A Prospective Study of the Association Between Plasma Calprotectin Levels and New-Onset CKD in the General Population.

Introduction: Systemic inflammation has been associated with chronic kidney disease (CKD). In this study, we aimed to investigate a potential association between the plasma biomarker of inflammation calprotectin and new-onset CKD in a population-based cohort study. Methods: Individuals without CKD at baseline (n = 4662) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) prospective population-based cohort study in the Netherlands were included. Baseline plasma calprotectin levels were assessed in samples that had been stored at -80 °C. Occurrence of new-onset CKD was defined as a composite outcome of an estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2, urinary albumin excretion (UAE) >30 mg/24h, or both. Results: Baseline median (interquartile range) plasma calprotectin levels were 0.49 (0.35-0.68) mg/l and baseline median eGFR was 95.9 (interquartile range: 85.0-105.7) ml/min per 1.73 m2. After median follow-up of 8.3 (7.8-8.9) years, 467 participants developed new-onset CKD. Baseline plasma calprotectin levels were significantly associated with an increased risk of new-onset CKD (hazard ratio [HR] per doubling 1.28 [95% confidence interval, CI: 1.14-1.44], P < 0.001), independent of potentially confounding factors (HR 1.14 [95% CI: 1.01-1.29], P = 0.034), except for baseline high-sensitive C-reactive protein (hs-CRP) (HR 1.05 [0.91-1.21], P = 0.494). In secondary analyses, the association between plasma calprotectin and occurrence of UAE >30 mg/24h remained significant (HR 1.17 [1.02-1.34], P = 0.027), but not significantly so for the incidence of eGFR <60 ml/min per 1.73 m2 as individual outcome (HR 1.15 [0.92-1.43], P = 0.218). Conclusion: Higher plasma calprotectin levels are associated with an increased risk of developing CKD in the general population. This association is mitigated after adjustment for hs-CRP, and more pronounced with new-onset CKD defined by UAE.

Determinants of Carotid Wall Echolucency in a Cohort of European High Cardiovascular Risk Subjects: A Cross-Sectional Analysis of IMPROVE Baseline Data.

Echolucency, a measure of plaque instability associated with increased cardiovascular risk, can be assessed in both the carotid plaque and the plaque-free common carotid intima-media (IM) complex as a gray-scale median (plaque-GSM and IM-GSM, respectively). The impact of specific vascular risk factors on these two phenotypes remains uncertain, including the nature and extent of their influence. This study aims to seek the determinants of plaque-GSM and IM-GSM. Plaque-GSM and IM-GSM were measured in subjects from the IMPROVE study cohort (aged 54-79, 46% men) recruited in five European countries. Plaque-GSM was measured in subjects who had at least one IMTmax ≥ 1.5 mm (n = 2138), whereas IM-GSM was measured in all subjects included in the study (n = 3188). Multiple regression with internal cross-validation was used to find independent predictors of plaque-GSM and IM-GSM. Plaque-GSM determinants were plaque-size (IMTmax), and diastolic blood pressure. IM-GSM determinants were the thickness of plaque-free common carotid intima-media complex (PF CC-IMTmean), height, systolic blood pressure, waist/hip ratio, treatment with fibrates, mean corpuscular volume, treatment with alpha-2 inhibitors (sartans), educational level, and creatinine. Latitude, and pack-yearscode were determinants of both plaque-GSM and IM-GSM. The overall models explain 12.0% of plaque-GSM variability and 19.7% of IM-GSM variability. A significant correlation (r = 0.51) was found between plaque-GSM and IM-GSM. Our results indicate that IM-GSM is a weighty risk marker alternative to plaque-GSM, offering the advantage of being readily measurable in all subjects, including those in the early phases of atherosclerosis where plaque occurrence is relatively infrequent.

Plasma calprotectin and new-onset type 2 diabetes in the general population: a prospective cohort study.

BACKGROUND: Systemic inflammation plays a pivotal role in the development of type 2 diabetes (T2D). Here we hypothesized that circulating levels of calprotectin, a myeloid cell-derived biomarker of inflammation, is associated with the development of new-onset T2D in the general population. METHODS: A total of 4,815 initially non-diabetic participants of the Prevention of Renal and Vascular ENd-stage Disease (PREVEND), a prospective population-based cohort study, were assessed for plasma levels of calprotectin at baseline. Circulating levels of calprotectin were investigated for potential associations with the risk of new-onset T2D, defined as a fasting plasma glucose level ≥7.0 mmol/l, a random plasma glucose level ≥11.1 mmol/l, a self-reported physician-based diagnosis of T2D, the use of glucose-lowering drugs, or any combinations thereof. RESULTS: Median plasma calprotectin levels were 0.49 [0.35-0.69] mg/l. Plasma calprotectin levels were significantly associated with the risk of new-onset T2D (hazard ratio [HR] per doubling 1.42 [95% confidence interval: 1.22-1.66], P<0.001). The association remained independent of adjustment for age and sex (HR 1.34 [95%CI: 1.14-1.57], P<0.001), but not after further adjustment for potentially confounding factors (HR 1.11 [95% CI: 0.90-1.37], P=0.326), with adjustment for hyperlipidemia and high-sensitivity C-reactive protein explaining the loss of significance. Stratified analyses showed significant effect modification by hypertension, history of cardiovascular disease and HOMA-IR (Pinteraction≤0.001 for each), with higher HRs in individuals without hypertension, without history of cardiovascular disease and with below-median HOMA-IR. CONCLUSIONS: Elevated plasma levels of calprotectin are associated with a higher risk of developing T2D in the general population and may represent a moveable inflammatory biomarker. This association, however, does not represent a direct effect, and seems dependent on hyperlipidemia and systemic inflammation.

Automated multiclass segmentation, quantification, and visualization of the diseased aorta on hybrid PET/CT-SEQUOIA.

BACKGROUND: Cardiovascular disease is the most common cause of death worldwide, including infection and inflammation related conditions. Multiple studies have demonstrated potential advantages of hybrid positron emission tomography combined with computed tomography (PET/CT) as an adjunct to current clinical inflammatory and infectious biochemical markers. To quantitatively analyze vascular diseases at PET/CT, robust segmentation of the aorta is necessary. However, manual segmentation is extremely time-consuming and labor-intensive. PURPOSE: To investigate the feasibility and accuracy of an automated tool to segment and quantify multiple parts of the diseased aorta on unenhanced low-dose computed tomography (LDCT) as an anatomical reference for PET-assessed vascular disease. METHODS: A software pipeline was developed including automated segmentation using a 3D U-Net, calcium scoring, PET uptake quantification, background measurement, radiomics feature extraction, and 2D surface visualization of vessel wall calcium and tracer uptake distribution. To train the 3D U-Net, 352 non-contrast LDCTs from (2-[18 F]FDG and Na[18 F]F) PET/CTs performed in patients with various vascular pathologies with manual segmentation of the ascending aorta, aortic arch, descending aorta, and abdominal aorta were used. The last 22 consecutive scans were used as a hold-out internal test set. The remaining dataset was randomly split into training (n = 264; 80%) and validation (n = 66; 20%) sets. Further evaluation was performed on an external test set of 49 PET/CTs. The dice similarity coefficient (DSC) and Hausdorff distance (HD) were used to assess segmentation performance. Automatically obtained calcium scores and uptake values were compared with manual scoring obtained using clinical softwares (syngo.via and Affinity Viewer) in six patient images. intraclass correlation coefficients (ICC) were calculated to validate calcium and uptake values. RESULTS: Fully automated segmentation of the aorta using a 3D U-Net was feasible in LDCT obtained from PET/CT scans. The external test set yielded a DSC of 0.867 ± 0.030 and HD of 1.0 [0.6-1.4] mm, similar to an open-source model with a DSC of 0.864 ± 0.023 and HD of 1.4 [1.0-1.8] mm. Quantification of calcium and uptake values were in excellent agreement with clinical software (ICC: 1.00 [1.00-1.00] and 0.99 [0.93-1.00] for calcium and uptake values, respectively). CONCLUSIONS: We present an automated pipeline to segment the ascending aorta, aortic arch, descending aorta, and abdominal aorta on LDCT from PET/CT and to accurately provide uptake values, calcium scores, background measurement, radiomics features, and a 2D visualization. We call this algorithm SEQUOIA (SEgmentation, QUantification, and visualizatiOn of the dIseased Aorta) and is available at https://github.com/UMCG-CVI/SEQUOIA. This model could augment the utility of aortic evaluation at PET/CT studies tremendously, irrespective of the tracer, and potentially provide fast and reliable quantification of cardiovascular diseases in clinical practice, both for primary diagnosis and disease monitoring.

Plasma Calprotectin Levels Associate With New-Onset Hypertension in the General Population: A Prospective Cohort Study.

BACKGROUND: Low-grade systemic inflammation is a relevant pathogenic mechanism underlying the development of hypertension. In this study, we hypothesized that plasma calprotectin levels, as a biomarker of neutrophil-mediated inflammation, is associated with developing new-onset hypertension in the general population. METHODS AND RESULTS: Plasma calprotectin levels were determined in 3524 participants who participated in the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study, a prospective population-based cohort study. Plasma calprotectin levels were studied for associations with the risk of new-onset hypertension, defined as systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or the first recorded use of antihypertensives. Participants with hypertension at baseline were excluded. Median plasma calprotectin levels were 0.48 (0.34-0.66) mg/L, and median systolic blood pressure was 117 (109-126) mm Hg. Plasma calprotectin levels were significantly associated with the risk of new-onset hypertension (hazard ratio [HR], per doubling 1.30 [95% CI, 1.21-1.41]; P<0.001), also after adjustment for age and sex (HR, 1.26 [95% CI, 1.16-1.37]; P<0.001), but not after additional adjustment for potentially confounding factors, including baseline systolic blood pressure (HR, 1.00 [95% CI, 0.90-1.11]; P=0.996). Stratified analyses showed significant effect modification by sex (Pinteraction=0.023) and urinary albumin excretion (Pinteraction=0.004), with higher HRs in men (compared with women) and in individuals with higher urinary albumin excretion (>9.3 mg per 24 hours) compared with lower urinary albumin excretion (≤9.3 mg per 24 hours). CONCLUSIONS: Higher plasma calprotectin levels are associated with an increased risk of new-onset hypertension in the general population. This association is dependent on baseline systolic blood pressure and is particularly prominent in men compared with women.

The soluble receptor for advanced glycation end products is potentially predictive of pulmonary arterial hypertension in systemic sclerosis.

Introduction: Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are the leading causes of death in systemic sclerosis (SSc). Until now, no prospective biomarker to predict new onset of SSc-ILD or SSc-PAH in patients with SSc has reached clinical application. In homeostasis, the receptor for advanced glycation end products (RAGE) is expressed in lung tissue and involved in cell-matrix adhesion, proliferation and migration of alveolar epithelial cells, and remodeling of the pulmonary vasculature. Several studies have shown that sRAGE levels in serum and pulmonary tissue vary according to the type of lung-related complication. Therefore, we investigated levels of soluble RAGE (sRAGE) and its ligand high mobility group box 1 (HMGB1) in SSc and their abilities to predict SSc-related pulmonary complications. Methods: One hundred eighty-eight SSc patients were followed retrospectively for the development of ILD, PAH, and mortality for 8 years. Levels of sRAGE and HMGB1 were measured in serum by ELISA. Kaplan-Meier survival curves were performed to predict lung events and mortality and event rates were compared with a log-rank test. Multiple linear regression analysis was performed to examine the association between sRAGE and important clinical determinants. Results: At baseline, levels of sRAGE were significantly higher in SSc-PAH-patients (median 4099.0 pg/ml [936.3-6365.3], p = 0.011) and lower in SSc-ILD-patients (735.0 pg/ml [IQR 525.5-1988.5], p = 0.001) compared to SSc patients without pulmonary involvement (1444.5 pg/ml [966.8-2276.0]). Levels of HMGB1 were not different between groups. After adjusting for age, gender, ILD, chronic obstructive pulmonary disease, anti-centromere antibodies, the presence of puffy fingers or sclerodactyly, use of immunosuppression, antifibrotic therapy, or glucocorticoids, and use of vasodilators, higher sRAGE levels remained independently associated with PAH. After a median follow-up of 50 months (25-81) of patients without pulmonary involvement, baseline sRAGE levels in the highest quartile were predictive of development of PAH (log-rank p = 0.01) and of PAH-related mortality (p = 0.001). Conclusions: High systemic sRAGE at baseline might be used as a prospective biomarker for patients with SSc at high risk to develop new onset of PAH. Moreover, high sRAGE levels could predict lower survival rates due to PAH in patients with SSc.

Higher skin autofluorescence in individuals at risk for rheumatoid arthritis: results from a large population-based cohort.

OBJECTIVES: To investigate skin autofluorescence (SAF) levels, an early indicator for cardiovascular disease, in relation to the presence of anticitrullinated protein antibodies (ACPA), joint complaints and rheumatoid arthritis (RA) in a large population-based cohort. METHODS: Cross-sectional data were used from 17346 participants of the Dutch Lifelines Cohort Study, of whom baseline SAF and ACPA levels were available. Individuals were divided into four groups: ACPA-negative controls (n=17211), ACPA-positive without joint complaints (n=49), ACPA-positive RA risk (n=31) and defined RA (n=52). Multinomial regression was used to compare SAF levels and correct for potential confounders. RESULTS: SAF levels were higher in the ACPA-positive RA risk group (OR 2.04, p=0.034) and the defined RA group (OR 3.10, p<0.001) compared to controls, but not in the ACPA-positive without joint complaints group (OR 1.07, p=0.875). The difference in SAF levels remained statistically significant in the defined RA group after adjusting for age (OR 2.09, p=0.011), smoking status, renal function or HbA1c. In the ACPA-positive RA risk group, the effect was found to be comparable (corrected for age: OR 2.09). CONCLUSIONS: Our results indicate that ACPA-positive individuals with RA risk have elevated SAF levels, which is regarded as a non-invasive marker for oxidative stress and a possible indicator for development of cardiovascular disease. Therefore, it is important to conduct further studies to explore if, in ACPA-positive individuals with RA risk and no diagnosis of RA, cardiovascular risk management should be considered in future clinical practice.

Ultrasound for the Detection of Inflammatory Abdominal Aortic Aneurysms: A Case and Validation Series.

Inflammatory abdominal aortic aneurysms (iAAA) are a form of noninfectious aortitis in patients with abdominal aortic aneurysms (AAA). Ultrasound could help to detect iAAA early. This retrospective observational study assessed the potential of using ultrasound to detect iAAA in a case series of iAAA patients, and the diagnostic value of ultrasound to detect iAAA in consecutive patients in a follow-up for AAA, referred to as a feasibility study. In both studies, diagnosis of iAAA was based on a cuff surrounding the aneurysm using CT (golden standard). The case series included 13 patients (age 64 (61; 72) years; 100% male). The feasibility study included 157 patients (age 75 (67; 80) years; 84% male). In the case series, all iAAA patients showed a cuff surrounding the aortic wall on ultrasound. In the feasibility study with AAA patients, ultrasound yielded no cuff in 147 (93.6%; CT negative in all cases), a typic cuff in 8 (5.1%; CT positive in all cases), and an inconclusive cuff in 2 (1.3%; CT negative in both cases) patients. Sensitivity and specificity were 100% and 98.7%, respectively. This study indicates that iAAA can be identified with ultrasound, and safely ruled out. In positive ultrasound cases, additional CT imaging might still be warranted.

Release of High-Mobility Group Box-1 after a Raynaud's Attack Leads to Fibroblast Activation and Interferon-γ Induced Protein-10 Production: Role in Systemic Sclerosis Pathogenesis.

Raynaud's Phenomenon (RP) leading to repetitive ischemia and reperfusion (IR) stress, is the first recognizable sign of systemic sclerosis (SSc) leading to increased oxidative stress. High-mobility group box-1 (HMGB1) is a nuclear factor released by apoptotic and necrotic cells after oxidative stress. Since HMGB1 can signal through the receptor for advanced glycation end products (RAGE), we investigated whether an RP attack promotes the release of HMGB1, leading to fibroblast activation and the upregulation of interferon (IFN)-inducible genes. A cold challenge was performed to simulate an RP attack in patients with SSc, primary RP (PRP), and healthy controls. We measured levels of HMGB1 and IFN gamma-induced Protein 10 (IP-10) at different time points in the serum. Digital perfusion was assessed by photoplethysmography. In vitro, HMGB1 or transforming growth factor (TGF-ß1) (as control) was used to stimulate healthy human dermal fibroblasts. Inflammatory, profibrotic, and IFN-inducible genes, were measured by RT-qPCR. In an independent cohort, sera were obtained from 20 patients with SSc and 20 age- and sex-matched healthy controls to determine HMGB1 and IP-10 levels. We found that HMGB1 levels increased significantly 30 min after the cold challenge in SSc compared to healthy controls. In vitro stimulation with HMGB1 resulted in increased mRNA expression of IP-10, and interleukin-6 (IL-6) while TGF-ß1 stimulation promoted IL-6 and Connective Tissue Growth Factor (CTGF). In serum, both HMGB1 and IP-10 levels were significantly higher in patients with SSc compared to healthy controls. We show that cold challenge leads to the release of HMGB1 in SSc patients. HMGB1 induces IP-10 expression in dermal fibroblasts partly through the soluble RAGE (sRAGE) axis suggesting a link between RP attacks, the release of HMGB1 and IFN-induced proteins as a putative early pathogenetic mechanism in SSc.

Positron Emission Tomography Imaging in Vasculitis.

Systemic vasculitides comprise a group of autoimmune diseases affecting blood vessels. [18F]-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT) plays an important role in the diagnosis and therapeutic monitoring of vasculitides affecting large-sized and medium-sized vessels. FDG-PET/CT also provides complementary information to other vascular imaging tools. The resolution and sensitivity of newer generation scanners continues to increase, hereby improving the ability of FDG-PET/CT to accurately assess the full disease extent in patients with vasculitis. Novel tracers targeting specific immune cells will allow for more detailed detection of vascular infiltrates.

Feasibility Study to Assess Canagliflozin Distribution and Sodium-Glucose Co-Transporter 2 Occupancy Using [18 F]Canagliflozin in Patients with Type 2 Diabetes.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, including canagliflozin, reduce the risk of cardiovascular and kidney outcomes in patients with and without type 2 diabetes, albeit with a large interindividual variation. The underlying mechanisms for this variation in response might be attributed to differences in SGLT2 occupancy, resulting from individual variation in plasma and tissue drug exposure and receptor availability. We performed a feasibility study for the use of [18 F]canagliflozin positron emission tomography (PET) imaging to determine the association between clinical canagliflozin doses and SGLT2 occupancy in patients with type 2 diabetes. We obtained two 90-minute dynamic PET scans with diagnostic intravenous [18 F]canagliflozin administration and a full kinetic analysis in 7 patients with type 2 diabetes. Patients received 50, 100, or 300 mg oral canagliflozin (n = 2:4:1) 2.5 hours before the second scan. Canagliflozin pharmacokinetics and urinary glucose excretion were measured. The apparent SGLT2 occupancy was derived from the difference between the apparent volume of distribution of [18 F]canagliflozin in the baseline and post-drug PET scans. Individual canagliflozin area under the curve from oral dosing until 24-hours (AUCP0-24h ) varied largely (range 1,715-25,747 µg/L*hour, mean 10,580 µg/L*hour) and increased dose dependently with mean values of 4,543, 6,525, and 20,012 µg/L*hour for 50, 100, and 300 mg, respectively (P = 0.046). SGLT2 occupancy ranged between 65% and 87%, but did not correlate with canagliflozin dose, plasma exposure, or urinary glucose excretion. We report the feasibility of [18 F]canagliflozin PET imaging to determine canagliflozin kidney disposition and SGLT2 occupancy. This suggests the potential of [18 F]canagliflozin as a tool to visualize and quantify clinically SGLT2 tissue binding.

Plasma Neutrophil Gelatinase-Associated Lipocalin Associates with New-Onset Chronic Kidney Disease in the General Population.

Circulating levels of neutrophil gelatinase-associated lipocalin (NGAL) have been associated with acute kidney injury and the severity and progression of chronic kidney disease (CKD). This study investigated its potential utility as a biomarker for the risk of new-onset CKD in a population-based cohort study. Individuals without CKD at baseline (n = 4660) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) prospective population-based cohort study in the Netherlands were included. Baseline plasma NGAL concentrations were investigated for their associations with new-onset CKD, defined as a composite outcome of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, urinary albumin excretion (UAE) > 30 mg/24-h, or both. Mean (±SD) plasma NGAL concentrations were 104.0 (±34.7) µg/L and median eGFR was 96 [IQR: 85.3-105.8] mL/min/1.73 m2. After median follow-up of 8.3 [IQR: 7.8-8.9] years, 467 participants developed new-onset CKD. Plasma NGAL concentrations were significantly associated with an increased risk of new-onset CKD (hazard ratio [HR] per doubling 1.35 [95% CI: 1.11-1.63], p = 0.002), even after adjustment for potentially confounding factors (1.37 [1.09-1.73], p = 0.007) except baseline eGFR (1.09 [0.86-1.37], p = 0.490). In secondary analyses, plasma NGAL concentrations were significantly associated with new-onset CKD as defined by eGFR < 60 mL/min/1.73 m2 alone (adjusted HR per doubling 2.54 [1.69-3.80], p < 0.001), which was abrogated after adjustment for eGFR (1.05 [0.69-1.59], p = 0.828), also when UAE > 30 mg/24-h was set as individual outcome (1.05 [0.82-1.35], p = 0.705). Higher plasma NGAL concentrations are associated with an increased risk of developing CKD in the general population. This association is dependent on renal function, and mainly driven by new-onset CKD as defined by renal function decline.

Macrophages as determinants and regulators of fibrosis in systemic sclerosis.

SSc is a multiphase autoimmune disease with a well-known triad of clinical manifestations including vasculopathy, inflammation and fibrosis. Although a plethora of drugs has been suggested as potential candidates to halt SSc progression, nothing has proven clinically efficient. In SSc, both innate and adaptive immune systems are abnormally activated fuelling fibrosis of the skin and other vital organs. Macrophages have been implicated in the pathogenesis of SSc and are thought to be a major source of immune dysregulation. Due to their plasticity, macrophages can initiate and sustain chronic inflammation when classically activated while, simultaneously or parallelly, when alternatively activated they are also capable of secreting fibrotic factors. Here, we briefly explain the polarization process of macrophages. Subsequently, we link the activation of macrophages and monocytes to the molecular pathology of SSc, and illustrate the interplay between macrophages and fibroblasts. Finally, we present recent/near-future clinical trials and discuss novel targets related to macrophages/monocytes activation in SSc.

Studying Telmisartan Plasma Exposure, Kidney Distribution, Receptor Occupancy, and Response in Patients With Type 2 Diabetes Using [11 C]Telmisartan.

The angiotensin receptor blocker telmisartan slows progression of kidney disease in patients with type 2 diabetes (T2D), yet many patients remain at high risk for progressive kidney function loss. The underlying mechanisms for this response variation might be attributed to differences in angiotensin-1 receptor occupancy (RO), resulting from individual variation in plasma drug exposure, tissue drug exposure, and receptor availability. Therefore, we first assessed the relationship between plasma telmisartan exposure and urinary-albumin-to-creatinine-ratio (UACR) in 10 patients with T2D and albuminuria (mean age 66 years, median UACR 297 mg/g) after 4 weeks treatment with 80 mg telmisartan once daily. Increasing telmisartan exposure associated with a larger reduction in UACR (Pearson correlation coefficient (PCC) = -0.64, P = 0.046, median change UACR: -40.1%, 95% confidence interval (CI): -22.9 to -77.4%, mean telmisartan area under the curve (AUC) = 2927.1 ng·hour/mL, 95% CI: 723.0 to 6501.6 ng·hour/mL). Subsequently, we assessed the relation among plasma telmisartan exposure, kidney distribution, and angiotensin-1 RO in five patients with T2D (mean age 60 years, median UACR 72 mg/g) in a separate positron emission tomography imaging study with [11 C]Telmisartan. Individual plasma telmisartan exposure correlated with telmisartan distribution to the kidneys (PCC = 0.976, P = 0.024). A meaningful RO could be calculated in three patients receiving 120 mg oral telmisartan, and although high exposure seems related to higher RO, with AUC0-last of 31, 840, and 274 ng·hour/mL and corresponding RO values 5.5%, 44%, and 59%, this was not significant (P = 0.64). Together these results indicate, for the first time, a relationship among interindividual differences in plasma exposure, kidney tissue distribution, RO, and ultimately UACR response after telmisartan administration.

A role for artificial intelligence in molecular imaging of infection and inflammation.

The detection of occult infections and low-grade inflammation in clinical practice remains challenging and much depending on readers' expertise. Although molecular imaging, like [18F]FDG PET or radiolabeled leukocyte scintigraphy, offers quantitative and reproducible whole body data on inflammatory responses its interpretation is limited to visual analysis. This often leads to delayed diagnosis and treatment, as well as untapped areas of potential application. Artificial intelligence (AI) offers innovative approaches to mine the wealth of imaging data and has led to disruptive breakthroughs in other medical domains already. Here, we discuss how AI-based tools can improve the detection sensitivity of molecular imaging in infection and inflammation but also how AI might push the data analysis beyond current application toward predicting outcome and long-term risk assessment.

Treatment of resistant Raynaud's phenomenon with single-port thoracoscopic sympathicotomy: One-year follow-up.

OBJECTIVE: Follow-up of patients with treatment-resistant Raynaud's phenomenon (RP) one-year after single-port thoracoscopic sympathicotomy (SPTS). METHODS: Eight patients (six males, two females, median age of 45 years) with treatment-resistant RP underwent left-sided SPTS at the third rib (R3), unilaterally. Questionnaires were taken, and number and duration of RP attacks were reported over a 2-week period. Perfusion was assessed with a cooling and recovery procedure at baseline and one year after SPTS. Furthermore, laser speckle contrast analysis, pulse wave velocity, heart rate variability and nailfold capillary microscopy were performed. RESULTS: One year after SPTS the duration of the attacks of was reduced with 1.9 h in the left hand versus 0.3 h in the right hand. Furthermore, three aspects of the questionnaire showed a significant improvement (role limitations due to physical health (p = 0.017), pain (p = 0.027) and physical functioning (p = 0.025)). The total area under the curve of the total cooling and recovery procedure of the left hand was larger one year after surgery (101 (75-140) at baseline versus 118 (95-190) one year post-operatively, p = 0.012), implying a better perfusion in the fingers. This was mainly due to the improvement during the recovery phase (21 (1-41) at baseline versus 38 (24-43) one year post-operatively, p = 0.028). CONCLUSION: One year after unilateral R3 SPTS the benefit with regard to the majority of outcome variables persisted, though some effects seem to attenuate. Long-term effects and long-term follow-up results will be investigated in an on-going study. CLINICAL TRIAL REGISTRATION NUMBER: NCT02680509.

Systemic oxidative stress associates with new-onset hypertension in the general population.

BACKGROUND: Oxidative stress is known to be involved in the development of hypertension, but accurate redox biomarkers predicting the risk of developing hypertension are scarce. Serum free sulfhydryl groups (R-SH, free thiols) have been shown to accurately reflect systemic oxidative stress in various conditions. In this study, we aimed to investigate associations between serum free thiols and the risk of developing new-onset hypertension in a population-based cohort study. METHODS: Subjects (n = 3,575) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, a prospective, population-based cohort study in the Netherlands, were included. Baseline protein-adjusted serum free thiols were studied for their associations with the development of hypertension, defined as a systolic blood pressure (SBP) of at least 140 mmHg, a diastolic blood pressure (DBP) of at least 90 mmHg, or the first usage of antihypertensive medication. Subjects with hypertension at baseline were excluded from the study. RESULTS: Mean protein-adjusted serum free thiols at baseline was 5.16 µmol/g of protein (range: 1.62-8.41 µmol/g). Protein-adjusted serum free thiols were significantly associated with the risk of incident hypertension (hazard ratio [HR] per doubling 0.60 [95% confidence interval [CI]: 0.49-0.72, P < 0.001), also after adjustment for age and sex (HR 0.81 [95% CI: 0.66-0.91], P < 0.05), but not after additional adjustment for relevant confounding factors (HR 0.90 [95% CI: 0.70-1.15], P = 0.382). CONCLUSION: Higher levels of serum free thiols, i.e. less oxidative stress, are associated with a decreased risk of developing incident hypertension in subjects from the general population.

Patient-Tailored Approach for Diagnostics and Treatment of Mycotic Abdominal Aortic Aneurysm.

BACKGROUND: The existing literature on mycotic aortic aneurysm is scarce and focuses on treatment. This study evaluates the clinical characteristics, diagnostics, treatment and outcome of patients with a mycotic abdominal aortic aneurysm treated in a tertiary referral center. METHODS: A retrospective cohort study was conducted including all patients with a proven mycotic abdominal aortic aneurysm admitted between May 2010 and July 2020. Primary outcome was mortality and secondary outcome included complications such as vascular graft/endograft infection. RESULTS: Twenty-four patients with a mycotic abdominal aortic aneurysm were included. Patients had a mean age of 68 ± 9 years and 20 (83%) were male. Thirteen patients (57%) had positive preoperative blood cultures. Streptococcus pneumoniae was most frequently isolated by blood culturing, pus, and vascular, or perivascular tissue cultures (17%). In 19 (83%) patients the mycotic abdominal aortic aneurysm was located infrarenally, in three (13%) patients suprarenally, and in one (4%) patient juxtarenally. Median follow-up was 20 (7-42) months. In 8 patients (33%) vascular graft and or endograft infection was diagnosed after surgical repair. Ten (42%) patients died during the follow-up period. The main causes of death were vascular graft/endograft infection-related (n = 4) and rupture of the mycotic abdominal aortic aneurysm (n = 3). No patient characteristics could be identified as predictive for mortality. CONCLUSIONS: This study shows a large variation in presentation, diagnostic approaches, and surgical and antibiotic treatment of mycotic abdominal aortic aneurysm. The detailed information about the diagnostic approaches to this rare disease and its antibiotic and/or other treatment contributes to existing knowledge of mycotic abdominal aortic aneurysm. Because of the individual variation patients should be discussed in a multidisciplinary team with a vascular surgeon, infectious disease specialist, and clinical microbiologist.

Capillary microscopy is a potential screening method for connective tissue disease in children with Raynaud's phenomenon.

BACKGROUND: Nailfold capillary microscopy (NCM) is a cornerstone in the diagnosis of Systemic Sclerosis (SSc) in adulthood. Although Raynaud's phenomenon (RP) is very common in childhood, studies on diagnostic methods to differentiate between primary RP (PRP) and secondary RP (SRP) at a young age are scarce. The aim of this study was to determine the value of NCM in differentiating between PRP and SRP in children and adolescents with RP. METHODS: In this nested case-control study, 83 patients diagnosed with RP and having underwent NCM in childhood were retrospectively included. Based on whether they were diagnosed with a connective tissue disease (CTD) during follow-up, patients were classified as PRP or SRP. NCM was performed by a vascular technician. PRP and SRP patients were compared on demographics, NCM and serology. Variables associated with SRP were included in a multivariate logistic regression model. Predictive values were calculated for NCM, ANA positivity and the combination of NCM and ANA positivity. RESULTS: At the time of the NCM, the mean age of the RP patients was 15.4 ± 2.3 years. Of these patients, 78.3% were classified as PRP and 21.7% as SRP at mean follow-up of 6.4 ± 3.20 years. CTDs were miscellaneous, with only one patient having developed SSc. Of the NCM parameters, only capillary loss was associated with SRP (p = 0.01). In a multivariate logistic regression model including ANA, capillary loss was not a predictor of SRP. In a model without ANAs, capillary loss was an independent predictor (OR = 3.98, CI 95% 1.22-12.99). Capillary loss had a sensitivity of 44.4% and a specificity of 84.4% for SRP. ANA combined with capillary loss had a sensitivity of 66.7% and a specificity of 85.7%. CONCLUSION: Whereas RP in adulthood is most strongly associated with SSc, children with RP seem to be at risk for developing other CTDs with less apparent NCM abnormalities. Of all NCM findings, only capillary loss was predictive for SRP. NCM did not add to the predictive value of ANA screening. However, with a specificity of 84.4% and being non-invasive, NCM shows potential as a screening method for SRP. More research with a larger study population is required before drawing conclusions.

Serum free sulfhydryl status associates with new-onset chronic kidney disease in the general population.

BACKGROUND: Serum sulfhydryl groups (R-SH, free thiols) reliably reflect the systemic redox status in health and disease. As oxidation of R-SH occurs rapidly by reactive oxygen species (ROS), oxidative stress is accompanied by reduced levels of free thiols. Oxidative stress has been implicated in the pathophysiology of chronic kidney disease (CKD), in which redox imbalance may precede the onset of CKD. Therefore, we aimed to investigate associations between serum free thiols and the risk of incident CKD as defined by renal function decline and albuminuria in a population-based cohort study. METHODS: Subjects without CKD (n = 4,745) who participated in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, a prospective, population-based cohort study in the Netherlands, were included. Baseline protein-adjusted serum free thiols were studied for their associations with the development of CKD, defined as a composite outcome of an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2, urinary 24-h albumin excretion (UAE) > 30 mg/24-h, or both. RESULTS: Median level of protein-adjusted serum free thiols at baseline was 5.14 µmol/g of protein (interquartile range [IQR]: 4.50-5.75 µmol/g) and median eGFR was 96 mL/min/1.73 m2 [IQR: 85-106]. Protein-adjusted serum free thiols were significantly associated with incident CKD (hazard ratio [HR] per doubling 0.42 [95% confidence interval [CI]: 0.36-0.52, P < 0.001), even after adjustment for traditional risk factors (HR 0.67 [95% CI: 0.47-0.94], P=0.022). In secondary analyses, the highest tertile of protein-adjusted serum free thiols was inversely associated with incident UAE >30 mg/24-h after full adjustment for confounding factors (HR per doubling 0.70 [95% CI: 0.51-0.96], P=0.028). CONCLUSION: Higher levels of serum R-SH, reflecting less oxidative stress, are associated with a decreased risk of developing CKD in subjects from the general population. This association is primarily driven by incident CKD as defined by UAE.