Risk assessment of electric shock to the general public without Personal Protective Equipment during defibrillation shock delivery: A simulation study.

Aim: This study aimed to elucidate the risk of electric shock when the general public, not wearing Personal Protective Equipment (PPE), is in contact with a patient, and a defibrillation shock is inadvertently delivered. Methods: A simulation study was conducted simulating the following scenarios. 1) Both the rescuer and the patient were isolated from the ground, with the rescuer making single-point contact with the patient. 2) Both the rescuer and the patient were in contact with the common ground, and the rescuer made single-point contact with the patient. 3) The rescuer made contact at two different points to the patient. A mannequin with a towel saturated with 3% saline solution placed on the chest was used. Defibrillation shocks were delivered using a defibrillator three times at each of three energies: 150 J, 200 J, and 360 J. The voltage across the simulated rescuer was measured with an oscilloscope. Results: In Scenario 1, all measurements were below the detection limit. In Scenario 2, the voltage and current across the rescuer increased with higher defibrillation shock energy, averaging 156.8 V and 156.8 mA at 360 J. In Scenario 3, voltage peaked at 326.0 V and current at 326.0 mA at 360 J. Conclusion: In a simulated setting of defibrillation, over 300 mA of current could pass through the rescuer without PPE when having two contact points between the manikin and the rescuer. However, due to the brief duration and low energy, immediate danger to the rescuer is considered low.

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy.

Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a cell surface antigen for therapeutic targeting in prostate cancer. Here, we report broad expression of STEAP1 relative to prostate-specific membrane antigen (PSMA) in lethal metastatic prostate cancers and the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrate reactivity in low antigen density, antitumor activity across metastatic prostate cancer models, and safety in a human STEAP1 knock-in mouse model. STEAP1 antigen escape is a recurrent mechanism of treatment resistance and is associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein combined with STEAP1 CAR T cell therapy enhances antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading.

Use of the Airstretcher with dragging may reduce rescuers' physical burden when transporting patients down stairs.

Transporting patients down stairs by carrying is associated with a particularly high fall risk for patients and the occurrence of back pain among emergency medical technicians. The present study aimed to verify the effectiveness of the Airstretcher device, which was developed to reduce rescuers' physical burden when transporting patients by dragging along the floor and down stairs. Forty-one paramedical students used three devices to transport a 65-kg manikin down stairs from the 3rd to the 1st floor. To verify the physical burden while carrying the stretchers, ratings of perceived exertion were measured using the Borg CR10 scale immediately after the task. Mean Borg CR10 scores (standard deviation) were 3.6 (1.7), 4.1 (1.8), 5.6 (2.4), and 4.2 (1.8) for the Airstretcher with dragging, Airstretcher with lifting, backboard with lifting, and tarpaulin with lifting conditions, respectively (p < 0.01). Multiple comparisons revealed that the Airstretcher with dragging condition was associated with significantly lower Borg CR10 scores compared with the backboard with lifting condition (p < 0.01). When the analysis was divided by handling position, estimated Borg CR10 values (standard error) for head position were 4.4 (1.3), 2.9 (0.9), 3.2 (0.8), and 4.0 (1.1) for the Airstretcher with dragging, Airstretcher with lifting, backboard with lifting, and tarpaulin with lifting conditions, respectively, after adjusting for participant and duration time (F = 1.4, p < 0.25). The estimated Borg CR10 value (standard error) for toe position in the Airstretcher with dragging condition was 2.0 (0.8), and the scores for the side position were 4.9 (0.4), 6.1 (0.3), and 4.7 (0.4) for the Airstretcher with lifting, backboard with lifting, and tarpaulin with lifting conditions, respectively, after adjusting for participant and duration time (F = 3.6, p = 0.02). Transferring a patient down stairs inside a house by dragging using the Airstretcher may reduce the physical burden for rescuers.

Emerging approaches for preventing cytokine release syndrome in CAR-T cell therapy.

Chimeric antigen receptor (CAR) T cells have demonstrated remarkable anti-tumor efficacy against hematological malignancies, such as leukemia and lymphoma. However, patients treated with CAR-T cells frequently experience cytokine release syndrome (CRS), one of the most life-threatening adverse events of the therapy induced by systemic concentrations of pro-inflammatory cytokines throughout the body. Immunosuppressants such as tocilizumab are currently administered to treat the onset and progression of CRS symptoms. In order to reduce the risk of CRS, newly designed next-generation CAR-T treatments are being developed for both hematopoietic malignancies and solid tumors. In this review, we discuss six classes of interesting approaches that control cytokine production of CAR-T cell therapy: adaptor-based strategies, orthogonal cytokine-receptor pairs, regulation of macrophage cytokine activity, autonomous neutralization of key cytokines, kill switches and methods of reversible suppression of CARs. With these strategies, future CAR-T cell therapies will be designed to preemptively inhibit CRS, minimize the patients' suffering, and maximize the number of benefiting patients.

Cooperative Catalysis of Vibrationally Excited CO2 and Alloy Catalyst Breaks the Thermodynamic Equilibrium Limitation.

Using nonthermal plasma (NTP) to promote CO2 hydrogenation is one of the most promising approaches that overcome the limitations of conventional thermal catalysis. However, the catalytic surface reaction dynamics of NTP-activated species are still under debate. The NTP-activated CO2 hydrogenation was investigated in Pd2Ga/SiO2 alloy catalysts and compared to thermal conditions. Although both thermal and NTP conditions showed close to 100% CO selectivity, it is worth emphasizing that when activated by NTP, CO2 conversion not only improves more than 2-fold under thermal conditions but also breaks the thermodynamic equilibrium limitation. Mechanistic insights into NTP-activated species and alloy catalyst surface were investigated by using in situ transmission infrared spectroscopy, where catalyst surface species were identified during NTP irradiation. Moreover, in in situ X-ray absorption fine-structure analysis under reaction conditions, the catalyst under NTP conditions not only did not undergo restructuring affecting CO2 hydrogenation but also could clearly rule out catalyst activation by heating. In situ characterizations of the catalysts during CO2 hydrogenation depict that vibrationally excited CO2 significantly enhances the catalytic reaction. The agreement of approaches combining experimental studies and density functional theory (DFT) calculations substantiates that vibrationally excited CO2 reacts directly with hydrogen adsorbed on Pd sites while accelerating formate formation due to neighboring Ga sites. Moreover, DFT analysis deduces the key reaction pathway that the decomposition of monodentate formate is promoted by plasma-activated hydrogen species. This work enables the high designability of CO2 hydrogenation catalysts toward value-added chemicals based on the electrification of chemical processes via NTP.

pH-Sensitive branched ß-glucan-modified liposomes for activation of antigen presenting cells and induction of antitumor immunity.

Induction of cellular immunity is important for effective cancer immunotherapy. Although various antigen carriers for cancer immunotherapy have been developed to date, balancing efficient antigen delivery to antigen presenting cells (APCs) and their activation via innate immune receptors, both of which are crucially important for the induction of strong cellular immunity, remains challenging. For this study, branched ß-glucan was selected as an intrinsically immunity-stimulating and biocompatible material. It was engineered to develop multifunctional liposomal cancer vaccines capable of efficient interactions with APCs and subsequent activation of the cells. Hydroxy groups of branched ß-glucan (Aquaß) were modified with 3-methylglutaric acid ester and decyl groups, respectively, to provide pH-sensitivity and anchoring capability to the liposomal membrane. The modification efficiency of Aquaß derivatives to the liposomes was significantly high compared with linear ß-glucan (curdlan) derivatives. Aquaß derivative-modified liposomes released their contents in response to weakly acidic pH. As a model antigenic protein, ovalbumin (OVA)-loaded liposomes modified with Aquaß derivatives interacted efficiently with dendritic cells, and induced inflammatory cytokine secretion from the cells. Subcutaneous administration of Aquaß derivative-modified liposomes suppressed the growth of the E.G7-OVA tumor significantly compared with curdlan derivative-modified liposomes. Aquaß derivative-modified liposomes induced the increase of CD8+ T cells, and polarized macrophages to the antitumor M1-phenotype within the tumor microenvironment. Therefore, pH-sensitive Aquaß derivatives can be promising materials for liposomal antigen delivery systems to induce antitumor immune responses efficiently.

Synthesis and biological evaluation of a monocyclic Fc-binding antibody-recruiting molecule for cancer immunotherapy.

Antibody-recruiting molecules (ARMs) are bispecific molecules composed of an antibody-binding motif and a target-binding motif that redirect endogenous antibodies to target cells to elicit immune responses. To enhance the translational potential of ARMs, it is crucial to design antibody/target-binding motifs that have strong affinity and are easy to synthesize. Here, we synthesized a novel Fc-binding ARM (Fc-ARM) that targets folate receptor (FR)-positive cancer cells, Reo-3, using a recently developed monocyclic peptide 15-Lys8Leu, which binds strongly to the Fc region of an antibody. Reo-3 bound to the Fc region of the antibody with a K d of 5.8 nM, and recruited a clinically used antibody mixture to attack FR-positive IGROV-1 cells as efficiently as Fc-ARM2, in which a bicyclic Fc-binding peptide was used. These results indicate that 15-Lys8Leu, which can be synthesized readily, is suitable for various applications including the development of Fc-ARMs.

Fc-Binding Antibody-Recruiting Molecules Targeting Prostate-Specific Membrane Antigen: Defucosylation of Antibody for Efficacy Improvement*.

Synthetic small molecules that redirect endogenous antibodies to target cells are promising drug candidates because they overcome the potential shortcomings of therapeutic antibodies, such as immunogenicity and the need for intravenous delivery. Previously, we reported a novel class of bispecific molecules targeting the antibody Fc region and folate receptor, named Fc-binding antibody-recruiting molecules (Fc-ARMs). Fc-ARMs can theoretically recruit most endogenous antibodies, inducing antibody-dependent cell-mediated cytotoxicity (ADCC) to eliminate cancer cells. Herein, we describe new Fc-ARMs that target prostate cancer (Fc-ARM-Ps). Fc-ARM-Ps recruited antibodies to cancer cells expressing prostate-specific membrane antigen but did so with lower efficiency compared with Fc-ARMs targeting the folate receptor. Upon recruitment by Fc-ARM-P, defucosylated antibodies efficiently activated natural killer cells and induced ADCC, whereas antibodies with intact N-glycans did not. The results suggest that the affinity between recruited antibodies and CD16a, a type of Fc receptor expressed on immune cells, could be a key factor controlling immune activation in the Fc-ARM strategy.

Modification of nitric oxide donors onto a monoclonal antibody boosts accumulation in solid tumors.

Although monoclonal antibodies (mAbs) have revolutionized cancer treatment, their accumulation in solid tumors is limited and requires improvement to enhance therapeutic efficacy. Here we developed a strategy to modify mAb with a donor of nitric oxide (NO) because NO functions to vasodilate as well as to enhance the permeability of vascular endothelium, which will contribute to enhancing the tumor accumulation of mAb. We selected S-nitrosothiol as a NO donor and established the procedure to modify S-nitrosothiol group on mAb under ambient conditions. The modified mAb (Ab-SNO) thus obtained released NO in a preferable speed and maintained its original properties such as binding affinity to a target antigen and efficacy to induce antibody-dependent cellular cytotoxicity. We demonstrated that Ab-SNO enhanced the tumor accumulation of co-administered proteins such as antibody and serum albumin.

Induction of ADCC by a folic acid-mAb conjugate prepared by tryptophan-selective reaction toward folate-receptor-positive cancer cells.

We developed conjugates between monoclonal antibody (mAb) and folic acid (FA) by using a tryptophan (Trp)-selective reaction, which yields relatively homogenous products compared to conventional methods. The obtained mAb-FA conjugates showed significant cellular cytotoxicity toward folate receptor-expressing cancer cells, demonstrating that the conjugates retained the Fc region's original function.

Fc-binding antibody-recruiting molecules exploit endogenous antibodies for anti-tumor immune responses.

Redirecting endogenous antibodies in the bloodstream to tumor cells using synthetic molecules is a promising approach to trigger anti-tumor immune responses. However, current molecular designs only enable the use of a small fraction of endogenous antibodies, limiting the therapeutic potential. Here, we report Fc-binding antibody-recruiting molecules (Fc-ARMs) as the first example addressing this issue. Fc-ARMs are composed of an Fc-binding peptide and a targeting ligand, enabling the exploitation of endogenous antibodies through constant affinity to the Fc region of antibodies, whose sequence is conserved in contrast to the Fab region. We show that Fc-ARM targeting folate receptor-α (FR-α) redirects a clinically used antibody mixture to FR-α+ cancer cells, resulting in cancer cell lysis by natural killer cells in vitro. Fc-ARMs successfully interacted with antibodies in vivo and accumulated in tumors. Furthermore, Fc-ARMs recruited antibodies to suppress tumor growth in a mouse model. Thus, Fc-ARMs have the potential to be a novel class of cancer immunotherapeutic agents.

Engineered collagen-binding serum albumin as a drug conjugate carrier for cancer therapy.

Serum albumin (SA) is used as a carrier to deliver cytotoxic agents to tumors via passive targeting. To further improve SA's tumor targeting capacity, we sought to develop an approach to retain SA-drug conjugates within tumors through a combination of passive and active targeting. SA was recombinantly fused with a collagen-binding domain (CBD) of von Willebrand factor to bind within the tumor stroma after extravasation due to tumor vascular permeability. Doxorubicin (Dox) was conjugated to the CBD-SA via a pH-sensitive linker. Dox-CBD-SA treatment significantly suppressed tumor growth compared to both Dox-SA and aldoxorubicin treatment in a mouse model of breast cancer. Dox-CBD-SA efficiently stimulated host antitumor immunity, resulting in the complete eradication of MC38 colon carcinoma when used in combination with anti-PD-1 checkpoint inhibitor. Dox-CBD-SA decreased adverse events compared to aldoxorubicin. Thus, engineered CBD-SA could be a versatile and clinically relevant drug conjugate carrier protein for treatment of solid tumors.

Targeted antibody and cytokine cancer immunotherapies through collagen affinity.

Cancer immunotherapy with immune checkpoint inhibitors (CPIs) and interleukin-2 (IL-2) has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune system activation. Here, we addressed this need by targeting both the CPI antibodies anti-cytotoxic T lymphocyte antigen 4 antibody (αCTLA4) + anti-programmed death ligand 1 antibody (αPD-L1) and the cytokine IL-2 to tumors via conjugation (for the antibodies) or recombinant fusion (for the cytokine) to a collagen-binding domain (CBD) derived from the blood protein von Willebrand factor (VWF) A3 domain, harnessing the exposure of tumor stroma collagen to blood components due to the leakiness of the tumor vasculature. We show that intravenously administered CBD protein accumulated mainly in tumors. CBD conjugation or fusion decreases the systemic toxicity of both αCTLA4 + αPD-L1 combination therapy and IL-2, for example, eliminating hepatotoxicity with the CPI molecules and ameliorating pulmonary edema with IL-2. Both CBD-CPI and CBD-IL-2 suppressed tumor growth compared to their unmodified forms in multiple murine cancer models, and both CBD-CPI and CBD-IL-2 increased tumor-infiltrating CD8+ T cells. In an orthotopic breast cancer model, combination treatment with CPI and IL-2 eradicated tumors in 9 of 13 animals with the CBD-modified drugs, whereas it did so in only 1 of 13 animals with the unmodified drugs. Thus, the A3 domain of VWF can be used to improve safety and efficacy of systemically administered tumor drugs with high translational promise.

The heparin binding domain of von Willebrand factor binds to growth factors and promotes angiogenesis in wound healing.

During wound healing, the distribution, availability, and signaling of growth factors (GFs) are orchestrated by their binding to extracellular matrix components in the wound microenvironment. Extracellular matrix proteins have been shown to modulate angiogenesis and promote wound healing through GF binding. The hemostatic protein von Willebrand factor (VWF) released by endothelial cells (ECs) in plasma and in the subendothelial matrix has been shown to regulate angiogenesis; this function is relevant to patients in whom VWF deficiency or dysfunction is associated with vascular malformations. Here, we show that VWF deficiency in mice causes delayed wound healing accompanied by decreased angiogenesis and decreased amounts of angiogenic GFs in the wound. We show that in vitro VWF binds to several GFs, including vascular endothelial growth factor-A (VEGF-A) isoforms and platelet-derived growth factor-BB (PDGF-BB), mainly through the heparin-binding domain (HBD) within the VWF A1 domain. VWF also binds to VEGF-A and fibroblast growth factor-2 (FGF-2) in human plasma and colocalizes with VEGF-A in ECs. Incorporation of the VWF A1 HBD into fibrin matrices enables sequestration and slow release of incorporated GFs. In vivo, VWF A1 HBD-functionalized fibrin matrices increased angiogenesis and GF retention in VWF-deficient mice. Treatment of chronic skin wounds in diabetic mice with VEGF-A165 and PDGF-BB incorporated within VWF A1 HBD-functionalized fibrin matrices accelerated wound healing, with increased angiogenesis and smooth muscle cell proliferation. Therefore, the VWF A1 HBD can function as a GF reservoir, leading to effective angiogenesis and tissue regeneration.

Prognostic Significance of Asymptomatic Brain Natriuretic Peptide Elevation at Nephrology Referral in Patients with Chronic Kidney Disease.

BACKGROUND: It is unclear whether asymptomatic elevation of brain natriuretic peptide (BNP) is associated with cardiovascular events (CVEs) or heart failure (HF) in predialysis chronic kidney disease (CKD) patients. METHODS: We measured BNP in 482 asymptomatic predialysis patients with CKD stages 2-5 at nephrology referral between August 2004 and October 2010, and followed them prospectively to investigate the prognostic significance of BNP using Cox models and receiver operating characteristic (ROC) analyses. The primary composite end point was the time to death or the first nonfatal CVEs. Secondary end points included CVEs including sudden death, HF and all-cause death. RESULTS: The median age was 67 years (male, 67.4%; diabetic nephropathy, 33.4%), and estimated glomerular filtration rate was 20.1 mL/min/1.73 m2. The primary end point occurred in 92 patients. CVEs including sudden death, HF and all-cause death occurred in 66, 35, and 54 patients, respectively during a median follow-up period of 37.7 months. Multivariate analyses showed that BNP level was significantly associated with the primary end point (hazard ratio [HR] 1.241; 95% CI 1.020-1.511; p = 0.031), CVEs (HR 1.337; 95% CI 1.067-1.675; p = 0.012) and HF (HR 1.489; 95% CI 1.059-2.091; p = 0.022), but not associated with all-cause death (HR 1.081; 95% CI 0.829-1.410; p = 0.565). The ROC curves showed that the optimal predictive BNP levels for the primary end point, CVEs and HF were 92.5, 127.0, and 274.6 (pg/mL) respectively. CONCLUSION: Asymptomatic elevation of BNP is strongly predictive for CVEs and HF, which might help to integrate cardio-renal risk stratification in predialysis CKD patients.

A peptide inhibitor of antibody-dependent cell-mediated cytotoxicity against EGFR/folate receptor-α double positive cells.

Antibody-dependent cell-mediated cytotoxicity (ADCC) is caused by natural killer (NK) cells upon recognition of antigen-bound IgG via FcγRIIIa. This mechanism is crucial for cytolysis of pathogen-infected cells and monoclonal antibody (mAb)-mediated elimination of cancer cells. However, there is concern that mAb-based cancer therapy induces ADCC against non-target cells expressing antigens. To date, no strategy has been reported to enhance the selectivity of ADCC to protect non-target cells expressing antigens. Here, we introduce a model inhibitor which specifically blocks ADCC of anti-EGFR mAbs towards EGFR/folate receptor α (FRα) double positive cells. This inhibitor recruits mAbs on the FRα of the cell surface independent of Fab antigen recognition. The resulting ternary and/or quaternary complexes formed on the cell surface suppress signal transduction of FcγRIIIa in NK cells, consequently leading to more specific ADCC.

Laminin heparin-binding peptides bind to several growth factors and enhance diabetic wound healing.

Laminin, as a key component of the basement membrane extracellular matrix (ECM), regulates tissue morphogenesis. Here, we show that multiple laminin isoforms promiscuously bind to growth factors (GFs) with high affinity, through their heparin-binding domains (HBDs) located in the α chain laminin-type G (LG) domains. These domains also bind to syndecan cell-surface receptors, promoting attachment of fibroblasts and endothelial cells. We explore the application of these multifunctional laminin HBDs in wound healing in the type-2 diabetic mouse. We demonstrate that covalent incorporation of laminin HBDs into fibrin matrices improves retention of GFs and significantly enhances the efficacy of vascular endothelial cell growth factor (VEGF-A165) and platelet-derived growth factor (PDGF-BB) in promoting wound healing in vivo, under conditions where the GFs alone in fibrin are inefficacious. This laminin HBD peptide may be clinically useful by improving biomaterial matrices as both GF reservoirs and cell scaffolds, leading to effective tissue regeneration.

Improvement in the rate of inadequate pharmaceutical treatment by orthopaedic surgeons for the prevention of a second fracture over the last 10 years.

BACKGROUND: We have previously reported that the low rate of osteoporosis patients treated with anti-osteoporotic drugs following surgical treatment for the first fragility fractures by orthopaedic surgeons during 3 years from 2000 to 2003 was only 13.1%. Ten years have now passed our previous study, and we hypothesized that the rate of appropriate pharmacologic treatment for the prevention of secondary fractures has improved. METHODS: We studied 730 osteoporosis patients (102 men and 628 women; average age of 78 years, range 33-102 years) who underwent surgical treatment for fragility fractures, during 3-year period from 2010 to 2012. The 730 cases consisted of 489 hip fractures and 241 distal radius fractures. All patients were admitted and underwent surgical intervention in hospitals. Variables were examined to ascertain whether pharmaceutical treatment was performed after discharge. Based on these data, we compared results for patients in the present study with those from our previous study. RESULTS: The rate of treatment with anti-osteoporosis medication in the present (16.2%) was slightly but significantly improved from that in our previous study (13.1%). The rate of pharmaceutical treatment following hip fractures increased significantly, while that following distal radius fractures showed no significant change. Regarding the categories of anti-osteoporotic drugs prescribed to the patients, the rate of treatment with bisphosphonate as a higher evidenced drug for the prevention of fractures in the present study was significantly higher than that in our previous study. CONCLUSION: We demonstrated that the rate of pharmacologic treatment by orthopaedic surgeons and the rate of more effective anti-osteoporotic drugs prescribed to the patients following surgical intervention for the first fragility fracture in the present study were improved in comparison with those of 10 years ago.

Cardiac troponin T elevation at dialysis initiation is associated with all-cause and cardiovascular mortality on dialysis in patients without diabetic nephropathy.

BACKGROUND: It is not known whether asymptomatic cardiac troponin T (cTnT) elevation is associated with all-cause or cardiovascular mortality in non-diabetic and advanced chronic kidney disease (CKD) patients. METHODS: We measured cTnT in 248 consecutive patients at 1-2 weeks before dialysis initiation between March 2005 and August 2010 and followed them prospectively. A Cox proportional hazard model was used to investigate the relationship between cTnT and all-cause and cardiovascular mortality on dialysis. RESULTS: The median age of the patients was 67 years (male 59.3 %), and the prevalence of diabetic nephropathy (DN) was 38.3 %. Asymptomatic cTnT elevation (>0.01 ng/mL) was observed in 196 (79 %) and 111 (73 %) patients among the overall patients and among patients without DN, respectively. A total of 51 patients died during a median follow-up period of 31.6 months. The cTnT level was associated with all-cause [hazard ratio (HR) 1.453; 95 % confidence interval (CI) 1.093-1.931; P = 0.010] and cardiovascular mortality [HR 1.973; 95 % CI 1.127-3.454; P = 0.017] on dialysis after extensive adjustment in the overall patient population. Patients without DN showed similar associations as those for the overall patient population (all-cause mortality: HR 1.566; 95 % CI 1.048-2.339; P = 0.029 and cardiovascular mortality: HR 2.657; 95 % CI 1.115-6.328; P = 0.027). CONCLUSION: Asymptomatic cTnT elevation might be strongly associated with all-cause and cardiovascular mortality in patients without DN, as well as in the overall advanced CKD patients. We suggest that cardiovascular risk in patients with pre-dialysis CKD should be stratified according to cTnT levels.