow ischemia.

Objective     To investigate the current status of constipation during postoperative hospitalization and the factors associated with moderate to severe constipation at discharge in lung cancer patients. Methods     Lung cancer patients who underwent surgery in 6 tertiary hospitals in Sichuan Province from November 2017 to January 2020 were enrolled. The MD Anderson Symptom Scale-Lung Cancer Module was used to collect postoperative constipation scores. Unconditional logistic stepwise regression was used to analyze the related influencing factors for moderate to severe constipation on the day of discharge. Results     Finally 337 patients were collected. There were 171 males and 166 females, with an average age of 55.0±10.3 years. Constipation scores of lung cancer patients increased from postoperative day 1 to day 3, and showed a decreasing trend from day 3 to day 7. Moderate to severe constipation was present in 68 (20.2%) patients at discharge. The postoperative hospital stay (OR=0.743, P<0.001) and the dose of morphine used during postoperative hospitalization (OR=1.002, P=0.015) were influencing factors for moderate to severe constipation at discharge in lung cancer patients. Conclusion    Lung cancer patients have the most severe constipation on postoperative day 3. Moderate to severe constipation at discharge is associated with the postoperative hospital stay and the dose of morphine used during postoperative hospitalization.

Objective:To explore the efficacy and safety of anti-B cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) for the retreatment of relapsed and refractory multiple myeloma (RRMM).Methods:The clinical data of 10 RRMM patients who received anti-BCMA CAR-T therapy for the second time (CART2) in Henan Province Hospital of Traditional Chinese Medicine due to failure or recurrence after their first anti-BCMA CAR-T (CART1) therapy from January 2017 to June 2021 were retrospectively analyzed. The treatment, efficacy and adverse events of patients receiving CART2 therapy were summarized; and the objective response rate (ORR), median duration of response (DOR) and incidence of adverse reactions were compared between CART1 and CART2.Results:Among 10 patients, 8 were males and 2 were females, with a median age of 57 years (41-70 years). Patients' 3-month ORR after CART1 therapy was 90%, and the median DOR was 16.0 months (3.0-27.0 months). CART2 used human-derived anti-BCMA CAR-T to treat 6 cases and mouse-derived anti-BCMA CAR-T to treat 4 cases. The 3-month ORR of patients receiving CART2 therapy was 40%, and the median DOR was 8.5 months (3.0-11.0 months). Among 9 patients who received mouse-derived anti-BCMA CAR-T in CART1 therapy, 4 of them received the same product again and none of them showed curative effect. Among 6 patients retreated with human-derived anti-BCMA CAR-T, 4 patients (66.7%) of them achieved partial remission (PR) or better. During CART1 therapy, 10 patients developed grade 1-2 cytokine release syndrome (CRS), and 7 patients developed different degrees of decrease in leukocyte, neutrophil absolute count (ANC) and platelet. Among patients who achieved effective outcomes after receiving CART2 therapy, 4 patients of them developed grade 1-2 CRS, and different degrees of decrease in white blood cell, ANC and thrombocytopenia. Immune effector cell-related neurotoxicity syndrome was not observed.Conclusions:Anti-BCMA CAR-T is effective and safe to retreat RRMM. The ORR and DOR of patients receiving CART2 therapy are lower than those of patients receiving CART1 therapy. CRS and cytopenia are common adverse reactions.