Comparative Efficacy of Advanced Therapies in the Treatment of Radiographic Axial Spondyloarthritis or Ankylosing Spondylitis as Evaluated by the ASDAS Low Disease Activity Criteria.

INTRODUCTION: With an increasing number of biologic/targeted synthetic disease-modifying antirheumatic drug options available for the treatment of active ankylosing spondylitis (AS), also known as radiographic axial spondyloarthritis, it is of clinical interest to determine the comparative efficacy of these advanced therapies among populations with differing prior advanced therapy exposure. This study aimed to assess the comparative efficacy of approved advanced therapies for AS in tumor necrosis factor inhibitor (TNFi)-naïve and, separately, in TNFi inadequate responder/intolerant (-IR) populations. METHODS: A systematic literature review was conducted to identify randomized clinical trials for TNFis, interleukin-17A inhibitors, and Janus kinase inhibitors used as advanced therapies for active AS. Clinical efficacy was considered by the Ankylosing Spondylitis Disease Activity Score low disease activity (ASDAS LDA) criteria, defined as ASDAS score less than 2.1, among approved therapies. Comparative efficacy in the TNFi-naïve population was assessed utilizing network meta-analysis, while comparative efficacy in the TNFi-IR population was assessed utilizing matching-adjusted indirect comparison. Odds ratios were calculated, from which absolute rates and numbers needed to treat were calculated. Safety in the form of trial-reported and placebo-adjusted rates of discontinuation due to adverse events (AEs) was reviewed. RESULTS: Among the TNFi-naïve population, the estimated ASDAS LDA rate between week 12 and 16 was highest for patients treated with upadacitinib (52.8%) and lowest for patients treated with placebo (11.6%). Among the TNFi-IR population, the estimated ASDAS LDA rate was 41.3% for patients treated with upadacitinib and 17.5% for patients treated with ixekizumab. The trial-reported and placebo-adjusted rates of discontinuation due to AEs were generally low across included advanced therapies. CONCLUSIONS: Relative to other assessed therapies, upadacitinib demonstrated greater clinical efficacy per ASDAS LDA in the treatment of active AS in both TNFi-naïve and TNFi-IR populations. Head-to-head and real-world data comparisons are warranted to both validate these findings and aid medical decision makers.

Single Intravenous Dose Dalbavancin Pathway for the Treatment of Acute Bacterial Skin and Skin Structure Infections: Considerations for Emergency Department Implementation and Cost Savings.

BACKGROUND: A pathway for the treatment of acute bacterial skin and skin structure infections (ABSSSI) with a single intravenous (IV) dose of dalbavancin was previously shown to reduce hospital admissions and shorten inpatient length of stay (LOS). OBJECTIVES: To describe pathway implementation at the emergency department (ED) and evaluate cost-effectiveness of a single-dose dalbavancin administered to ED patients who would otherwise be hospitalized to receive usual care with multidose IV antibiotics. METHODS: The dalbavancin pathway was previously implemented at 11 U.S. EDs (doi:10.1111/acem.14258). Patients with ABSSSI, without an unstable comorbidity or infection complication requiring complex management, were treated with a single dose of dalbavancin. At the emergency physicians' discretion, patients were either discharged and received outpatient follow-up or were hospitalized for continued management. A decision analytic cost-effectiveness model was developed from the U.S. healthcare's perspective to evaluate costs associated with the dalbavancin pathway compared with inpatient usual care. Costs (2021 USD) were modeled over a 14-day horizon and included ED visits, drug costs, inpatient stay, and physician visits. One-way and probabilistic sensitivity analyses examined input parameter uncertainty. RESULTS: Driven largely by the per diem inpatient cost and LOS for usual care, the dalbavancin pathway was associated with savings of $5133.20 per patient and $1211.57 per hospitalization day avoided, compared with inpatient usual care. The results remained robust in sensitivity and scenario analyses. CONCLUSION: The new single-dose dalbavancin ED pathway for ABSSSI treatment, which was previously implemented at 11 U.S. EDs, offers robust cost savings compared to inpatient usual care.

Evaluation of the accuracy of seven intraoral scanners for the full dentate and partially edentulous complete-arch mandibular casts: An in vitro comparison.

Statement of problem: Intraoral scanners (IOSs) are widely used in dentistry, providing high accuracy in short-range scanning. Nevertheless, when scanning the full dental arch, it remains a challenge. Furthermore, there is a lack of studies reporting the differences in scan accuracy between dental arches with large-span mucosal areas and fully dentate casts or optimal IOS selection for different dental statuses. Purpose: This study aimed to evaluate the accuracy and scanning time of different IOSs for full dentate (FD) and partially edentulous (PE) casts with missing teeth in the #34-#44 range and to determine the IOSs with the optimal clinical adaptability and scanning accuracy for different complete-arch casts. Material and methods: Reference scans of two complete-arch (FD and PE) casts were obtained using a laboratory scanner (Ceramill Map 600). Subsequently, the same casts were scanned ten times each by seven IOSs (3Shape Trios 3, CS3600, Planmeca Emerald, iTero Element 5D, Medit i500, BAMBOO B1, and Shining Aoralscan 3), and the scanning time was recorded. The test data were superimposed on the reference scans for the selected areas, and three-dimensional deviations between the reference and test casts (trueness), and between test casts (precision) were determined using reverse engineering software (Geomagic Wrap). The dataset was analyzed using a two-factor analysis of variance with post-hoc Bonferroni tests. Results: Two-factor analysis of variance revealed significant differences in accuracy and scanning time for different casts (P < 0.001) and IOSs (P < 0.001). For the FD cast, the i500 (0.35 ± 0.11 mm trueness) and CS3600 (0.23 ± 0.12 mm precision) performed worse than the remaining scanners. For the PE cast, the BAMBOO B1(0.89 ± 0.58 mm trueness; 0.88 ± 0.48 mm precision) performed worse than the remaining scanners. There were no differences in the accuracy of scanning between the Element 5D and Emerald for both cast types. However, the scanning time differed significantly between the different IOSs (P < 0.001). Regardless of the cast type, the fastest and slowest scans were performed by the Trios3 and CS3600 scanners respectively. Conclusions: The accuracy and scanning time differed between the different IOSs and types of complete-arch casts.

Coordinate-based data analysis of the accuracy of five intraoral scanners for scanning completely dentate and partially edentulous mandibular arches.

STATEMENT OF PROBLEM: Current methods for assessing the accuracy of intraoral scanners (IOSs) that reduce errors and provide comprehensive data compared with previous methods are lacking. PURPOSE: The purpose of this in vitro study was to present a coordinate-based data analysis method to compare the accuracy of 5 IOSs for scanning completely dentate and partially edentulous casts. MATERIAL AND METHODS: Reference scans of 2 complete arch casts (completely and partially dentate) were digitized using a high-precision laboratory scanner (Ceramill Map 600). Each cast was scanned 10 times each using 5 IOSs (3Shape TRIOS 3, Planmeca Emerald, iTero Element 5D, Medit i500, and Shining Aoralscan 3). The dataset of all 10 test groups was analyzed by using a reverse engineering software program (Geomagic Wrap). Each test cast was aligned with the reference cast by 3-dimensional (3D) superimposition to determine the translation and rotation along the x-, y-, and z-axes. The dataset was analyzed using the Kruskal-Wallis and post hoc Bonferroni tests (α=.05). RESULTS: Significant differences were observed in all parameters among all scanners when scanning the same cast (P<.05). Significant differences were observed in at least 1 parameter for all scanners, except Element 5D after scanning different casts using the same scanner. Deviations in the test data generally relocated toward the mesial, buccal, and apical sides, and the casts were almost always rotated clockwise around the y-axis and counterclockwise around the z-axis. For the completely dentate cast, among all IOSs, Element 5D demonstrated the highest accuracy in most of the measured parameters, specifically in the y-axis translation (0.06[0.07] mm), z-axis translation (0.08[0.05] mm), and y-axis rotation (0.21[0.16] degree) (P<.05). For the partially edentulous cast, Element 5D displayed higher accuracy in most of the measured parameters, including the x-axis translation (0.11[0.14] mm) and z-axis rotation (0.12[0.18] degree) (P<.05). Emerald also displayed higher accuracy in most of the measured parameters, including the y-axis translation (0.05[0.08] mm) and y-axis rotation (0.14[0.12] degree) (P<.05). Element 5D exhibited no difference in the scanning accuracy between the 2 types of casts (P>.05). CONCLUSIONS: Element 5D offered a high level of accuracy and was an appropriate scanner for both situations. The method presented in this study provides a good assessment of accuracy deviations in complete arch scans using 3D coordinate-based data analysis.

Irisflorentin promotes bacterial phagocytosis and inhibits inflammatory responses in macrophages during bacterial infection.

Bacterial infection remains a big concern in the patients of ICU, which is the main cause of life-threatening organ dysfunction, or even sepsis. The poor control of bacterial infection caused by antibiotic resistance, etc. or the overwhelming immune response are the most important patho genic factors in intensive care unit (ICU) patients. As main pathogens, antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), impose serious challenges during sepsis and require alternative therapeutic options. Irisflorentin (IFL) is one of the major bioactive compounds isolated from the roots of Belamcanda chinensis (Shegan). In this study, IFL could suppress inflammatory response induced by MRSA or a synthetic mimic of bacterial lipoprotein (Pam3CSK4). IFL treatment enhanced the ability of macrophages to phagocytose bacteria likely through up-regulating the expression of phagocytic receptors SR-A1 and FcγR2a. Furthermore, IFL inhibited Pam3CSK4-induced production of pro-inflammatory cytokines, including IL-6 and TNF-α in Raw 264.7 cells, mouse primary macrophages or dendritic cells. IFL treatment also inhibited heat-killed MRSA-induced secretion of IL-6 and TNF-α in mouse bone marrow-derived macrophages. Moreover, IFL attenuated M1 polarization of macrophages as indicated by the down-regulated expression of its polarization markers CD86 and iNOS. Mechanistically, IFL markedly decreased the Pam3CSK4-induced activation of ERK, JNK or p38 MAPK pathways in macrophages. Taken together, IFL may serve as a promising compound for the therapy of bacterial infection, particularly those caused by antibiotic-resistant bacteria, such as MRSA.

Drug-related problems in hospitalized patients with chronic kidney diseases and clinical pharmacist interventions.

BACKGROUND: Patients with chronic kidney disease (CKD) are at high risk of drug-related problems (DRPs) because of extensive comorbidities and pharmacokinetic changes. This study aimed to identify DRPs and possible contributing factors in hospitalized patients with CKD, and evaluate the efficacy of the clinical pharmacist services in detection and intervention of DRPs in a large general hospital in Zhejiang Province, eastern China. METHODS: With the approval of the Ethics Committee, patients with CKD admitted to the nephrology ward from January to December 2020 were enrolled in this prospective study. The clinical pharmacist identified and intervened the DRPs during hospitalization. The DRPs were classified using the Pharmaceutical Care Network Europe (PCNE) DRP classification system, and all data were statistically analyzed using Statistical Package for Social Science (SPSS) version 26.0. RESULTS: A total of 914 patients with CKD were included, with 463 DRPs observed among 420 (45.95%) participants; the average DRP per patient was 0.51 (standard deviation [SD], 0.60) before pharmacist intervention. Treatment safety accounted for the highest proportion of problems (43.84%), followed by treatment efficacy, accounting for 43.20%. Drug selection was the most common cause of DRPs (60.26%), and antibiotics and cardiovascular agents were the most common drugs associated with DRPs (32.84% and 28.66%, respectively). A total of 85.53% of pharmaceutical intervention recommendations were followed, and 84.23% of DRPs were completely resolved after intervention by the clinical pharmacist. The proportion of patients who experienced DRPs decreased to 7.77%, with an average of 0.08 (SD 0.28) DRPs during hospitalization after pharmacist's intervention. Significant contributing factors for DRPs were CKD stage 4, number of comorbid diseases, number of prescribed medications, and hospitalization days in both the univariate and multivariate logistic regression models. CONCLUSION: DRPs are common among hospitalized patients with CKD in China. CKD stage 4, the number of comorbidities, use of multiple prescription drugs, and extended length of hospital stay are contributing factors for DRPs. Even only one clinical nephrology pharmacist in the nephrology ward, clinical pharmacist can play an important role in facilitating the identification of DRPs in patients with CKD and assisting physicians resolve DRPs in this single center study in China.

Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits Potent Efficacy as Monotherapy for Primary Central Nervous System Lymphoma.

BACKGROUND: The efficacy of systemic treatment for primary central nervous system lymphoma (PCNSL) is limited because of the blood-brain barrier (BBB) and the ineffectiveness of chemotherapy. The dual PI3K/HDAC inhibitor BEBT-908 has exhibited favorable in vivo distribution and activity in various cancers. OBJECTIVES: The aims of this study were to assess the efficacy of BEBT-908 in brain orthotopic mouse models of hematological malignancies, to investigate its pharmacologic properties, and to elucidate the underlying mechanism of action. METHODS: We evaluated the anticancer activity of BEBT-908 in various hematological malignancies through cell viability assays. The impact of BEBT-908 on c-Myc expression and ferroptosis signaling pathways was assessed using Western blotting, qPCR, ROS detection, GSH/GSSG detection, and IHC. Pharmacokinetic and pharmacodynamic profiles were assessed through LC-MS/MS and Western blotting. The effects of BEBT-908 in vivo were examined using xenografts and brain orthotopic mouse models. RESULTS: Our findings demonstrate that BEBT-908 exhibits promising anti-tumor activity in vitro and in vivo across multiple subtypes of hematological malignancies. Furthermore, BEBT-908 exhibits excellent BBB penetration and inhibits tumor growth in a brain orthotopic lymphoma model with prolonged survival of host mice. Mechanistically, BEBT-908 downregulated c-Myc expression, which contributed to ferroptosis, ultimately leading to tumor shrinkage. CONCLUSION: Our study provides robust evidence for the dual PI3K/HDAC inhibitor BEBT-908 as an effective anti-cancer agent for PCNSL.

Cytokine Storm in Acute Viral Respiratory Injury: Role of Qing-Fei-Pai-Du Decoction in Inhibiting the Infiltration of Neutrophils and Macrophages through TAK1/IKK/NF-[Formula: see text]B Pathway.

COVID-19 has posed unprecedented challenges to global public health since its outbreak. The Qing-Fei-Pai-Du decoction (QFPDD), a Chinese herbal formula, is widely used in China to treat COVID-19. It exerts an impressive therapeutic effect by inhibiting the progression from mild to critical disease in the clinic. However, the underlying mechanisms remain obscure. Both SARS-CoV-2 and influenza viruses elicit similar pathological processes. Their severe manifestations, such as acute respiratory distress syndrome (ARDS), multiple organ failure (MOF), and viral sepsis, are correlated with the cytokine storm. During flu infection, QFPDD reduced the lung indexes and downregulated the expressions of MCP-1, TNF-[Formula: see text], IL-6, and IL-1[Formula: see text] in broncho-alveolar lavage fluid (BALF), lungs, or serum samples. The infiltration of neutrophils and inflammatory monocytes in lungs was decreased dramatically, and lung injury was ameliorated in QFPDD-treated flu mice. In addition, QFPDD also inhibited the polarization of M1 macrophages and downregulated the expressions of IL-6, TNF-[Formula: see text], MIP-2, MCP-1, and IP-10, while also upregulating the IL-10 expression. The phosphorylated TAK1, IKK[Formula: see text]/[Formula: see text], and I[Formula: see text]B[Formula: see text] and the subsequent translocation of phosphorylated p65 into the nuclei were decreased by QFPDD. These findings indicated that QFPDD reduces the intensity of the cytokine storm by inhibiting the NF-[Formula: see text]B signaling pathway during severe viral infections, thereby providing theoretical and experimental support for its clinical application in respiratory viral infections.

Retrospective Analysis of Azithromycin-Resistant Ureaplasma urealyticum and Mycoplasma hominis Cervical Infection Among Pregnant Women.

Purpose: Ureaplasma urealyticum and Mycoplasma hominis began to show resistance to azithromycin, a macrolide antibiotic commonly used in pregnancy. Unfortunately, there are few effective and safe drugs in the clinic for genital mycoplasmas in pregnant women. In the present study, we investigated the prevalence of azithromycin-resistant U. urealyticum and M. hominis infections in pregnant women. The secondary research objects were possible influencing factors and consequences of insensitive Mycoplasma infection. Patients and methods: A retrospective analysis was carried out in pregnant women who underwent cervical Mycoplasma culture between October 2020 and October 2021 at a large general hospital in eastern China. The sociological characteristics and clinical information of these women were collected and analyzed. Results: A total of 375 pregnant women were enrolled, and 402 cultured mycoplasma specimens were collected. Overall, 186 (49.60%) patients tested positive cervical Mycoplasma infection, and 37 (9.87%) had infections caused by azithromycin-resistant Mycoplasma. In total, 39 mycoplasma samples were insensitive to azithromycin in vitro, also showing extremely high resistance to erythromycin, roxithromycin, and clarithromycin. Azithromycin was the only antibiotic used in women with Mycoplasma cervical infection, regardless of azithromycin resistance in vitro. Statistical results showed that azithromycin-resistant cervical Mycoplasma infection in pregnant women was unrelated to age, body mass index (BMI), gestational age, number of embryos, and assisted reproductive technology (ART) use, but led to a significantly increased incidence of adverse pregnancy outcomes (spontaneous abortion (SA), preterm birth (PTB), preterm prelabor rupture of membranes (PPROM), and stillbirth). Conclusion: Azithromycin-resistant U. urealyticum and M. hominis cervical infections are relatively common during pregnancy, and can increase the risk of adverse pregnancy outcomes; however, there is currently a lack of safe and effective drug treatments. Herein, we show that azithromycin-resistant mycoplasma infection requires timely intervention.

Development and validation of a nomogram to predict protein-energy wasting in patients with peritoneal dialysis: a multicenter cohort study.

Background: Protein-energy wasting (PEW) is a common complication in patients with peritoneal dialysis (PD). Few investigations involved risk factors identification and predictive model construction related to PEW. We aimed to develop a nomogram to predict PEW risk in patients with peritoneal dialysis. Methods: We collected data from end-stage renal disease (ESRD) patients who regularly underwent peritoneal dialysis between January 2011 and November 2022 at two hospitals retrospectively. The outcome of the nomogram was PEW. Multivariate logistic regression screened predictors and established a nomogram. We measured the predictive performance based on discrimination ability, calibration, and clinical utility. Evaluation indicators were receiver operating characteristic (ROC), calibrate curve, and decision curve analysis (DCA). The performance calculation of the internal validation cohort validated the nomogram. Results: In this study, 369 enrolled patients were divided into development (n = 210) and validation (n = 159) cohorts according to the proportion of 6:4. The incidence of PEW was 49.86%. Predictors were age, dialysis duration, glucose, C-reactive protein (CRP), creatinine clearance rate (Ccr), serum creatinine (Scr), serum calcium, and triglyceride (TG). These variables showed a good discriminate performance in development and validation cohorts (ROC = 0.769, 95% CI [0.705-0.832], ROC = 0.669, 95% CI [0.585-0.753]). This nomogram was adequately calibrated. The predicted probability was consistent with the observed outcome. Conclusion: This nomogram can predict the risk of PEW in patients with PD and provide valuable evidence for PEW prevention and decision-making.

Progressive supranuclear palsy's economical burden: the use and costs of healthcare resources in a large health provider in Israel.

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative movement disorder with no disease modifying therapy currently available. Data on the costs associated with PSP are scarce. This study aims to assess the direct medical expenditure of patients with PSP (PwPSP) throughout disease course. METHODS: This retrospective cohort study is based on the data of a large state-mandated health provider in Israel. We identified PwPSP who were initially diagnosed between 2000 and 2017. Each PwPSP was randomly matched to three health-plan members without PSP by birth-year, sex, and socioeconomic status. Healthcare resources' utilization and related costs were assessed. RESULTS: We identified 88 eligible PwPSP and 264 people in the reference group; mean age at diagnosis was 72.6 years (SD = 8.4) and 53.4% were female. The annual direct costs of PwPSP have risen over time, reaching US$ 21,637 in the fifth year and US$ 36,693 in the tenth year of follow-up vs US$ 8910 in the year prior diagnosis. Compared to people without PSP, PwPSP had substantially higher medical expenditure during the years prior- and post-index date. CONCLUSION: The present study demonstrates higher economic burden, which increases with time, in PwPSP as compared to those without.

Olfactory and neuropeptide inputs to appetite neurons in the arcuate nucleus.

The sense of smell has potent effects on appetite, but the underlying neural mechanisms are largely a mystery. The hypothalamic arcuate nucleus contains two subsets of neurons linked to appetite: AgRP (agouti-related peptide) neurons, which enhance appetite, and POMC (pro-opiomelanocortin) neurons, which suppress appetite. Here, we find that AgRP and POMC neurons receive indirect inputs from partially overlapping areas of the olfactory cortex, thus identifying their sources of odor signals. We also find neurons directly upstream of AgRP or POMC neurons in numerous other areas, identifying potential relays between the olfactory cortex and AgRP or POMC neurons. Transcriptome profiling of individual AgRP neurons reveals differential expression of receptors for multiple neuromodulators. Notably, known ligands of the receptors define subsets of neurons directly upstream of AgRP neurons in specific brain areas. Together, these findings indicate that higher olfactory areas can differentially influence AgRP and POMC appetite neurons, that subsets of AgRP neurons can be regulated by different neuromodulators, and that subsets of neurons upstream of AgRP neurons in specific brain areas use different neuromodulators, together or in distinct combinations to modulate AgRP neurons and thus appetite.

A network meta-analysis of the efficacy of hypoxia-inducible factor prolyl-hydroxylase inhibitors in dialysis chronic kidney disease.

BACKGROUND: Five types of HIF-PHIs have been authorized for anemia treatment in CKD patients in China and Japan. These are enarodustat, roxadustat, daprodustat, vadadustat, and molidustat. How effectively they compare to ESAs about clinical results in CKD-DD patients is uncertain. This study examined the RCT evidence about the benefits and risks of HIF-PHIs and ESAs in dialysis CKD patients. METHODS: We conducted an extensive investigation and network meta-analysis of RCTs. In these RCTs, patients with CKD-DD received one of five different HIF-PHI or ESAs, a placebo, and no medical intervention. Outcomes included hemoglobin, iron parameters, and adverse events, and there were four weeks of follow-up at least. A frequentist framework for multivariate random effects meta-analyzed the results. The effect sizes of categorical variables were displayed as odds ratios. Mean differences were employed for computing continuous outcomes with common units; otherwise, standardized mean differences were applied. The Cochrane tool evaluated the bias risk in RCTs. RESULTS: 26 RCTs with 14945 patients were qualified for inclusion. Compared to the placebo, HIF-PHIs and ESAs dramatically boosted hemoglobin without affecting serum iron. Roxadustat performed better hemoglobin levels than ESAs (MD 0.32, 95% CI 0.10 to 0.53) and daprodustat (0.46, 0.09 to 0.84). Roxadustat (91.8%) was the top hemoglobin treatment among all medical interventions, as determined by the SUCRA ranking. However, roxadustat caused more thrombosis and hypertension than ESAs (1.61, 1.22 to 2.12) and vadadustat (1.36, 1.01 to 1.82). The lowest rates of hypertension and thrombosis were seen in molidustat (80.7%) and ESAs (88.5%). Compared with a placebo, ESAs and HIF-PHIs all affected TSAT levels. Except for molidustat, the other four HIF-PHIs impact different iron parameters. Regarding ferritin reduction, roxadustat (90.9%) and daprodustat (60.9%) came out on top. Enarodustat (80.9%) and roxadustat (74%) placed best and second in lowering hepcidin levels. The former two medicines for TIBC improvement were vadadustat (98.7%) and enarodustat (80.9%). CONCLUSION: The most effective treatment for hemoglobin correction is roxadustat. The superior efficacy of reducing hepcidin makes roxadustat and enarodustat appropriate for patients with inflammation. However, the increased risk of hypertension and thrombosis associated with roxadustat should be noted. In patients at risk for hypertension and thrombosis, molidustat and ESAs may be preferable options. When administering roxadustat and daprodustat, clinicians should check ferritin to assess iron storage. Lower TSAT in patients receiving HIF-PHIs and ESAs treatment suggests intravenous iron supplements are needed.

Development and validation of a nomogram for predicting pulmonary infection in patients receiving immunosuppressive drugs.

Objective: Pulmonary infection (PI), a severe complication of immunosuppressive therapy, affects patients' prognosis. As part of this study, we aimed to construct a pulmonary infection prediction (PIP) model and validate it in patients receiving immunosuppressive drugs (ISDs). Methods: Totally, 7,977 patients being treated with ISDs were randomised 7:3 to the developing (n = 5,583) versus validation datasets (n = 2,394). Our predictive nomogram was established using the least absolute shrinkage and selection operator (LASSO) and multivariate COX regression analyses. With the use of the concordance index (C-index) and calibration curve, the prediction performance of the final model was evaluated. Results: Among the patients taking immunosuppressive medication, PI was observed in 548 (6.9%). The median time of PI occurrence after immunosuppressive therapy was 123.0 (interquartile range: 63.0, 436.0) days. Thirteen statistically significant independent predictors (sex, age, hypertension, DM, malignant tumour, use of biologics, use of CNIs, use of methylprednisolone at 500 mg, use of methylprednisolone at 40 mg, use of methylprednisolone at 40 mg total dose, use of oral glucocorticoids, albumin level, and haemoglobin level) were screened using the LASSO algorithm and multivariate COX regression analysis. The PIP model built on these features performed reasonably well, with the developing C-index of 0.87 (sensitivity: 85.4%; specificity: 81.0%) and validation C-indices of 0.837, 0.829, 0.832 and 0.830 for predicting 90-, 180-, 270- and 360-day PI probability, respectively. The decision curve analysis (DCA) and calibration curves displayed excellent clinical utility and calibration performance of the nomogram. Conclusion: The PIP model presented herein could aid in the prediction of PI risk in individual patients who receive immunosuppressive treatment and help personalise clinical decision-making.

[Reduning Injection protects flu-infected mice by inhibiting infiltration of inflammatory cells in lung and down-regulating cytokine storm].

This study aimed to explore the protective effect of Reduning Injection(RDN) on mice infected by influenza virus A/PR/8(PR8) and its immune regulatory roles during viral infection. In in vivo experiments, female C57 BL/6 mice were randomly divided into phosphate buffered saline(PBS) group, PR8-infected group, oseltamivir treatment group(OSV) and RDN treatment group. After 2 h of PR8 infection, mice in the oseltamivir group were gavaged with oseltamivir 30 mg·kg~(-1), and those in the RDN treatment group were injected intraperitoneally with RDN 1.5 mL·kg~(-1)once per day for seven consecutive days. The body weight of mice in each group was recorded at the same time every morning for 16 consecutive days. The line chart of body weight change was created to analyze the protective effect of RDN on flu-infected mice. The relative mRNA expression of different cytokines(IL-6, TNF-α, MCP-1, IL-1ß, MIP-2, IP-10 and IL-10) in lung samples of flu-infected mice was detected by PCR. Flow cytometry was utilized to analyze the composition of immune cells of mouse BALF samples on day 5 after infection. Mouse macrophage cell line RAW264.7 was planted and treated by different concentrations of RDN(150, 300, 600 µg·mL~(-1)) for 24 h or 48 h, and cell proliferation was detected by CCK-8 assay. RAW264.7 cells and mouse primary peritoneal macrophages were stimulated with synthetic single stranded RNA(R837), which elicited the inflammatory response by mimicking the infection of single-stranded RNA viruses. The expression of cytokines and chemokines in the supernatants of above culture system was detected by ELISA and qPCR. On days 4, 5, 6, 7 and 15 after infection, the body weight loss of mice in the RDN treatment group was alleviated compared with that of PR8-infected mice(P<0.05). RDN treatment obviously reduced lung index and the production of IL-6, TNF-α, MCP-1 and MIP-2 in lung tissues of flu-infected mice(P<0.05). The proportions of macrophages, neutrophils and T cells in mouse BALF samples were analyzed by flow cytometry, and compared with PR8-infected mice, RDN decreased the proportion of macrophages in BALF of flu-infected mice(P<0.05), and the proportion of T cells was recovered dramatically(P<0.001). In CCK-8 assay, the concentrations of RDN(150, 300, 600 µg·mL~(-1)) failed to cause cytotoxicity to RAW264.7 cells. In addition, RDN lowered the expression of inflammatory cytokines such as IL-6, TNF-α,MCP-1, IL-1ß, RANTES, and IP-10 and even anti-inflammatory cytokine IL-10 in R837-induced macrophages. RDN reduced the infiltration of inflammatory macrophages and the production of excessive inflammatory cytokines, alleviated the body weight loss of flu-infected mice. What's more, RDN restored the depletion of T cells, which might prevent secondary infection and deteriorative progression of the disease. Taken together, RDN may inhibit cytokine production and therefore down-regulate cytokine storm during the infection of influenza virus.

Epidemiology of Progressive Supranuclear Palsy: Real World Data from the Second Largest Health Plan in Israel.

Progressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative movement disorder and no disease modifying therapy (DMT) is currently available. This study aims to assess the epidemiology of PSP in Israel and to describe its clinical features. This retrospective analysis identified patients with PSP between 2000 and 2018 over the age of 40 years at first diagnosis (index date). We identified 209 patients with ≥1 diagnosis of PSP. Of those, 88 patients satisfied the inclusion criteria with a mean age at diagnosis of 72 years (SD = 8) and 53% were female. The 2018 prevalence and incidence rates were 5.3 and 1 per 100,000 persons, respectively. Median survival time was 4.9 years (95% CI 3.6-6.1) and median time from initial symptom to diagnosis was 4.2 years. The most common misdiagnoses were Parkinson's disease, cognitive disorder and depression. The present study demonstrates that the clinic-epidemiological features of PSP in Israel are similar to PSP worldwide. In light of PSP's rarity, investigation of PSP cohorts in different countries may create a proper platform for upcoming DMT trials.

LASSO-derived nomogram predicting new-onset diabetes mellitus in patients with kidney disease receiving immunosuppressive drugs.

WHAT IS KNOWN AND OBJECTIVE: Patients with kidney disease receiving immunosuppressive drugs (ISDs) (tacrolimus, cyclosporine and glucocorticoids) have a high risk of developing new-onset diabetes mellitus (NODM). We aimed to establish a precise and convenient model for predicting NODM in patients receiving immunosuppressive drugs. METHODS: This retrospective study recruited 1883 patients receiving ISDs between January 2010 and October 2018. The occurrence of NODM was the primary endpoint. The patients were randomly divided into training (n = 1318) and validation cohorts (n = 565) at a 7:3 ratio. A nomogram was established based on a least absolute shrinkage and selection operator (LASSO)-derived logistic regression model. The nomogram's discrimination and calibration abilities were evaluated in both cohorts using the Hosmer-Lemeshow test and calibration curves. Decision curve analysis (DCA) was used to evaluate the net benefit of the predictive efficacy. RESULTS AND DISCUSSION: Amongst the 1883 patients with kidney disease receiving immunosuppressive drugs, 375 (28.5%) and 169 (29.9%) developed NODM in the training (n = 1318) and validation cohorts (n = 565), respectively. Nine clinic predictors were included in this LASSO-derived nomogram, which is easy to be operated clinically. The discriminative ability, determined by the area under the receiver operating characteristic curve (AUC), was 0.816 (95% confidence interval [CI] 0.790-0.841) and 0.831 (95%CI 0.796-0.867) in the training and validation cohorts, respectively. Calibration was confirmed with the Hosmer-Lemeshow test in the training and validation cohorts (p = 0.238, p = 0.751, respectively). WHAT IS NEW AND CONCLUSION: Nearly one-third of patients with kidney disease receiving immunosuppressive drugs developed NODM. The nomogram established in this study may aid in predicting the occurrence of NODM in patients with kidney disease receiving immunosuppressive drugs.