Different roles of protein biomarkers predicting eGFR trajectories in people with chronic kidney disease and diabetes mellitus: a nationwide retrospective cohort study.

BACKGROUND: Chronic kidney disease (CKD) is a common comorbidity in people with diabetes mellitus, and a key risk factor for further life-threatening conditions such as cardiovascular disease. The early prediction of progression of CKD therefore is an important clinical goal, but remains difficult due to the multifaceted nature of the condition. We validated a set of established protein biomarkers for the prediction of trajectories of estimated glomerular filtration rate (eGFR) in people with moderately advanced chronic kidney disease and diabetes mellitus. Our aim was to discern which biomarkers associate with baseline eGFR or are important for the prediction of the future eGFR trajectory. METHODS: We used Bayesian linear mixed models with weakly informative and shrinkage priors for clinical predictors (n = 12) and protein biomarkers (n = 19) to model eGFR trajectories in a retrospective cohort study of people with diabetes mellitus (n = 838) from the nationwide German Chronic Kidney Disease study. We used baseline eGFR to update the models' predictions, thereby assessing the importance of the predictors and improving predictive accuracy computed using repeated cross-validation. RESULTS: The model combining clinical and protein predictors had higher predictive performance than a clinical only model, with an [Formula: see text] of 0.44 (95% credible interval 0.37-0.50) before, and 0.59 (95% credible interval 0.51-0.65) after updating by baseline eGFR, respectively. Only few predictors were sufficient to obtain comparable performance to the main model, with markers such as Tumor Necrosis Factor Receptor 1 and Receptor for Advanced Glycation Endproducts being associated with baseline eGFR, while Kidney Injury Molecule 1 and urine albumin-creatinine-ratio were predictive for future eGFR decline. CONCLUSIONS: Protein biomarkers only modestly improve predictive accuracy compared to clinical predictors alone. The different protein markers serve different roles for the prediction of longitudinal eGFR trajectories potentially reflecting their role in the disease pathway.

Validation of the Spanish Acute Cystitis Symptoms Score (ACSS) in native Spanish-speaking women of Europe and Latin America.

INTRODUCTION AND OBJECTIVES: The Acute Cystitis Symptom Score (ACSS) is a patient self-reporting questionnaire for clinical diagnostics and patient-reported outcome (PRO), which may assess the symptoms and the effect on the quality of life in women with acute cystitis (AC). The current study aimed to create a validated Spanish version of the ACSS questionnaire. MATERIAL AND METHODS: The process of linguistic validation of the Spanish version of the ACSS consisted of the independent forward and backward translations, revision and reconciliation, and cognitive assessment. Clinical evaluation of the study version of the ACSS was carried out in clinics in Spain and Latin America. Statistical tests included the calculation of Cronbach's α, split-half reliability, specificity, sensitivity, diagnostic odds ratio, positive and negative likelihood ratio, and area under the receiver-operating characteristic curve (AUC). RESULTS: The study was performed on 132 patients [age (mean;SD) 45.0;17.8 years] with AC and 55 controls (44.5;12.2 years). Cronbach's α of the ACSS was 0.86, and the split-half reliability was 0.82. The summary scores of the ACSS domains were significantly higher in patients than in controls, 16.0 and 2.0 (p < 0.001), respectively. The predefined cut-off point of ≥6 for a summary score of the "Typical" domain resulted in a specificity of 83.6% and a sensitivity of 99.2% for the Spanish version of the ACSS. AUC was 0.91 [0.85; 0.97]. CONCLUSIONS: The validated Spanish ACSS questionnaire evaluates the symptoms and clinical outcomes of patients with AC. It can be used as a patient's self-diagnosis of AC, as a PRO measure tool, and help to rule out other pathologies in patients with voiding syndrome.

Validation of the classification for type 2 diabetes into five subgroups: a report from the ORIGIN trial.

AIMS/HYPOTHESIS: Data analyses from Swedish individuals with newly diagnosed diabetes have suggested that diabetes could be classified into five subtypes that differ with respect to the progression of dysglycaemia and the incidence of diabetes consequences. We assessed this classification in a multiethnic cohort of participants with established and newly diagnosed diabetes, randomly allocated to insulin glargine vs standard care. METHODS: In total, 7017 participants from the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were assigned to the five predefined diabetes subtypes (namely, severe auto-immune diabetes, severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes, mild age-related diabetes) based on the age at diabetes diagnosis, BMI, HbA1c, fasting C-peptide levels and the presence of glutamate decarboxylase antibodies at baseline. Differences between diabetes subtypes in cardiovascular and renal outcomes were investigated using Cox regression models for a median follow-up of 6.2 years. We also compared the effect of glargine vs standard care on hyperglycaemia, defined by having a mean post-randomisation HbA1c ≥6.5%, between subtypes. RESULTS: The five diabetes subtypes were replicated in the ORIGIN trial and exhibited similar baseline characteristics in Europeans and Latin Americans, compared with the initially described clusters in the Swedish cohort. We confirmed differences in renal outcomes, with a higher incidence of events in the severe insulin-resistant diabetes subtype compared with the mild age-related diabetes subtype (i.e., chronic kidney disease stage 3A: HR 1.49 [95% CI 1.31, 1.71]; stage 3B: HR 2.25 [1.82, 2.78]; macroalbuminuria: HR 1.56 [1.22, 1.99]). No differences were observed in the incidence of retinopathy and cardiovascular diseases after adjusting for multiple hypothesis testing. Diabetes subtypes also differed in glycaemic response to glargine, with a particular benefit of receiving glargine (vs standard care) in the severe insulin-deficient diabetes subtype compared with the mild age-related diabetes subtype, with a decreased occurrence of hyperglycaemia by 13% (OR 1.36 [1.30, 1.41] on glargine; OR 1.49 [1.43, 1.57] on standard care; p for interaction subtype × intervention = 0.001). CONCLUSIONS/INTERPRETATION: Cluster analysis enabled the characterisation of five subtypes of diabetes in a multiethnic cohort. Both the incidence of renal outcomes and the response to insulin varied between diabetes subtypes. These findings reinforce the clinical utility of applying precision medicine to predict comorbidities and treatment responses in individuals with diabetes. TRIAL REGISTRATION: ORIGIN trial, ClinicalTrials.gov NCT00069784.

Effect of prior antibiotic or chemotherapy treatment on immunotherapy response in non-small cell lung cancer.

BACKGROUND: Treatment outcomes of advanced non-small cell lung cancer (NSCLC) have substantially improved with immune checkpoint inhibitors (ICI), although only approximately 19% of patients respond to immunotherapy alone, increasing to 58% with the addition of chemotherapy. The gut microbiome has been recognized as a modulator of ICI response via its priming effect on the host immune response. Antibiotics as well as chemotherapy reduce gut microbial diversity, hence altering composition and function of the gut microbiome. Since the gut microbiome may modify ICI efficacy, we conducted a retrospective study evaluating the effects of prior antibiotic or chemotherapy use on NSCLC patient response to ICI. METHODS: We retrospectively evaluated 256 NSCLC patients treated between 2011-2017 at Moffitt Cancer Center with ICI ± chemotherapy, examining the associations between prior antibiotic or chemotherapy use, overall response rate and survival. Relative risk regression using a log-link with combinatorial expectation maximization algorithm was performed to analyze differences in response between patients treated with antibiotics or chemotherapy versus patients who didn't receive antibiotics or chemotherapy. Cox proportional hazards models were constructed to evaluate associations between risk factors and overall survival. RESULTS: Only 46 (18% of 256) patients used antibiotics prior to and/or during ICI treatment, and 146 (57%) had prior chemotherapy. Antibiotic users were 8% more likely to have worse overall response rate (RR:1.08; CI:0.93-1.26; p = 0.321), as well as a 35% worse overall survival (HR:1.35; CI:0.91-2.02; p = 0.145), although results were not statistically significant. However, prior use of chemotherapy was significantly associated with poor ICI response (RR:1.24; CI:1.05-1.47; p = 0.013) and worse overall survival (HR:1.47; CI:1.07-2.03; p = 0.018). CONCLUSIONS: Patients receiving antibiotics prior to and/or during ICI therapy might experience worse treatment outcomes and survival than unexposed patients, although these associations were not statistically significant and hence warrant further prospective study. Prior chemotherapy significantly reduced ICI response and overall survival. Antibiotic or chemotherapy exposure may negatively impact ICI response, perhaps through disruption of the eubiotic gut microbiome.

A regression discontinuity analysis of the social distancing recommendations for older adults in Sweden during COVID-19.

BACKGROUND: This article investigates the impact of a non-mandatory and age-specific social distancing recommendation on isolation behaviours and disease outcomes in Sweden during the first wave of the coronavirus disease 2019 (COVID-19) pandemic (March to July 2020). The policy stated that people aged 70 years or older should avoid crowded places and contact with people outside the household. METHODS: We used a regression discontinuity design-in combination with self-reported isolation data from COVID Symptom Study Sweden (n = 96 053; age range: 39-79 years) and national register data (age range: 39-100+ years) on severe COVID-19 disease (hospitalization or death, n = 21 804) and confirmed cases (n = 48 984)-to estimate the effects of the policy. RESULTS: Our primary analyses showed a sharp drop in the weekly number of visits to crowded places (-13%) and severe COVID-19 cases (-16%) at the 70-year threshold. These results imply that the age-specific recommendations prevented approximately 1800-2700 severe COVID-19 cases, depending on model specification. CONCLUSIONS: It seems that the non-mandatory, age-specific recommendations helped control COVID-19 disease during the first wave of the pandemic in Sweden, as opposed to not implementing a social distancing policy aimed at older adults. Our study provides empirical data on how populations may react to non-mandatory, age-specific social distancing policies in the face of a novel virus.

Glucose-dependent insulinotropic peptide and risk of cardiovascular events and mortality: a prospective study.

AIMS/HYPOTHESIS: Evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk. METHODS: GIP concentrations were successfully measured during OGTTs in two independent populations (Malmö Diet Cancer-Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD. RESULTS: In meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 × 10-5) and death from CVD (HR[95% CI] 1.30 [1.11, 1.52]; p = 0.001). In accordance, 2SMR analysis revealed that increasing GIP concentrations were associated with CAD and myocardial infarction, and an additional reverse 2SMR revealed no significant effect of CAD on GIP levels, thus confirming a possible effect solely of GIP on CAD. CONCLUSIONS/INTERPRETATION: In two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5-9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.

Prognostic imaging biomarkers for diabetic kidney disease (iBEAt): study protocol.

BACKGROUND: Diabetic kidney disease (DKD) remains one of the leading causes of premature death in diabetes. DKD is classified on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)) but these have modest value for predicting future renal status. There is an unmet need for biomarkers that can be used in clinical settings which also improve prediction of renal decline on top of routinely available data, particularly in the early stages. The iBEAt study of the BEAt-DKD project aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim) and whether they have potential as prognostic biomarkers in DKD (secondary aim). METHODS: iBEAt is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR ≥30 ml/min/1.73m2. At baseline, blood and urine will be collected, clinical examinations will be performed, and medical history will be obtained. These assessments will be repeated annually for 3 years. At baseline each participant will also undergo quantitative renal MRI and US with central processing of MRI images. Biological samples will be stored in a central laboratory for biomarker and validation studies, and data in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers improve the prediction of DKD progression. Ancillary substudies will: (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow measurements against H2O15 positron-emission tomography (PET); (3) validate methods for (semi-)automated processing of renal MRI; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether glycocalyx and microvascular measures are associated with imaging biomarkers and eGFR decline; (6) explore whether the findings in T2D can be extrapolated to type 1 diabetes. DISCUSSION: iBEAt is the largest DKD imaging study to date and will provide valuable insights into the progression and heterogeneity of DKD. The results may contribute to a more personalised approach to DKD management in patients with T2D. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT03716401 ).

Integrative analysis of prognostic biomarkers derived from multiomics panels helps discrimination of chronic kidney disease trajectories in people with type 2 diabetes.

Clinical risk factors explain only a fraction of the variability of estimated glomerular filtration rate (eGFR) decline in people with type 2 diabetes. Cross-omics technologies by virtue of a wide spectrum screening of plasma samples have the potential to identify biomarkers for the refinement of prognosis in addition to clinical variables. Here we utilized proteomics, metabolomics and lipidomics panel assay measurements in baseline plasma samples from the multinational PROVALID study (PROspective cohort study in patients with type 2 diabetes mellitus for VALIDation of biomarkers) of patients with incident or early chronic kidney disease (median follow-up 35 months, median baseline eGFR 84 mL/min/1.73 m2, urine albumin-to-creatinine ratio 8.1 mg/g). In an accelerated case-control study, 258 individuals with a stable eGFR course (median eGFR change 0.1 mL/min/year) were compared to 223 individuals with a rapid eGFR decline (median eGFR decline -6.75 mL/min/year) using Bayesian multivariable logistic regression models to assess the discrimination of eGFR trajectories. The analysis included 402 candidate predictors and showed two protein markers (KIM-1, NTproBNP) to be relevant predictors of the eGFR trajectory with baseline eGFR being an important clinical covariate. The inclusion of metabolomic and lipidomic platforms did not improve discrimination substantially. Predictions using all available variables were statistically indistinguishable from predictions using only KIM-1 and baseline eGFR (area under the receiver operating characteristic curve 0.63). Thus, the discrimination of eGFR trajectories in patients with incident or early diabetic kidney disease and maintained baseline eGFR was modest and the protein marker KIM-1 was the most important predictor.

A Customized At-Home Stool Collection Protocol for Use in Microbiome Studies Conducted in Cancer Patient Populations.

Fecal specimen collection in the clinical setting is often unfeasible for large population studies, especially because cancer patients on immunotherapy often experience constipation. A method for constructing and using an at-home stool collection kit designed for epidemiological studies in cancer patients is presented. Participation and compliance rates of the collection kit among late-stage cancer patients from an ongoing, longitudinal study are also discussed. The kit includes three different media on which samples are introduced. Using one stool sample, patients collect specimens by smearing stool onto a fecal occult blood test (FOBT) card, containing three slides for collection. Additional specimens from the same stool sample are added to one tube containing 8 mL of RNAlater preservative and one tube containing 8 mL of 95% ethanol. Stool specimens are stored at room temperature and returned to researchers within 3 days of collection. The purpose of this kit is to yield stool specimens on a variety of media that can be preserved for extended periods of time at room temperature and are compatible with multi-omics approaches for specimen analysis. According to leading microbiome researchers and published literature, each collection method is considered optimal for use in large epidemiological studies. Moreover, the kit is comprised of various components that make stool collection easy, so as not to burden the patient and hence maximize overall compliance. Use of this kit in a study of late-stage lung cancer patients had a participation rate of 83% and baseline compliance rate of 58%.

Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways.

Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system.

MicroRNA-dependent regulation of KLF4 by glucose in vascular smooth muscle.

Diabetes is a major risk factor for cardiovascular disease and this is in part due to the effects of hyperglycemia on vascular smooth muscle cells. Small non-coding microRNAs are known to control smooth muscle phenotype and arterial contractility and are dysregulated in diabetes. The effect of microRNAs on smooth muscle differentiation is in part mediated by the transcription factor KLF4 but the role of this mechanism in diabetic vascular disease is not fully understood. Herein, we have investigated the importance of hyperglycemia and diabetes for the expression of KLF4 in vascular smooth muscle and the involvement of miRNAs in this regulation. Hyperglycemia down-regulated KLF4 in vascular smooth muscle cells and similar results were found in arteries of diabetic mice and patients. This correlated with a Foxa2-dependent up-regulation of miR-29c, which targeted KLF4 in vascular smooth muscle cells. Importantly, by preventing downregulation of KLF4, the induction of smooth muscle contractile protein markers by glucose was inhibited. In conclusion, miR-29 mediated inhibition of KLF4 in hyperglycemic conditions contributes to increased expression of contractile markers in vascular smooth muscle cells. Further studies are warranted to determine the therapeutic implications of miR-29 inhibition in diabetic vascular disease.

Efficacy of a Spanish-Language Self-Administered Stress Management Training intervention for Latinas undergoing chemotherapy.

BACKGROUND: Cancer patients often report increased stress during chemotherapy. Stress management training has been shown to reduce this adverse outcome, but few interventions exist for Spanish-speaking Hispanic and Latina women (Latinas). METHODS: Following community feedback (including focus groups/in-depth interviews), we transcreated the Spanish-Language Self-Administered Stress Management Training (SL-SAT) intervention based on our previously developed and implemented English-based intervention. Latinas about to begin chemotherapy were randomized to SL-SAT (n = 121) or usual care (n = 119). A Spanish-speaking interventionist met with SL-SAT participants who received the SL-SAT toolkit containing instructions in 3 well-established stress management techniques (deep breathing, progressive muscle relaxation and guided imagery, and use of coping self-statements). Usual care participants received an educational booklet about coping with chemotherapy. All patients were instructed by nurses on their chemotherapy medications and given a resource listing of local support groups. Outcomes were obtained at baseline, and 7 and 13 weeks after starting chemotherapy. Primary outcomes included anxiety and depression, cancer-related distress, emotional well-being, and spiritual well-being. Secondary outcomes included functional well-being, social/family well-being, physical well-being, symptom severity, and self-efficacy for managing stress. Data were analyzed by using mixed models. RESULTS: In both groups, improvements were observed in emotional well-being (P = .01), and declines were observed in functional well-being (P = .05), and physical well-being (P < .0001). Symptom severity increased across the follow-up period (P < .001). CONCLUSIONS: To be effective, stress management interventions for Latinas receiving chemotherapy may necessitate more attention from an interventionist, delivery of the intervention over a longer interval, and/or a group-based format.

Elevated Glucose Levels Promote Contractile and Cytoskeletal Gene Expression in Vascular Smooth Muscle via Rho/Protein Kinase C and Actin Polymerization.

Both type 1 and type 2 diabetes are associated with increased risk of cardiovascular disease. This is in part attributed to the effects of hyperglycemia on vascular endothelial and smooth muscle cells, but the underlying mechanisms are not fully understood. In diabetic animal models, hyperglycemia results in hypercontractility of vascular smooth muscle possibly due to increased activation of Rho-kinase. The aim of the present study was to investigate the regulation of contractile smooth muscle markers by glucose and to determine the signaling pathways that are activated by hyperglycemia in smooth muscle cells. Microarray, quantitative PCR, and Western blot analyses revealed that both mRNA and protein expression of contractile smooth muscle markers were increased in isolated smooth muscle cells cultured under high compared with low glucose conditions. This effect was also observed in hyperglycemic Akita mice and in diabetic patients. Elevated glucose activated the protein kinase C and Rho/Rho-kinase signaling pathways and stimulated actin polymerization. Glucose-induced expression of contractile smooth muscle markers in cultured cells could be partially or completely repressed by inhibitors of advanced glycation end products, L-type calcium channels, protein kinase C, Rho-kinase, actin polymerization, and myocardin-related transcription factors. Furthermore, genetic ablation of the miR-143/145 cluster prevented the effects of glucose on smooth muscle marker expression. In conclusion, these data demonstrate a possible link between hyperglycemia and vascular disease states associated with smooth muscle contractility.

Emerging roles of the myocardin family of proteins in lipid and glucose metabolism.

Members of the myocardin family bind to the transcription factor serum response factor (SRF) and act as coactivators controlling genes of relevance for myogenic differentiation and motile function. Binding of SRF to DNA is mediated by genetic elements called CArG boxes, found often but not exclusively in muscle and growth controlling genes. Studies aimed at defining the full spectrum of these CArG elements in the genome (i.e. the CArGome) have in recent years, unveiled unexpected roles of the myocardin family proteins in lipid and glucose homeostasis. This coactivator family includes the protein myocardin (MYOCD), the myocardin-related transcription factors A and B (MRTF-A/MKL1 and MRTF-B/MKL2) and MASTR (MAMSTR). Here we discuss growing evidence that SRF-driven transcription is controlled by extracellular glucose through activation of the Rho-kinase pathway and actin polymerization. We also describe data showing that adipogenesis is influenced by MLK activity through actions upstream of peroxisome proliferator-activated receptor γ with consequences for whole body fat mass and insulin sensitivity. The recently demonstrated involvement of myocardin coactivators in the biogenesis of caveolae, Ω-shaped membrane invaginations of importance for lipid and glucose metabolism, is finally discussed. These novel roles of myocardin proteins may open the way for new unexplored strategies to combat metabolic diseases such as diabetes, which, at the current incidence, is expected to reach 333 million people worldwide by 2025. This review highlights newly discovered roles of myocardin-related transcription factors in lipid and glucose metabolism as well as novel insights into their well-established role as mediators of stretch-dependent effects in smooth muscle. As co-factors for serum response factor (SRF), MKLs regulates transcription of genes involved in the contractile function of smooth muscle cells. In addition to mechanical stimuli, this regulation has now been found to be promoted by extracellular glucose levels in smooth muscle. Recent reports also suggest that MKLs can regulate a subset of genes involved in the formation of lipid-rich invaginations in the cell membrane called caveolae. Finally, a potential role of MKLs in non-muscle cells has been discovered as they negatively influence adipocyte differentiation.

Epigenetic regulation of the thioredoxin-interacting protein (TXNIP) gene by hyperglycemia in kidney.

Diabetic kidney disease is the leading cause of end-stage renal disease. Genetic factors have been suggested to contribute to its susceptibility. However, results from genetic studies are disappointing possibly because the role of glucose in diabetic kidney disease predisposed by epigenetic mechanisms has not been taken into account. Since thioredoxin-interacting protein (TXNIP) has been shown to play an important role in the pathogenesis of diabetic kidney disease, we tested whether glucose could induce expression of TXNIP in the kidney by epigenetic mechanisms. In kidneys from diabetic Sur1-E1506K(+/+) mice, hyperglycemia-induced Txnip expression was associated with stimulation of activating histone marks H3K9ac, H3K4me3, and H3K4me1, as well as decrease in the repressive histone mark H3K27me3 at the promoter region of the gene. Glucose also coordinated changes in histone marks and TXNIP gene expression in mouse SV40 MES13 mesangial cells and the normal human mesangial cell line NHMC. The involvement of histone acetylation in glucose-stimulated TXNIP expression was confirmed by reversing or enhancing acetylation using the histone acetyltransferase p300 inhibitor C646 or the histone deacetylase inhibitor trichostatin A. Thus, glucose is a potent inducer of histone modifications, which could drive expression of proinflammatory genes and thereby predispose to diabetic kidney disease.

Nuclear factor of activated T cells regulates neutrophil recruitment, systemic inflammation, and T-cell dysfunction in abdominal sepsis.

The signaling mechanisms regulating neutrophil recruitment, systemic inflammation, and T-cell dysfunction in polymicrobial sepsis are not clear. This study explored the potential involvement of the calcium/calcineurin-dependent transcription factor, nuclear factor of activated T cells (NFAT), in abdominal sepsis. Cecal ligation and puncture (CLP) triggered NFAT-dependent transcriptional activity in the lung, spleen, liver, and aorta in NFAT-luciferase reporter mice. Treatment with the NFAT inhibitor A-285222 prior to CLP completely prevented sepsis-induced NFAT activation in all these organs. Inhibition of NFAT activity reduced sepsis-induced formation of CXCL1, CXCL2, and CXCL5 chemokines and edema as well as neutrophil infiltration in the lung. Notably, NFAT inhibition efficiently reduced the CLP-evoked increases in HMBG1, interleukin 6 (IL-6), and CXCL5 levels in plasma. Moreover, administration of A-285222 restored sepsis-induced T-cell dysfunction, as evidenced by markedly decreased apoptosis and restored proliferative capacity of CD4 T cells. Along these lines, treatment with A-285222 restored gamma interferon (IFN-γ) and IL-4 levels in the spleen, which were markedly reduced in septic mice. CLP-induced formation of regulatory T cells (CD4(+) CD25(+) Foxp3(+)) in the spleen was also abolished in A-285222-treated animals. All together, these novel findings suggest that NFAT is a powerful regulator of pathological inflammation and T-cell immune dysfunction in abdominal sepsis. Thus, our data suggest that NFAT signaling might be a useful target to protect against respiratory failure and immunosuppression in patients with sepsis.

Attenuation of experimental atherosclerosis by interleukin-19.

OBJECTIVE: Interleukin-19 (IL-19) is a putative Th2, anti-inflammatory interleukin. Its expression and potential role in atherogenesis are unknown. IL-19 is not detected in normal artery and is expressed to a greater degree in plaque from symptomatic versus asymptomatic patients, suggesting a compensatory counter-regulatory function. We tested whether IL-19 could reduce atherosclerosis in susceptible mice and identified plausible mechanisms. APPROACH AND RESULTS: LDLR(-/-) mice fed an atherogenic diet and injected with either 1.0 or 10.0 ng/g per day recombinant mouse IL-19 had significantly less plaque area in the aortic arch compared with controls (P<0.0001). Weight gain, cholesterol, and triglyceride levels were not significantly different. Gene expression in splenocytes from IL-19-treated mice demonstrated immune cell Th2 polarization, with decreased expression of T-bet, interferon-γ, interleukin-1ß, and interleukin-12ß and increased expression of GATA3 and FoxP3 mRNA. A greater percentage of lymphocytes were Th2 polarized in IL-19-treated mice. Cellular characterization of plaque by immunohistochemistry demonstrated that IL-19-treated mice have significantly less macrophage infiltrate compared with controls (P<0.001). Intravital microscopy revealed significantly less leukocyte adhesion in wild-type mice injected with IL-19 and fed an atherogenic diet compared with controls. Treatment of cultured endothelial cells, vascular smooth muscle cells, and bone marrow-derived macrophages with IL-19 resulted in a significant decrease in chemokine mRNA and mRNA stability protein human antigen R. CONCLUSIONS: These data suggest that IL-19 is a potent inhibitor of experimental atherosclerosis, with diverse mechanisms including immune cell polarization, decrease in macrophage adhesion, and decrease in gene expression. This may identify IL-19 as a novel therapeutic to limit vascular inflammation.

Machine Learning Models for Prediction of Diabetic Microvascular Complications.

IMPORTANCE AND AIMS: Diabetic microvascular complications significantly impact morbidity and mortality. This review focuses on machine learning/artificial intelligence (ML/AI) in predicting diabetic retinopathy (DR), diabetic kidney disease (DKD), and diabetic neuropathy (DN). METHODS: A comprehensive PubMed search from 1990 to 2023 identified studies on ML/AI models for diabetic microvascular complications. The review analyzed study design, cohorts, predictors, ML techniques, prediction horizon, and performance metrics. RESULTS: Among the 74 identified studies, 256 featured internally validated ML models and 124 had externally validated models, with about half being retrospective. Since 2010, there has been a rise in the use of ML for predicting microvascular complications, mainly driven by DKD research across 27 countries. A more modest increase in ML research on DR and DN was observed, with publications from fewer countries. For all microvascular complications, predictive models achieved a mean (standard deviation) c-statistic of 0.79 (0.09) on internal validation and 0.72 (0.12) on external validation. Diabetic kidney disease models had the highest discrimination, with c-statistics of 0.81 (0.09) on internal validation and 0.74 (0.13) on external validation, respectively. Few studies externally validated prediction of DN. The prediction horizon, outcome definitions, number and type of predictors, and ML technique significantly influenced model performance. CONCLUSIONS AND RELEVANCE: There is growing global interest in using ML for predicting diabetic microvascular complications. Research on DKD is the most advanced in terms of publication volume and overall prediction performance. Both DR and DN require more research. External validation and adherence to recommended guidelines are crucial.

Recurrent Bacteriuria as a Prognosis Marker in the Adjuvant Treatment of Non-Muscle Invasive Bladder Cancer.

PURPOSE: Bacteriuria may affect the response to adjuvant therapy in non-muscle invasive bladder cancer (NMIBC). The main aim of this study was to examine the effect of recurrent bacteriuria (RB) on the prognosis of NMIBC in women receiving intravesical therapy. MATERIALS AND METHODS: We designed a prospective observational study from 2012 to 2019. We included women with bladder cancer treated with transurethral resection of the bladder (TURB) and adjuvant intravesical treatment. Significant bacteriuria was defined as a presence in urine cultures at or above 100,000 colony-forming units per millilitre. The recurrent bacteriuria group included patients with significant bacteriuria in at least two determinations in 6 months or in 3 or more determinations in a year. The institutional board approved the study. RESULTS: One hundred thirty-six patients diagnosed with NMIBC participate in the study, of whom 100 met the inclusion criteria. During follow-up, 48 were categorized in the RB group and 52 formed the non-bacteriuria group (NB). RB GROUP HAD A BETTER OUTCOME: Eight patients (16.67%) experiencing a recurrence of the same grade, with no progression to a higher-grade tumor or muscle-invasive tumor. In the NB group, 18 (34.6%) patients presented a recurrence (P = .001) and 22 (42.3%) progressed to a higher-grade tumor or muscular invasion (P = .001). The presence of RB was identified as a predictor of good response in multivariate regression with a relative risk of 0.13 (P = .018) CONCLUSIONS: Female patients with RB had a better response to adjuvant treatment for NMIBC. The RB group showed lower rates of tumor recurrences and progression.