Association of physical activity and sports participation with insulin resistance and non-alcoholic fatty liver disease in people with type 1 diabetes.

AIM: To evaluate the association between physical activity (PA) and sports participation with insulin resistance and non-alcoholic fatty liver disease (NAFLD) in people with type 1 diabetes (T1D). METHODS: People with T1D from a secondary and tertiary care centre were included. Questionnaire-derived PA was expressed in metabolic equivalent of task hours per week (METh/week). Insulin sensitivity was calculated with the estimated glucose disposal rate (eGDR). NAFLD was assessed by transient elastography (TE). Multivariate linear and logistic regression models were conducted, adjusted for age, sex, diabetes duration and BMI. RESULTS: In total, 254 participants were included (men 56%, age 44 ± 14 years, diabetes duration 24 ± 14 years, median BMI 24.8 kg/m2), of which 150 participants underwent TE. Total PA (median 50.7 METh/week) was not significantly associated with insulin resistance (median eGDR 7.31 mg/kg/min) (beta -0.00, 95% CI -0.01 to 0.00) or with NAFLD (OR 1.00, 95% CI 0.99-1.01). Participating in sports was significantly associated with eGDR (beta 0.94, 95% CI 0.48-1.41) and with NAFLD (OR 0.21, 95% CI 0.08-0.56). CONCLUSIONS: In our T1D population, we could not find any dose-dependent association between PA, insulin resistance and NAFLD. People participating in sports had a lower degree of insulin resistance and lower odds for NAFLD.

Nitrogen-Phosphorus-Potassium containing liquid fertilizer intoxication presenting with extreme hyperkalemia, metabolic acidosis and ECG changes.

Liquid fertilizers are widely used for fertilizing in- and outdoor vegetation. Despite the easy accessibility and widespread use, serious intoxications are rare. This case report describes a 61-year-old woman who was treated for life-threatening hyperkalemia, metabolic acidosis and ECG changes after intentional ingestion of liquid fertilizer. Our case shows that intake of liquid fertilizer, though infrequent, can cause serious, life threatening complications.

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.

Current treatment strategies for primary upper extremity deep venous thrombosis; a retrospective observational multicenter case series.

Introduction: Current treatment strategies for primary upper extremity deep venous thrombosis (pUEDVT) range from conservative treatment with anticoagulation therapy to invasive treatment with thoracic outlet decompression surgery (TOD), frequently combined with catheter directed thrombolysis, percutaneous transluminal angioplasty, or stenting. Due to a lack of large prospective series with uniform data collection or a randomized trial, the optimal treatment strategy is still under debate. We conducted a multicenter observational study to assess the efficacy and safety of both the conservative and invasive treatment strategies for patients with pUEDVT. Methods: We retrospectively collected data from patients treated in five vascular referral and teaching hospitals in the Netherlands between 2008 and 2019. Patients were divided into a conservative (Group 1), an invasive treatment group (Group 2) and a cross-over group (Group 3) of patients who received surgical treatment after initial conservative therapy. Follow-up consisted of outpatient clinic visits and an electronic survey. Primary outcome was symptom free survival defined as absence of any symptom of the affected arm reported at last follow-up regardless of severity, or extent of functional disability. Secondary outcomes were incidence of bleeding complications, recurrent venous thromboembolism, surgical complications, and reinterventions. Results: A total of 115 patients were included (group 1 (N = 45), group 2 (N = 53) or group 3 (N = 27). The symptom free survival was 35.6%, 54.7% and 48.1% after a median follow-up of 36, 26 and 22 months in groups 1, 2 and 3 respectively. Incidence of bleeding complications was 8.6%, 3.8% and 18.5% and recurrent thrombosis occurred in 15.6%, 13.2% and 14.8% in groups 1-3 respectively. Conclusion: In this multicenter retrospective observational cohort analysis the conservative and direct invasive treatments for pUEDVT were deemed safe with low percentages of bleeding complications. Symptom free survival was highest in the direct surgical treatment group but still modest in all subgroups. Perioperative complications were infrequent with no related long term morbidity. Of relevance, pUEDVT patients with confirmed VTOS and recurrent symptoms after conservative treatment may still benefit from TOD surgery. However, symptom free survival of this delayed TOD seems lower than direct surgical treatment and bleeding complications seem to occur more frequently.

Validity of electrodermal activity-based measures of sympathetic nervous system activity from a wrist-worn device.

Measuring electrodermal activity (EDA) on the wrist with the use of dry electrodes is a promising method to help identify person-specific stressors during prolonged recordings in daily life. While the feasibility of this method has been demonstrated, detailed testing of validity of such ambulatory EDA is scarce. In a controlled laboratory study, we examine SCL and ns.SCR derived from wrist-based dry electrodes (Philips DTI) and palm-based wet electrodes (VU-AMS) in 112 healthy adults (57% females, mean age = 22.3, SD = 3.4) across 26 different conditions involving mental stressors or physical activities. Changes in these EDA measures were compared to changes in the Pre-ejection period (PEP) and stressor-induced changes in affect. Absolute SCL and ns.SCR frequency were lower at the wrist compared to the palm. Wrist-based ns.SCR and palm-based ns.SCR and SCL responded directionally consistent with our experimental manipulation of sympathetic nervous system (SNS) activity. Average within-subject correlations between palm-based and wrist-based EDA were significant but modest (r SCL = 0.31; r ns.SCR = 0.42). Changes in ns.SCR frequency at the palm (r = -0.44) and the wrist (r = -0.36) were correlated with changes in PEP. Both palm-based and wrist based EDA predicted changes in affect (6.5%-14.5%). Our data suggest that wrist-based ns.SCR frequency is a useful addition to the psychophysiologist's toolkit, at least for epidemiology-sized ambulatory studies of changes in sympathetic activity during daily life.

The Impact of a Standardized Pre-visit Laboratory Testing Panel in the Internal Medicine Outpatient Clinic: a Controlled "On-Off" Trial.

BACKGROUND: In several settings, a shorter time to diagnosis has been shown to lead to improved clinical outcomes. The implementation of a rapid laboratory testing allows for a pre-visit testing in the outpatient clinic, meaning that test results are available during the first outpatient visit. OBJECTIVE: To determine whether the pre-visit laboratory testing leads to a shorter time to diagnosis in the general internal medicine outpatient clinic. DESIGN: An "on-off" trial, allocating subjects to one of two treatment arms in consecutive alternating blocks. PARTICIPANTS: All new referrals to the internal medicine outpatient clinic of a university hospital were included, excluding second opinions. A total of 595 patients were eligible; one person declined to participate, leaving data from 594 patients for analysis. INTERVENTION: In the intervention group, patients had a standardized pre-visit laboratory testing before the first visit. MAIN MEASURES: The primary outcome was the time to diagnosis. Secondary outcomes were the correctness of the preliminary diagnosis on the first day, health care utilization, and patient and physician satisfaction. KEY RESULTS: There was no difference in time to diagnosis between the two groups (median 35 days vs 35 days; hazard ratio 1.03 [0.87-1.22]; p = .71). The pre-visit testing group had higher proportions of both correct preliminary diagnoses on day 1 (24% vs 14%; p = .003) and diagnostic workups being completed on day 1 (10% vs 3%; p < .001). The intervention group had more laboratory tests done (50.0 [interquartile range (IQR) 39.0-69.0] vs 43.0 [IQR 31.0-68.5]; p < .001). Otherwise, there were no differences between the groups. CONCLUSIONS: Pre-visit testing did not lead to a shorter overall time to diagnosis. However, a greater proportion of patients had a correct diagnosis on the first day. Further studies should focus on customizing pre-visit laboratory panels, to improve their efficacy. TRIAL REGISTRATION: NL5009.

Predicting 10-year risk of recurrent cardiovascular events andcardiovascular interventions in patients with established cardiovascular disease: results from UCC-SMART and REACH.

BACKGROUND: Existing cardiovascular risk scores for patients with established cardiovascular disease (CVD) estimate residual risk of recurrent major cardiovascular events (MACE). The aim of the current study is to develop and externally validate a prediction model to estimate the 10-year combined risk of recurrent MACE and cardiovascular interventions (MACE+) in patients with established CVD. METHODS: Data of patients with established CVD from the UCC-SMART cohort (N = 8421) were used for model development, and patient data from REACH Western Europe (N = 14,528) and REACH North America (N = 19,495) for model validation. Predictors were selected based on the existing SMART risk score. A Fine and Gray competing risk-adjusted 10-year risk model was developed for the combined outcome MACE+. The model was validated in all patients and in strata of coronary heart disease (CHD), cerebrovascular disease (CeVD), peripheral artery disease (PAD). RESULTS: External calibration for 2-year risk in REACH Western Europe and REACH North America was good, c-statistics were moderate: 0.60 and 0.58, respectively. In strata of CVD at baseline good external calibration was observed in patients with CHD and CeVD, however, poor calibration was seen in patients with PAD. C-statistics for patients with CHD were 0.60 and 0.57, for patients with CeVD 0.62 and 0.61, and for patients with PAD 0.53 and 0.54 in REACH Western Europe and REACH North America, respectively. CONCLUSIONS: The 10-year combined risk of recurrent MACE and cardiovascular interventions can be estimated in patients with established CHD or CeVD. However, cardiovascular interventions in patients with PAD could not be predicted reliably.

Assessing the clinical significance of echocardiograms in determining treatment of patent ductus arteriosus in neonates.

BACKGROUND: To evaluate the utility of echocardiogram (ECHO) in detection and treatment of patent ductus arteriosus (PDA) and hemodynamically significant PDA (hsPDA) in preterm neonates. METHODS: This was a retrospective case-control study of all preterm infants born or admitted to the level III Neonatal Intensive Care Unit in McMaster Children's Hospital from January 2009 to January 2013. These cases were further classified into the following sub-groups: group A) hsPDA confirmed on ECHO; and the control, group B) PDA (but not hemodynamically significant) confirmed on ECHO. Patients without an ECHO were excluded from all analyses. The primary outcome was incidence of treatment for PDA. RESULTS: PDA treatment was administered in 83.3% and 11.2% of patients in groups A and B respectively (P < 0.05). Among patients with a hsPDA within group A, 17% did not receive treatment, while 11% of patients with non-hemodynamically significant PDA received treatment for the PDA. Within the cohort of patients who received treatment for a hsPDA, gestational age below 35 weeks as well as murmurs heard on auscultation were both found to be predictors of treatment. CONCLUSION: While the ECHO remains the gold standard for detecting pathological PDA, there is evidence that other traditional clinical measures continue to guide clinical practice and treatment decisions. Further research is required to gain an understanding of how clinical measures and ECHO may be used in conjunction to optimize resource utilization.

The relation between healthy lifestyle changes and decrease in systemic inflammation in patients with stable cardiovascular disease.

BACKGROUND AND AIMS: Pharmacological lowering of inflammation has proven effective in reducing recurrent cardiovascular event rates. Aim of the current study is to evaluate lifestyle changes (smoking cessation, weight loss, physical activity level increase, alcohol moderation, and a summary lifestyle improvement score) in relation to change in plasma C-reactive protein (CRP) concentration in patients with established cardiovascular disease. METHODS: In total, 1794 patients from the UCC-SMART cohort with stable cardiovascular disease and CRP levels ≤10 mg/L, who returned for a follow-up study visit after median 9.9 years (IQR 5.4-10.8), were included. The relation between changes in smoking status, weight, physical activity, alcohol consumption, a summary lifestyle improvement score and change in plasma CRP concentration was evaluated with linear regression analyses. RESULTS: Smoking cessation was related to a 0.40 mg/L decline in CRP concentration (ß-coefficient -0.40; 95%CI -0.73,-0.07). Weight loss (per 1SD = 6.4 kg) and increase in physical activity (per 1 SD = 48 MET hours per week) were related to a decrease in CRP concentration (ß-coefficients -0.25; 95%CI -0.33,-0.16 and -0.09; 95%CI -0.17,-0.01 per SD). Change in alcohol consumption was not related to CRP difference. Every point higher in the summary lifestyle improvement score was related to a decrease in CRP concentration of 0.17 mg/L (ß-coefficient -0.17; 95%CI -0.26,-0.07). CONCLUSIONS: Smoking cessation, increase in physical activity, and weight loss are related to a decrease in CRP concentration in patients with stable cardiovascular disease. Patients with the highest summary lifestyle improvement score have the most decrease in CRP concentration. These results may indicate that healthy lifestyle changes contribute to lowering systemic inflammation, potentially leading to a lower cardiovascular risk in patients with established cardiovascular disease.

The short Sing-a-Song Stress Test: A practical and valid test of autonomic responses induced by social-evaluative stress.

The Sing-a-Song Stress Test (SSST) was recently developed as an alternative to the Trier Social Stress Test (TSST) to investigate autonomic nervous system responses to social-evaluative stress. In the SSST, participants are suddenly cued to sing a song in the presence of confederates. However, the SSST is still quite long (~15 min) and the requirement for confederates makes it labor-intensive. The current study tested whether a shorter (~6.5 min), single-experimenter, version of the SSST can still reliably elicit subjective and physiological stress reactivity. Our sample consisted of 87 healthy young adult participants (age range: 18-35 years). During the short SSST and a speeded reaction time task, in which aversive loud tones were to be avoided (TA), we measured heart period (HP), sympathetic nervous system (SNS) activity using pre-ejection-period (PEP), skin conductance level (SCL), and non-specific skin conductance responses (ns.SCR), and parasympathetic nervous system (PNS) activity using respiratory-sinus-arrhythmia (RSA) and the root-mean-square of successive differences (RMSSD). The short SSST induced significant decreases in positive affect and increases in negative affect. MANOVAs on the clusters of SNS and PNS variables showed that the short SSST elicited significant HP (-118.46 ms), PEP (-7.76 ms), SCL (+4.85 µS), ns.SCR (+8.42 peaks/min) and RMSSD (-14.67) reactivity. Affective, SNS, and PNS reactivity to the new SSST social-evaluative stress task were of comparable magnitude to that evoked by the TA mental stressor. We conclude that the short SSST is a valid and cost-effective task for large scaled studies to induce social-evaluative stress to a sufficient degree to evoke measurable changes in PNS and SNS activity and affective state.

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.

Diagnosing and treating antiphospholipid syndrome: a consensus paper.

INTRODUCTION: The antiphospholipid syndrome (APS) is defined by the occurrence of venous and/or arterial thrombosis and/or pregnancy-related morbidity, combined with the presence of antiphospholipid antibodies (aPL) and/or a lupus anticoagulant (LAC). Large, controlled, intervention trials in APS are limited. This paper aims to provide clinicians with an expert consensus on the management of APS. METHODS: Relevant papers were identified by literature search. Statements on diagnostics and treatment were extracted. During two consensus meetings, statements were discussed, followed by a Delphi procedure. Subsequently, a final paper was written. RESULTS: Diagnosis of APS includes the combination of thrombotic events and presence of aPL. Risk stratification on an individual base remains challenging. 'Triple positive' patients have highest risk of recurrent thrombosis. aPL titres > 99th percentile should be considered positive. No gold standard exists for aPL testing; guidance on assay characteristics as formulated by the International Society on Thrombosis and Haemostasis should be followed. Treatment with vitamin K-antagonists (VKA) with INR 2.0-3.0 is first-line treatment for a first or recurrent APS-related venous thrombotic event. Patients with first arterial thrombosis should be treated with clopidogrel or VKA with target INR 2.0-3.0. Treatment with direct oral anticoagulants is not recommended. Patients with catastrophic APS, recurrent thrombotic events or recurrent pregnancy morbidity should be referred to an expert centre. CONCLUSION: This consensus paper fills the gap between evidence-based medicine and daily clinical practice for the care of APS patients.

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.

Limited benefit of haemoglobin glycation index as risk factor for cardiovascular disease in type 2 diabetes patients.

BACKGROUND: The haemoglobin glycation index (HGI) has been proposed as a marker of interindividual differences in haemoglobin glycosylation. Previous studies have shown a relationship between high HGI and risk of cardiovascular disease (CVD) in patients with diabetes. However, no studies have investigated the role of previous CVD in this association. METHODS: The study cohort comprised patients with type 2 diabetes mellitus (T2DM; n=1910) included in the Second Manifestations of Arterial Disease (SMART) study. The relationship between either HGI or HbA1c and a composite of cardiovascular events as the primary outcome, and mortality, cardiovascular mortality, myocardial infarction and stroke as secondary outcomes, was investigated using Cox proportional-hazards models. Similar analyses were performed after stratification according to previous CVD. RESULTS: A 1-unit higher HGI was associated with a 29% greater risk of a composite of cardiovascular events (HR: 1.29, 95% CI: 1.06-1.57) in patients without previous CVD, whereas no such relationship was seen in patients with previous CVD (HR: 0.96, 95% CI: 0.86-1.08). The direction and magnitude of the hazard ratios (HRs) of HGI and HbA1c in relation to outcomes were similar. Additional adjustment for HbA1c in the association between HGI and outcomes lowered the HRs. CONCLUSION: Similar to HbA1c, higher HGI is related to higher risk of cardiovascular events in patients with T2DM without CVD. As HbA1c has proved to be a comparable risk factor, and obtaining and interpreting the HGI is complicated, any additional benefit of applying the HGI in clinical settings is likely to be limited.

Association between bone metabolism regulators and arterial stiffness in type 2 diabetes patients.

BACKGROUND AND AIM: Osteopontin (OPN), osteonectin (ON) and osteocalcin (OC) play an important role in the development of vascular calcifications, but it is unclear whether these bone metabolism regulators contribute to the development of arterial stiffness in type 2 diabetes patients. We therefore aim to determine the relationship between plasma concentrations of OPN, ON, OC and arterial stiffness in type 2 diabetes patients. METHODS: Cross-sectional study of 1003 type 2 diabetes patients included in the Second Manifestations of ARTerial disease (SMART)-cohort. Generalized linear models were used to evaluate the relation between plasma levels of OPN, ON and OC and arterial stiffness as measured by pulse pressure (PP), ankle-brachial index (ABI) (≥0.9), carotid artery distension and an arterial stiffness summary score. Analyses were adjusted for age, sex, kidney function, diabetes duration and diastolic blood pressure. Higher OPN plasma levels were significantly related to a lower ABI (ß-0.013; 95%CI -0.024 to -0.002) and a higher arterial stiffness summary score (OR1.24; 95%CI 1.03-1.49). OPN levels were not related to PP (ß 0.59; 95%CI -0.63-1.81) or absolute carotid artery distention (ß -7.03; 95%CI -20.00-5.93). ON and OC plasma levels were not related to any of the arterial stiffness measures. CONCLUSION: Only elevated plasma levels of OPN are associated with increased arterial stiffness in patients with type 2 diabetes as measured by the ankle-brachial index and arterial stiffness summary score. These findings indicate that OPN may be involved in the pathophysiology of arterial stiffness and call for further clinical investigation.

Relation between adiposity and vascular events, malignancy and mortality in patients with stable cerebrovascular disease.

BACKGROUND: Abdominal adiposity is associated with various risk factors including hypertension, and is therefore particularly relevant in patients with stable cerebrovascular disease (CeVD). A U-shaped relation between body mass index (BMI, kg m-2) and cardiovascular events is often described. Whether this U-shape persists for abdominal adiposity, and consequently which reference values should guide clinical practice, is unclear. We described the relation between multiple adiposity measurements and risk of vascular events, vascular mortality, malignancy and all-cause mortality in patients with clinically stable CeVD. METHODS: During a median follow-up time of 6.8 years, 1767 patients were prospectively followed. Relations were assessed using multivariable adjusted Cox proportional hazards models. Adiposity was assessed with BMI, waist circumference (stratified by gender) and the contribution of visceral fat to total abdominal fat (VAT%) measured using ultrasound. Relations were nonlinear if the χ2-statistic of the nonlinear term was significant (P-value<0.05). Nadirs were reported for nonlinear and hazard ratios (HRs) for linear relations. RESULTS: The relations between BMI and outcomes were nonlinear with nadirs ranging between 27.1 (95% confidence interval (CI) 21.9-29.3) kg m2 for vascular mortality and 28.1 (95% CI, 19.0-38.2)) kg m-2 for malignancy. The relation between waist circumference and all-cause mortality was nonlinear with a nadir of 84.0 (95% CI, 18.7-134.8) cm for females and 94.8 (95% CI, 80.3-100.1) cm for males. No nonlinearity was detected for VAT%. A 1-s.d. (9.8%) increase in VAT% was related to both vascular (HR, 1.23, 95% CI 1.00-1.51) and all-cause mortality (HR, 1.22, 95% CI 1.05-1.42). CONCLUSIONS: In patients with CeVD, a BMI around 27-28 kg m-2 relates to the lowest risk of vascular events, vascular mortality, malignancy and all-cause mortality. However, increasing abdominal adiposity confers a higher risk of all-cause mortality. Thus, whereas traditional BMI cutoffs may be re-evaluated in this population, striving for low abdominal obesity should remain a goal.

Anticoagulant bridging in left-sided mechanical heart valve patients.

BACKGROUND: In preparation for an invasive procedure with a high bleeding risk, patients with a mechanical heart valve temporarily have to discontinue their anticoagulant therapy and are usually bridged with either intravenous unfractionated heparin (UFH) or subcutaneous low-molecular-weight heparin (LMWH). In this study we retrospectively analyzed the safety of UFH versus LMWH as bridging strategy in left-sided mechanical heart valve patients. METHODS: We performed a retrospective multicenter study in four surgical centers in The Netherlands. Patients with a mechanical heart valve implantation bridged from January 2010 until January 2015 were included. The cumulative incidence of adverse events in the 30days following the procedure was recorded. Main outcomes were major bleeding according to International Society on Thrombosis and Haemostasis (ISTH) criteria, symptomatic thromboembolism, and mortality. RESULTS: In total, 238 (174 aortic, 42 mitral, 22 aortic+mitral) bridging episodes were included. The incidence of major bleeding was 16 (19%) events in the UFH group versus 29 (19%) events in the LMWH group (p=0.97). Incidences of thromboembolism were 2 (2.4%) versus 1 (0.6%). The incidence of death was 1 (1.2%) patient in the UFH group versus 3 (1.9%) patients in the LMWH group. More than 50% of all bleeding complications were categorized as a major bleeding. CONCLUSIONS: Bridging anticoagulation in patients with aortic and mitral mechanical valves is associated with considerable risk, but no difference was apparent between UFH and LMWH strategy. The rate of thromboembolism and death was low with either strategy and the vast majority of adverse events were bleedings.

Maturity onset diabetes of the young: Seek and you will find.

Maturity onset diabetes of the young (MODY) is a monogenic, autosomal dominant form of diabetes characterised by mutations in genes resulting in dysfunction of pancreatic ß-cells and subsequent insulin production. We present a family with HNF1A-MODY due to a likely pathogenic mutation in HNF1A (c.59G>A, p.Gly20Glu), diagnosed a long time after the first diagnosis of diabetes. Currently 13 MODY subtypes caused by mutations in 13 genes, are known. We describe the four most prevalent forms in more detail, i.e. HNF4A-MODY, GCK-MODY, HNF1A-MODY and HNF1B-MODY, together responsible for probably 99% of MODY cases. The different forms of MODY vary in prevalence, severity of diabetes, occurrence and severity of diabetic complications and response to treatment. New tools, such as the MODY probability calculator, may be of assistance in finding those patients in whom further genetic testing for possible MODY is warranted. However, as our described family shows, a doctor's clinical eye and taking the time for a detailed family history may be equal to, or even better than, the best prediction rule.

Definition and solution of a stochastic inverse problem for the Manning's n parameter field in hydrodynamic models.

The uncertainty in spatially heterogeneous Manning's n fields is quantified using a novel formulation and numerical solution of stochastic inverse problems for physics-based models. The uncertainty is quantified in terms of a probability measure and the physics-based model considered here is the state-of-the-art ADCIRC model although the presented methodology applies to other hydrodynamic models. An accessible overview of the formulation and solution of the stochastic inverse problem in a mathematically rigorous framework based on measure theory is presented. Technical details that arise in practice by applying the framework to determine the Manning's n parameter field in a shallow water equation model used for coastal hydrodynamics are presented and an efficient computational algorithm and open source software package are developed. A new notion of "condition" for the stochastic inverse problem is defined and analyzed as it relates to the computation of probabilities. This notion of condition is investigated to determine effective output quantities of interest of maximum water elevations to use for the inverse problem for the Manning's n parameter and the effect on model predictions is analyzed.

Influence of APOE-2 genotype on the relation between adiposity and plasma lipid levels in patients with vascular disease.

BACKGROUND: Apolipoprotein E (APOE) genotypes are associated with different plasma lipid levels. People with the APO ɛ2 genotype can develop a disorder called dysbetalipoproteinemia (DBL). A possible predisposing factor for DBL is adiposity. We evaluated whether and to what extent the APOE genotype modifies the relation between adiposity and lipids in patients with manifest arterial disease and we looked at possible determinants of DBL in ɛ2 homo- and heterozygote patients. METHODS: This prospective cohort study was performed in 5450 patients with manifest arterial disease from the Secondary Manifestations of ARTerial disease (SMART) study. The APOE genotype was measured in all patients and revealed 58 ɛ2 homozygotes, 663 ɛ2 heterozygotes, 3181 ɛ3 homozygotes and 1548 ɛ4 carriers. The main dependent variable was non-high-density lipoprotein cholesterol (non-HDL-c). The relation between adiposity (including body mass index (BMI), waist circumference (waist), visceral adipose tissue (VAT) and metabolic syndrome (MetS)) and lipids was evaluated with linear regression analyses. Determinants of DBL were evaluated using logistic regression. RESULTS: There was significant effect modification by the APOE genotype on the relation between non-HDL-c and BMI, waist, VAT and MetS. There was an association between BMI and non-HDL-c in ɛ2 homozygotes (ß 0.173, 95% confidence interval (CI) 0.031-0.314, P=0.018) and ɛ4 carriers (ß 0.033, 95% CI 0.020-0.046, P<0.001). In all genotypes, there was an effect of waist, VAT and MetS on non-HDL-c, but these effects were most distinct in ɛ2 homozygotes (waist ß 0.063, 95% CI 0.015-0.110, P=0.011; VAT ß 0.580, 95% CI 0.270-0.889, P=0.001; MetS ß 1.760, 95% CI 0.668-2.852, P=0.002). Determinants of DBL in ɛ2 homo- and heterozygotes were VAT and MetS. CONCLUSION: The APOE genotype modifies the relation between adiposity and plasma lipid levels in patients with vascular disease. The relation between adiposity and lipids is present in all patients, but it is most distinct in ɛ2 homozygote patients. Abdominal fat and MetS are determinants of DBL.