Impaired metabolism predicts coronary artery calcification in women with systemic lupus erythematosus.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) exhibit a high risk for cardiovascular diseases (CVD) which is not fully explained by the classical Framingham risk factors. SLE is characterized by major metabolic alterations which can contribute to the elevated prevalence of CVD. METHODS: A comprehensive analysis of the circulating metabolome and lipidome was conducted in a large cohort of 211 women with SLE who underwent a multi-detector computed tomography scan for quantification of coronary artery calcium (CAC), a robust predictor of coronary heart disease (CHD). FINDINGS: Beyond traditional risk factors, including age and hypertension, disease activity and duration were independent risk factors for developing CAC in women with SLE. The presence of coronary calcium was associated with major alterations of circulating lipidome dominated by an elevated abundance of ceramides with very long chain fatty acids. Alterations in multiple metabolic pathways, including purine, arginine and proline metabolism, and microbiota-derived metabolites, were also associated with CAC in women with SLE. Logistic regression with bootstrapping of lipidomic and metabolomic variables were used to develop prognostic scores. Strikingly, combining metabolic and lipidomic variables with clinical and biological parameters markedly improved the prediction (area under the curve: 0.887, p < 0.001) of the presence of coronary calcium in women with SLE. INTERPRETATION: The present study uncovers the contribution of disturbed metabolism to the presence of coronary artery calcium and the associated risk of CHD in SLE. Identification of novel lipid and metabolite biomarkers may help stratifying patients for reducing CVD morbidity and mortality in SLE. FUNDING: INSERM and Sorbonne Université.

Monitoring lineages of growing and dividing bacteria reveals an inducible memory of mar operon expression.

In Gram negative bacteria, the multiple antibiotic resistance or mar operon, is known to control the expression of multi-drug efflux genes that protect bacteria from a wide range of drugs. As many different chemical compounds can induce this operon, identifying the parameters that govern the dynamics of its induction is crucial to better characterize the processes of tolerance and resistance. Most experiments have assumed that the properties of the mar transcriptional network can be inferred from population measurements. However, measurements from an asynchronous population of cells can mask underlying phenotypic variations of single cells. We monitored the activity of the mar promoter in single Escherichia coli cells in linear micro-colonies and established that the response to a steady level of inducer was most heterogeneous within individual colonies for an intermediate value of inducer. Specifically, sub-lineages defined by contiguous daughter-cells exhibited similar promoter activity, whereas activity was greatly variable between different sub-lineages. Specific sub-trees of uniform promoter activity persisted over several generations. Statistical analyses of the lineages suggest that the presence of these sub-trees is the signature of an inducible memory of the promoter state that is transmitted from mother to daughter cells. This single-cell study reveals that the degree of epigenetic inheritance changes as a function of inducer concentration, suggesting that phenotypic inheritance may be an inducible phenotype.

Feasibility of a New Regional Myocardial Strain Parameter for the Detection of Wall Motion Abnormalities in Arrhythmogenic Right Ventricular Cardiomyopathy.

Purpose: To evaluate a cardiac MRI feature tracking (FT)-derived parameter that combines right ventricular (RV) longitudinal and radial motions in detecting arrhythmogenic right ventricular cardiomyopathy (ARVC). Materials and Methods: Patients with ARVC (n = 47; median age, 46 [IQR, 30-52] years; 31 men) were compared with controls (n = 39; median age, 46 [IQR, 33-53] years; 23 men) and separated into two groups based on fulfillment of major structural 2020 International criteria. Cine data from 1.5-T cardiac MRI examinations were analyzed using FT, resulting in conventional strain parameters and a novel composite index named the longitudinal-to-radial strain loop (LRSL). Receiver operating characteristic (ROC) analysis was used to assess diagnostic performance of RV parameters. Results: Volumetric parameters differed significantly between patients in the major structural criteria group and controls but not between patients in the no major structural criteria group and controls. Patients in the major structural criteria group had significantly lower magnitudes of all FT parameters than controls, including RV basal longitudinal strain, radial motion fraction, circumferential strain, and LRSL (-15.6% ± 6.4 vs -26.7% ± 13.9; -9.6% ± 4.89 vs -13.8% ± 4.7; -6.9% ± 4.6 vs -10.1% ± 3.8; and 217.0 ± 128.9 versus 618.6 ± 356.3, respectively). Only LRSL differed between patients in the no major structural criteria group and controls (359.5 ± 195.8 vs 618.6 ± 356.3; P < .0001). Parameters with the highest area under the ROC curve values for discriminating patients in the no major structural criteria group from controls were LRSL, RV ejection fraction, and RV basal longitudinal strain (0.75, 0.70, and 0.61, respectively). Conclusion: A new parameter combining RV longitudinal and radial motions showed good diagnostic performance in ARVC, even in patients without major structural abnormalities.Keywords: Arrhythmogenic Right Ventricular Dysplasia, Strain, Wall Motion Abnormalities, Right Ventricle, MRI, Inherited Cardiomyopathy Supplemental material is available for this article. © RSNA, 2023.

Resonant learning in scale-free networks.

Large networks of interconnected components, such as genes or machines, can coordinate complex behavioral dynamics. One outstanding question has been to identify the design principles that allow such networks to learn new behaviors. Here, we use Boolean networks as prototypes to demonstrate how periodic activation of network hubs provides a network-level advantage in evolutionary learning. Surprisingly, we find that a network can simultaneously learn distinct target functions upon distinct hub oscillations. We term this emergent property resonant learning, as the new selected dynamical behaviors depend on the choice of the period of the hub oscillations. Furthermore, this procedure accelerates the learning of new behaviors by an order of magnitude faster than without oscillations. While it is well-established that modular network architecture can be selected through evolutionary learning to produce different network behaviors, forced hub oscillations emerge as an alternative evolutionary learning strategy for which network modularity is not necessarily required.

Prevalence, patterns and outcomes of cardiac involvement in Erdheim-Chester disease.

AIMS: Cardiac involvement of Erdheim-Chester disease (ECD), a rare L group histiocytosis, has been reported to be associated with poor outcomes, but systematic studies are lacking. The present study aimed to investigate the prevalence, clinical features, imaging features, and prognosis of cardiac involvement in ECD in a large series. METHODS AND RESULTS: All patients with ECD who underwent cardiac magnetic resonance (CMR) imaging between 2003 and 2019 at a French tertiary center were retrospectively included. Primary outcome was all-cause mortality. Secondary outcomes were pericarditis, cardiac tamponade, conduction disorders, device implantation and coronary artery disease (CAD). A total of 200 patients were included [63 (54-71) years, 30% female, 58% BRAFV600E mutated]. Median follow-up was 5.5 years (3.3-9 years). On CMR, right atrioventricular sulcus infiltration was observed in 37% of patients, and pericardial effusion was seen in 24% of patients. In total, 8 patients (4%) had pericarditis (7 acute, 1 constrictive), 10 patients (5%) had cardiac tamponade, 5 patients (2.5%) had ECD-related high-degree conduction disorders, and 45 patients (23%) had CAD. Overall, cardiac involvement was present in 96 patients (48%) and was associated with BRAFV600E mutation [Odds ratio (OR) = 7.4, 95% confidence interval (CI) (3.5-16.8), P < 0.001] and ECD-related clinical events [OR = 5, 95%CI (1.5-21.2), P = 0.004] but not with lower survival in multivariate analysis [adjusted hazard ratio (HR) = 1.4, 95% CI (0.8-2.5), P = 0.2]. CONCLUSION: Cardiac involvement is present in nearly half of ECD patients and is associated with BRAFV600E mutation and complications (pericarditis, cardiac tamponade, and conduction disorders) but not with lower survival.

A history of variceal bleeding is associated with further bleeding under atezolizumab-bevacizumab in patients with HCC.

BACKGROUND: Atezolizumab-bevacizumab is the new standard for advanced hepatocellular carcinoma (HCC) but its impact on portal hypertension (PHT) is unknown. We aimed to identify predictive factors of acute variceal bleeding (AVB) and to monitor PHT parameters under treatment. METHODS: We conducted a prospective study including all cirrhotic patients treated with atezolizumab-bevacizumab since 2020. We performed monitoring of PHT using upper endoscopy at inclusion and at 6 months and hepatic venous pressure gradient (HVPG) at inclusion, 3 and 6 months after the beginning of treatment. We also included a retrospective series of patients treated with sorafenib. Time-to-events data were estimated by Kaplan-Meier with the log-rank test, along with Cox models. RESULTS: Forty-three patients treated with atezolizumab-bevacizumab were included (male 79.1%, Child-Pugh A 86%). At baseline, 48.8% were treated with curative anticoagulation, 16.3% already experienced AVB and 25.6% had large oesophageal varices (EV). Sorafenib group characteristics were similar. Vascular invasion was present in 60.5% and median was HVPG 8.5 mm Hg. No significant modification in HVPG and EV size was observed at 6 months in the whole cohort but also when considering vascular invasion and radiological response. 14% presented AVB within a median time of occurrence of 3 months, without bleeding-related death. In multivariate analysis, history of AVB (HR = 10.58, p = .03) was associated with AVB. AVB incidence was higher in atezolizumab-bevacizumab compared to sorafenib group (21% vs. 5% at 1 year, p = .02). CONCLUSIONS: Atezolizumab-bevacizumab treatment was associated with a higher risk of AVB compared to sorafenib. A history of AVB was associated with AVB during follow-up, which questions the use of bevacizumab in this setting.

Robustness of DNA looping across multiple cell divisions in individual bacteria.

DNA looping has emerged as a central paradigm of transcriptional regulation, as it is shared across many living systems. One core property of DNA looping-based regulation is its ability to greatly enhance repression or activation of genes with only a few copies of transcriptional regulators. However, this property based on a small number of proteins raises the question of the robustness of such a mechanism with respect to the large intracellular perturbations taking place during growth and division of the cell. Here we address the issue of sensitivity to variations of intracellular parameters of gene regulation by DNA looping. We use the lac system as a prototype to experimentally identify the key features of the robustness of DNA looping in growing Escherichia coli cells. Surprisingly, we observe time intervals of tight repression spanning across division events, which can sometimes exceed 10 generations. Remarkably, the distribution of such long time intervals exhibits memoryless statistics that is mostly insensitive to repressor concentration, cell division events, and the number of distinct loops accessible to the system. By contrast, gene regulation becomes highly sensitive to these perturbations when DNA looping is absent. Using stochastic simulations, we propose that the observed robustness to division emerges from the competition between fast, multiple rebinding events of repressors and slow initiation rate of the RNA polymerase. We argue that fast rebinding events are a direct consequence of DNA looping that ensures robust gene repression across a range of intracellular perturbations.

Cerebrovascular Ischemic Events in Patients With Takayasu Arteritis.

BACKGROUND: Takayasu arteritis (TA) is a large vessel vasculitis that may complicate with cerebrovascular ischemic events. The objective was to describe clinical and vascular features of TA patients with cerebrovascular ischemic events and to identify risk factors for these events. METHODS: We analyzed the prevalence and type of stroke/transient ischemic attack (TIA), factors associated with cerebrovascular ischemic events, and stroke-free survival in a large cohort fulfilling the American College of Rheumatology or Ishikawa criteria of TA. RESULTS: Among 320 patients with TA (median age at diagnosis, 36 [25-47] years; 261 [86%] women), 63 (20%) had a stroke (n=41; 65%) or TIA (n=22; 35%). Ischemic event localized in the carotid territory for 55 (87%) patients and the vertebral artery territory in 8 (13%) patients. Multiple stenosis were observed in 33 (52%) patients with a median number of stenosis of 2 (minimum, 0 to maximum, 11), and aneurysms were observed in 10 (16%) patients. A history of stroke or TIA before TA diagnosis (hazard ratio [HR], 4.50 [2.45-8.17]; P<0.0001), smoking (HR, 1.75 [1.01-3.02]; P=0.05), myocardial infarction history (HR, 0.21 [0.05-0.89]; P=0.039), thoracic aorta involvement (HR, 2.05 [1.30-3.75]; P=0.023), time from first symptoms to diagnosis >1 year (HR, 2.22 [1.30-3.80]; P=0.005), and aspirin treatment (HR, 1.82 [1.04-3.19]; P=0.035) were associated with cerebrovascular ischemic event. In multivariate analysis, time from first symptoms to TA diagnosis >1 year (HR, 2.16 [1.27-3.70]; P=0.007) was independently associated with cerebrovascular ischemic events in patients with TA. The HR for cerebrovascular ischemic event in patients who already experienced a stroke/TIA was 5.11 (2.91-8.99; P<0.0001), compared with those who had not. CONCLUSIONS: Carotid stroke/TIA is frequent in TA. We identified factors associated with cerebrovascular ischemic events.

TIPS for patients with early HCC: A bridge to liver transplantation.

Portal hypertension (PHT) and hepatocellular carcinoma (HCC) are complications of cirrhosis which often coexist, rending the management more complex. HCC is generally considered as a contraindication for transjugular intrahepatic portosystemic shunt (TIPS). We studied the outcome of 8 patients treated by TIPS after HCC diagnosis between 2010 and 2020. TIPS wasn't associated with worsening of liver function or tumor spreading and all patients underwent liver transplantation. TIPS should be considered in case of HCC, especially for variceal bleeding or as a bridge to HCC treatments that are discarded due to PHT levels/ascites by improving liver function before liver transplantation.

Myocardial fibrosis assessed by magnetic resonance imaging in asymptomatic heterozygous familial hypercholesterolemia: the cholcoeur study.

BACKGROUND: Familial Hypercholesterolemia (FH) is an underdiagnosed condition with an increased cardiovascular risk. It is unknown whether lipid accumulation plays a role in structural myocardial changes. Cardiovascular Magnetic Resonance (CMR) is the reference technique for the morpho-functional evaluation of heart chambers through cine sequences and for myocardial tissue characterization through late gadolinium enhancement (LGE) and T1 mapping images. We aimed to assess the prevalence of myocardial fibrosis in FH patients. METHODS: Seventy-two asymptomatic subjects with genetically confirmed FH (mean age 49·24, range 40 to 60 years) were prospectively recruited along with 31 controls without dyslipidaemia matched for age, sex, BMI, and other cardiovascular risk factors. All underwent CMR including cine, LGE, pre- and post-contrast T1 mapping. Extracellular volume (ECV) and enhancement rate of the myocardium (ERM = difference between pre- and post-contrast myocardial T1, normalized by pre-contrast myocardial T1) were calculated. FINDINGS: Five FH patients and none of the controls had intramyocardial LGE (p= 0·188). While no changes in Native T1 and ECV were found, post-contrast T1 was significantly lower (430·6 ± 55ms vs. 476·1 ± 43ms, p<0·001) and ERM was higher (57·44± 5·99 % vs 53·04±4·88, p=0·005) in HeFH patients compared to controls. Moreover, low post-contrast T1 was independently associated with the presence of xanthoma (HR 5·221 [1·04-26·28], p= 0·045). A composite score combining the presence of LGE, high native T1 and high ERM (defined as ≥ mean ± 1·5 SD) was found in 20·8% of the HeFH patients vs. 0% in controls (p<0·000, after adjustment for main confounders). INTERPRETATION: CMR revealed early changes in myocardial tissue characteristics in HeFH patients, that should foster further work to better understand and prevent the underlying pathophysiological processes.

Diabetic foot ulcer management in a multidisciplinary foot centre: one-year healing, amputation and mortality rate.

OBJECTIVE: To describe the rates of healing, major amputation and mortality after 12 months in patients with a new diabetic foot ulcer (DFU) and their care in a French diabetic foot service (DFS). METHOD: A prospective single-centre study including patients from March 2009 to December 2010. The length of time to healing, minor amputation, major amputation and mortality rate after inclusion were analysed using the Kaplan-Meier method. RESULTS: Some 347 patients were included (3% lost to follow-up), with a median follow-up (IQR) of 19 (12-24) months. The mean (SD) age was 65±12 years, 68% were male, and the median duration of the ulcer was 49 (19-120) days. Complications of the DFU were ischaemia (70%), infection (55%) and osteomyelitis (47%). Of the patients, 50% were inpatients in the DFS at inclusion (median duration of hospitalisation 26 (15-41) days). The rate of healing at one year was 67% (95% confidence interval (CI): 61-72); of major amputation 10% (95% CI: 7-17); of minor amputation 19% (95% CI: 14-25), and the death rate was 9% (95% CI: 7-13). Using an adjusted hazard ratio, the predictive factors of healing were perfusion and the area of the wound. The risk factors for a major amputation were active smoking and osteomyelitis. The risk factors for mortality were perfusion and age. CONCLUSION: This study confirms the need to treat DFUs rapidly, in a multidisciplinary DFS.

Randomised trial of first-line bronchial artery embolisation for non-severe haemoptysis of mild abundance.

BACKGROUND: Whereas first-line bronchial artery embolisation (BAE) is considered standard of care for the management of severe haemoptysis, it is unknown whether this approach is warranted for non-severe haemoptysis. RESEARCH QUESTION: To assess the efficacy on bleeding control and the safety of first-line BAE in non-severe haemoptysis of mild abundance. STUDY DESIGN AND METHODS: This multicentre, randomised controlled open-label trial enrolled adult patients without major comorbid condition and having mild haemoptysis (onset <72 hours, 100-200 mL estimated bleeding amount), related to a systemic arterial mechanism. Patients were randomly assigned (1:1) to BAE associated with medical therapy or to medical therapy alone. RESULTS: Bleeding recurrence at day 30 after randomisation (primary outcome) occurred in 4 (11.8%) of 34 patients in the BAE strategy and 17 (44.7%) of 38 patients in the medical strategy (difference -33%; 95% CI -13.8% to -52.1%, p=0.002). The 90-day bleeding recurrence-free survival rates were 91.2% (95% CI 75.1% to 97.1%) and 60.2% (95% CI 42.9% to 73.8%), respectively (HR=0.19, 95% CI 0.05 to 0.67, p=0.01). No death occurred during follow-up and no bleeding recurrence needed surgery.Four adverse events (one major with systemic emboli) occurred during hospitalisation, all in the BAE strategy (11.8% vs 0%; difference 11.8%, 95% CI 0.9 to 22.6, p=0.045); all eventually resolved. CONCLUSION: In non-severe haemoptysis of mild abundance, BAE associated with medical therapy had a superior efficacy for preventing bleeding recurrences at 30 and 90 days, as compared with medical therapy alone. However, it was associated with a higher rate of adverse events. TRIAL REGISTRATION NUMBER: NCT01278199.

Prognosis of patients undergoing salvage TIPS is still poor in the preemptive TIPS era.

BACKGROUND: Salvage transjugular intrahepatic portosystemic shunts (TIPS) are associated with poor prognosis, especially in patients with Child-Pugh C cirrhosis. Since preemptive TIPS improved prophylaxis of variceal bleeding in those patients, recourse to salvage TIPS may now affect patients with a better prognosis. AIM: To assess the impact of the preemptive TIPS policy on outcomes after salvage TIPS placement. METHODS: We conducted a retrospective monocentric study on cirrhotic patients undergoing salvage TIPS with polytetrafluoroethylene-covered stents from 2002 to 2017 (period 1 until February 2011; period 2 after the preemptive TIPS policy in March 2011). The primary endpoint was one-year transplant-free survival. RESULTS: We included 106 patients (period 1/2 = 53/53 patients, male gender 82%, age 54 ±â€¯9 years, alcoholic cirrhosis 70%, Child-Pugh score B/C 94%). One-year transplant-free survival was 46.0% during period 1 compared to 40.2% during period 2 (p = 0.65). Amongst 61 patients with history of variceal bleeding, 32 (52.5%) had an inadequate secondary prophylaxis, including 19 (59.4%) with a previous indication of preemptive TIPS. One-year transplant-free survival was 33.2% if inadequate secondary prophylaxis vs 65.2% if adequate (p = 0.008). Independent factors associated with survival were a lower Child-Pugh or MELD score, infection, failure to control bleeding, and hepatic encephalopathy after TIPS. CONCLUSION: Prognosis after salvage TIPS remained poor in our series. Optimizing secondary prophylaxis, including preemptive TIPS placement, should be the main concern to improve prognosis.

High TG to HDL ratio plays a significant role on atherosclerosis extension in prediabetes and newly diagnosed type 2 diabetes subjects.

AIMS: We investigated the role of TG to HDL ratio (TG/HDL) on atherosclerosis extension, defined as presence of coronary artery calcium (CAC), carotid and femoral plaque, in prediabetes or newly diagnosed type 2 diabetes (T2D). METHODS: We performed a retrospective, cross-sectional, single centre study involving 440 prediabetes or newly diagnosed controlled T2D subjects. Participants underwent CAC analysis by computed tomography and carotid and femoral plaque evaluation by ultrasonography and were stratified in high TG/HDL (H-TG/HDL) or low TG/HDL (L-TG/HDL) group according to TG/HDL median value. We estimated atherosclerosis extension according to the number of involved vascular districts. RESULTS: CAC was higher in the H-TG/HDL group than L-TG/HDL group (29.15 [0.0-95.68] vs 0.0 [0.0-53.97] AU, P < .01) and CAC > 0 was more prevalent in the H-TG/HDL group than L-TG/HDL group (64.5% vs 45%, P < .001). Femoral atherosclerosis was higher in the H-TG/HDL group than L-TG/HDL group (57.3% vs 43.6%, P < .01). H-TG/HDL group exhibited a lower prevalence of subjects with 0-TWP compared to L-TG/HDL group (21.8% vs 38.6%, P < .01) and higher percentages of subjects with 2-TWP or 3-TWP than L-TG/HDL group (for 2-TWP 29.5% vs 21.5%, P < .05; for 3-TWP 32.7% vs 20.9%, P < .01). Multiple logistic regression analysis showed that a H-TG/HDL was inversely associated to 0-TWP (P < .05) and positively associated with 2-TWP (P < .05) and 3-TWP (P < .01). CONCLUSIONS: Our data suggest that TG/HDL is a marker of increased atherosclerotic extension in prediabetes and newly diagnosed T2D and may be useful to identify subjects with a higher cardiovascular risk profile.

COVID-19-associated collapsing glomerulopathy: a report of two cases and literature review.

Nephrotic range proteinuria has been reported during the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease (COVID-19). However, the pathological mechanisms underlying this manifestation are unknown. In this article, we present two cases of collapsing glomerulopathy (CG) associated with acute tubular necrosis during the course of COVID-19, and review the literature for similar reports. In our two cases, as in the 14 cases reported so far, the patients were of African ancestry. The 14 patients assessed had an APOL1 high-risk genotype. At the end of the reported period, two patients had died and five patients were still requiring dialysis. The 16 cases detailed in the present report strongly argue in favour of a causal link between SARS-CoV-2 infection and the occurrence of CG in patients homozygous for APOL1 high-risk genotype for which the term COVID-associated nephropathy (COVIDAN) can be put forward.

Pairwise Stimulations of Pathogen-Sensing Pathways Predict Immune Responses to Multi-adjuvant Combinations.

The immune system makes decisions in response to combinations of multiple microbial inputs. We do not understand the combinatorial logic governing how higher-order combinations of microbial signals shape immune responses. Here, using coculture experiments and statistical analyses, we discover a general property for the combinatorial sensing of microbial signals, whereby the effects of triplet combinations of microbial signals on immune responses can be predicted by combining the effects of single and pairs. Mechanistically, we find that singles and pairs dictate the information signaled by triplets in mouse and human DCs at the levels of transcription, chromatin, and protein secretion. We exploit this simplifying property to develop cell-based immunotherapies prepared with adjuvant combinations that trigger protective responses in mouse models of cancer. We conclude that the processing of multiple input signals by innate immune cells is governed by pairwise effects, which will inform the rationale combination of adjuvants to manipulate immunity.

Filtering input fluctuations in intensity and in time underlies stochastic transcriptional pulses without feedback.

Stochastic pulsatile dynamics have been observed in an increasing number of biological circuits with known mechanism involving feedback control and bistability. Surprisingly, recent single-cell experiments in Escherichia coli flagellar synthesis showed that flagellar genes are activated in stochastic pulses without the means of feedback. However, the mechanism for pulse generation in these feedbackless circuits has remained unclear. Here, by developing a system-level stochastic model constrained by a large set of single-cell E. coli flagellar synthesis data from different strains and mutants, we identify the general underlying design principles for generating stochastic transcriptional pulses without feedback. Our study shows that an inhibitor (YdiV) of the transcription factor (FlhDC) creates a monotonic ultrasensitive switch that serves as a digital filter to eliminate small-amplitude FlhDC fluctuations. Furthermore, we find that the high-frequency (fast) fluctuations of FlhDC are filtered out by integration over a timescale longer than the timescale of the input fluctuations. Together, our results reveal a filter-and-integrate design for generating stochastic pulses without feedback. This filter-and-integrate mechanism enables a general strategy for cells to avoid premature activation of the expensive downstream gene expression by filtering input fluctuations in both intensity and time so that the system only responds to input signals that are both strong and persistent.

Circulating Receptor Activator of Nuclear Factor kB Ligand and triglycerides are associated with progression of lower limb arterial calcification in type 2 diabetes: a prospective, observational cohort study.

BACKGROUND: Lower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes. METHODS: Lower limb arterial calcification scores were determined by computed tomography at baseline and after a mean follow up of 31.20 ± 3.86 months. Serum RANKL (Receptor Activator of Nuclear factor kB Ligand) and bone remodeling, inflammatory and metabolic parameters were measured at baseline. The predictive effect of these markers on calcification progression was analyzed by a multivariate linear regression model. RESULTS: At baseline, mean ± SD and median lower limb arterial calcification scores were, 2364 ± 5613 and 527 respectively and at the end of the study, 3739 ± 6886 and 1355 respectively. Using multivariate analysis, the progression of lower limb arterial log calcification score was found to be associated with (ß coefficient [slope], 95% CI, p-value) baseline log(calcification score) (1.02, 1.00-1.04, p < 0.001), triglycerides (0.11, 0.03-0.20, p = 0.007), log(RANKL) (0.07, 0.02-0.11, p = 0.016), previous ischemic cardiomyopathy (0.36, 0.15-0.57, p = 0.001), statin use (0.39, 0.06-0.72, p = 0.023) and duration of follow up (0.04, 0.01-0.06, p = 0.004). CONCLUSION: In patients with type 2 diabetes, lower limb arterial calcification is frequent and can progress rapidly. Circulating RANKL and triglycerides are independently associated with this progression. These results open new therapeutic perspectives in peripheral diabetic calcifying arteriopathy. Trial registration NCT02431234.