Increased Intracranial Arterial Pulsatility and Microvascular Brain Damage in Pseudoxanthoma Elasticum.

BACKGROUND AND PURPOSE: Carotid siphon calcification might contribute to the high prevalence of cerebrovascular disease in pseudoxanthoma elasticum through increased arterial flow pulsatility. This study aimed to compare intracranial artery flow pulsatility, brain volumes, and small-vessel disease markers between patients with pseudoxanthoma elasticum and controls and the association between arterial calcification and pulsatility in pseudoxanthoma elasticum. MATERIALS AND METHODS: Fifty patients with pseudoxanthoma elasticum and 40 age- and sex-matched controls underwent 3T MR imaging, including 2D phase-contrast acquisitions for flow pulsatility in the assessment of ICA and MCA and FLAIR acquisitions for brain volumes, white matter lesions, and infarctions. All patients with pseudoxanthoma elasticum underwent CT scanning to measure siphon calcification. Flow pulsatility (2D phase-contrast), brain volumes, white matter lesions, and infarctions (3D T1 and 3D T2 FLAIR) were compared between patients and controls. The association between siphon calcification and pulsatility in pseudoxanthoma elasticum was tested with linear regression models. RESULTS: Patients with pseudoxanthoma elasticum (mean age, 57 [SD, 12] years; 24 men) had significantly higher pulsatility indexes (1.05; range, 0.94-1.21 versus 0.94; range, 0.82-1.04; P = .02), lower mean GM volumes (597 [SD, 53] mL versus 632 [SD, 53] mL; P < .01), more white matter lesions (2.6; range, 0.5-7.5 versus 1.1; range, 0.5-2.4) mL; P = .05), and more lacunar infarctions (64 versus 8, P = .04) than controls (mean age, 58 [SD, 11] years; 20 men). Carotid siphon calcification was associated with higher pulsatility indexes in patients with pseudoxanthoma elasticum (ß = 0.10; 95% CI, 0.01-0.18). CONCLUSIONS: Patients with pseudoxanthoma elasticum have increased intracranial artery flow pulsatility and measures of small-vessel disease. Carotid siphon calcification might underlie the high prevalence of cerebrovascular disease in pseudoxanthoma elasticum.

Halved contrast medium dose coronary dual-layer CT-angiography - phantom study of tube current and patient characteristics.

Virtual mono-energetic images (VMI) using dual-layer computed tomography (DLCT) enable substantial contrast medium (CM) reductions. However, the combined impact of patient size, tube voltage, and heart rate (HR) on VMI of coronary CT angiography (CCTA) remains unknown. This phantom study aimed to assess VMI levels achieving comparable contrast-to-noise ratio (CNR) in CCTA at 50% CM dose across varying tube voltages, patient sizes, and HR, compared to the reference protocol (100% CM dose, conventional at 120 kVp). A 5 mm artificial coronary artery with 100% (400 HU) and 50% (200 HU) iodine CM-dose was positioned centrally in an anthropomorphic thorax phantom. Horizontal coronary movement was matched to HR (at 0, < 60, 60-75, > 75 bpm), with varying patient sizes simulated using phantom extension rings. Raw data was acquired using a clinical CCTA protocol at 120 and 140 kVp (five repetitions). VMI images (40-70 keV, 5 keV steps) were then reconstructed; non-overlapping 95% CNR confidence intervals indicated significant differences from the reference. Higher CM-dose, reduced VMI, slower HR, higher tube voltage, and smaller patient sizes demonstrated a trend of higher CNR. Regardless of HR, patient size, and tube voltage, no significant CNR differences were found compared to the reference, with 100% CM dose at 60 keV, or 50% CM dose at 40 keV. DLCT reconstructions at 40 keV from 120 to 140 kVp acquisitions facilitate 50% CM dose reduction for various patient sizes and HR with equivalent CNR to conventional CCTA at 100% CM dose, although clinical validation is needed.

The effect of six-month oral vitamin K supplementation on calcification propensity time in individuals with type 2 diabetes mellitus: A post hoc analysis of a randomized, double-blind, placebo-controlled trial.

BACKGROUND AND AIMS: Experimental studies suggested that vitamin K supplementation may retard arterial calcification. Recently, serum calcification propensity time (T50) has been suggested as a functional biomarker for arterial wall calcification propensity. In this post-hoc analysis of a clinical trial, we evaluated the effect of six-month oral vitamin K supplementation on T50 and assessed the correlation between T50 and imaging arterial calcification parameters in people with type 2 diabetes (T2DM). METHODS: This double-blind, randomized, placebo-controlled trial included 68 participants (age = 69 ± 8 years, 76% male) with T2DM. Participants were assigned to menaquinone-7 (360 µg/day; n = 35) or placebo (n = 33). T50 was measured via nephelometry in serum collected at baseline, three and six months. Arterial calcification was measured at baseline and six months via 18F-Na PET-CT and conventional CT using Target-to-Background ratio (TBR) and Agatston score. Longitudinal analysis of covariance adjusted for baseline T50 was used to study the treatment effect. Spearman's correlation was used to assess the correlation between T50 and imaging calcification parameters. RESULTS: Median baseline T50 was similar in the vitamin K (350 [321-394] minutes) and placebo groups (363 [320-398]). There was no significant difference in T50 between treatment arms over time (ẞ = 1.00, 95%C.I. = 0.94-1.07, p = 0.982). The correlation coefficient of T50 with TBR and Agatston score at baseline were -0.185 (p = 0.156) and -0.121 (p = 0.358), respectively. CONCLUSIONS: No effect of vitamin K supplementation on T50 was observed in T2DM. Moreover, T50 did not correlate with TBR and Agatston score. Further research on vitamin K in arterial calcification and on the validity of T50 as arterial calcification marker is warranted.

Impact of body composition and physical strength changes during chemoradiotherapy on complications and survival after oesophagectomy.

BACKGROUND: The aim of this study was to assess body composition and physical strength changes during neoadjuvant chemoradiotherapy (nCRT) and assess their predictive value for (severe) postoperative complications and overall survival in patients who underwent oesophagectomy for oesophageal cancer. METHODS: Consecutive patients who underwent nCRT and oesophagectomy with curative intent in a tertiary referral center were included in the study. Perioperative data were collected in a prospectively maintained database. The CT images before and after nCRT were used to assess skeletal muscle index (SMI), subcutaneous fat index (SFI), and visceral fat index (VFI). To assess physical strength, handgrip strength (HGS) and the exercise capacity of the steep ramp test (SRT Wpeak) were acquired before and after nCRT. RESULTS: Between 2015 and 2020, 126 patients were included. SMI increased in female subgroups and decreased in male subgroups (35.38 to35.60 cm2/m2 for females, P value 0.048, 46.89 to 45.34 cm2/m2 for males, P value < 0.001). No significant changes in SFI, VFI, HGS, and SRT Wpeak were observed. No predictive value of changes in SMI, HGS, and SRT Wpeak was shown for (severe) postoperative complications and overall survival. CONCLUSIONS: A significant but minimal decrease in SMI during nCRT was observed for males only, it was not associated with postoperative complications or overall survival. Physical strength measurements did not decrease significantly over the course of nCRT. No associations with postoperative complications or overall survival were observed.

Systemic arterial calcium burden in patients with chronic limb-threatening ischemia.

INTRODUCTION: 5-year mortality of chronic limb-threatening ischemia (CLTI) is 50-60% and coronary artery disease (CAD) is the main cause of death of CLTI patients, followed by stroke. The aim of this study is to quantify and qualify the calcium load in different arterial territories in patients with CLTI. METHODS: Prospectively, 60 patients with CLTI were included and received a full-body CT scan. 6 patients were excluded. Different arterial territories (the peripheral lower extremity arteries, coronary arteries, extracranial and intracranial carotid arteries, thoracic and abdominal aorta) were analyzed. Analysis and interrelations of both quantitative and semi-quantitative CT measurements was performed. RESULTS: Mean age was 72 years (range 47-95; SD 11.4). Almost all CLTI patients had calcified arterial beds (femoropopliteal 100%, crural 98.1%, coronary 100%, carotid bifurcation 96.2%, internal carotid artery 98.1%, thoracic aorta 96.2%, abdominal aorta 92.3%). Nearly all arterial territories had severe calcifications. 57% had a very high coronary Agatston score (>1000), and 35% extremely high (>2000). Calcifications in the lower extremity were significantly correlated to CAC score, carotid artery bifurcation calcification score, and to a lesser extent correlated to annular calcifications in the aorta. Very high and extremely high total CAC scores were strongly correlated with severe lower extremity arterial calcifications and severe carotid and intracranial internal carotid artery, thoracic and abdominal aorta calcifications in patients with CLTI patients. CONCLUSIONS: In CLTI patients nearly all arterial territories are severely calcified, suggesting that systemic calcification plays an important role in the poor outcome of this disease.

Treatment of arterial calcification in patients with chronic limb threatening ischemia with etidronate: protocol of an investigator-initiated multicenter, double blind, placebo-controlled, randomized clinical trial.

BACKGROUND: Pathologic studies have shown that in patients with critical limb threatening ischaemia (CLTI) medial arterial calcifications are frequently found and may be responsible for aggravating the disease. These extensive calcifitcations are found not only in arteries of the leg but also in the coronary arteries and the aorta. The progression of these calcifications is fast and they stiffen the vessel wall and may thus increase the cardiovascular risk. Reduction of progression of calcification may not only reduce the burden of CLTI but may also reduce the high residual cardiovascular risk. Medial calcifications have been halted by etidronate in other trials. Its potential to reduce the burden from peripheral vascular disease in CLTI and residual cardiovascular risk remains to be established. METHODS: This is an investigator-initiated multicenter, double blind, placebo-controlled, randomized trial comparing the effects of etidronate versus placebo in patients with CLTI. Subjects will be randomized to either treatment with etidronate for 12 months (cyclical 20 mg/kg for 2 weeks on and 10 weeks off) orally or placebo for 12 months (in a similar routine). The primary endpoint is the change in arterial calcification as quantified by CT-scan. Secondary endpoints are the number of amputations above and below the ankle, mortality, number of vascular interventions and quality of life. DISCUSSION: Up to now, the inert end stage of vascular disease in patients with CLTI, has been considered calcification of vessel walls. We believe there is reason to reverse causation and hypothesize that calcification causes vascular disease. This reversal can be proven in a clinical trial if halting the calcification process improves the outcome of the patient. Therefore we use etidronate, a bisphosphate that has proven to stop the calcification in several rare monogenetic calcifying diseases. We aim to perform this mechanistic proof-of-concept study hopefully leading to a clinical outcome study later on.

The ISCON-trial protocol: laparoscopic ischemic conditioning prior to esophagectomy in patients with esophageal cancer and arterial calcifications.

BACKGROUND: Anastomotic leakage is the most important surgical complication following esophagectomy. A major cause of leakage is ischemia of the gastric tube that is used for reconstruction of the gastrointestinal tract. Generalized cardiovascular disease, expressed by calcifications of the aorta and celiac axis stenosis on a pre-operative CT scan, is associated with an increased risk of anastomotic leakage. Laparoscopic ischemic conditioning (ISCON) aims to redistribute blood flow and increase perfusion at the anastomotic site by occluding the left gastric, left gastroepiploic and short gastric arteries prior to esophagectomy. This study aims to assess the safety and feasibility of laparoscopic ISCON in selected patients with esophageal cancer and concomitant arterial calcifications. METHODS: In this prospective single-arm safety and feasibility trial based upon the IDEAL recommendations for surgical innovation, a total of 20 patients will be included recruited in 2 European high-volume centers for esophageal cancer surgery. Patients with resectable esophageal carcinoma (cT1-4a, N0-3, M0) with "major calcifications" of the thoracic aorta accordingly to the Uniform Calcification Score (UCS) or a stenosis of the celiac axis accordingly to the modified North American Symptomatic Carotid Endarterectomy Trial (NASCET) score on preoperative CT scan, who are planned to undergo esophagectomy are eligible for inclusion. The primary outcome variables are complications grade 2 and higher (Clavien-Dindo classification) occurring during or after laparoscopic ISCON and before esophagectomy. Secondary outcomes include intra- and postoperative complications of esophagectomy and the induction of angiogenesis by biomarkers of microcirculation and redistribution of blood flow by measurement of indocyanine green (ICG) fluorescence angiography. DISCUSSION: We hypothesize that in selected patients with impaired vascularization of the gastric tube, laparoscopic ISCON is feasible and can be safely performed 12-18 days prior to esophagectomy. Depending on the results, a randomized controlled trial will be needed to investigate whether ISCON leads to a lower percentage and less severe course of anastomotic leakage in selected patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03896399 . Registered 4 January 2019.

Low skeletal muscle mass predicts frailty in elderly head and neck cancer patients.

PURPOSE: Treatment of head and neck cancer (HNC) carries a high risk of adverse outcomes in patients, especially in frail elderly. Therefore, it is important to identify patients in which treatment benefits outweigh the risk of any adverse outcome. Although the comprehensive geriatric assessment (CGA) identifies frailty, it is a time-consuming tool. Instead, measurement of skeletal muscle mass and strength (sarcopenia) may be a promising and time-efficient biomarker for frailty. The aim of this study was to examine the association between sarcopenia and frailty assessment tools, such as the CGA, Fried criteria and the Groningen Frailty Indicator (GFI). METHODS: A retrospective study was performed in elderly patients (≥ 70-years) with HNC. Sarcopenia was defined as the combination of reduced handgrip strength (HGS) and low skeletal muscle mass (SMM), according to the EWGSOP-2 criteria. SMM was measured on routinely available diagnostic imaging and corrected height: skeletal muscle index (SMI). A CGA was performed by a geriatrician. Frailty screening was performed using the GFI and the Fried criteria. RESULTS: In total, 73 patients were included of which 33 were men (45.2%) and 40 women (54.8%). Frail patients diagnosed by CGA were more likely to have low SMI, sarcopenia, more comorbidities and were at high risk for malnutrition (all p < 0.05). In multivariate regression analysis, the only significant predictor for frailty diagnosed by CGA was SMI (OR 0.9, p < 0.01) independent of comorbidity and muscle strength. CONCLUSION: Low SMI and sarcopenia are associated with frailty in elderly HNC patients. Low SMI predicts frailty and is a promising time-efficient and routinely available tool for clinical practice.

Residual cardiovascular risk reduction guided by lifetime benefit estimation in patients with symptomatic atherosclerotic disease: effectiveness and cost-effectiveness.

AIMS: To determine the (cost)-effectiveness of blood pressure lowering, lipid-lowering, and antithrombotic therapy guided by predicted lifetime benefit compared to risk factor levels in patients with symptomatic atherosclerotic disease. METHODS AND RESULTS: For all patients with symptomatic atherosclerotic disease in the UCC-SMART cohort (1996-2018; n = 7697) two treatment strategies were compared. The lifetime benefit-guided strategy was based on individual estimation of gain in cardiovascular disease (CVD)-free life with the SMART-REACH model. In the risk factor-based strategy, all patients were treated the following: low-density lipoprotein cholesterol (LDL-c) < 1.8 mmol/L, systolic blood pressure <140 mmHg, and antithrombotic medication. Outcomes were evaluated for the total cohort using a microsimulation model. Effectiveness was evaluated as total gain in CVD-free life and events avoided, cost-effectiveness as incremental cost-effectivity ratio (ICER). In comparison to baseline treatment, treatment according to lifetime benefit would lead to an increase of 24 243 CVD-free life years [95% confidence interval (CI) 19 980-29 909] and would avoid 940 (95% CI 742-1140) events in the next 10 years. For risk-factor based treatment, this would be an increase of 18 564 CVD-free life years (95% CI 14 225-20 456) and decrease of 857 (95% CI 661-1057) events. The ICER of lifetime benefit-based treatment with a treatment threshold of ≥1 year additional CVD-free life per therapy was €15 092/QALY gained and of risk factor-based treatment €9933/QALY gained. In a direct comparison, lifetime benefit-based treatment compared to risk factor-based treatment results in 1871 additional QALYs for the price of €36 538/QALY gained. CONCLUSION: Residual risk reduction guided by lifetime benefit estimation results in more CVD-free life years and more CVD events avoided compared to the conventional risk factor-based strategy. Lifetime benefit-based treatment is an effective and potentially cost-effective strategy for reducing residual CVD risk in patients with clinical manifest vascular disease.

Validation of skeletal muscle mass assessment at the level of the third cervical vertebra in patients with head and neck cancer.

BACKGROUND: Low skeletal muscle mass (SMM) is associated with adverse outcomes. SMM is often assessed at the third lumbar vertebra (L3) on abdominal imaging. Abdominal imaging is not routinely performed in patients with head and neck cancer (HNC). We aim to validate SMM measurement at the level of the third cervical vertebra (C3) on head and neck imaging. MATERIAL AND METHODS: Patients with pre-treatment whole-body computed tomography (CT) between 2010 and 2018 were included. Cross-sectional muscle area (CSMA) was manually delineated at the level of C3 and L3. Correlation coefficients and intraclass correlation coefficients (ICCs) were calculated. Cohen's kappa was used to assess the reliability of identifying a patient with low SMM. RESULTS: Two hundred patients were included. Correlation between CSMA at the level of C3 and L3 was good (r = 0.75, p < 0.01). Using a multivariate formula to estimate CSMA at L3, including gender, age, and weight, correlation improved (r = 0.82, p < 0.01). The agreement between estimated and actual CSMA at L3 was good (ICC 0.78, p < 0.01). There was moderate agreement in the identification of patients with low SMM based on the estimated lumbar skeletal muscle mass index (LSMI) and actual LSMI (Cohen's κ: 0.57, 95%CI 0.45-0.69). CONCLUSIONS: CSMA at C3 correlates well with CSMA at L3. There is moderate agreement in the identification of patients with low SMM based on the estimated lumbar SMI (based on measurement at C3) and actual LSMI.

Pulsatility Attenuation along the Carotid Siphon in Pseudoxanthoma Elasticum.

We compared velocity pulsatility, distensibility, and pulsatility attenuation along the intracranial ICA and MCA between 50 patients with pseudoxanthoma elasticum and 40 controls. Patients with pseudoxanthoma elasticum had higher pulsatility and lower distensibility at all measured locations, except for a similar distensibility at C4. The pulsatility attenuation over the siphon was similar between patients with pseudoxanthoma elasticum and controls. This finding suggests that other disease mechanisms are the main contributors to increased intracranial pulsatility in pseudoxanthoma elasticum.

Sex differences in intracranial and extracranial atherosclerosis in patients with acute ischemic stroke.

BACKGROUND AND AIM: To investigate sex differences with respect to presence and location of atherosclerosis in acute ischemic stroke patients. METHODS: Participants with acute ischemic stroke were included from the Dutch acute stroke trial, a large prospective multicenter cohort study performed between May 2009 and August 2013. All patients received computed tomography/computed tomography-angiography within 9 h of stroke onset. We assessed presence of atherosclerosis in the intra- and extracranial internal carotid and vertebrobasilar arteries. In addition, we determined the burden of intracranial atherosclerosis by quantifying internal carotid and vertebrobasilar artery calcifications, resulting in calcium volumes. Prevalence ratios between women and men were calculated with Poisson regression analysis and adjusted prevalence ratio for potential confounders (age, hypertension, hyperlipidemia, diabetes, smoking, and alcohol use). RESULTS: We included 1397 patients with a mean age of 67 years, of whom 600 (43%) were women. Presence of atherosclerosis in intracranial vessel segments was found as frequently in women as in men (71% versus 72%, adjusted prevalence ratio 0.95; 95% CI 0.89-1.01). In addition, intracranial calcification volume did not differ between women and men in both intracranial internal carotid (large burden 35% versus 33%, adjusted prevalence ratio 0.93; 95% CI 0.73-1.19) and vertebrobasilar arteries (large burden 26% versus 40%, adjusted prevalence ratio 0.69; 95% CI 0.41-1.12). Extracranial atherosclerosis was less common in women than in men (74% versus 81%, adjusted prevalence ratio 0.86; 95% CI 0.81-0.92). CONCLUSIONS: In patients with acute ischemic stroke the prevalence of intracranial atherosclerosis does not differ between women and men, while extracranial atherosclerosis is less often present in women compared with men.

The predictive and prognostic value of low skeletal muscle mass for dose-limiting toxicity and survival in head and neck cancer patients receiving concomitant cetuximab and radiotherapy.

PURPOSE: This study aims to investigate the predictive value of low skeletal muscle mass (SMM) for cetuximab dose-limiting toxicity (DLT) and its prognostic value in head and neck squamous cell carcinoma (HNSCC) patients treated with concomitant cetuximab and radiotherapy. METHODS: Patients diagnosed with HNSCC and treated with primary or adjuvant concomitant cetuximab and radiotherapy were included. Clinical and demographic variables were retrospectively retrieved and SMM was measured at the level of the third cervical vertebra using pre-treatment diagnostic computed tomography or magnetic resonance imaging. An optimal cut-off value for low SMM was determined based on the lowest log-likelihood associated with cetuximab DLT. A multivariate linear regression model was used to determine predictive factors for cetuximab DLT. The prognostic value of low SMM for disease-free and overall survival was analyzed using Kaplan-Meier curves. RESULTS: The optimal cut-off value for low SMM as a predictor of cetuximab DLT was an LSMI ≤ 45.2 cm2/m2. Of the 91 included patients, 74.7% had low SMM and 30.8% experienced cetuximab DLT. At multivariate analysis, low SMM had no predictive value for DLT (OR 0.83; 95% CI 0.27-2.56; p = 0.74). The Kaplan-Meier curve demonstrated that patients with low SMM had significantly lower overall survival (Log Rank χ2 = 5.87; p = 0.02). CONCLUSION: Low SMM is highly prevalent in HNSCC patients treated with concomitant cetuximab and radiotherapy. Low SMM has no predictive value for cetuximab DLT in HNSCC patients. Low SMM is probably not a prognostic factor for overall survival in highly selected HNSCC patients treated with concomitant cetuximab and radiotherapy and unfit for platin-based chemotherapy.

An automated workflow based on hip shape improves personalized risk prediction for hip osteoarthritis in the CHECK study.

OBJECTIVE: To design an automated workflow for hip radiographs focused on joint shape and tests its prognostic value for future hip osteoarthritis. DESIGN: We used baseline and 8-year follow-up data from 1,002 participants of the CHECK-study. The primary outcome was definite radiographic hip osteoarthritis (rHOA) (Kellgren-Lawrence grade ≥2 or joint replacement) at 8-year follow-up. We designed a method to automatically segment the hip joint from radiographs. Subsequently, we applied machine learning algorithms (elastic net with automated parameter optimization) to provide the Shape-Score, a single value describing the risk for future rHOA based solely on joint shape. We built and internally validated prediction models using baseline demographics, physical examination, and radiologists scores and tested the added prognostic value of the Shape-Score using Area-Under-the-Curve (AUC). Missing data was imputed by multiple imputation by chained equations. Only hips with pain in the corresponding leg were included. RESULTS: 84% were female, mean age was 56 (±5.1) years, mean BMI 26.3 (±4.2). Of 1,044 hips with pain at baseline and complete follow-up, 143 showed radiographic osteoarthritis and 42 were replaced. 91.5% of the hips had follow-up data available. The Shape-Score was a significant predictor of rHOA (odds ratio per decimal increase 5.21, 95%-CI (3.74-7.24)). The prediction model using demographics, physical examination, and radiologists scores demonstrated an AUC of 0.795, 95%-CI (0.757-0.834). After addition of the Shape-Score the AUC rose to 0.864, 95%-CI (0.833-0.895). CONCLUSIONS: Our Shape-Score, automatically derived from radiographs using a novel machine learning workflow, may strongly improve risk prediction in hip osteoarthritis.

Eliminating biasing signals in lung cancer images for prognosis predictions with deep learning.

Deep learning has shown remarkable results for image analysis and is expected to aid individual treatment decisions in health care. Treatment recommendations are predictions with an inherently causal interpretation. To use deep learning for these applications in the setting of observational data, deep learning methods must be made compatible with the required causal assumptions. We present a scenario with real-world medical images (CT-scans of lung cancer) and simulated outcome data. Through the data simulation scheme, the images contain two distinct factors of variation that are associated with survival, but represent a collider (tumor size) and a prognostic factor (tumor heterogeneity), respectively. When a deep network would use all the information available in the image to predict survival, it would condition on the collider and thereby introduce bias in the estimation of the treatment effect. We show that when this collider can be quantified, unbiased individual prognosis predictions are attainable with deep learning. This is achieved by (1) setting a dual task for the network to predict both the outcome and the collider and (2) enforcing a form of linear independence of the activation distributions of the last layer. Our method provides an example of combining deep learning and structural causal models to achieve unbiased individual prognosis predictions. Extensions of machine learning methods for applications to causal questions are required to attain the long-standing goal of personalized medicine supported by artificial intelligence.

The accuracy of diagnostic Imaging techniques in patients with a suspected Fracture-related Infection (IFI) trial: study protocol for a prospective multicenter cohort study.

INTRODUCTION: The optimal diagnostic imaging strategy for fracture-related infection (FRI) remains to be established. In this prospective study, the three commonly used advanced imaging techniques for diagnosing FRI will be compared. Primary endpoints are (1) determining the overall diagnostic performances of white blood cell (WBC) scintigraphy, fluorodeoxyglucose positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI) in patients with suspected FRI and (2) establishing the most accurate imaging strategy for diagnosing FRI. METHODS AND ANALYSIS: This study is a non-randomised, partially blinded, prospective cohort study involving two level 1 trauma centres in The Netherlands. All adult patients who require advanced medical imaging for suspected FRI are eligible for inclusion. Patients will undergo all three investigational imaging procedures (WBC scintigraphy, FDG-PET and MRI) within a time frame of 14 days after inclusion. The reference standard will be the result of at least five intraoperative sampled microbiology cultures, or, in case of no surgery, the clinical presence or absence of infection at 1 year follow-up. Initially, the results of all three imaging modalities will be available to the treating team as per local protocol. At a later time point, all scans will be centrally reassessed by nuclear medicine physicians and radiologists who are blinded for the identity of the patients and their clinical outcome. The discriminative ability of the imaging modalities will be quantified by several measures of diagnostic accuracy. ETHICS AND DISSEMINATION: Approval of the study by the Institutional Review Board has been obtained prior to the start of this study. The results of this trial will be disseminated by publication of peer-reviewed manuscripts, presentation in abstract form at scientific meetings and data sharing with other investigators through academically established means. TRIAL REGISTRATION NUMBER: The IFI trial is registered in the Netherlands Trial Register (NTR7490).

The effect of menaquinone-7 supplementation on vascular calcification in patients with diabetes: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Vitamin K occurs in the diet as phylloquinone and menaquinones. Observational studies have shown that both phylloquinone and menaquinone intake might reduce cardiovascular disease (CVD) risk. However, the effect of vitamin K on vascular calcification is unknown. OBJECTIVES: The aim of this study was to assess if menaquinone supplementation, compared to placebo, decreases vascular calcification in people with type 2 diabetes and known CVD. METHODS: In this double-blind, randomized, placebo-controlled trial, we randomly assigned men and women with type 2 diabetes and CVD to 360 µg/d menaquinone-7 (MK-7) or placebo for 6 mo. Femoral arterial calcification at baseline and 6 mo was measured with 18sodium fluoride positron emission tomography (18F-NaF PET) scans as target-to-background ratios (TBRs), a promising technique to detect active calcification. Calcification mass on conventional computed tomography (CT) scan was measured as secondary outcome. Dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP) concentrations were measured to assess compliance. Linear regression analyses were performed with either TBR or CT calcification at follow-up as the dependent variable, and treatment and baseline TBR or CT calcification as independent variables. RESULTS: We randomly assigned 35 patients to the MK-7 group (33 completed follow-up) and 33 to the placebo group (27 completed follow-up). After the 6-mo intervention, TBR tended to increase in the MK-7 group compared with placebo (0.25; 95% CI: -0.02, 0.51; P = 0.06), although this was not significant. Log-transformed CT calcification mass did not increase in the intervention group compared with placebo (0.50; 95% CI: -0.23, 1.36; P = 0.18). MK-7 supplementation significantly reduced dp-ucMGP compared with placebo (-205.6 pmol/L; 95% CI: -255.8, -155.3 pmol/L). No adverse events were reported. CONCLUSION: MK-7 supplementation tended to increase active calcification measured with 18F-NaF PET activity compared with placebo, but no effect was found on conventional CT. Additional research investigating the interpretation of 18F-NaF PET activity is necessary. This trial was registered at clinicaltrials.gov as NCT02839044.

Arterial stiffness as a risk factor for cardiovascular events and all-cause mortality in people with Type 2 diabetes.

AIM: To quantify the risk of different non-invasive arterial stiffness measurements with macrovascular disease and all-cause mortality in high-risk people with Type 2 diabetes. METHODS: We conducted a prospective cohort study of 1910 people with Type 2 diabetes included in the Second Manifestations of ARTerial disease (SMART) study. Arterial stiffness was assessed by brachial artery pulse pressure, normal range (≥0.9) ankle-brachial index and carotid artery distension. Cox regression was used to evaluate the effects of arterial stiffness on risk of cardiovascular events (composite of myocardial infarction, stroke and vascular mortality) and all-cause mortality. RESULTS: A total of 380 new cardiovascular events and 436 deaths occurred during a median (interquartile range) follow-up of 7.5 (4.1-11.0) years. A 10-mmHg higher brachial pulse pressure was related to higher hazard of cardiovascular events (hazard ratio 1.09, 95% CI 1.02 to 1.16) and all-cause mortality (hazard ratio 1.10, 95% CI 1.03 to 1.16). A 0.1-point lower ankle-brachial index within the normal range was related to a higher hazard of cardiovascular events (hazard ratio 1.13, 95% CI 1.01 to 1.27) and all-cause mortality (hazard ratio 1.17, 95% CI 1.04 to 1.31). A one-unit (10-3 ×kPa-1 ) lower carotid artery distensibility coefficient was related to a higher hazard of vascular mortality (hazard ratio 1.04, 95% CI 1.00 to 1.09) and all-cause mortality (hazard ratio 1.04, 95% CI 1.00 to 1.07). CONCLUSION: Increased arterial stiffness, as measured by either increased pulse pressure, normal-range ankle-brachial index or carotid artery distensibility coefficient, is related to increased hazard of cardiovascular events and all-cause mortality in people with Type 2 diabetes.