Association of stress hyperglycemia with clinical outcomes in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention: a cohort study.

BACKGROUND: In recent years, several studies have demonstrated that stress hyperglycemia is significantly associated with poor prognosis in patients diagnosed with acute coronary syndrome (ACS). In the present study, we aimed to investigate the potential associations between various markers of stress hyperglycemia, such as admission blood glucose (ABG), fasting blood sugar (FBS), and stress hyperglycemia ratio (SHR) with different definitions, and the occurrence of adverse cardiovascular events in patients diagnosed with ST-elevation myocardial infarction (STEMI) who have undergone percutaneous coronary intervention (PCI). METHODS: Our study enrolled a total of 1099 patients diagnosed with STEMI who underwent PCI from 2016 to 2021. The primary outcomes of this study were in-hospital death and all-cause mortality. RESULTS: Stress hyperglycemia was associated with a higher incidence of in-hospital death (ABG OR: 1.27 95% CI 1.19-1.36; FBS OR: 1.25 95% CI 1.16-1.35; SHR1 OR: 1.61 95% CI 1.21-2.14; SHR2 OR: 1.57, 95%CI 1.22-2.01; SHR3 OR: 1.59, 95%CI 1.24-2.05) and all-cause mortality (ABG HR: 1.10, 95% CI 1.07-1.14; FBS HR: 1.12, 95 CI 1.07-1.17; SHR1 HR: 1.19 95% CI 1.03-1.39; SHR2 HR: 1.28, 95%CI 1.14-1.44; SHR3 HR: 1.29, 95%CI 1.14-1.45) after adjusting for ischemic time, age, gender, BMI, hypertension, hyperlipidemia, diabetes mellitus (DM), current smoking history, chronic kidney disease (CKD), previous history of coronary artery disease (CAD), atrial fibrillation (AF), heart failure (HF), stroke, cancer, culprit vessel, multi-vessel disease. These associations exhibited a non-linear, J-shaped pattern, wherein the risk significantly increased when the ABG and FBS levels exceeded 5mmol/L. Moreover, the inflection point for SHR was estimated to be 1.2. CONCLUSIONS: Stress hyperglycemia was significantly associated with an increased risk of in-hospital death and all-cause mortality in STEMI patients treated with PCI. Stress hyperglycemia should be considered a high-risk prognostic marker in all STEMI patients, regardless of with or without diabetes.

Impact of stress hyperglycemia ratio, derived from glycated albumin or hemoglobin A1c, on mortality among ST-segment elevation myocardial infarction patients.

BACKGROUND: Stress hyperglycemia ratio (SHR), associated with adverse outcomes in patients with ST-segment elevation myocardial infarction (STEMI), has several definitions. This study aims to assess the prognostic value of SHR, derived from hemoglobin A1c (HbA1c) or glycated albumin (GA), to mortality. METHODS: The study comprised 1,643 STEMI patients who underwent percutaneous coronary intervention (PCI) in two centers. SHR1 was calculated using fasting blood glucose (FBG)/GA, while SHR2 was calculated using the formula FBG/(1.59*HbA1c-2.59). The primary endpoints were in-hospital death and all-cause mortality, with a median follow-up duration of 1.56 years. RESULTS: Higher SHR1 and SHR2 values are associated with increased risks of in-hospital death and all-cause mortality. Each standard deviation increase in SHR1 corresponded to a 39% and 22% escalation in in-hospital death and all-cause mortality, respectively. The respective increases for SHR2 were 51% and 26%. Further examinations validated these relationships as linear. Additionally, the areas under the curve (AUC) for in-hospital death were not significantly different between SHR1 and SHR2 (p > 0.05). Incorporating SHR1 or SHR2 into the base model significantly improved the discrimination and risk reclassification for in-hospital and all-cause mortality. A subgroup analysis revealed that the effects of SHR1 and SHR2 were more pronounced in patients with hypercholesteremia. CONCLUSION: SHR1 and SHR2 have emerged as robust and independent prognostic markers for STEMI patients undergoing PCI. The SHR calculation based on either HbA1c or GA can provide additional predictive value for mortality beyond traditional risk factors, helping to identify high-risk STEMI patients.

Association of systemic immune inflammatory index with all-cause and cause-specific mortality among individuals with type 2 diabetes.

BACKGROUND: The evidence regarding the association between the systemic immune inflammatory index (SII) and mortality among individuals with diabetes is limited. This study aims to evaluate the associations between SII and all-cause and cause-specific mortality among individuals with diabetes. METHODS: The study included 8,668 participants with diabetes from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 with follow-up until 31 December 2019. The calculation of SII in this study was performed using the following formula: the neutrophil-to-lymphocyte ratio multiplied by the platelet count (10^9 cells/µL). RESULTS: The study documented 2,463 deaths over 68,542 person-years, including 853 deaths from CVD and 424 from cancer. An increase in SII was significantly associated with higher all-cause and CVD mortality risk after multivariate adjustment. For each standard deviation increment in natural log transformed SII (lnSII), all-cause mortality increased by 17%, and CVD mortality increased by 34% (both P < 0.001). Additionally, the association between SII and all-cause mortality was U-shaped, with the inflection point at 6.02. The association between SII and CVD mortality was non-linear and J-shaped, where the risk increased significantly when lnSII exceeded 6.22. Furthermore, the association between SII and CVD mortality was attenuated in female and hyperlipidemia patients. CONCLUSION: In this study, we observed a significant positive association between the SII and both all-cause and CVD mortality in patients with diabetes. Additionally, it was discovered that this association exhibited a non-linear pattern. These findings suggest that maintaining SII within an optimal range may play a critical role in mitigating the risk of mortality.

Potassium supplementation inhibits IL-17A production induced by salt loading in human T lymphocytes via p38/MAPK-SGK1 pathway.

High salt intake contributes to the development of autoimmune/inflammatory diseases, while potassium supplementation antagonizes the effects. Interleukin (IL)-17A are tightly related with autoimmune/inflammatory diseases. Thus, we explored the effects and underlying molecular mechanism of high salt and potassium supplementation on IL-17A production in T lymphocytes. Forty-nine healthy participants received a low-salt, high-salt, followed by a high-salt diet plus potassium supplement for 7 days, respectively. Human T lymphocyte Jurkat cells were treated with different concentrations of NaCl and KCl. In the participants, IL-17A levels in plasma and in peripheral blood mononuclear cells (PBMC) were significantly increased after a high-salt diet, which was dramatically reversed when potassium was supplemented. In Jurkat cells, the addition of 40 mM NaCl markedly enhanced IL-17A production and the expression of phosphorylated p38/mitogen-activated protein kinase (MAPK) and its downstream target, serum/glucocorticoid-regulated kinase (SGK)1, whereas combined treatment with additional 2 mM KCl significantly decreased them. Respective inhibition of p38/MAPK and SGK1 suppressed IL-17A expression induced by NaCl, and KCl inhibited IL-17A production induced by specific activator of p38/MAPK. We conclude potassium supplementation has a blocking effect on IL-17A production in T lymphocytes induced by salt loading. This protective effect is mediated through the direct suppression of p38/MAPK-SGK1 pathway.

Curcumin induces M2 macrophage polarization by secretion IL-4 and/or IL-13.

AIMS: To address the underlying mechanisms by which curcumin facilitates M2 phenotype polarization of macrophages and its roles in the protective effects during experimental autoimmune myocarditis (EAM). METHODS AND RESULTS: The expression of classic M2 markers, including macrophage mannose receptor (MMR), arginase-1 (Arg-1) and peroxisome proliferator-activated receptor-γ (PPAR-γ) was upregulated in curcumin-treated Raw264.7 macrophages. Curcumin increased interleukin-4 (IL-4) and interleukin-13 (IL-13) mRNA expression and protein secretion. Curcumin notably increased STAT6 phosphorylation. Leflunomide, a STAT6 inhibitor, and IL-4 and/or IL-13 neutralizing antibodies antagonized the induction of MMR, Arg-1 and PPAR-γ by curcumin in Raw264.7 cells. In vivo, 6-week old male Lewis rats were used to induce EAM and orally administrated with curcumin or corn oil for 3weeks after myosin injection. Cardiac functional parameters, including left ventricular fractional shortening (LVFS), ejection fraction (EF), left ventricular end-systolic diameter (LVEDs) and heart rate (HR) were significantly improved by curcumin treatment. Curcumin also reduced the inflammatory cell infiltration and myocardial mRNA levels of interleukin-1ß (IL-1ß) and inducible nitric oxide synthase (iNOS). Meanwhile, the myocardial mRNA levels of MMR and Arg-1 were markedly up-regulated by curcumin. Immunofluorescence assay showed that the number of CD68(+) MMR(+) and CD68(+) Arg-1(+) double positive macrophages in curcumin-treated myocardial tissue was significantly higher than untreated control. The number of CD68(+) iNOS(+) double positive macrophages was increased obviously in EAM group, but decreased markedly by curcumin treatment. CONCLUSIONS: Taken together, these results show that curcumin induces macrophage M2 polarization by secretion of IL-4 and/or IL-13. Curcumin ameliorates EAM by reducing infiltration inflammatory macrophages and by polarizing M0 and M1 macrophages to M2 phenotype.

The impact of digital transformation of infrastructure on carbon emissions: Based on a "local-neighborhood" perspective.

In light of the recent worldwide scientific and technological revolution, it is imperative that urban infrastructure undergo a digital transformation in order to lower carbon emissions and support sustainable urban growth. However, to date, there is a lack of empirical research on carbon emissions based on the digital transformation of urban infrastructure. This paper uses data from 178 prefecture-level cities in China from 2005 to 2020 to study the impact of digital transformation of urban infrastructure on carbon emissions based on the "local-neighbourhood" perspective using a spatial difference-in-differences model. The results show that the digital transformation of urban infrastructure reduces the intensity of local carbon emissions while also reducing the carbon emissions of neighbouring cities, with a spatial spillover effect, and the boundary of this spatial spillover is 600 km. Mechanistic analyses suggest that digital transformation of urban infrastructure can reduce carbon emissions locally as well as in nearby areas by promoting green technological innovations. In light of this, this study has important policy implications for maximising the contribution of digital transformation of infrastructure to reducing carbon emissions.

Microelectronic printed chitosan/chondroitin sulfate/ZnO flexible and environmentally friendly triboelectric nanogenerator.

The triboelectric nanogenerator (TENG) of natural biomaterials is a new type of energy harvesting device and can be used as a self-powered sensor, which has received extensive research and attention. In this paper, based on the biocompatibility of chitosan and chondroitin sulfate, ZnO-modified chitosan/chondroitin sulfate/ZnO TENG was prepared for research on wearable devices and sustainable power supply devices. This study employs molecular dynamics to compute the interaction energy between chitosan and ZnO molecules. Theoretical calculations have unequivocally substantiated the occurrence of a binding interaction between these two molecular entities. The effect of ZnO on chitosan/chondroitin sulfate morphology was investigated by atomic force microscopy. The chitosan/chondroitin sulfate/ZnO TENG has high flexibility and electrical output performance. It can reach 105 V and 3.3 µA of open-circuit voltage and short-circuit current. Chitosan/chondroitin Sulfate/ZnO TENG successfully converts the mechanical energy of human motion into electrical energy. Strong electrical signals are exhibited when making fists and waving fingers and wrists. The TENG is a self-powered source and lights up 70 blue light-emitting diodes (LEDs). The chitosan/chondroitin sulfate/ZnO TENG has demonstrated its capabilities in energy harvesting and wearable self-powered sensors.

Minimally Invasive Surgery for Posterior Atlantoaxial Lateral Mass Joint Fusion (MIS-PALF): A Muscle-Sparing Procedure for Atlantoaxial Instability or Dislocation.

BACKGROUND: Conventional surgical procedures for atlantoaxial instability or dislocation (AAI/D) have been associated with a high prevalence of postoperative occipitocervical pain and dysfunction, as well as substantial perioperative blood loss. We hypothesized that minimally invasive surgery for posterior atlantoaxial lateral mass joint fusion (MIS-PALF), a procedure that can largely avoid disruption of suboccipital musculature, would be superior to the standard Goel-Harms technique in terms of postoperative pain and perioperative blood loss. METHODS: This was a prospective cohort study of patients undergoing MIS-PALF for AAI/D at Peking University Third Hospital's Department of Orthopaedics from January 2021 to December 2021 and a historical control group of patients with the same diagnoses who were treated with the Goel-Harms technique. The duration of surgery, perioperative blood loss, postoperative length of hospital stay, postoperative body temperature, pain, supplementary use of narcotics, spinal cord function/improvement (assessed using the Japanese Orthopaedic Association [JOA] scores), reduction of AAI/D (determined based on radiographic parameters), rate of successful fusion, and complication rate were all compared between the 2 groups. RESULTS: No significant differences were noted between the groups (43 MIS-PALF cases, 86 control cases) regarding baseline data, operative time, spinal cord function or improvement, reduction of AAI/D, rate of successful fusion, and complication rate. MIS-PALF was associated with significantly less perioperative blood loss, a shorter postoperative hospital stay (decreased by 30.8%), lower intensity and frequency of postoperative pain (decreased by 10.6% and 61.9%, respectively), less need for supplementary narcotics, and less frequent postoperative fever (decreased by 48.7%). CONCLUSIONS: This was the first prospective cohort study of which we are aware on minimally invasive procedures for atlantoaxial fusion. Clinical efficacy (AAI/D reduction, rate of successful atlantoaxial fusion, JOA score improvement), efficiency (operative time), and safety (complications) of MIS-PALF appeared to be noninferior to those of the Goel-Harms technique. MIS-PALF was superior in terms of postoperative occipitocervical pain and length of hospital stay, both of which directly affect overall patient satisfaction and postoperative recovery of quality of life. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

NRF2-HIF2α Signaling Attenuates Endothelial Cell Senescence and Maintains Intercellular Junctions in Diabetes.

In the context of diabetes, endothelial cells frequently exhibit compromised intercellular junctions and accelerated cellular senescence simultaneously. The precise mechanisms underlying these issues and the identification of effective treatments remain largely undefined. Our findings reveal that human umbilical vein endothelial cells (HUVECs) can counteract senescence and uphold the integrity of intercellular junctions under mildly to moderately elevated glucose levels (10 mM and 15 mM) via two primary mechanisms: i) The acetylation of NRF2 at lysine residues K56, K68, and K52 prevents its ubiquitination, enhancing the transcription of antioxidant genes GST, SOD1, and GPX1. This activity diminishes cytoplasmic oxidative stress, thereby mitigating endothelial cell senescence. ii) The interaction between the Neh2 domain of NRF2 and the PAS-B domain of HIF-2α within the nucleus curtails the attachment of HIF-2α to the NOX4/p22phox promoter. This action lessens oxidative stress near the cell membrane, maintaining intercellular junctions by safeguarding the disulfide bonds in occludin and E-cadherin from disruption. However, these protective strategies prove insufficient under severe hyperglycemic conditions (25 mM). Further investigation has identified Oltipraz, an activator of NRF2, as also promoting the degradation of HIF-2α. Through its simultaneous modulation of NRF2 and HIF-2α, Oltipraz significantly reduces cellular senescence and prevents the deterioration of intercellular junctions in HUVECs subjected to high glucose concentrations (25 mM). Our research positions Oltipraz as a promising therapeutic candidate for mitigating diabetes-induced vascular endothelial damage, potentially offering benefits against diabetes-related atherosclerosis and valvular calcification.

Association of kidney disease index with all-cause and cardiovascular mortality among individuals with hypertension.

BACKGROUND: This study aimed to investigate the association between a novel kidney disease index (KDI), which combines information from both estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (uACR), and all-cause and cardiovascular disease (CVD) mortality among individuals with hypertension. METHODS: We analyzed data from 19 988 adults with hypertension who participated in the National Health and Nutrition Examination Survey from 1999 to 2018. Mortality outcomes were determined by linking to National Death Index records through December 31, 2019. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for all-cause and CVD mortality. RESULTS: Baseline KDI levels were positively associated with glucose, insulin resistance, hemoglobin A1c, triglycerides, and C-reactive protein (p value for trend <.05). During a follow-up period of 179 859 person-years, a total of 5069 deaths were documented, including 1741 from cardiovascular causes. After multivariable adjustment, each standard deviation increment in KDI level was associated with a 27% increased risk of all-cause mortality and a 31% increased risk of cardiovascular deaths (both p < .05). Further analysis showed a J-shaped association between KDI and mortality, with the risk increasing dramatically when KDI exceeded 0.27. CONCLUSION: Elevated KDI levels were significantly associated with increased mortality from all causes and CVD among individuals with hypertension. We recommend routine testing of eGFR and uACR in hypertensive patients, and using KDI as a tool to identify individuals who are most likely to benefit from preventive therapies.

Pure Retroperitoneal Laparoscopic Peritoneum Incision Technique in Right Nephrectomy and Inferior Vena Cava Tumor Thrombectomy: A Novel Surgical Technique and Long-Term Outcomes from a Large Chinese Center.

Purpose: To explore the safety and effectiveness of the Pure Retroperitoneal Laparoscopic Peritoneum Incision Technique (PREP-IT) in laparoscopic radical nephrectomy (LRN) and inferior vena cave (IVC) tumor thrombectomy for right renal-cell carcinoma (RCC) with level Mayo I to III venous tumor thrombus (VTT). Patients and Methods: From May 2015 to September 2020, 92 patients with right RCC and Mayo I to III VTT were retrospectively reviewed, including 57 patients who underwent retroperitoneal LRN and IVC thrombectomy using PREP-IT, and 35 patients who underwent open surgery. PREP-IT refers to dissecting the retroperitoneum and temporarily placing the right kidney into the abdominal cavity to enlarge the retroperitoneal workspace for a safer and faster IVC operation. Results: Compared with the open surgery group, the PREP-IT group had a larger tumor diameter, while a larger proportion of Mayo I tumor thrombus and smaller maximum tumor thrombus width. Two patients (3.5%) in the PREP-IT group had a history of abdominal surgery. No conversion to open surgery or standard laparoscopic surgery occurred in PREP-IT group. Laparoscopic surgery with PREP-IT was characterized by shorter operative time, less surgical blood loss, shorter postoperative hospital stay, and lower postoperative complication rate. With a 33-month (ranges: 2-86) follow-up time period, the estimated mean overall survival time was 57.2 ± 5.3 and 58.1 ± 71.5 months in the PREP-IT group and open surgery group, respectively. Log-rank test indicated no significant difference between the two groups in terms of overall survival and cancer-specific survival. Conclusions: The PREP-IT is relatively safe and feasible for retroperitoneal LRN with right renal tumor and IVC tumor thrombus, allowing for a large workspace and wide exposure for IVC operations.

External validation of the SWEDEHEART score for predicting in-hospital major bleeding among East Asian patients with acute myocardial infarction.

Background: Risk scores for predicting in-hospital major bleeding in patients with acute myocardial infarction (AMI) are rare. The Swedish web-system for the enhancement and development of evidence-based care in heart disease evaluated according to recommended therapies (SWEDEHEART) score (SS), consisting of five common clinical variables, is a novel model for predicting in-hospital major bleeding. External validation of SS has not yet been completed. Methods and results: A retrospective study recruiting consecutive East Asian patients diagnosed with AMI was conducted in the Second Affiliated Hospital, Zhejiang University. The primary endpoint was the ability of SS to predict in-hospital major bleeding, which was defined as Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding. To validate SS, the discrimination and calibration were assessed in the overall population and several subgroups. The receiver operating characteristic (ROC) curves and the areas under ROC curves (AUCs) were calculated for discrimination. The calibration of SS was evaluated with the unreliability U test. A total of 2,841 patients diagnosed with AMI during hospitalization were included, and 1.94% (55) of them experienced in-hospital major bleeding events. The AUC of SS for the whole population was only 0.60 [95% confidence interval (CI), 0.52-0.67], without an acceptable calibration (p = 0.001). Meanwhile, the highest AUC (0.72; 95% CI, 0.61-0.82) of SS for the primary endpoint was found in the diabetes subgroup, with an acceptable calibration (p = 0.87). Conclusion: This external validation study showed that SS failed to exhibit sufficient accuracy in predicting in-hospital major bleeding among East Asian patients with AMI despite demonstrating acceptable performance in the diabetic subgroup of patients. Studies to uncover optimal prediction tools for in-hospital major bleeding risk in AMI are urgently warranted.

The activation of p38 MAPK limits the abnormal proliferation of vascular smooth muscle cells induced by high sodium concentrations.

The aim of the present study was to ascertain whether high sodium levels can directly promote the proliferation of vascular smooth muscle cells (VSMCs) and to elucidate the underlying mechanisms. Additional sodium chloride (NaCl) was added to the routine culture medium. Cell proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay. The mRNA expression level of proliferating cell nuclear antigen (PCNA) was measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The protein expression levels of PCNA and phosphorylated c-Jun amino N-terminal kinase (p-JNK), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) were measured by western blot analysis. Cell proliferation assay revealed that Na+ rather than Cl- or osmotic pressure promoted the proliferation of the VSMCs. The high sodium level upregulated the expression of PCNA and the phosphorylation levels of JNK, ERK1/2 and p38 MAPK. The inhibition of JNK and ERK1/2 decreased PCNA expression. Of note, the inhibition of p38 MAPK using the inhibitor, SB203580, increased PCNA expression. However, when p38 MAPK was activated by anisomycin, PCNA expression was decreased. On the whole, our findings demonstrate that a relatively high sodium level per se directly promotes the proliferation of VSMCs through the JNK/ERK1/2/PCNA pathway. At the same time, this induction of the proliferation of VSMCs due to high sodium levels can be maintained at a low level via the activation of p38 MAPK.

IL-17 intensifies IFN-γ-induced NOS2 upregulation in RAW 264.7 cells by further activating STAT1 and NF-κB.

Interleukin-17 (IL-17) is a signature cytokine of Th17 cells. Previous research has indicated that IL-17 plays a proinflammatory role by exacerbating interferon-γ (IFN-γ)-induced inflammation. However, prior to this study, it was not known whether inducible nitric oxide synthase (iNOS or NOS2), a signature molecule of inflammation, could be intensified by IL-17 when combined with IFN-γ. Thus, we explored the roles and underlying mechanisms of IL-17 and IFN-γ in the regulation of NOS2 expression in RAW 264.7 cells using qPCR, western blot analysis, colorimetric analysis, ChIP assay and statistical analysis. Although IL-17 alone did not induce NOS2 expression or nitric oxide (NO) production, as shown by western blot analysis and colorimetric analysis, it intensified IFN-γ-induced NOS2 upregulation and NO production in RAW 264.7 cells. The alteration of relevant transcription factors demonstrated that a combination of IFN-γ and IL-17 enhanced Tyr701-phosphorylated signal transducer and activator of transcription 1 [p-STAT1(Y701)] and nuclear factor-κB (NF-κB) activation, nuclear translocations and their binding to the NOS2 promoter, compared with IFN-γ alone, as illustrated by the results of the western blot analysis and ChIP assay. Also, using the corresponding inhibitors of STAT1 and NF-κB, we noted downregulation of the expression of NOS2 induced by IFN-γ alone or in combination with IL-17, respectively. In addition, IFN-γ increased phosphorylated (p-)p38 mitogen-activated protein kinase (MAPK), and accelerated the activation of the NF-κB pathway and the expression of NOS2, but phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) was reduced by treatment with IFN-γ and IL-17. IL-17 intensified the activation of the NF-κB pathway and NOS2 upregulation induced by IFN-γ by increasing the phosphorylation of p38 MAPK and limiting the phosphorylation of ERK1/2. Taken together, these results suggest that IL-17 intensified IFN-γ-induced NOS2 upregulation and NO production by increasing the transcription activity of p-STAT1(Y701) and NF-κB in RAW 264.7 cells. Further activation of the NF-κB pathway induced by IL-17 relied on enhanced phosphorylation of p38 MAPK and decreased phosphorylation of ERK1/2. The mechanism suggested in this study provides novel information which may be used for anti-inflammatory therapy with IL-17.