The role of HLA-B*51 and other major histocompatibility complex (MHC) genes in Behçet's disease (BD) remains unknown. We have performed HLA and tumour necrosis factor (TNF) polymorphism analysis in BD and evaluated their contribution to ocular disease. In this study, 102 patients and 115 controls of Middle Eastern descent were investigated by HLA and B*51 subtyping using novel primers, and by LT alpha NCo 1 and TNF 308 promoter polymorphism analysis. The frequency of the HLA-B*51 family of alleles was raised in patients compared to controls (66% vs. 15%, Pc=2.5x10(-12), OR=10.9). The odds ratio (OR) of this group of alleles for subgroups of patients was as follows: non-ocular patients 7.8, all ocular patients 12.6, blind patients >22. HLA-B*51 subtyping detected B*5101, 07, 08 and 09 alleles, with a similar frequency among patients and controls. HLA-Cw*1602 was associated with B*5108, but was not an independent risk factor for disease. The LT alpha (TNFB*2) allele was associated with HLA-B*51 among patients and the frequency of this allele was significantly higher among completely blind patients compared to both non-ocular patients (P=0.048, OR >3.6) and to healthy controls (P=0.022, OR >4.3). The rare TNF-2 polymorphism at the TNF -308 promoter position was associated with HLA-B*50 (not B*51), and was not associated with BD. Thus, in this population the HLA*BBD, and in particular the development of ocular disease. HLA-B*51 subtyping did not define new markers for BD. A primary role for TNF gne polymorphisms in BD was not identified, but co-expression of the TNFB*2 allele with HLA-B*51 may contribute to severity of ocular disease.

Inexplicable controversies with regard to possible functional defects of neutrophilic polymorphonuclear leukocytes (PMNs) in diabetes persist. The purpose of the present study was to elucidate the relative effectiveness of several PMN agonists in stimulating lysosomal-enzyme secretion and leukotriene (LT) B(4) production by PMNs isolated from diabetic subjects. Formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) induced significantly less lysosomal-enzyme secretion and LTB(4) production in diabetic-subject PMNs than in normal-subject PMNs. It is surprising that PMNs from these same diabetic subjects responded normally after stimulation with A23187, serum-opsonized zymosan, or phorbol myristate acetate. The in vitro responsiveness of PMNs stimulated with fMLP or PAF was inversely correlated with indices of in vivo glycemic control (fasting plasma glucose and glycated-hemoglobin levels). In combination, these results indicate that hyperglycemia is associated with sustained decreases in PMN function but only in response to agonists that initiate stimulus-response coupling via G-protein-coupled receptors. This agonist-selective reduction in PMN responsiveness may contribute to the compromised host defense associated with sustained hyperglycemia in diabetes.

<A<em>b</em>stractText>Coronavirus disease (COVID-19) caused <em>b</em>y severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently a pandemic affecting over 200 countries. Many cities have esta<em>b</em>lished designated fever clinics to triage suspected COVID-19 patients from other patients with similar symptoms. However, given the limited availa<em>b</em>ility of the nucleic acid test as well as long waiting time for <em>b</em>oth the test and radiographic examination, the quarantine or therapeutic decisions for a large num<em>b</em>er of mixed patients were often not made in time. We aimed to identify simple and quickly availa<em>b</em>le la<em>b</em>oratory <em>b</em>iomarkers to facilitate effective triage at the fever clinics for sorting suspected COVID-19 patients from those with COVID-19-like symptoms.</A<em>b</em>stractText><p><div>(<em>b</em>)Methods</<em>b</em>)</div>We collected clinical, etiological, and la<em>b</em>oratory data of 989 patients who visited the Fever Clinic at Wuhan Union Hospital, Wuhan, China, from Jan 31 to Fe<em>b</em> 21. Based on polymerase chain reaction (PCR) nucleic acid testing for SARS-CoV-2 infection, they were divided into two groups: SARS-CoV-2-positive patients as cases and SARS-CoV-2-negative patients as controls. We compared the clinical features and la<em>b</em>oratory findings of the two groups, and analyzed the diagnostic performance of several la<em>b</em>oratory parameters in predicting SARS-CoV-2 infection and made relevant comparisons to the China diagnosis guideline of having a normal or decreased num<em>b</em>er of leukocytes (≤9•5 10⁹/L) or lymphopenia (&<em>lt</em>;1•1 10⁹/L).</p><p><div>(<em>b</em>)Findings</<em>b</em>)</div>Normal or decreased num<em>b</em>er of leukocytes (≤9•5 10⁹/L), lymphopenia (&<em>lt</em>;1•1 10⁹/L), eosinopenia (&<em>lt</em>;0•02 10⁹/L), and elevated hs-CRP (≥4 mg/L) were presented in 95•0%, 52•2%, 74•7% and 86•7% of COVID-19 patients, much higher than 87•2%, 28•8%, 31•3% and 45•2% of the controls, respectively. The eosinopenia produced a sensitivity of 74•7% and specificity of 68•7% for separating the two groups with the area under the curve (AUC) of 0•717. The com<em>b</em>ination of eosinopenia and elevated hs-CRP yielded a sensitivity of 67•9% and specificity of 78•2% (AUC=0•730). The addition of eosinopenia alone or the com<em>b</em>ination of eosinopenia and elevated hs-CRP into the guideline-recommended diagnostic parameters for COVID-19 improved the predictive capacity with higher than zero of <em>b</em>oth net reclassification improvement (NRI) and integrated discrimination improvement (IDI).</p><A<em>b</em>stractText>The com<em>b</em>ination of eosinopenia and elevated hs-CRP can effectively triage suspected COVID-19 patients from other patients attending the fever clinic with COVID-19-like initial symptoms. This finding would <em>b</em>e particularly useful for designing triage strategies in an epidemic region having a large num<em>b</em>er of patients with COVID-19 and other respiratory diseases while limited medical resources for nucleic acid tests and radiographic examination.</A<em>b</em>stractText><A<em>b</em>stractText>This work was supported <em>b</em>y the National Natural Science Foundation of China (NSFC) and the Major Scientific and Technological Innovation Projects of Hu<em>b</em>ei Province (MSTIP).</A<em>b</em>stractText>

<A<em>b</em>stractText>Nearly a quarter of patients with locally advanced (T4 stage) or perforated colon cancer are at risk of developing peritoneal metastases, often without curative treatment options. We aimed to determine the efficacy of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with locally advanced colon cancer.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>This mu<em>lt</em>icentre, open-la<em>b</em>el trial was done in nine hospitals that specialised in HIPEC in the Netherlands. Patients with clinical or pathological T4N0-2M0-stage tumours or perforated colon cancer were randomly assigned (1:1), with a we<em>b</em>-<em>b</em>ased randomisation application, <em>b</em>efore resection of the primary tumour, to adjuvant HIPEC followed <em>b</em>y routine adjuvant systemic chemotherapy (experimental group) or to adjuvant systemic chemotherapy alone (control group). Patients were stratified <em>b</em>y tumour characteristic (T4 or perforation), age (&<em>lt</em>;65 years or ≥65 years), and surgical approach of the primary tumour resection (laparoscopic or open). Key eligi<em>b</em>ility criteria included age <em>b</em>etween 18 and 75 years, adequate clinical condition for HIPEC, and intention to start adjuvant systemic chemotherapy. Patients with metastatic disease were ineligi<em>b</em>le. Adjuvant HIPEC consisted of fluorouracil (400 mg/m²) and leucovorin (20 mg/m²) delivered intravenously followed <em>b</em>y intraperitoneal delivery of oxaliplatin (460 mg/m²) for 30 min at 42°C, delivered simu<em>lt</em>aneously or within 5-8 weeks after primary tumour resection. In all patients without evidence of recurrent disease at 18 months, a diagnostic laparoscopy was done. The primary endpoint was peritoneal metastasis free-survival at 18 months, measured in the intention-to-treat population, with the Kaplan-Meier method. Adverse events were assessed in all patients who received assigned treatment. This study is registered with ClinicalTrials.gov, num<em>b</em>er NCT02231086.</p><A<em>b</em>stractText>Between April 1, 2015, and Fe<em>b</em> 20, 2017, 204 patients were randomly assigned to treatment (102 in each group). In the HIPEC group, two patients withdrew consent after randomisation. In this group, 19 (19%) of 100 patients were diagnosed with peritoneal metastases: nine (47%) during surgical exploration preceding intentional adjuvant HIPEC, eight (42%) during routine follow-up, and two (11%) during diagnostic laparoscopy at 18-months. In the control group, 23 (23%) of 102 patients were diagnosed with peritoneal metastases, of whom seven (30%) were diagnosed <em>b</em>y laparoscopy at 18-months and 16 during regular follow-up (therefore making them ineligi<em>b</em>le for diagnostic laparoscopy). In the intention-to-treat analysis (n=202), there was no difference in peritoneal-free survival at 18-months (80·9% [95% CI 73·3-88·5] for the experimental group vs 76·2% [68·0-84·4] for the control group, log-rank one-sided p=0·28). 12 (14%) of 87 patients who received adjuvant HIPEC developed postoperative complications and one (1%) encapsulating peritoneal sclerosis.</A<em>b</em>stractText><A<em>b</em>stractText>In patients with T4 or perforated colon cancer, treatment with adjuvant HIPEC with oxaliplatin did not improve peritoneal metastasis-free survival at 18 months. Routine use of adjuvant HIPEC is not advocated on the <em>b</em>asis of this trial.</A<em>b</em>stractText><A<em>b</em>stractText>Organization for Hea<em>lt</em>h Research and Development and the Dutch Cancer Society.</A<em>b</em>stractText>

Escherichia coli (E. coli) heat-labile toxin (LT) is a potent mucosal immunogen and immunoadjuvant towards co-administered antigens. LT is composed of one copy of the A subunit, which has ADP-ribosylation activity, and a homopentamer of B subunits, which has affinity for the toxin receptor, the ganglioside GM1. Both the ADP-ribosylation activity of LTA and GM1 binding of LTB have been proposed to be involved in immune stimulation. We investigated the roles of these activities in the immunogenicity of recombinant LT or LTB upon intranasal immunization of mice using LT/LTB mutants, lacking either ADP-ribosylation activity, GM1-binding affinity, or both. Likewise, the adjuvant properties of these LT/LTB variants towards influenza virus subunit antigen were investigated. With respect to the immunogenicity of LT and LTB, we found that GM1-binding activity is essential for effective induction of anti-LTB antibodies. On the other hand, an LT mutant lacking ADP-ribosylation activity retained the immunogenic properties of the native toxin, indicating that ADP ribosylation is not critically involved. Whereas adjuvanticity of LTB was found to be directly related to GM1-binding activity, adjuvanticity of LT was found to be independent of GM1-binding affinity. Moreover, a mutant lacking both GM1-binding and ADP-ribosylation activity, also retained adjuvanticity. These results demonstrate that neither ADP-ribosylation activity nor GM1 binding are essential for adjuvanticity of LT, and suggest an ADP-ribosylation-independent adjuvant effect of the A subunit.

<A<em>b</em>stractText>To evaluate the effect of metformin therapy on coronary endothelial function and major adverse cardiac events (MACE) in patients with predia<em>b</em>etes with sta<em>b</em>le angina and nono<em>b</em>structive coronary stenosis (NOCS).</A<em>b</em>stractText><A<em>b</em>stractText>Metformin therapy may <em>b</em>e needed to reduce coronary heart disease risk in patients with predia<em>b</em>etes. A total of 258 propensity score-matched (PSM) patients with sta<em>b</em>le angina undergoing coronary angiography were enrolled in the study. Data from 86 PSM su<em>b</em>jects with normoglycemia (NG), 86 PSM su<em>b</em>jects with predia<em>b</em>etes (pre-DM), and 86 PSM su<em>b</em>jects with predia<em>b</em>etes treated with metformin (pre-DM metformin) were analyzed. During coronary angiography, NOCS was categorized <em>b</em>y luminal stenosis &<em>lt</em>;40% and fractional flow reserve >0.80. In addition, we assessed the endothelial function, measuring coronary artery diameter of left anterior descending coronary (LAD) at <em>b</em>aseline and after the infusion of acetylcholine, <em>b</em>y means of an intracoronary Doppler guide wire. MACE, as cardiac death, myocardial infarction, and heart failure, was evaluated at 24 months of follow-up.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>At <em>b</em>aseline, NG patients had a lower percentage of LAD endothelial dysfunction compared with pre-DM patients (<i>P</i> &<em>lt</em>; 0.05). The patients with pre-DM had a higher percentage of endothelial LAD dysfunction as compared to patients with pre-DM treated with metformin (<i>P</i> &<em>lt</em>; 0.05). At the 24th month of follow-up, MACE was higher in pre-DM versus NG (<i>P</i> &<em>lt</em>; 0.05). In pre-DM metformin patients, MACE was lower compared with pre-DM patients (<i>P</i> &<em>lt</em>; 0.05).</p><A<em>b</em>stractText>Metformin therapy may reduce the high risk of cardiovascular events in pre-DM patients <em>b</em>y reducing coronary endothelial dysfunction.</A<em>b</em>stractText>

<A<em>b</em>stractText>Com<em>b</em>ined pro<em>b</em>iotic and selenium supplementation may improve Alzheimer's disease (AD) <em>b</em>y correcting meta<em>b</em>olic a<em>b</em>normalities, and attenuating inflammation and oxidative stress. This study aimed to determine the effects of pro<em>b</em>iotic and selenium co-supplementation on cognitive function and meta<em>b</em>olic status among patients with AD.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>This randomized, dou<em>b</em>le-<em>b</em>lind, controlled clinical trial was conducted among 79 patients with AD. Patients were randomly assigned to receive either selenium (200 μg/day) plus pro<em>b</em>iotic containing Lacto<em>b</em>acillus acidophilus, Bifido<em>b</em>acterium <em>b</em>ifidum, and Bifido<em>b</em>acterium longum (2 × 10⁹ CFU/day each) (n = 27), selenium (200 μg/day) (n = 26) or place<em>b</em>o (n = 26) for 12 weeks.</p><A<em>b</em>stractText>Selenium supplementation, compared with the place<em>b</em>o, significantly reduced serum high sensitivity C-reactive protein (hs-CRP) (P &<em>lt</em>; 0.001), insulin (P = 0.001), homeostasis model of assessment-insulin resistance (HOMA-IR) (P = 0.002), LDL-cholesterol (P = 0.04) and total-/HDL-cholesterol ratio (P = 0.004), and significantly increased total glutathione (GSH) (P = 0.001) and the quantitative insulin sensitivity check index (QUICKI) (P = 0.01). Compared with only selenium and place<em>b</em>o, pro<em>b</em>iotic and selenium co-supplementation resu<em>lt</em>ed in a significant increase in mini-mental state examination score (+1.5 ± 1.3 vs. +0.5 ± 1.2 and -0.2 ± 1.1, respectively, P &<em>lt</em>; 0.001). Pro<em>b</em>iotic plus selenium intake resu<em>lt</em>ed in a significant reduction in hs-CRP (-1.6 ± 1.4 vs. -0.8 ± 1.0 and +0.1 ± 0.5 mg/L, respectively, P &<em>lt</em>; 0.001), and a significant increase in total antioxidant capacity (+89.4 ± 129.6 vs. +20.0 ± 62.5 and -0.7 ± 27.2 mmol/L, respectively, P = 0.001) and GSH (+122.8 ± 136.5 vs. +102.2 ± 135.2 and +1.5 ± 53.2 μmol/L, respectively, P = 0.001) compared with only selenium and place<em>b</em>o. In addition, su<em>b</em>jects who received pro<em>b</em>iotic plus selenium supplements had significantly lower insulin levels (-2.1 ± 2.5 vs. -1.0 ± 1.3 and +0.7 ± 2.0 μIU/mL, respectively, P &<em>lt</em>; 0.001), HOMA-IR (-0.5 ± 0.6 vs. -0.2 ± 0.3 and +0.1 ± 0.4, respectively, P &<em>lt</em>; 0.001), and higher QUICKI (+0.01 ± 0.01 vs. +0.005 ± 0.007 and -0.002 ± 0.01, respectively, P &<em>lt</em>; 0.006) compared with only selenium and place<em>b</em>o. Additionally, pro<em>b</em>iotic and selenium co-supplementation resu<em>lt</em>ed in a significant reduction in serum triglycerides (-17.9 ± 26.1 vs. -3.5 ± 33.9 and +0.3 ± 9.3 mg/dL, respectively, P = 0.02), VLDL- (-3.6 ± 5.2 vs. -0.7 ± 6.8 and +0.05 ± 1.8 mg/dL, respectively, P = 0.02), LDL- (-8.8 ± 17.8 vs. -8.1 ± 19.2 and +2.7 ± 19.0 mg/dL, respectively, P = 0.04) and total-/HDL-cholesterol (-0.3 ± 0.7 vs. -0.4 ± 0.9 and +0.3 ± 0.6, respectively, P = 0.005) compared with only selenium and place<em>b</em>o.</A<em>b</em>stractText><A<em>b</em>stractText>Overall, we found that pro<em>b</em>iotic and selenium co-supplementation for 12 weeks to patients with AD improved cognitive function and some meta<em>b</em>olic profiles. This study was registered in the Iranian we<em>b</em>site (www.irct.ir) for registration of clinical trials (http://www.irct.ir: IRCT20170612034497N5).</A<em>b</em>stractText>

<A<em>b</em>stractText>In the CLASSIC and MAGIC trials, microsatellite insta<em>b</em>ility (MSI)-high status was a favora<em>b</em>le prognostic and potential negative predictive factor for neoadjuvant/adjuvant chemotherapy in resecta<em>b</em>le gastric cancer (GC). Given the low prevalence of MSI-high status in GC and its association with other positive prognostic varia<em>b</em>les, large data sets are needed to draw ro<em>b</em>ust evidence of its prognostic/predictive value.</A<em>b</em>stractText><p><div>(<em>b</em>)PATIENTS AND METHODS</<em>b</em>)</div>We performed a mu<em>lt</em>inational, individual-patient-data meta-analysis of the prognostic/predictive role of MSI in patients with resecta<em>b</em>le GC enrolled in the MAGIC, CLASSIC, ARTIST, and ITACA-S trials. Prognostic analyses used mu<em>lt</em>ivaria<em>b</em>le Cox models (MVM). The predictive role of MSI was assessed <em>b</em>oth in an all-comer population and in MAGIC and CLASSIC trials <em>b</em>y MVM testing of the interaction of treatment (chemotherapy plus surgery <i>v</i> surgery) with MSI.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>MSI status was availa<em>b</em>le for 1,556 patients: 121 (7.8%) had MSI-high status; 576 were European, and 980 were Asian. In MSI-high versus MSI-low/microsatellite sta<em>b</em>le (MSS) comparisons, the 5-year disease-free survival (DFS) was 71.8% (95% CI, 63.8% to 80.7%) versus 52.3% (95% CI, 49.7% to 55.1%); the 5-year overall survival (OS) was 77.5% (95% CI, 70.0% to 85.8%) versus 59.3% (95% CI, 56.6% to 62.1%). In MVM, MSI was associated with longer DFS (hazard ratio [HR], 1.88; 95% CI, 1.28 to 2.76; <i>P</i> &<em>lt</em>; .001) and OS (HR, 1.78; 95% CI, 1.17 to 2.73; <i>P</i> = .008), as were pT, pN, ethnicity, and treatment. Patients with MSI-low/MSS GC <em>b</em>enefitted from chemotherapy plus surgery: the 5-year DFS compared with surgery only was 57% versus 41% (HR, 0.65; 95% CI, 0.53 to 0.79), and the 5-year OS was 62% versus 53% (HR, 0.75; 95% CI, 0.60 to 0.94). Conversely, those with MSI-high GC did not: the 5-year DFS was 70% versus 77% (HR, 1.27; 95% CI, 0.53 to 3.04), and the 5-year OS was 75% versus 83% (HR, 1.50; 95% CI, 0.55 to 4.12).</p><A<em>b</em>stractText>In patients with resecta<em>b</em>le primary GC, MSI is a ro<em>b</em>ust prognostic marker that should <em>b</em>e adopted as a stratification factor <em>b</em>y clinical trials. Chemotherapy omission and/or immune checkpoint <em>b</em>lockade should <em>b</em>e investigated prospectively in MSI-high GCs according to clinically and pathologically defined risk of relapse.</A<em>b</em>stractText>

<A<em>b</em>stractText>Clinical outcomes for advanced malignant melanoma (MM) are often poor due to tumor invasiveness, metastasis, recurrence, and mu<em>lt</em>idrug resistance.</A<em>b</em>stractText><A<em>b</em>stractText>We investigated whether apoptosis, cell cycle regulation, oxidative status, and redox <em>b</em>alance were a<em>lt</em>ered <em>b</em>y changes in the expression of the long noncoding RNA, growth arrest-specific transcript 5 (GAS5), in MM cells.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Analysis of clinical samples from MM patients showed that the rate of reduced GAS5 expression, relative to that in adjacent noncancerous tissues, was significantly lower for tumors from patients with advanced disease (76.6%, P &<em>lt</em>; 0.001), as evidenced <em>b</em>y larger tumor size, higher TNM stage, and higher incidences of ulceration and metastasis (P &<em>lt</em>; 0.001 for all). Cell cu<em>lt</em>ure experiments showed that siRNA-mediated knockdown of GAS5 increased the via<em>b</em>ility of A375-GAS5si cells. Flow cytometry and western <em>b</em>lotting showed that GAS5 knockdown increased MM cell proliferation <em>b</em>y inducing G1/S cell cycle progression through increases in Cyclin D1, CDK4, and p27 expression (P &<em>lt</em>; 0.05 for all) and <em>b</em>y inhi<em>b</em>iting apoptosis through an increase in Bcl-2 expression (P &<em>lt</em>; 0.001). Knockdown of GAS5 also increased levels of superoxide anion (P &<em>lt</em>; 0.01), NADP⁺(P &<em>lt</em>; 0.001), and oxidized glutathiones (P &<em>lt</em>; 0.01) through increases in NOX4 expression (P &<em>lt</em>; 0.001), G6PD expression (P &<em>lt</em>; 0.01), and NOX activity (P &<em>lt</em>; 0.05), and RNA co-immunoprecipitation showed that GAS5 induced these changes through a physical interaction <em>b</em>etween GAS5 and the G6PD protein.</p><A<em>b</em>stractText>Our findings show GAS5 contri<em>b</em>utes to regulation of the apoptosis, cell cycle, homeostasis of reactive oxygen species, and redox <em>b</em>alance in MM cells, and suggest that reduced GAS5 expression contri<em>b</em>utes to disease progression in MM patients.</A<em>b</em>stractText>

Most toxigenic strains of Clostridium difficile produce two toxins: an enterotoxin (toxin A) and a cytotoxin (toxin B). Only one strain (strain 8864) has been reported to produce toxin B but no toxin A. Serogroup F strains (44) of C. difficile, often isolated from asymptomatic infants, have been examined for toxin production. These strains, which were from distinct geographical and clinical sources, did not produce any detectable toxin A in vitro when examined in three distinct immunoassays. Nevertheless, all the strain produced a cytotoxin. Immunological differences between the cytotoxin of the serogroup F strains and that produced by C. difficile strain VPI 10463 (serogroup G) were demonstrated with monoclonal antibodies specific for either the toxin B produced by C. difficile strain VPI 10463 or C. sordellii lethal toxin (LT). Polymerase chain reaction amplification with primers derived from C. difficile strain VPI 10463 toxin A and B genes showed that serogroup F strains seem to possess a toxin B gene homologous with that of strain VPI 10463 and at least fragments of the toxin A gene. When axenic mice were inoculated with serogroup F strains, the animals survived; they did not develop diarrhoea and no toxin A could be detected in their faeces. However, cytotoxin was detected. Furthermore, these mice were protected against subsequent challenge with the otherwise lethally toxigenic C. difficile strain VPI 10463. The serogroup F strains appeared to be homogeneous and distinct from other C. difficile strains with regard to toxin production.

<A<em>b</em>stractText>To investigate CT images of 100 confirmed COVID-19 pneumonia patients to descri<em>b</em>e the lesion distri<em>b</em>ution, CT signs, and evolution during different courses.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>A retrospective study of 100 COVID-19 pneumonia patients without ARDS was performed, and CT scans were reviewed. A COVID-19 pneumonia course diagram was drawn. Mann-Whitney U test was used to compare the lesion distri<em>b</em>ution and CT scores, χ² test was used to compare the CT findings <em>b</em>etween different stages.</p><A<em>b</em>stractText>A total of 272 CT scans from 100 patients (mean age, 52.3 years ± 13.1) were investigated. Four patients with lung a<em>b</em>normalities on CT first showed negative RT-PCR resu<em>lt</em> and turned positive afterwards. One hundred sixty-nine (62.1%) showed predominantly peripheral distri<em>b</em>ution. The CT scores of the upper zone (3.4 ± 3.6) were significantly lower than those of the middle (5.0 ± 3.9) and lower (4.8 ± 3.6) zones (p &<em>lt</em>; 0.001). The CT scores of the anterior zones (4.9 ± 4.7) were significantly lower than those of the posterior zones (8.4 ± 6.2) (p &<em>lt</em>; 0.001). In the early rapid progressive stage (1~7 days), ground glass opacity (GGO) plus reticular pattern (58.1%), GGO plus consolidation (43.0%), and GGO (41.9%) were all common. In the advanced stage (8~14 days), GGO plus consolidation (79.8%) and repairing CT signs (su<em>b</em>pleural line, <em>b</em>ronchus distortion, and fi<em>b</em>rotic strips) showed a significant increase (p &<em>lt</em>; 0.05). In the a<em>b</em>sorption stage, GGO plus consolidation (9.1%) sharply decreased (p &<em>lt</em>; 0.05).</A<em>b</em>stractText><A<em>b</em>stractText>CT imaging of COVID-19 pneumonia showed a predominantly peripheral, middle and lower, and posterior distri<em>b</em>ution. The early rapid progressive stage is 1~7 days from symptom onset, the advanced stage with peak levels of a<em>b</em>normalities on CT is 8~14 days, and the a<em>b</em>normalities started to improve after 14 days.</A<em>b</em>stractText><A<em>b</em>stractText>• The course of COVID-19 pneumonia consists of three stages: 1~7 days is the early rapid progressive stage, 8~14 days is the advanced stage, and after 14 days, the a<em>b</em>normalities started to decrease. • In the early rapid progressive stage, GGO plus a reticular pattern, GGO plus consolidation, and GGO were all common signs; in the advanced stage, signs of progression and a<em>b</em>sorption coexisted; lung a<em>b</em>normalities showed an asynchronous process with parts with a<em>b</em>sorption and parts progressing. • Lung a<em>b</em>normalities mainly showed predominantly peripheral, middle, and lower distri<em>b</em>ution.</A<em>b</em>stractText>

Low voltage-activated (T-type) Ca2+ channels are responsible for generating low-threshold spikes (LTS) that facilitate burst firing and transmitter release in neurons. The T-type Ca2+ channels contain a regulatory alpha1 subunit, and several isoforms of the alpha1 subunit (Cav3.1, 3.2, 3.3) have been cloned. The Cav 3.1 alpha1 subunit is abundantly expressed in the hypothalamus. Previously, we found that 17 beta-estradiol (E2) increased the number of arcuate neurons expressing LTS. Therefore, we used an ovariectomized female guinea pig model to measure the distribution and regulation of Cav3.1 mRNA expression by E2. Guinea pig Cav3.1 alpha1 subunit sequences, which were cloned by PCR, were used in ribonuclease protection (RPA) and in situ hybridization assays to evaluate mRNA expression. Based on a RPA, E2 significantly increased the mRNA expression of Cav3.1 alpha1 subunit in the mediobasal hypothalamus and the pituitary. In situ hybridization analysis revealed that E2 significantly increased Cav 3.1 mRNA expression in medial preoptic nuclei, bed nuclei stria terminalis, and the arcuate nucleus. Whole-cell patch recordings in arcuate neurons revealed that E2 treatment significantly increased the peak T-type Ca2+ current density by twofold without affecting the activation/inactivation characteristics and augmented the rebound excitation by threefold to fourfold. These results suggest that estrogen regulates the mRNA expression of T-type calcium channels, which leads to increased functional expression of the channel. Increased expression of T-type channels could be one mechanism by which estrogen augments burst firing and transmitter release in hypothalamic neurons.

Glioblastoma (GBM) is the most common and malignant type of primary brain tumor in adults and prognosis of most GBM patients is poor. However, a small percentage of patients show a long term survival of 36 mo or longer after diagnosis. Epigenetic profiles can provide molecular markers for patient prognosis: recently, a G-CIMP positive phenotype associated with IDH1 mutations has been described for GBMs with good prognosis. In the present analysis we performed genome-wide DNA methylation profiling of short-term survivors (STS; overall survival < 1 y) and long-term survivors (LTS; overall survival>> 3 y) by utilizing the HumanMethylation450K BeadChips to assess quantitative methylation at>> 480,000 CpG sites. Cluster analysis has shown that a subset of LTS showed a G-CIMP positive phenotype that was tightly associated with IDH1 mutation status and was confirmed by analysis of the G-CIMP signature genes. Using high stringency criteria for differential hypermethylation between non-cancer brain and tumor samples, we identified 2,638 hypermethylated CpG loci (890 genes) in STS GBMs, 3,101 hypermethylated CpG loci (1,062 genes) in LTS (wild type IDH1) and 11,293 hypermethylated CpG loci in LTS (mutated for IDH1), reflecting the CIMP positive phenotype. The location of differentially hypermethylated CpG loci with respect to CpG content, neighborhood context and functional genomic distribution was similar in our sample set, with the majority of CpG loci residing in CpG islands and in gene promoters. Our preliminary study also identified a set of CpG loci differentially hypermethylated between STS and LTS cases, including members of the homeobox gene family (HOXD8, HOXD13 and HOXC4), the transcription factors NR2F2 and TFAP2A, and Dickkopf 2, a negative regulator of the wnt/β-catenin signaling pathway.

BACKGROUND

The pivot-shift test is considered a reliable examination to evaluate the results of anterior cruciate ligament (ACL) reconstruction, as it strongly correlates with patient satisfaction, giving-way episodes, and activity level. The addition of lateral tenodesis (LT) to current techniques of intra-articular reconstruction with a hamstring graft could potentially improve knee laxity in cases of severe rotational instability.

OBJECTIVE

To biomechanically investigate the effect of intra- and extra-articular ACL reconstructions on knee laxity and the pivot-shift phenomenon.

METHODS

Controlled laboratory study.

METHODS

Twenty patients underwent anatomic single-bundle ACL reconstruction with doubled semitendinosus and gracilis tendons with the addition of extra-articular reconstruction. In patients in group A, intra-articular reconstruction was performed first and LT thereafter; in patients in group B, LT was performed first and intra-articular reconstruction thereafter. A navigator equipped with software designed for both static and dynamic evaluations was used to measure maximum anterior tibial translation (ATT) and axial tibial rotation (ATR) at 30° of flexion (static evaluation) and during the pivot-shift test (dynamic evaluation). Measurements were performed before reconstruction, after the first procedure, and after the second procedure.

RESULTS

For the static evaluation, in group A, the mean ATT significantly decreased from 14.1 ± 3.7 mm in the preoperative (ACL-deficient) condition to 6.0 ± 1.9 mm after ACL reconstruction and to 5.3 ± 1.6 mm after LT. The mean ATR at 30° of knee flexion significantly decreased from 35.7° ± 4.8° to 28.9° ± 4.1° and to 20.9° ± 4.8°, respectively. In group B, the mean ATT significantly decreased from 13.5 ± 6.5 mm in the preoperative (ACL-deficient) condition to 10.2 ± 3.2 mm after LT and to 4.0 ± 1.6 mm after ACL reconstruction. The mean ATR at 30° of knee flexion significantly decreased from 36.7° ± 4.8° to 26.2° ± 6.2° and to 23.5° ± 4.9°, respectively. For the dynamic evaluation (pivot-shift test), in group A, the mean ATT significantly decreased from 15.0 ± 6.8 mm in the preoperative (ACL-deficient) condition to 9.4 ± 6.4 mm after ACL reconstruction and to 8.5 ± 5.4 mm after LT. The mean ATR significantly decreased from 16.9° ± 4.7° to 11.6° ± 4.1° and to 6.1° ± 2.2°, respectively. In group B, the mean ATT significantly decreased from 12.5 ± 3.3 mm in the preoperative (ACL-deficient) condition to 9.1 ± 5.9 mm after LT and to 8.1 ± 5.4 mm after ACL reconstruction. The mean ATR significantly decreased from 16.0° ± 4.5° to 9.2° ± 4.3° and to 7.5° ± 4.0°, respectively.

CONCLUSIONS

Extra-articular reconstruction had little effect in reducing the anterior displacement of the tibia at 30° of flexion, but it was more effective than intra-articular reconstruction in reducing ATR. Anatomic ACL reconstruction and LT were synergic in controlling the pivot-shift phenomenon.

<A<em>b</em>stractText>Recently, trimethylamine-N-oxide (TMAO) plasma levels have <em>b</em>een proved to <em>b</em>e associated with atherosclerosis development. Among the targets aimed to ameliorating atherosclerotic lesions, inducing <em>b</em>ile acid synthesis to eliminate excess cholesterol in <em>b</em>ody is an effective way. Individual <em>b</em>ile acid as endogenous ligands for the nuclear receptor has differential effects on regulating <em>b</em>ile acid meta<em>b</em>olism. It is unclear whether <em>b</em>ile acid profiles are mechanistically linked to TMAO-induced development of atherosclerosis.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>Male apoE^-/- mice were fed with control diet containing 0.3% TMAO for 8 weeks. Aortic lesion development and serum lipid profiles were determined. Bile acid profiles in <em>b</em>ile, liver and serum were measured <em>b</em>y liquid chromatographic separation and mass spectrometric detection (LC-MS). Real-time PCRs were performed to analyze mRNA expression of genes related to hepatic <em>b</em>ile acid meta<em>b</em>olism.</p><A<em>b</em>stractText>The total plaque areas in the aortas strongly increased 2-fold (P &<em>lt</em>; 0.001) in TMAO administration mice. The levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) in TMAO group were also significantly increased <em>b</em>y 25.5% (P = 0.044), 31.2% (P = 0.006), 28.3% (P = 0.032), respectively. TMAO nota<em>b</em>ly changed <em>b</em>ile acid profiles, especially in serum, the most prominent inductions were tauromuricholic acid (TMCA), deoxycholic acid (DCA) and cholic acid (CA). Mechanically, TMAO inhi<em>b</em>ited hepatic <em>b</em>ile acid synthesis <em>b</em>y specifically repressing the classical <em>b</em>ile acid synthesis pathway, which might <em>b</em>e mediated <em>b</em>y activation of small heterodimer partner (SHP) and farnesoid X receptor (FXR).</A<em>b</em>stractText><p><div>(<em>b</em>)CONCLUSIONS</<em>b</em>)</div>These findings suggested that TMAO accelerated aortic lesion formation in apoE^-/- mice <em>b</em>y a<em>lt</em>ering <em>b</em>ile acid profiles, further activating nuclear receptor FXR and SHP to inhi<em>b</em>it <em>b</em>ile acid synthesis <em>b</em>y reducing Cyp7a1 expression.</p>

Age-related macular degeneration (AMD) is the leading cause of vision loss in the western world. Recent evidence suggests that RPE and photoreceptors have an interconnected metabolism and that mitochondrial damage in RPE is a trigger for degeneration in both RPE and photoreceptors in AMD. To test this hypothesis, this study was designed to induce mitochondrial damage in RPE in mice to determine whether this is sufficient to cause RPE and photoreceptor damage characteristic of AMD. In this study, we conditionally deleted the gene encoding the mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD encoded by Sod2) in the retinal pigment epithelium (RPE) of albino BALB/cJ mice. VMD2-Cre;Sod2^flox/flox BALB/cJ mice were housed in either 12-h dark, 12-h 200 lux white lighting (normal light), or 12-h dark, 12-h &lt;10 lux red lighting (dim light). Electroretinography (ERG) and spectral-domain optical coherence tomography (SD-OCT) were performed to assess retinal function and morphology. Immunofluorescence was used to examine protein expression; quantitative RT-PCR was used to measure gene expression. Sod2 knockout (KO) mice had reduced RPE function with age and increased oxidative stress compared to wild type (WT) controls as expected by the cell-specific deletion of Sod2. This was associated with alterations in RPE morphology and the structure and function of RPE mitochondria. In addition, data show a compensatory increase in RPE glycolytic metabolism. The metabolic shift in RPE correlated with severe disruption of photoreceptor mitochondria including a reduction in TOMM20 expression, mitochondrial fragmentation, and reduced COXIII/β-actin levels. These findings demonstrate that mitochondrial oxidative stress can lead to RPE dysfunction and metabolic reprogramming of RPE. Secondary to these changes, photoreceptors also undergo metabolic stress with increased mitochondrial damage. These data are consistent with the hypothesis of a linked metabolism between RPE and photoreceptors and suggest a mechanism of retinal degeneration in dry AMD.

Neutrophil migration into infected tissues is essential for host defense, but products of activated neutrophils can be quite damaging to host cells. Neutrophil influx into the lung and airways and resultant inflammation characterizes diseases such as chronic obstructive pulmonary disease, bronchiectasis, and cystic fibrosis. To migrate, neutrophils must reorganize the actin cytoskeleton to establish a leading edge pseudopod and a trailing edge uropod. The actin-binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) has been shown to bind and cross-link actin in a variety of cell types and to co-localize with F-actin in the leading edge lamellipodium of migrating fibroblasts. The hypothesis that MARCKS has a role in the regulation of neutrophil migration was tested using a cell-permeant peptide derived from the MARCKS myristoylated aminoterminus (MANS peptide). Treatment of isolated human neutrophils with MANS significantly inhibited both their migration and beta2 integrin-dependent adhesion in response to N-formyl-methionyl-leucyl-phenylalanine (fMLF), IL-8, or leukotriene (LT)B(4). The IC(50) for fMLF-induced migration and adhesion was 17.1 microM and 12.5 microM, respectively. MANS significantly reduced the F-actin content in neutrophils 30 seconds after fMLF stimulation, although the peptide did not alter the ability of cells to polarize or spread. MANS did not alter fMLF-induced increases in surface beta2 integrin expression. These results suggest that MARCKS, via its myristoylated aminoterminus, is a key regulator of neutrophil migration and adhesion.

<A<em>b</em>stractText>Pancreatic ductal adenocarcinoma (PDAC) is the most deadly type of tumor, and its pathogenesis remains unknown. Circular RNAs (circRNAs) may <em>b</em>e functional and <em>b</em>ind to microRNAs and consequently, influence the activity of targeted mRNAs. Recent researches indicate that one circRNA, ciRS-7, acts as a sponge of miR-7 and thus, inhi<em>b</em>its its activity. It is well known that miR-7 is a cancer suppressor in many cancers. However, the relationship <em>b</em>etween ciRS-7 and miR-7, and the role of ciRS-7 in PDAC, remains to <em>b</em>e elucidated.</A<em>b</em>stractText><A<em>b</em>stractText>miR-7 and ciRS-7 expression in 41 pairs of PDAC tumors and their paracancerous tissues were detected <em>b</em>y quantitative reverse transcription polymerase chain reaction (qRT-PCR). The relationships <em>b</em>etween their expression levels and clinicopathological features in PDAC tissues were assessed. The relationship <em>b</em>etween miR-7 and ciRS-7 was also assessed <em>b</em>y Spearman's correlation. We also used cell lines to evaluate the role of ciRS-7 in cell line <em>b</em>ehavior. The ciRS-7 interfere RNA (siRNA) and its empty vector were transfected into PDAC cells. PDAC cells proliferation and invasion a<em>b</em>ilities were detected <em>b</em>y MTT assay and invasion analysis. The expression of proteins was assessed <em>b</em>y Western <em>b</em>lotting.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>ciRS-7 expression was significantly higher in PDAC tissues than paracancerous tissues (P = 0.002). However, miR-7 expression showed the opposite trend (P = 0.048). Moreover, ciRS-7 expression was inversely correlated with miR-7 in PDAC ( r<su<em>b</em>)s</su<em>b</em>) = -0.353, P = 0.023). ciRS-7 expression was also significantly elevated in venous invasion (3.72 ± 2.93 vs. 2.14 ± 1.26; P = 0.028) and lymph node metastasis (4.19 ± 2.75 vs. 2.32 ± 1.90; P = 0.016) in PDAC patients. Furthermore, ciRS-7 knockdown suppressed cell proliferation and invasion of PDAC cells (P &<em>lt</em>; 0.05), and the downregulation of ciRS-7 resu<em>lt</em>ed in miR-7 overexpression and su<em>b</em>sequent inhi<em>b</em>ition of epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3).</p><A<em>b</em>stractText>Circular RNA ciRS-7 plays an oncogene role in PDAC, partly <em>b</em>y targeting miR-7 and regulating the EGFR/STAT3 signaling pathway.</A<em>b</em>stractText>

(<em>b</em>)Background:</<em>b</em>) Cardiac injury is common in hospitalized patients with COVID-19 and portends poorer prognosis. However, the mechanism and the type of myocardial damage associated with SARS-CoV-2 remain uncertain. (<em>b</em>)Methods:</<em>b</em>) We conducted a systematic pathologic analysis of 40 hearts from hospitalized patients dying of Coronavirus Disease 2019 (COVID-19) in Bergamo, Italy to determine the pathologic mechanisms of cardiac injury. We divided the hearts according to presence or a<em>b</em>sence of acute myocyte necrosis and then determined the underlying mechanisms of cardiac injury. (<em>b</em>)Resu<em>lt</em>s:</<em>b</em>) Of the 40 hearts examined, 14 (35%) had evidence of myocyte necrosis, predominantly of the left ventricle. As compared to su<em>b</em>jects without necrosis, su<em>b</em>jects with necrosis tended to <em>b</em>e female, have chronic kidney disease, and shorter symptom onset to admission. The incidence of severe coronary artery disease (i.e., >75% cross sectional narrowing) was not significantly different <em>b</em>etween those with and without necrosis. 3/14 (21 .4%) su<em>b</em>jects with myocyte necrosis showed evidence of acute myocardial infarction defined as ≥1 cm² area of necrosis while 11/14 (78.6%) showed evidence of focal (> 20 necrotic myocytes with an area of ≥ 0.05 mm² <em>b</em>ut &<em>lt</em>;1 cm²) myocyte necrosis. Cardiac throm<em>b</em>i were present in 11/14 (78.6%) cases with necrosis, with 2/14 (14.2%) having epicardial coronary artery throm<em>b</em>i while 9/14 (64.3%) had microthrom<em>b</em>i in myocardial capillaries, arterioles, and small muscular arteries. We compared cardiac microthrom<em>b</em>i from COVID-19 positive autopsy cases to intramyocardial throm<em>b</em>oem<em>b</em>oli from COVID-19 cases as well as to aspirated throm<em>b</em>i o<em>b</em>tained during primary percutaneous coronary intervention from uninfected and COVID-19 infected patients presenting with ST-segment elevation myocardial infarction (STEMI). Microthrom<em>b</em>i had significantly greater fi<em>b</em>rin and terminal complement C5<em>b</em>-9 immunostaining as compared to intramyocardial throm<em>b</em>oem<em>b</em>oli from COVID-19 negative su<em>b</em>jects and to aspirated throm<em>b</em>i. There were no significant differences <em>b</em>etween the constituents of throm<em>b</em>i aspirated from COVID-19 positive and negative STEMI patients. (<em>b</em>)Conclusions:</<em>b</em>) The most common pathologic cause of myocyte necrosis was microthrom<em>b</em>i. Microthrom<em>b</em>i were different in composition as compared to intramyocardial throm<em>b</em>oem<em>b</em>oli from COVID-19 negative su<em>b</em>jects and to coronary throm<em>b</em>i retrieved from COVID-19 positive and negative STEMI patients. Tailored anti-throm<em>b</em>otic strategies may <em>b</em>e useful to counteract the cardiac effects of COVID-19 infection.

Keywords: COVID-19; SARS-CoV-2; cardiovascular disease; heart.

Background and aims: The COVID-19 spreads rapidly around the world which has brought a global health crisis. The pathogen of COVID-19 is SARS-COV-2, and previous studies have proposed the relationship between ABO blood group and coronavirus. Here, we aim to delve into the association between ABO blood group and COVID-19 infection, severity and demise.

Methods: The relevant studies were retrieved from five databases: PubMed, MedRxiv, BioRxiv,Web of Science and CNKI. Members of cases(symptomatic cases, severe cases, died cases) and controls(asymptomatic controls, non-severe controls, alive controls) were extracted from collected studies. Odds ratios (OR) and 95% confidence intervals (CI) were calculated and interpreted from extracted data. Publication bias and sensitivity analysis were also applied to confirm our discovery.

Results: Overall 31,100 samples were included in the analysis. Compared to other ABO blood type, an increased odds of infecting COVID-19 among individuals with A blood group (OR: 1.249, 95%CI: 1.114-1.440, P &lt; 0.001) and a decreased odds of infecting COVID-19 among individuals with blood group O (OR: 0.699, 95%CI: 0.635-0.770, P &lt; 0.001) were found. Besides, individuals with blood group AB seems to link a higher risk to COVID-19 severity (OR: 2.424, 95%CI: 0.934-6.294) and demise (OR: 1.348, 95%CI: 0.507-3.583). Meantime, individuals with O blood group might had lower risk to COVID-19 severity (OR: 0.748, 95%CI: 0.556-1.007), and individuals with B blood group were likely to relate a lower risk to COVID-19 demise.

Conclusions: The current meta-analysis suggest that blood type A might be more susceptible to infect COVID-19 while blood type O might be less susceptible to infect COVID-19; there were no correlation between ABO blood group and severity or demise of COVID-19. However, more investigation and research are warranted to clarify the relationship between COVID-19 and ABO blood type.

Keywords: ABO blood group system; COVID-19; Meta-analysis; Mortality; Susceptibility; Systematic review.

<p><div>(<em>b</em>)AIM</<em>b</em>)</div>The use of sodium glucose co-transporter 2 (SGLT2) inhi<em>b</em>itors in patients with type 2 dia<em>b</em>etes mellitus (T2DM) and chronic kidney disease (CKD) has <em>b</em>een limited, primarily <em>b</em>ecause glycaemic efficacy is dependent on kidney function. We performed a systematic review and meta-analysis to assess the efficacy and safety of SGLT2 inhi<em>b</em>itors in patients with T2DM and CKD, defined as estimated glomerular fi<em>lt</em>ration rate (eGFR) &<em>lt</em>;60 mL/min/1.73 m² .</p><A<em>b</em>stractText>We searched MEDLINE, EMBASE and the Cochrane Li<em>b</em>rary until 7 August 2018 and we<em>b</em>sites of the US, European and Japanese regulatory authorities until 27 July 2018 for data from randomized controlled trials of SGLT2 inhi<em>b</em>itors that included reporting of effects on <em>b</em>iomarkers, cardiovascular, renal or safety outcomes in individuals with T2DM and CKD. Random effects models and inverse variance weighting were used to calculate relative risks with 95% confidence intervals.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Data were o<em>b</em>tained from 27 studies with up to 7363 participants involved. In patients with T2DM and CKD, SGLT2 inhi<em>b</em>itors lowered glycated haemoglo<em>b</em>in (-0.29%; 95% CI, -0.39 to -0.19) as well as <em>b</em>lood pressure, <em>b</em>ody weight and al<em>b</em>uminuria. SGLT2 inhi<em>b</em>ition reduced the risk of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (RR, 0.81; 95% CI, 0.70-0.94) and heart failure (RR, 0.61; 95% CI, 0.48-0.78), without a clear effect on all-cause mortality (HR, 0.86; 95% CI, 0.73-1.01). These agents also attenuated the annual decline in eGFR slope (place<em>b</em>o-su<em>b</em>tracted difference of 1.35 mL/1.73 m² /y; 95% CI, 0.78-1.93) and reduced the risk of the composite renal outcome (HR, 0.71; 95% CI, 0.53-0.95). There was no evidence of additional risks with SGLT2 inhi<em>b</em>ition in CKD <em>b</em>eyond those already known for the class, a<em>lt</em>hough heterogeneity was o<em>b</em>served across individual agents for some safety outcomes.</p><A<em>b</em>stractText>Currently availa<em>b</em>le data suggest that, despite only modest reductions in glycated haemoglo<em>b</em>in, SGLT2 inhi<em>b</em>itors reduce the risk of cardiovascular and renal outcomes in patients with T2DM and CKD, without clear evidence of additional safety concerns.</A<em>b</em>stractText>