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Results | PMC10511465 | |||
Pseudovirus neutralization potencies | Pseudovirus microneutralization assays were performed as previously describedPseudovirus neutralization potencies of NAS. | PMC10511465 | ||
Biocompatibility assessment | A biocompatibility assessment was performed, which included several in vitro and in vivo studies (Fig. Biocompatibility study of NAS. | PMC10511465 | ||
Circulatory levels of human IgG1 anti-SARS-CoV-2 antibodies after intranasal application of NAS | In order to assess the potential systemic effects of intranasal application of NAS, quantitative measurement of human IgG1 anti-SARS-CoV-2 antibodies after intranasal application of NAS was determined in rats. A single dose of NAS (20 µg/kg) was intranasally applied to 10-week-old female Sprague–Dawley rats (n=13). This dose was calculated based on the intended single-use amount in humans (2 µg/kg) multiplied by a human-to-rat conversion factor of ten | PMC10511465 | ||
Safety of NAS application | inflammation | CHRONIC RHINOSINUSITIS, INFLAMMATION, ADVERSE EVENTS, ALLERGIC RHINITIS, ADVERSE EVENT | To evaluate the safety and tolerability of NAS, 38 healthy volunteers were enrolled (Fig. Study flow chart. Thirty-eight healthy volunteers were enrolled to evaluate the safety and detect intranasal neutralizing antibodies before and after a placebo or NAS application. Thirty-six volunteers were randomized into a 1:3 ratio to receive a placebo (n=9) and NAS (n=27), while the other 2 were excluded due to nasal polyps. Safety was assessed using sinuscopy, adverse event recording, and self-reporting questionnaires. SARS-CoV-2 neutralizing antibodies were detected in the nasal fluids taken from volunteers pre- and post-administration.Baseline characteristics of participants in the study.Representative nasal sinuscopy images after NAS application. The participants’ nasal sinus in both nostrils was imaged using a sinuscope on days 0, 7, and 14. No inflammation signs or any appearance changes were observed.Safety assessment via nasal sinuscopy.SNOT-22 and TNSS questionnaires were used to evaluate nasal symptoms throughout the 2 weeks of the study period. These questionnaires have been validated for patient-reported outcomes of chronic rhinosinusitis, allergic rhinitis, and other sinonasal outcomesSelf-reported symptoms by SNOT-22 questionnaire (14-day accumulative events).SNOT-22 score: 0 = No problem, 1 = Very mild problem, 2 = Mild or slight problem, 3 = Moderate problem, 4 = Severe problem, or 5 = Problem as bad as it can be.Self-reported symptoms by TNSS questionnaire (14-day accumulative events).TNSS score: 0 = None, 1 = Mild, 2 = Moderate, or 3 = Severe.Additionally, treatment-emergent adverse events (TEAEs) were evaluated over 14 days of the study. No adverse events were reported from participants in either group (Table Self-reported treatment emergent adverse events (TEAEs). | PMC10511465 |
Detection of SARS-CoV-2 neutralizing antibodies in nasal fluids | VIRUS | Nasal fluid was collected by swabbing from both nostrils before and immediately or 6 h after the study product application in both the NAS and placebo groups (see Fig. Assessment of SARS-CoV-2 neutralizing antibodies in nasal fluids before and after a placebo or NAS application. SARS-CoV-2 neutralizing antibodies in nasal fluids swabbed from pre- and post-product administration were detected using the cPass SARS-CoV-2 surrogate virus neutralization test. (The neutralizing antibodies against ancestral, Delta, or Omicron BA.2 RBD proteins were detected based on the signal inhibition percent (SIP) of the cPass assay. The SIP values against the ancestral variant in the nasal fluid from the NAS group were significantly increased from baseline at both time points (median of baseline vs. immediate time point: 12.41% vs. 97.58%; | PMC10511465 | |
Discussion | toxicity | VIRUS, ADVERSE EVENTS, INFLAMMATION, CAVITY, CYTOTOXICITY | NAS is a medical device innovated to support mucosal immunity against SARS-CoV-2 via a dual mechanism of action in which a potent broadly neutralizing human IgG1 anti-SARS-CoV-2 monoclonal antibody cocktail produces inhibitory effects against multiple variants of concern (VOCs) in nasal fluid, and a steric barrier-forming agent, HPMC, fortifies the mucus layer. NAS exhibited broadly neutralizing activities against SARS-CoV-2 pseudoviruses of ancestral, Alpha, Delta, Omicron BA.1, BA.2, BA.4/5, and BA.2.75 variants. To evaluate the safety and efficacy of NAS, preclinical studies were conducted following the ISO 10993 standards of medical devices. These studies showed good biocompatibility based on cytotoxicity, skin sensitization, and intracutaneous reactivity evaluations as well as satisfactory safety profiles by both acute and subacute systemic toxicity investigations. In animal studies, intranasal administration of NAS did not result in any detection of human IgG1 anti-SARS-CoV-2 antibodies in the bloodstream of rats at any time point during the 120 h of follow-up. This finding agrees with the knowledge that the nasal epithelial barrier only allows the passage of molecules smaller than 1000 DaThe randomized, placebo-controlled trial was conducted to assess the tolerability and effects of intranasal administration of NAS in 36 healthy participants. The trial revealed that NAS was well tolerated, without any changes in nasal mucosa appearance, any signs of inflammation, or any treatment-emergent adverse events for the entire 14 days of the study. Recently, the neutralizing antibody level in nasal fluids has been shown to correlate with the potential protective effects against Omicron infectionThe formulation of the NAS appears to be a significant factor contributing to its efficacy. This nasal spray uses HPMC, a compound commonly employed in pharmaceutical applications, especially as a viscosity enhancer that helps extend the retention time of the antibodies in the nasal cavity by reducing mucociliary clearanceNasal sprays with antibodies hold potential for protecting individuals at risk of virus exposure according to the classic susceptible-exposed-infectious-removed (SEIR) mathematical modelWhile NAS shows promise in supporting mucosal immunity against SARS-CoV-2, it is important to acknowledge its limitations. Widespread and long-term administration of nasal sprays with antibodies poses logistical challenges. Additionally, relying solely on intranasal antibody prophylaxis cannot prevent the widespread transmission of the virus within a community. Therefore, NAS should be used in conjunction with other protective measures, such as non-pharmaceutical interventions, to fill the gap during the time needed to develop and manufacture effective vaccines. This approach can complement active immunization strategies and provide an additional layer of protection.Collectively, NAS has shown safety and efficacy in increasing neutralizing antibodies in nasal fluids. However, to fully demonstrate the effectiveness of NAS in preventing COVID-19, a large-scale efficacy trial measuring COVID-19 incidence would be necessary. Further research and evaluation are needed to determine the potential role of NAS as a complementary tool in the fight against SARS-CoV-2. | PMC10511465 |
Methods | PMC10511465 | |||
Study product | Nasal Antibody Spray or NAS is an HPMC-based nasal spray solution containing human IgG1 anti-SARS-CoV-2 monoclonal antibodies, clones 1D1 and 3D2 | PMC10511465 | ||
Pseudovirus-based neutralization assay | Lentiviral pseudoviruses containing SARS-CoV-2 spike were produced with slight modifications, as previously described by Di Genova et al.To assess the neutralizing activities of Nasal Antibody Spray, a two-fold serial dilution of the NAS was conducted in a culture medium starting at a ratio of 1:40 (high-glucose DMEM without FBS). In a 96-well culture plate, the diluted samples were mixed with pseudoviruses bearing the SARS-CoV-2 spike of interest at a 1:1 v/v ratio. The input pseudovirus was adjusted to 1 × 10 | PMC10511465 | ||
Biocompatibility testing | toxicity | CYTOTOXICITY | The biocompatibility of NAS was evaluated by the following 5 assessments conforming to the standards of medical devices (ISO 10993-5:2009, ISO 10993-10:2021, ISO 10993 Part 23: 2021, and ISO 10993-11:2017): (1) in vitro cytotoxicity using the direct contact method, (2) skin sensitization using the guinea pig maximization test, (3) intracutaneous reactivity potentials in New Zealand white rabbits, (4) acute systemic toxicity study via oral administration in mice, and (5) 28-day subacute systemic toxicity study via oral administration in rats (see details in | PMC10511465 |
Enzyme-linked immunosorbent assay (ELISA) | ELISA was employed to quantify human IgG1 anti-SARS-CoV-2 antibody levels in the circulation after intranasal application of NAS in rats. In brief, rat serum samples diluted in 3% BSA in PBS buffer at a 1:10 dilution were added (100 µl/well) to an ELISA plate coated with 100 ng/well of Delta-variant RBD proteins (40592-V08H90, Sino Biological). Human IgG1 anti-SARS-CoV-2 antibodies were detected with goat anti-human IgG Fcγ-HRP antibody (109-005-098, Jackson Immuno Research) diluted 1:2,000 in 3% BSA in PBS buffer. The SIGMA | PMC10511465 | ||
Clinical study design | This study was designed as a single-center, double-blind, randomized, placebo-controlled trial to evaluate the safety, tolerability, and clinical performance of NAS in healthy volunteers. | PMC10511465 | ||
Ethical considerations | This study was approved by the Ethics Committee of the Department of Medical Services, Ministry of Public Health, Thailand (Approval No. 0001/2565, approval date: 12/04/2022) and registered with the ClinicalTrials.gov; Date of first registration: 03/05/2022; Registration number: NCT05358873. All procedures were performed following the principles of the Declaration of Helsinki and the ICH-GCP guidelines. All participants provided written informed consent before the commencement of the study and voluntarily participated in this clinical trial. | PMC10511465 | ||
Participants | We calculated the sample size based on previous recommendationsTo ensure an adequate sample size in case participants dropped out, we added 4 more participants to attain the total number of 36 participants. Healthy volunteers interested in participating in the study were screened according to the inclusion and exclusion criteria described on ClinicalTrials.gov (NCT05358873).All volunteers were randomly assigned in a 1:3 ratio into 2 groups: placebo (n = 9) and NAS (n = 27), as shown in Fig. | PMC10511465 | ||
Product application | NAS and normal saline solution (placebo) were produced, packaged, and labeled with a double-blind, randomized code by the Government Pharmaceutical Organization (GPO), Ministry of Public Health, Thailand. Each participant was randomly assigned to receive either NAS or a placebo. Site staff gave participants instructions on the study product application, storage, and return. In brief, a trained nurse administered the study products into the nostrils of all participants for the first application to ensure that the correct dosage was delivered and that the application technique was consistent across all participants allowing for direct observation and immediate feedback to ensure proper administration by all participants. The participants were then instructed to self-administer the study products by spraying two puffs into their nostrils (100 µl per puff) thrice daily at 8 am, 2 pm, and 8 pm for 7 days. The training ensures that participants understand the correct technique, dosage, and frequency of administration. The volume and frequency of the study product application were based on reports of other nasal spray products containing anti-SARS-CoV-2 antibodies | PMC10511465 | ||
Safety evaluation | ADVERSE EVENTS | Safety was assessed based on nasal sinuscopy examination, treatment-emergent adverse events (TEAEs), and Sino-Nasal Outcome Test-22 (SNOT-22) and Total Nasal Symptom Score (TNSS) questionnaires | PMC10511465 | |
SARS-CoV-2 surrogate virus neutralization test | VIRUS | SARS-CoV-2 surrogate virus neutralization test in nasal fluid specimens against the ancestral, Delta, and Omicron BA.2 HRP-conjugated RBD proteins were determined using a SARS-CoV-2 surrogate virus neutralization test (cPass SARS-CoV-2 neutralization antibody detection kit, GenScript; A02087, Z03614, and Z03741). Nasal fluid specimens were diluted ~ tenfold in sample dilution buffer, and then the SARS-CoV-2 inhibitory effects were measured according to the instruction manual and reported as % inhibition against SARS-CoV-2. | PMC10511465 | |
Statistical analysis | For the safety assessments of NAS, an unpaired two-tailed Mann–Whitney U test was used, and Dunn’s test was applied for multiple testing corrections. For the assessments of intranasal SARS-CoV-2 inhibitory effects of NAS, the difference in % inhibition before and after the study product applications was compared using a one-tailed Wilcoxon signed-rank test. | PMC10511465 | ||
Supplementary Information |
Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.Supplementary Information 4.Supplementary Information 5. | PMC10511465 | ||
Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-42539-7. | PMC10511465 | ||
Acknowledgements | Data collection and analysis were supported by Ever Medical Technology Co., Ltd. (Thailand). | PMC10511465 | ||
Author contributions | Conceptualization: T.I., C.B., T.Pisitkun, A.J., and P.A.; Project administration: T.I., S.B., C.B., T.Pisitkun, and S.A.; Funding acquisition: C.B. and T.Pisitkun; Methodology: T.I., T.J., N.Pojdoung, N.Meesiripan, S.Sakarin, C.B., T.W., T.Phakham, T.A., C.A., P.S., P.M., M.X.T., S.Tongchusak, C.S., W.R., Q.D.L., S.D.P., K.V., S.N., K.S., R.V., N.Pesirikan, L.N., J.P., T.N., B.M., K.C., P.A., K.A., P.P., P.O., S.Sirilak, B.U., S.Sapsutthipas, S.Trisiriwanich, T.S., A.U., N.Mingngamsup, and S.P.; Data curation: T.I., C.B., T.W., T.A., T.Phakham, C.A., L.W., and C.S.; Data analysis: T.I., C.B., T.W., T.Phakham, T.A., C.A., T.Pisitkun, L.W., and C.S.; Statistical analysis: C.B., T.W., T.Phakham, and T.Pisitkun; Illustrations: T.W. and T.Phakham; Writing–review & editing manuscript: T.I., C.B., T.Phakham, C.A., B.S., A.J., and T.Pisitkun; Access to all data: T.I., C.B., and T.Pisitkun. All authors reviewed the manuscript. | PMC10511465 | ||
Funding | This study was sponsored by HIBIOCY Co., Ltd. and funded by the Program Management Unit Competitiveness (PMU-C), Ministry of Higher Education, Science, Research and Innovation, Thailand (Grant No. C10F650051). The funders had no role in the conceptualization, conduct, or interpretation of this work. | PMC10511465 | ||
Data availability | All data generated or analyzed during this study are included in this published article. | PMC10511465 | ||
Competing interests | The authors declare no competing interests. | PMC10511465 | ||
References | PMC10511465 | |||
Abstract | PMC9873524 | |||
Background | stroke, hemiplegic, task‐based | STROKE | Motor imagery training (MIT) has been widely used to improve hemiplegic upper limb function in stroke rehabilitation. The effectiveness of MIT is associated with the functional neuroplasticity of the motor network. Currently, brain activation and connectivity changes related to the motor recovery process after MIT are not well understood.Aim: We aimed to investigate the neural mechanisms of MIT in stroke rehabilitation through a longitudinal intervention study design with task‐based functional magnetic resonance imaging (fMRI) analysis. | PMC9873524 |
Methods | stroke, upper limb motor impairment | STROKE | We recruited 39 stroke patients with moderate to severe upper limb motor impairment and randomly assigned them to either the MIT or control groups. Patients in the MIT group received 4 weeks of MIT therapy plus conventional rehabilitation, while the control group only received conventional rehabilitation. The assessment of Fugl‐Meyer Upper Limb Scale (FM‐UL) and Barthel Index (BI), and fMRI scanning using a passive hand movement task were conducted on all patients before and after treatment. The changes in brain activation and functional connectivity (FC) were analyzed. Pearson's correlation analysis was conducted to evaluate the association between neural functional changes and motor improvement. | PMC9873524 |
Results | The MIT group achieved higher improvements in FM‐UL and BI relative to the control group after the treatment. Passive movement of the affected hand evoked an abnormal bilateral activation pattern in both groups before intervention. A significant | PMC9873524 | ||
Conclusions | stroke, upper limb motor impairments | STROKE | MIT could help decrease the compensatory activation at both hemispheres and reshape the FC within the ipsilesional hemisphere along with functional recovery in stroke patients.The neural mechanism of motor imagery training in stroke patients with moderate to severe upper limb motor impairments was investigated using task‐based fMRI. The results revealed that motor imagery training during motor recovery decreased overaction at both hemispheres and reorganized the motor network within the ipsilesional hemisphere.
Hewei Wang and Xin Xiong contributed equally to this work. | PMC9873524 |
INTRODUCTION | stroke, upper limb impairment, Stroke, long‐term adult disability | STROKE, STROKE | Stroke represents a major cause of long‐term adult disability worldwide.Mental practice of movements, also known as motor imagery training (MIT), has attracted much interest for its potential for neurorehabilitation to improve upper limb function.Neural plasticity forms the intrinsic basis of neurorehabilitation for modern rehabilitation medicine and has been applied in restoring motor functions after stroke. Recently, motor task‐based neuroimaging studies have demonstrated that motor relearning is accompanied by reorganizing of motor networks.Passive movements are an alternative to the task of active movements. An fMRI study showed that an active or passive palm‐finger brushing task produced broadly equivalent brain activation in the sensorimotor areas in healthy adults.In addition to the activation analysis, the functional connectivity (FC) analysis may provide more information about the mechanism underlying the treatment effects of MIT at the brain network level. Simple task‐related brain activity is frequently more intensive and with a broader range of activation in stroke patients than in healthy controls, while more complex tasks usually involve lower levels of cortical activity.To deepen our understanding of the neural mechanism of MIT in stroke patients with poor motor function, we recruited patients with moderate to severe upper limb impairment and adopted a passive hand movement task for fMRI scanning. We hypothesized that in this major target patient population, the efficacy of MIT is associated with specific reorganizations in the motor network, which we aimed to reveal in this study from brain activation and seed‐based FC analyses. | PMC9873524 |
METHODS | PMC9873524 | |||
Patients and interventions | Spasticity, spasticity, cognitive impairment, stroke, apraxia, pain, aphasia, hemorrhage, first‐ever stroke, upper extremity motor function, excessive sensory disturbance, hand hemiplegia, infarct | MULTIPLE ORGAN FAILURE, STROKE, HEMORRHAGE, INFARCT, MALIGNANT DISEASE | This study was a randomized, single‐blind, controlled trial conducted at Huashan Hospital in Shanghai, China. All potential participants were screened by the physicians for eligibility. Each participant signed a written informed consent before participation. This study was approved by the Review Board of Ethics Committee of Huashan Hospital and registered at the Chinese Clinical Trial Registry (ChiCTR‐TRC‐08003005). The study design and protocol are shown in a flow diagram according to CONSORT guidelines (Figure. CONSORT flow diagram of the study designInclusion criteria: (1) first‐ever stroke (infarct or hemorrhage); (2) stroke onset between 3 and 12 months before enrollment for the study; (3) no significant cognitive impairment (Mini‐Mental State Examination ≥ 27); (4) age between 18 and 80 years; (5) unilateral upper limb and hand hemiplegia (Brunnstrom stage ≤ grade IV); and (6) right‐handed before stroke according to the Edinburgh Handedness scale.Exclusion criteria: (1) severe spasticity (Modified Ashworth Spasticity Scale > 2) of the affected upper extremity; (2) significant pain on the affected side (Ten‐point Visual Analog Scale > 4); (3) excessive sensory disturbance, aphasia, neglect, or apraxia; (4) active malignant disease or multiple organ failure; (5) presently enrolled in any other rehabilitation or drug studies.The sample size was calculated before the start of the study using the stepped rules of thumb for pilot trials.All recruited patients were randomly assigned to one of the two groups, that is, the control group (CON group, All patients underwent rehabilitation interventions 5 days a week for 4 weeks. Daily interventions included 3 h of conventional rehabilitation therapy and 30 min of group‐specific treatments; motor imagery training for the MIT group and health education on stroke information or patient–physician consultation for the CON group.All the patients were assessed for upper extremity motor function and activities of daily living by an independent physician blinded to the treatment condition, before and after the 4‐week interventions. The primary outcome measure was the Upper Extremity Fugl‐Meyer score which is a valid and reliable tool for evaluating upper limb motor level within and between raters in stroke survivors, | PMC9873524 |
fMRI data acquisition | ischemia, stroke, hemorrhage, clench | STROKE, HEMORRHAGE, ISCHEMIA | T1‐ and T2‐weighted structural and task‐based functional images were acquired on a 3 T MRI scanner (Siemens) at Shanghai Key Laboratory of Magnetic Resonance. T1‐weighted images were obtained using a magnetization‐prepared rapid gradient echo sequence (TR = 1900 ms, TE = 3.42 ms, TI = 900 ms, FOV = 240 × 240 mmThe fMRI scanning included two sessions, each with the affected and unaffected hands performing passive finger flexion–extension tasks. A 6 s dummy scan was performed at the start of each session to stabilize the BOLD signal, which was then discarded in the subsequent analysis. A block design was then adopted with 5 rest blocks and 5 task blocks in each session (10 volumes/30 s for each block). During each task block, passive movements were conducted with an experimenter who was blinded to the treatment condition. The experimenter was instructed to clench the hands of the subject into a fist following a voice prompt at 1 Hz under stable movement amplitude (Figure Block design for task‐based fMRI. The patients clutched their hands passively at 1 Hz with the help of an experimenter. An air‐filled rubber bulb was placed in the patient's hand to maintain consistency in movement amplitude. A total of 10 blocks including 5 REST and 5 TASK were adopted for the tb‐based fMRI. Each block spanned for 30 s. R, REST; T, TASKDemographic and clinical information for the stroke patients0.709(0.124(0.643(0.455(0.131(1.000(0.644(0.052(Abbreviations: BG, basal ganglia; CO, centrum ovale; CON, control group; CR, corona radiate; F, female; FM‐UL‐1, Fugl‐Meyer Assessment Upper Limb subscale before intervention; FM‐UL‐2, Fugl‐Meyer Assessment Upper Limb subscale after the intervention; H, hemorrhage; I, ischemia; IC, internal capsule; L, left; M, male; MIT, motor imagery training group; R, right; Tha, thalamus. | PMC9873524 |
fMRI preprocessing | Images of the patients with left‐sided lesions were flipped before preprocessing. After flipping, the right hemisphere was tagged as the ipsilesional side and the left hemisphere as the contralesional side. fMRI preprocessing was carried out using DPARSF, | PMC9873524 | ||
Activation and FC analysis | A general linear model (GLM) was set for each individual in SPM first‐level statistical analysis to estimate the task‐related activation by contrasting passive movement and rest conditions (Passive movement > Rest). In this model, head motion in the six directions estimated in the preprocessing was added as a regressor of no interest.In addition to activation analysis, seed‐based FC analysis was performed with the CONN toolbox. | PMC9873524 | ||
Statistical analysis | stroke | STROKE | The normality of variables (age, days after stroke onset, lesion volume, FM‐UL, and BI score) was tested by Shapiro–Wilk's test, showing that none of these variables conform to the normal distribution. Group differences were tested by chi‐square tests on sex, stroke type, and lesion side, and Mann–Whitney Voxel‐wise 2 × 2 ( | PMC9873524 |
RESULTS | PMC9873524 | |||
Clinical outcome | Detailed demographic and clinical data for the patients are shown in Table Improvement in FM‐UL score after rehabilitation in the motor imagery training group (MIT) and control group (CON). (A) FM‐UL score before and after rehabilitation in the two groups; (B) Comparison of FM‐UL improvement between the two groups; (C, D) Correlations between FM‐UL improvement (ΔFM‐UL) and FM‐UL score before intervention in the CON (C) and MIT (D) groups. Error bars indicate standard deviation, **To investigate the dependency of the treatment efficacy of motor imagery training on preserved motor ability, we analyzed the correlation between the improvement in FM‐UL score and the baseline FM‐UL score before rehabilitation. Spearman's correlation revealed a significant correlation in the CON group ( | PMC9873524 | ||
Brain activation to passive movements | Twenty‐nine | BRAIN | Twenty‐nine patients (15 in the MIT group and 14 in the CON group) who had completed task‐fMRI scanning before and after intervention and with good image quality were included in the fMRI analysis.The general activation to passive movements of the affected/unaffected hand is shown in Figure Brain activation in response to hand passive movements. (A‐D) Brain activation in response to passive movement of the unaffected hand before and after intervention in the CON group and MIT group; (E‐H) Brain activation in response to passive movement of the affected hand before and after intervention in the CON and MIT groups. All clusters are significant at voxel‐level uncorrected ANOVA and correlation analysis results are shown in Figure Alterations in brain activation in response to passive movement of the affected hand between the MIT and CON groups. (A) Brain regions in which activation exhibited significant Group × Time interactions (threshold‐free cluster enhancement [TFCE] corrected | PMC9873524 |
Functional connectivity | BRAIN | The two clusters mentioned above, showing significant Changes in functional connectivity (FC) with the ipsilesional precentral cluster between MIT and CON groups. (A) Brain regions in which FC showed significant Group × Time interactions (threshold‐free cluster enhancement [TFCE] corrected When taking the cluster in the contralesional S1 as the seed, no FC with both significant | PMC9873524 | |
DISCUSSION | excessive head motion, stroke, upper limb motor recovery, upper limb motor function, hand motor tasks | STROKE, CORTEX | Emerging neuroimaging studies have identified neuroimaging biomarkers of functional recovery in stroke patients.The activation of the passive movement of the affected hand showed an abnormal bilateral activation pattern compared with the contralateral‐lateralized activation of the passive movement of the unaffected hand. When stroke patients passively moved the unaffected hand, the activation focused on the contralateral sensorimotor cortex (contralesional M1, S1, SMA) and ipsilateral (ipsilesional) cerebellum, presenting a typical activation pattern that was similar to cortical representation for hand motor tasks in healthy individuals.After MIT, the compensatory activation of bilateral sensorimotor networks decreased. The decrease was associated with the adjunctive efficacy of MIT. The activation of the passive movement of the affected hand in the contralesional S1 and ipsilesional M1 decreased significantly after the intervention in the MIT group compared with the control group. Correlation analyses further demonstrated that decreased activation in these two areas was significantly negatively correlated with FM‐UL improvement. These findings suggest that the withdrawal of bilateral compensation was associated with better motor recovery in the MIT group. Previous studies have suggested that although the temporary compensatory activation could support the functional improvement in the acute and subacute phases after stroke, in the long run, overreliance on compensatory brain activation may hinder the recovery of motor ability.Moreover, it was observed that the effects of MIT were found only on the brain activation of the affected hand and had no effect on the unaffected hand. The findings indicate that the training‐induced brain plasticity was restricted to BOLD responses of the MIT‐targeted hand since patients were only instructed to imagine moving the hand and upper limb at the affected side during the training. Likewise, TMS studies have revealed that the increase in cortico‐spinal excitability is specific to the muscles involved in the imagined movement.MIT potential mechanisms for stroke treatment may also associate with the changes in FC with the ipsilesional M1. The FC of the ipsilesional M1 significantly decreased in the ipsilesional IPL and increased in the ipsilesional putamen after MIT but remained unchanged after sole CRT. The change in these FCs was significantly correlated with FM‐UL improvement. The change of FC patterns indicated that the remodeling of activation time course synchronization mainly occurred within the damaged hemisphere and reflected the possible neural substrate underlying the rehabilitation effects of MIT on the motor functions of the patient. Similarly, change in FC has been observed in a resting‐state fMRI study. Zhang et al.The IPL of the human brain is engaged in numerous mental processes such as visuospatial attention, memory, and mathematical cognition.The enhanced FC resulting from MIT therapy might improve upper limb fine movements, creating a positive correlation between FM‐UL improvement and change in FC relative to the ipsilesional putamen. The lentiform nucleus comprises putamen and globus pallidus which combine with the caudate nucleus to shape the striatum. The striatum receives afferent input from different parts of the cortex and sends efferent output to the cortex through the thalamus.The current study has several limitations that should be noted. Firstly, the FM‐UL was used as the only clinical assessment of upper limb motor function. Thus, additional comprehensive assessments, such as the Wolf Motor Function Test, Action Research Arm Test, and Box and Block Test, should be applied in future studies to improve the interpretation of results. Secondly, we calculated the sample size based on our preliminary data and related studies. However, only 29/39 patients with complete fMRI data were included in the analysis due to the dropout and excessive head motion during MRI scanning. Therefore, more participants should be recruited in the future to increase the validity of the results. Thirdly, our results indicated that the contralesional S1, the ipsilesional M1, IPL, and putamen were key sensorimotor nodes which correlated with upper limb motor recovery after MIT. Although these brain areas modulate motor planning, motor execution, and motor learning, it remains unclear whether these nodes participate in neuromodulation when combined with MIT. In the future, an intervention study combining MIT and noninvasive brain stimulation is advocated to promote the development of novel treatment paradigms to improve stroke recovery. | PMC9873524 |
CONCLUSION | stroke, upper limb motor impairments | STROKE | In conclusion, this is an inaugural study that uses task‐based fMRI to investigate the neural mechanism of MIT in stroke patients with moderate to severe upper limb motor impairments. This work expands our understanding of the effects of MIT on brain reorganization both at the activation and brain network levels. Besides, our findings demonstrate that MIT can decrease overaction at both hemispheres and reorganize the motor network within the ipsilesional hemisphere, thereby promoting upper limb motor function during stroke recovery. | PMC9873524 |
AUTHOR CONTRIBUTIONS | LMS, HWW | LMS and XLG were involved in the development and design of the study concept; CHS, BZ, and YMX were involved in intervention and assessment; XX, KXZ, XW, MXF, and SBT were involved in data acquisition and analysis; HWW and XX contributed to the initial manuscript writing. All authors revised and agreed to the final version of this article. | PMC9873524 | |
CONFLICT OF INTEREST | All the authors declared no conflicts of interest. | PMC9873524 | ||
Supporting information |
Table S1‐S3
Click here for additional data file. | PMC9873524 | ||
ACKNOWLEDGMENTS | This work was supported by the National Natural Science Foundation of China (No. 81974356, No.61771313, and No.82102665), the National Key R&D Program of China (2020YFC2004200), and the Shanghai Sailing Program (No.21YF1404600). The sponsor played no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript. The authors are indebted and thank all patients for participating in this study, Dr. Jerry for English revision, and Ms. Yefan Cao for assistance on figure drawing. | PMC9873524 | ||
DATA AVAILABILITY STATEMENT | The data that support the findings of this study are available from the corresponding author upon reasonable request. | PMC9873524 | ||
REFERENCES | PMC9873524 | |||
Purpose | Edited by: Sheikh Mohd Saleem, Ministry of Health and Family Welfare, IndiaReviewed by: György Purebl, Semmelweis University, Hungary; Yanfeng Wang, Xiangya Hospital, Central South University, ChinaThis article was submitted to Public Mental Health, a section of the journal Frontiers in Public Health†These authors have contributed equally to this workSuicide is a global concern, especially among young people. Suicide prediction models have the potential to make it easier to identify patients who are at a high risk of suicide, but they have very little predictive power when there is a positive value for suicide mortality. Therefore, the aim of the study is to uncover potential risk factors associated with suicide by self-poisoning and further to provide a trustworthy nomogram to predict self-poisoning suicide among poisoned patients. | PMC10031109 | ||
Methods | poisoning | MAY | This study prospectively enrolled 237 patients who were treated for poisoning at the Fifth Medical Center of PLA General Hospital (Beijing) between May 2021 and May 2022. Patient's basic characteristics, daily activities, mental health status, and history of psychological illnesses were gathered to examine their predictive power for self-poisoning suicide. On developing a prediction model, patients were split 8:2 into a training ( | PMC10031109 |
Results | anxiety | Of all poisoned patients, 64.6% committed suicide by self-poisoning. With regard to self-poisoning attempted suicide, multivariate analysis demonstrated that female gender, smoking, generalized anxiety disorder-7 (GAD-7), and beck hopelessness scale-20 (BHS-20) were significant risk factors, whereas married status, relatively higher education level, a sedentary time of 1–3 h per day, higher sport frequency per week, higher monthly income were significant protective features. The nomogram contained each of the aforementioned nine features. In the training group, the area under curve (AUC) of the nomogram was up to 0.938 (0.904–0.972), whereas in the validation group, it reached a maximum of 0.974 (0.937–1.000). Corresponding accuracy rates were up to 0.883 and 0.927, respectively, and the | PMC10031109 | |
Conclusions | psychiatric, anxiety | This study proposes a prediction model to stratify patients at a high risk of suicide by self-poisoning and to guide individual preventive strategies. Patients in the high-risk group require further mental health counseling to alleviate anxiety and hopelessness, healthy lifestyle like quitting smoking and exercising more, and restriction of access to poison and psychiatric drugs. | PMC10031109 | |
Introduction | ideations, death, cancer | REGRESSION, CANCER | Suicide is the behavior of deliberately causing one's own death, and it is one of serious causes of death all over the world (It is extremely helpful to identify suicide risk factors in order to direct preventive and treatment strategies. Currently, a number of variables haven been shown to be relevant to suicide ideations or attempts, such as sex (Several studies have developed models to predict suicide ideation among cancer patients (Nomogram is combined as a magnificent visual depiction of a discrimination procedure from a predictive regression model (Therefore, the purpose of this study was to identify risk variables for self-poisoning suicide as well as to suggest an accurate nomogram for predicting self-poisoning suicide. | PMC10031109 |
Patients and methods | PMC10031109 | |||
Patients | poisoning, psychiatric | MAY | In this study, 267 patients who were admitted to the Fifth Medical Center of PLA General Hospital (Beijing) for poisoning treatment between May 2021 and May 2022 were prospectively examined. Basic patient characteristics, lifestyle, poison type, length of stay, medical costs, mental health condition, and history of psychiatric illnesses were collected for this investigation. Patients were included if he/she was admitted to our department due to poisoning. Patients were excluded if he/she was (1) unwilling to take part in the survey, (2) unconsciousness, (3) unable to cooperate with doctors due to any other reasons, and (4) dead during hospitalization.Based on the exclusive and inclusive criteria, a total of 237 patients were enrolled for analysis in the study. Patient's flowchart is depicted in Patient's flowchart and creation of a nomogram. | PMC10031109 |
Data collection | depression, greasy, anxiety, poisoning | DISEASE, EVENT | The following variables were gathered for this study: (1) basic characteristics (age, gender, marital status, education level, and residence), (2) lifestyle (bland diet, greasy food, smoking, drinking, sedentary time per day, sport frequency per week, and monthly income), (3) mental health status (anxiety, depression, self-esteem, beck hopelessness, and social support), and (4) history of psychological disease (history of depression and history of psychiatry disease). Patient's lifestyle was self-reported and mental health status was evaluated using five scales In addition, type of poison, length of stay, and medical expense were also collected for analysis. In the study, type of poison was categorized into four main categories, including sleeping pills, pesticides, psychotropic drugs, and others. Length of stay was the time interval between patient's admission and discharge date. Medical expense was the total of expense that used to the treatment of poisoning in the hospital. In the study, self-poisoning was regarded as the positive event, and patients who admitted to our medical center not due to self-poisoning were served as the negative control. Poisoned patients who were not self-poisoning were served as the healthy controls, because those patients admitted to our medical center usually due to accidental poisoning. | PMC10031109 |
Nomogram development and validation | Multivariate analysis was utilized to build the nomogram and discover variables linked to self-poisoning suicide. A nomogram was created using variables that reached statistical significance. The nomogram was displayed | PMC10031109 | ||
Feature importance analysis | For clinical applicability, Shaley Additive exPlanation (SHAP) was used to interpret feature contributions. On explaining SHAP, we adopted the following formula, and in the formula | PMC10031109 | ||
Statistical analysis | In the study, quantitative features were presented as means with standard deviation, and qualitative features were summarized as proportion. Comparison between quantitative features were evaluated using | PMC10031109 | ||
Results | PMC10031109 | |||
Patient's basic characteristics and clinical features | hopelessness, anxiety | A total of 237 patients were enrolled for analysis in the study with a mean age of 33.33 ± 15.83 years. The majority of patients were female (55.3%), married (48.5%), primary education level (37.1%), and lived in city (71.7%). Regarding dietary preference, 54.4% patients intended to bland diet and 84.4% patients had not an inclination to greasy food. The number of patients who were smoking and drinking accounted for 32.1 and 18.1%, respectively. Regarding sport habit, only 33.8% patients did exercise for three or above times each week, and also 33.8% patients had a sedentary time of three or above hours each day. A multitude of patients were in a relatively low-income status since up to 50.2% had a monthly income of <3,000¥. Type of poison mainly included sleeping pills (21.9%), pesticides (25.3%), and psychotropic drugs (10.6%). The mean length of stay was 12.36 days and the mean medical expense was 44,822.25¥. Patient's basic characteristics, living habit, and mental health status.SD, standard deviation; GAD-7, generalized anxiety disorder-7; PHQ-9, patient health questionnaire-9; SES-10, self-esteem scale-10; BHS-20, beck hopelessness scale-20; SSQ-10, social support questionnaire-10. | PMC10031109 | |
A comparison analysis based on the presence of suicide | hopelessness, anxiety | Between patients who committed suicide and those who did not, significant differences in gender (A comparison between patients with and without suicide in the training group.SD, standard deviation; GAD-7, generalized anxiety disorder-7; PHQ-9, patient health questionnaire-9; SES-10, self-esteem scale-10; BHS-20, beck hopelessness scale-20; SSQ-10, social support questionnaire-10. | PMC10031109 | |
Development of the nomogram | hopelessness, anxiety | Multivariate analysis demonstrated that female gender (Selection of nomogram predictor based on the univariate and multivariate analyses in the training group.OR, odds ratio; CI, confident interval; GAD-7, generalized anxiety disorder-7; PHQ-9, patient health questionnaire-9; SES-10, self-esteem scale-10; BHS-20, beck hopelessness scale-20; SSQ-10, social support questionnaire-10.A nomogram to predict risk of self-poisoning. The red dot in each characteristic in the supplied case showed the case's current condition. For instance, the red dot was placed at the “No” box because the case was not a smoker. To determine a unique score for the feature, a line was drawn upward from the box to the score axis. All nine features were combined to create the final score (−2.76). We were able to determine the patients' final suicide risk (91.7%) by drawing a line downward to the projected risk axis. | PMC10031109 | |
Validation of the nomogram | The area under curve (AUC) of the nomogram was up to 0.938 (0.904–0.972) in the training group (Area under the curve (AUC) for the nomogram. Probability curve and discrimination slope for the nomogram. Calibrating evaluation and clinical usefulness of the nomogram. Predictive measures of the nomogram in the training and validation groups.AUC, area under the curve; CI, confident interval; NPV, negative predictive value; PPV, positive predictive value.Additionally, feature importance analysis was employed using SHAP, and it identified that the top three important variables were BHS-20, GAD-7, and marital status (Feature importance analysis. | PMC10031109 | ||
Classification of patients at different risk probability of suicide | The average threshold of the training (53.7%) and validation (24.6%) cohorts was regarded as the optimal cut-off value (40%). Based on the best cut-off value of the nomogram, patients in the high-risk group had a nearly 6-time larger likelihood of committing suicide by self-poisoning than patients in the low-risk group (88.68 vs. 15.38%, Patients stratified by risk group based on the optimal threshold of the nomogram.Indicates a comparison of actual probability between the low- and high-risk groups. | PMC10031109 | ||
Discussion | PMC10031109 | |||
Main findings | cancer | CANCER | In order to stratify patients at various risk levels for self-poisoning suicide, this study presented a nomogram, and nine features were added to the nomogram for analysis and model building. The predictive performance of the nomogram showed excellent effectiveness of prediction based on the AUC, accuracy rates, and the Hosmer and Lemeshow test. For instance, the AUC value could be up to 0.974 and accuracy rate was 0.927 in the validation group, whereas other studies showed the AUC value ranged from 0.715 to 0.860 in nomograms to suicide ideation among cancer patients (Additionally, risk stratification was used in the study to conduct personalized medication, and patients in the high-risk group had a nearly 6-time greater chance of committing suicide by self-poisoning than patients in the low-risk group. As a result, this nomogram was useful for identifying those who were at a high risk of self-poisoning suicide. Feature importance analysis demonstrated that the top three important variables were BHS-20, GAD-7, and marital status. Thus, more attention such as effectively preventive strategies in terms of their mental health should be paid to patients in the high-risk group. | PMC10031109 |
Risk factors associated with suicide behaviors | depression | EVENTS | Studies have shown that a series of variables were associated with suicide attempts, such as sex, grade, residence, family integrity, feeling meaningless in life, depression, bullying perpetrator, autonomy parenting, self-esteem, hopelessness, and stressful life events ( | PMC10031109 |
Prediction models of suicide managements | acute organophosphorus poisoning, cancer, self-poisoning | CANCER | Several prediction models have been developed, according to the literature that is currently accessible, to guide management among self-poisoning patients. For instance, researchers created a nomogram with six features, including age, white cells, albumin, cholinesterase, blood pH, and lactic acid levels, for the bedside assessment of patients with acute organophosphorus poisoning (Additionally, a number of studies have developed nomograms to predict suicide ideation among cancer patients ( | PMC10031109 |
Approaches to prevent self-poisoning suicide | Identification of risk and protective factors is a crucial step in developing effective suicide prevention methods since it can be used to choose the right interventions and how to carry them out. In these situations, risk factors serve as markers of whether a person or society has a propensity for suicide, hence the development of prediction models is necessary (Because patients in the high-risk group had a nearly six-time greater likelihood of committing suicide by self-poisoning than those in the low-risk group, this model was effective at identifying risk categories. To reduce the risk of suicide at the individual level as much as possible, patients in the high-risk category require extra care while the entire population needs to be the focus at the same time. From an individual standpoint, it will be highly advantageous to promote a healthy lifestyle, treat mental illnesses, and establish solid relationships with families and social communities. These steps should be taken from a sociocultural perspective, including removing obstacles to mental healthcare and drug rehab, reducing media exposure to suicidal behavior and the influence of those who have committed suicide, and limiting access to fatal substances ( | PMC10031109 | ||
Limitations | There are still a few issues with the study. Firstly, because we can only get data from patients who are still alive, the study may pose a risk of survival bias. Patients who had poisoned themselves and died at home or on the way to hospitals were not accessible to us. Additionally, some suicide attempts could be mistakenly labeled as accidents, making selection bias harder to prevent. Secondly, several ambiguous or conflicting definitions of suicide have complicated international comparisons and impeded development in the area of theory and research ( | PMC10031109 | ||
Conclusions | anxiety | This study proposes a prediction model to stratify patients at a high risk of suicide by self-poisoning so that individual preventive strategies can be timely performed. Patients in the high-risk group need more healthcare guidance, including education of health lifestyle such as quitting smoking and doing more exercise, restricted access to poison and psychotropic substances, and alleviation of anxiety and hopelessness. | PMC10031109 | |
Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC10031109 | ||
Ethics statement | The Ethics Committee of the Fifth Medical Center of PLA General Hospital approved the study protocol (No. KY-2021-12-34-1). Data were anonymously analyzed and informed written consent was obtained from all patients. The Ethics Committee waived the requirement of written informed consent for participation. | PMC10031109 | ||
Author contributions | WZ, LG, and CW conceived and designed this study together. WZ and YL undertook the data analysis, results interpretation, and manuscript preparation. CL and XP performed supervision. All authors read and approved the final manuscript. | PMC10031109 | ||
Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10031109 | ||
Publisher's note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10031109 | ||
Supplementary material | The Supplementary Material for this article can be found online at: Click here for additional data file. | PMC10031109 | ||
References | PMC10031109 | |||
Key Points | PMC9975910 | |||
Question | ischemia-reperfusion injury | Can a combined drug approach targeting the preimplantation liver graft and recipient attenuate the degree of ischemia-reperfusion injury? | PMC9975910 | |
Findings | COLD | In this open-label randomized clinical trial of 72 liver transplant recipients allocated to either static cold storage (standard of care) with an add-on combined drug approach delivered to the preimplantation liver and recipient or to standard of care only, peak aspartate aminotransferase serum levels and other functional, laboratory, and survival outcomes were similar between groups. | PMC9975910 | |
Meaning | ischemia-reperfusion injury | The findings suggest that use of a downstream combined drug approach that targets the preimplantation liver graft and recipient is not clinically effective for decreasing ischemia-reperfusion injury. | PMC9975910 | |
Importance | In a porcine model of liver transplant, a combined drug approach that targeted the donor graft and graft recipient reduced ischemia-reperfusion injury, a major hurdle to the success of liver transplant. | PMC9975910 | ||
Objective | ischemia-reperfusion injury | To assess the effect of a clinical form of a perioperative combined drug approach delivered immediately before implantation to the procured liver and to the liver recipient on the degree of ischemia-reperfusion injury. | PMC9975910 | |
Design, Setting, and Participants | death | KIDNEY FAILURE, MAY, ACUTE LIVER FAILURE | This unicentric, investigator-driven, open-label randomized clinical trial with 2 parallel arms was conducted in Belgium from September 2013 through February 2018, with 1-year follow-up. Adults wait-listed for a first solitary full-size liver transplant were screened for eligibility. Exclusion criteria were acute liver failure, kidney failure, contraindication to treatment, participation in another trial, refusal, technical issues, and death while awaiting transplant. Included patients were enrolled and randomized at the time of liver offer. Data were analyzed from May 20, 2019, to May 27, 2020. | PMC9975910 |
Interventions | COLD | Participants were randomized to a combined drug approach with standard of care (static cold storage) or standard of care only (control group). In the combined drug approach group, following static cold preservation, donor livers were infused with epoprostenol (ex situ, portal vein); recipients were given oral α-tocopherol and melatonin prior to anesthesia and intravenous antithrombin III, infliximab, apotransferrin, recombinant erythropoietin-β, C1-inhibitor, and glutathione during the anhepatic and reperfusion phase. | PMC9975910 | |
Main Outcomes and Measures | allograft dysfunction, ischemia-reperfusion injury, postreperfusion syndrome, ischemic cholangiopathy, acute kidney injury | SURGICAL COMPLICATIONS | The primary outcome was the posttransplant peak serum aspartate aminotransferase (AST) level within the first 72 hours. Secondary end points were the frequencies of postreperfusion syndrome, ischemia-reperfusion injury score, early allograft dysfunction, surgical complications, ischemic cholangiopathy, acute kidney injury, acute cellular rejection, and graft and patient survival. | PMC9975910 |
Results | Of 93 randomized patients, 21 were excluded, resulting in 72 patients (36 per study arm) in the per protocol analysis (median recipient age, 60 years [IQR, 51.7-66.2 years]; 52 [72.2%] men). Peak AST serum levels were not different in the combined drug approach and control groups (geometric mean, 1262.9 U/L [95% CI, 946.3-1685.4 U/L] vs 1451.2 U/L [95% CI, 1087.4-1936.7 U/L]; geometric mean ratio, 0.87 [95% CI, 0.58-1.31]; | PMC9975910 | ||
Conclusions and Relevance | ischemic-reperfusion injury | COLD | In this randomized clinical trial, the combined drug approach targeting the post–cold storage graft and the recipient did not decrease ischemic-reperfusion injury. The findings suggest that in addition to a downstream strategy that targets the preimplantation liver graft and the graft recipient, a clinically effective combined drug approach may need to include an upstream strategy that targets the donor graft during preservation. Dynamic preservation strategies may provide an appropriate delivery platform. | PMC9975910 |
Trial Registration | ClinicalTrials.gov Identifier: | PMC9975910 | ||
Introduction | LIVER FAILURE, LIVER, CDA | Liver transplant is a life-saving therapy for liver failure, but its success is limited by a marked shortage of organs and high mortality among individuals on the waiting list.Livers from extended-criteria donors are more susceptible to ischemia-reperfusion injury (IRI),Over the past decades, evidence from small- and large-animal models has indicated that pharmacological targeting of IRI pathways is a promising strategy to attenuate IRI,Although advocated over the past decade, to our knowledge, a CDA strategy has so far not been tested in the clinic. | PMC9975910 | |
Methods | PMC9975910 | |||
Study Design | RECRUITMENT | This investigator-initiated, open-label RCT (Combined Drug Approach to Prevent Ischemia-Reperfusion Injury During Transplantation of Livers [CAPITL]) with 2 parallel arms was conducted between September 2013 and February 2018, with 1-year follow-up, at the University Hospitals Leuven, Belgium. Ethical approval was obtained from the Ethics Committee Research UZ / KU Leuven and the Federal Agency for Medicines and Health Products of Belgium. Before recruitment started, the trial was registered at ClinicalTrials.gov ( | PMC9975910 | |
Study Population | death | BRAIN DEATH | Adults aged 18 years or older who were wait-listed for a first solitary full-size liver transplant were screened for eligibility at the time of liver offer. Recipients of whole livers from donations after brain death and/or circulatory death (Maastricht category 3 | PMC9975910 |
Components, Doses, Mechanisms, and Relevant Experimental and Clinical Evidence of the Combined Drug Approach | thrombosis, death, TNF-α, tumor necrosis, toxicity, inflammation, kidney reperfusion injury, parenchymal injury, congestion, myocardial injury, ischemia reperfusion, hepatocellular injury | THROMBOSIS, PRINGLE, TUMOR NECROSIS, INFLAMMATION, ACUTE KIDNEY FAILURE, LIVER REGENERATION, CONGESTION, ADHESION, HEPATOCELLULAR INJURY | Improvement of IRI severity, elimination of primary nonfunction, reduction of inflammatory cytokines such as TNF-α, improvement in liver function, reduction of bile salt toxicity, and increase of survival in a stringent pig DCD model of LT Improvement of hepatocellular injury, lipid peroxidation, and function in rat liver in situ reperfusion model Reduction of AST levels and ICU LOS after human partial liver resection Prevention of inflammation and parenchymal injury in isolated rat liver perfusion model Included in proof of concept; improvement in IRI severity, elimination of primary nonfunction, reduction of inflammatory cytokines such as TNF-α, improvement in liver function, reduction of bile salt toxicity, and increase in survival in a stringent pig DCD model of LT Improvement of hepatocellular injury and survival rate in pig liver in situ reperfusion model Decrease of serum aminotransferase and lactate and sinusoidal congestion in pig LT model Improvement of hepatocellular injury Improvement in creatinine values, malondialdehyde levels, myeloperoxidase activity, and histological damage in rat kidney in situ reperfusion model Reduction of neutrophil rolling and adhesion in a feline mesentery in situ reperfusion model Increase in the release of prostacyclin, improvement of blood flow, and decrease of cytokine-induced neutrophil chemoattractant and myeloperoxidase in rat liver in situ reperfusion model Reduction of graft thrombosis incidence in human simultaneous pancreas kidney transplant Prolonging of long-term survival after human intestinal transplant when used as a component of an immunomodulatory strategy Improvement of hepatocellular injury and decrease of myeloperoxidase in rat liver in situ reperfusion model Improvement of hepatocellular injury, apoptosis, and survival in mice liver in situ reperfusion model Included in proof of concept; improvement of IRI severity, elimination of primary nonfunction, reduction of inflammatory cytokines such as TNF-α, improvement of liver function, reduction of bile salt toxicity, and increase in survival in a stringent pig DCD model of LT Improvement of kidney reperfusion injury and acute kidney failure, decrease of complement activation and ROS formation in mice in situ reperfusion model Improvement of hepatocellular injury and apoptosis in pig liver in situ reperfusion model Reduction of inflammatory cytokine (IL-6 and TNF-α) and hospital LOS after human partial liver resection and Pringle maneuver Improvement of hepatocellular injury and function in rat liver in situ reperfusion model Improvement of hepatocellular injury and decrease of inflammatory cell infiltration and histological damage in pig liver ex situ reperfusion model Improvement of hepatocellular injury, liver regeneration, and survival in mice liver in situ reperfusion model Improvement of myocardial injury, hemodynamic parameters, and hospital LOS in human coronary artery bypass graftingAbbreviations: AST, aspartate aminotransferase; DCD, donation after circulatory death; EPO-β, recombinant erythropoietin-β; ICU, intensive care unit; IL-6, interleukin 6; IRI, ischemia reperfusion injury; LOS, length of stay; LT, liver transplant; ROS, reactive oxygen species; TNF-α, tumor necrosis factor α. | PMC9975910 |
Randomization | End-stage Liver Disease | At the time of organ offer, eligible patients were enrolled and randomized. A random allocation sequence was generated using computer-based random numbers with permuted block sizes of 2, 4, and 6. No stratification was performed on a priori–defined potential confounders such as CIT and priority on the waiting list through the Model for End-stage Liver Disease (MELD) | PMC9975910 |
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