Does high hepatic bioavailability enhance the effect of oral compared to subcutaneous glucocorticoids?

OBJECTIVES: Glucocorticoids (GC) are important in the treatment of autoinflammatory disorders. Oral prednisolone ≤5 mg/day can be effective, but such doses are at or even below physiological daily endogenous GC production. We hypothesised that their immunosuppressive effect might be explained by high hepatic bioavailability of oral GC, exposing the liver to supraphysiological GC via the portal circulation. We tested this by comparing the effect of oral versus subcutaneous low-dose prednisolone, on erythrocyte sedimentation rate (ESR). METHODS: Patients with rheumatoid arthritis or psoriatic arthritis, elevated ESR (≥30 mm/h) and no current or recent GC therapy were eligible. In a pilot study (n=5), 5 mg/day oral prednisolone decreased ESR significantly, suggesting a sample size of 10 patients for a randomised, non-blinded crossover trial. Patients received 5 mg/day prednisolone for 2 periods of 4 days: one treatment period orally and one subcutaneously with a 10-day washout period between treatments. ESR was measured before (day 1 and 15) and after (day 5 and 19) each treatment course. RESULTS: 10 patients were included. ESR decreased after both oral and subcutaneous prednisolone, by -5.6 (20.9) and -5.8 (3.0) mm/h, respectively (p=0.98). The treatment order had no effect on the outcome. CONCLUSIONS: . Short-term oral low-dose GC therapy is not more effective than parental GC in decreasing ESR, arguing against therapeutic high hepatic bioavailability effects. More likely, systemic concentration peaks following administration explain why oral physiological steroid doses are clinically effective.

Three-month tapering and discontinuation of long- term, low-dose glucocorticoids in senior patients with rheumatoid arthritis is feasible and safe: placebo-controlled double blind tapering after the GLORIA trial.

OBJECTIVE: The randomised placebo-controlled GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) trial evaluated the benefits and harms of prednisolone 5 mg/day added to standard care for 2 years in patients aged 65+ years with rheumatoid arthritis (RA). Here, we studied disease activity, flares and possible adrenal insufficiency after blinded withdrawal of study medication. METHODS: Per protocol, patients successfully completing the 2-year trial period linearly tapered and stopped blinded study medication in 3 months. We compared changes in disease activity after taper between treatment groups (one-sided testing). Secondary outcomes (two-sided tests) comprised disease flares (DAS28 (Disease Activity Score 28 joints) increase >0.6, open-label glucocorticoids or disease-modifying antirheumatic drug (DMARD) increase/switch after week 4 of tapering) and symptoms/signs of adrenal insufficiency. In a subset of patients from 3 Dutch centres, cortisol and ACTH were measured in spot serum samples after tapering. RESULTS: 191 patients were eligible; 36 met treatment-related flare criteria and were only included in the flare analysis. Mean (SD) DAS28 change at follow-up: 0.2 (1.0) in the prednisolone group (n=76) vs 0.0 (1.2) in placebo (n=79). Adjusted for baseline, the between-group difference in DAS28 increase was 0.16 (95% confidence limit -0.06, p=0.12). Flares occurred in 45% of prednisolone patients compared with 33% in placebo, relative risk (RR) 1.37 (95% CI 0.95 to 1.98; p=0.12). We found no evidence for adrenal insufficiency. CONCLUSIONS: Tapering prednisolone moderately increases disease activity to the levels of the placebo group (mean still at low disease activity levels) and numerically increases the risk of flare without evidence for adrenal insufficiency. This suggests that withdrawal of low-dose prednisolone is feasible and safe after 2 years of administration.

Effect of anti-inflammatory therapy on vascular biomarkers for subclinical cardiovascular disease in rheumatoid arthritis patients.

OBJECTIVE: To assess the effect of 4 years of anti-inflammatory therapy on markers of subclinical vascular disease in rheumatoid arthritis patients. METHODS: Carotid intima media thickness (IMT), augmentation index (AIx@75) and pulse wave velocity (PWV) measurements were performed repeatedly in 61 RA patients (30 early RA starting with csDMARDs and 31 established RA starting with adalimumab) for 4 years. These markers were also measured in 29 controls with osteoarthritis at baseline (BL). RESULTS: IMT and AIx@75 at BL were higher in RA compared to OA, while PWV was higher in OA. In RA patients, AIx@75 and PWV decreased in the first 6 months after starting anti-inflammatory therapy. At 48 M, the level of AIx@75 remained lower than before therapy, while PWV at 48 M was comparable to BL (AIx@75: BL 28% (95% confidence interval 25-30%), 6 M 23% (20-26%), 48 M 25% (22-28%); PWV: BL 8.5 (7.8-9.2), 6 M 8.0 (7.1-8.9), 48 M 8.6 (7.6-9.6) m/s). IMT remained stable. There was an effect of disease activity (longitudinally, adjusted for changes over time) on IMT, AIx@75 and PWV. CONCLUSION: This study suggests modest beneficial changes in some surrogate markers of subclinical vascular disease after anti-inflammatory therapy. These changes were associated with improvement in disease activity markers. Whether or not these beneficial changes ultimately predict a reduction in clinicalcardiovascular endpoints remains to be established in prospective studies.

The Prognostic Accuracy of Clinical Judgment Versus a Validated Frailty Screening Instrument in Older Patients at the Emergency Department: Findings of the AmsterGEM Study.

STUDY OBJECTIVE: To compare the prognostic accuracy of clinical judgment for frailty in older patients at the emergency department with a validated screening instrument and patient-perceived frailty. METHODS: A prospective cohort study in patients 70 years of age and older in 2 Dutch EDs with a follow-up of 3 months. A dichotomous question was asked to the physician and patient: "Do you consider the patient / yourself to be frail?" The Identification of Seniors At Risk-Hospitalized Patients (ISAR-HP) was used as a validated screening instrument. The primary composite outcome consisted of either functional decline, institutionalization, or mortality. RESULTS: A total of 736 patients were included. The physician identified 59% as frail, compared with 49% by ISAR-HP and 43% by patients themselves. The level of agreement was fair (Fleiss Kappa, 0.31). After 3 months, 31% of the patients experienced at least 1 adverse health outcome. The sensitivity was 79% for the physician, 72% for ISAR-HP, 61% for the patient, and 48% for all 3 combined. The specificity was 50% for the physician, 63% for ISAR-HP, 66% for the patient, and 85% for all 3 positive. The highest positive likelihood ratio was 3.03 (physician, ISAR-HP, patient combined), and the lowest negative likelihood ratio was 0.42 (physician). The areas under the receiver operating curves were all poor: 0.68 at best for ISAR-HP. CONCLUSION: Clinical judgment for frailty showed fair agreement with a validated screening instrument and patient-perceived frailty. All 3 instruments have poor prognostic accuracy, which does not improve when combined. These findings illustrate the limited prognostic value of clinical judgment as a frailty screener in older patients at the ED.

Arterial wall inflammation is increased in rheumatoid arthritis compared with osteoarthritis, as a marker of early atherosclerosis.

OBJECTIVE: RA is associated with higher risk of cardiovascular (CV) disease. Ongoing systemic inflammation is presumed to accelerate atherosclerosis by increasing inflammation in the arterial wall. However, evidence supporting this hypothesis is limited. We aimed to investigate arterial wall inflammation in RA vs OA, and its association with markers of inflammation and CV risk factors. METHODS: 18-fluorodeoxyglucose PET combined with CT (18F-FDG-PET/CT) was performed in RA (n = 61) and OA (n = 28) to investigate inflammatory activity in the wall of large arteries. Secondary analyses were performed in patients with early untreated RA (n = 30), and established RA, active under DMARD treatment (n = 31) vs OA. RESULTS: Patients with RA had significantly higher 18F-FDG uptake in the wall of the carotid arteries (beta 0.27, 95%CI 0.11-0.44, P <0.01) and the aorta (beta 0.47, 95%CI 0.17-0.76, P <0.01) when compared with OA, which persisted after adjustment for traditional CV risk factors. Patients with early RA had the highest 18F-FDG uptake, followed by patients with established RA and OA respectively. Higher ESR and DAS of 28 joints values were associated with higher 18F-FDG uptake in all arterial segments. CONCLUSION: Patients with RA have increased 18F-FDG uptake in the arterial wall compared with patients with OA, as a possible marker of early atherosclerosis. Furthermore, a higher level of clinical disease activity and circulating inflammatory markers was associated with higher arterial 18F-FDG uptake, which may support a role of arterial wall inflammation in the pathogenesis of vascular complications in patients with RA.

The Accuracy of Four Frequently Used Frailty Instruments for the Prediction of Adverse Health Outcomes Among Older Adults at Two Dutch Emergency Departments: Findings of the AmsterGEM Study.

STUDY OBJECTIVE: Older adults presenting to the emergency department (ED) are at high risk of adverse health outcomes. This study aimed to evaluate the accuracy of 4 frequently used screening instruments for the prediction of adverse health outcomes among older adults in the ED. METHODS: This was a prospective cohort study in patients ≥70 years of age presenting to the ED in 2 hospitals in the Netherlands. Screening instruments included the acutely presenting older patient screening program (APOP) (providing 2 risk scores-functional decline [APOP1] and mortality [APOP2]), the International Resident Assessment Instrument Emergendy Department screener (InterRAI ED), the Identification of Seniors At Risk-Hospitalized Patients (ISAR-HP), and the safety management system (VMS). The primary outcome measure was a composite outcome encompassing functional decline, institutionalization, and mortality at 3 months after ED presentation. Other follow-up time points were 1 and 6 months. Analyses were performed to assess prognostic accuracy. RESULTS: In total, 889 patients were included. After 3 months, 267 (31%) patients experienced at least 1 adverse outcome. The positive likelihood ratio ranged from 1.67 (VMS) to 3.33 (APOP1), and the negative likelihood ratio ranged from 0.41 (ISAR-HP) to 0.88 (APOP2). Sensitivity ranged from 17% (APOP2) to 74% (ISAR-HP), and specificity ranged from 63% (ISAR-HP) to 94% (APOP2). The area under the curve ranged from 0.62 (APOP2) to 0.72 (APOP1 and ISAR-HP). Calibration was reasonable for APOP1 and VMS. The prognostic accuracy was comparable across all outcomes and at all follow-up time points. CONCLUSION: The frailty screening instruments assessed in this study showed poor to moderate prognostic accuracy, which brings into question their usability in the prediction of adverse health outcomes among older adults who present to the ED.

Effect of Low-Normal vs High-Normal Oxygenation Targets on Organ Dysfunction in Critically Ill Patients: A Randomized Clinical Trial.

Importance: Hyperoxemia may increase organ dysfunction in critically ill patients, but optimal oxygenation targets are unknown. Objective: To determine whether a low-normal Pao2 target compared with a high-normal target reduces organ dysfunction in critically ill patients with systemic inflammatory response syndrome (SIRS). Design, Setting, and Participants: Multicenter randomized clinical trial in 4 intensive care units in the Netherlands. Enrollment was from February 2015 to October 2018, with end of follow-up to January 2019, and included adult patients admitted with 2 or more SIRS criteria and expected stay of longer than 48 hours. A total of 9925 patients were screened for eligibility, of whom 574 fulfilled the enrollment criteria and were randomized. Interventions: Target Pao2 ranges were 8 to 12 kPa (low-normal, n = 205) and 14 to 18 kPa (high-normal, n = 195). An inspired oxygen fraction greater than 0.60 was applied only when clinically indicated. Main Outcomes and Measures: Primary end point was SOFARANK, a ranked outcome of nonrespiratory organ failure quantified by the nonrespiratory components of the Sequential Organ Failure Assessment (SOFA) score, summed over the first 14 study days. Participants were ranked from fastest organ failure improvement (lowest scores) to worsening organ failure or death (highest scores). Secondary end points were duration of mechanical ventilation, in-hospital mortality, and hypoxemic measurements. Results: Among the 574 patients who were randomized, 400 (70%) were enrolled within 24 hours (median age, 68 years; 140 women [35%]), all of whom completed the trial. The median Pao2 difference between the groups was -1.93 kPa (95% CI, -2.12 to -1.74; P < .001). The median SOFARANK score was -35 points in the low-normal Pao2 group vs -40 in the high-normal Pao2 group (median difference, 10 [95% CI, 0 to 21]; P = .06). There was no significant difference in median duration of mechanical ventilation (3.4 vs 3.1 days; median difference, -0.15 [95% CI, -0.88 to 0.47]; P = .59) and in-hospital mortality (32% vs 31%; odds ratio, 1.04 [95% CI, 0.67 to 1.63]; P = .91). Mild hypoxemic measurements occurred more often in the low-normal group (1.9% vs 1.2%; median difference, 0.73 [95% CI, 0.30 to 1.20]; P < .001). Acute kidney failure developed in 20 patients (10%) in the low-normal Pao2 group and 21 patients (11%) in the high-normal Pao2 group, and acute myocardial infarction in 6 patients (2.9%) in the low-normal Pao2 group and 7 patients (3.6%) in the high-normal Pao2 group. Conclusions and Relevance: Among critically ill patients with 2 or more SIRS criteria, treatment with a low-normal Pao2 target compared with a high-normal Pao2 target did not result in a statistically significant reduction in organ dysfunction. However, the study may have had limited power to detect a smaller treatment effect than was hypothesized. Trial Registration: ClinicalTrials.gov Identifier: NCT02321072.

Amplified prevalence and incidence of cardiovascular disease in patients with inflammatory arthritis and coexistent autoimmune disorders.

OBJECTIVE: This study aims to assess the prevalence proportion and incidence rate of cardiovascular morbidity in patients with inflammatory arthritis compared with that in controls, and to determine whether the co-existence of multiple autoimmune disorders is associated with an amplified risk of cardiovascular disease. METHODS: Data from the Nivel Primary Care Database were used to assess prevalence proportion and incidence rate of cardiovascular disease in patients with inflammatory arthritis only, patients with inflammatory arthritis coexistent with another autoimmune disorder, and controls. Hazard ratios were calculated using Cox regression models. RESULTS: The prevalence proportions in inflammatory arthritis patients were increased for type 1 diabetes [odds ratio (OR) 1.80, 95% CI: 1.27, 2.55], hypothyroidism (OR 1.49, 95% CI: 1.37, 1.61), psoriasis (OR 2.72, 95% CI: 2.49, 2.97) and IBD (OR 2.64, 95% CI: 2.28, 3.07) compared with that in controls. Cardiovascular disease prevalence (OR 1.34, 95% CI: 1.28, 1.41) and incidence rates (incidence rate ratio 1.3, 95% CI: 1.23, 1.41) were higher in inflammatory arthritis patients compared with that in controls, and were further increased in the presence of a second autoimmune disorder. The hazard ratio for cardiovascular disease was 1.32 (95% CI: 1.23, 1.41) for patients with inflammatory arthritis only, and 1.49 (95% CI: 1.31, 1.68) for patients with inflammatory arthritis co-existent with another autoimmune disorder. CONCLUSION: The amplification of cardiovascular disease risk in inflammatory arthritis patients with multiple autoimmune disorders warrants greater awareness, and since autoimmune disorders often co-exist, the need for cardiovascular risk management in these patients is once again emphasized.

JNK2 in myeloid cells impairs insulin's vasodilator effects in muscle during early obesity development through perivascular adipose tissue dysfunction.

Reduced vasodilator properties of insulin in obesity are caused by changes in perivascular adipose tissue and contribute to microvascular dysfunction in skeletal muscle. The causes of this dysfunction are unknown. The effects of a short-term Western diet on JNK2-expressing cells in perivascular adipose tissue (PVAT) on insulin-induced vasodilation and perfusion of skeletal muscle were assessed. In vivo, 2 wk of Western diet (WD) reduced whole body insulin sensitivity and insulin-stimulated muscle perfusion, determined using contrast ultrasonography during the hyperinsulinemic clamp. Ex vivo, WD triggered accumulation of PVAT in skeletal muscle and blunted its ability to facilitate insulin-induced vasodilation. Labeling of myeloid cells with green fluorescent protein identified bone marrow as a source of PVAT in muscle. To study whether JNK2-expressing inflammatory cells from bone marrow were involved, we transplanted JNK2-/- bone marrow to WT mice. Deletion of JNK2 in bone marrow rescued the vasodilator phenotype of PVAT during WD exposure. JNK2 deletion in myeloid cells prevented the WD-induced increase in F4/80 expression. Even though WD and JNK2 deletion resulted in specific changes in gene expression of PVAT; epididymal and subcutaneous adipose tissue; expression of tumor necrosis factor-α, interleukin-1ß, interleukin-6, or protein inhibitor of STAT1 was not affected. In conclusion, short-term Western diet triggers infiltration of JNK2-positive myeloid cells into PVAT, resulting in PVAT dysfunction, nonclassical inflammation, and loss of insulin-induced vasodilatation in vivo and ex vivo.NEW & NOTEWORTHY We demonstrate that in the earliest phase of weight gain, changes in perivascular adipose tissue in muscle impair insulin-stimulated muscle perfusion. The hallmark of these changes is infiltration by inflammatory cells. Deletion of JNK2 from the bone marrow restores the function of perivascular adipose tissue to enhance insulin's vasodilator effects in muscle, showing that the bone marrow contributes to regulation of muscle perfusion.

Short-term LPS induces aortic valve thickening in ApoE*3Leiden mice.

BACKGROUND: Recently, it was shown that 12 weeks of lipopolysaccharide (LPS) administration to nonatherosclerotic mice induced thickening of the aortic heart valve (AV). Whether such effects may also occur even earlier is unknown. As most patients with AV stenosis also have atherosclerosis, we studied the short-term effect of LPS on the AVs in an atherosclerotic mouse model. METHODS: ApoE*3Leiden mice, on an atherogenic diet, were injected intraperitoneally with either LPS or phosphate buffered saline (PBS), and sacrificed 2 or 15 days later. AVs were assessed for size, fibrosis, glycosaminoglycans (GAGs), lipids, calcium deposits, iron deposits and inflammatory cells. RESULTS: LPS injection caused an increase in maximal leaflet thickness at 2 days (128.4 µm) compared to PBS-injected mice (67.8 µm; P = 0.007), whereas at 15 days this was not significantly different. LPS injection did not significantly affect average AV thickness on day 2 (37.8 µm), but did significantly increase average AV thickness at day 15 (41.6 µm; P = 0.038) compared to PBS-injected mice (31.7 and 32.3 µm respectively). LPS injection did not affect AV fibrosis, GAGs and lipid content. Furthermore, no calcium deposits were found. Iron deposits, indicative for valve haemorrhage, were observed in one AV of the PBS-injected group (a day 2 mouse; 9.1%) and in five AVs of the LPS-injected group (both day 2- and 15 mice; 29.4%). No significant differences in inflammatory cell infiltration were observed upon LPS injection. CONCLUSION: Short-term LPS apparently has the potential to increase AV thickening and haemorrhage. These results suggest that systemic inflammation can acutely compromise AV structure.

Correction to: Association of HIV-infection, antiretroviral treatment and metabolic syndrome with large artery stiffness: a cross-sectional study.

Following publication of the original article [1], the authors reported that they have provided the wrong caption.

Aspirin intake in the morning is associated with suboptimal platelet inhibition, as measured by serum Thromboxane B2, during infarct-prone early-morning hours.

Aspirin is traditionally taken once daily in the morning and considered to be effective throughout the 24h interval. Cardiovascular events occur most frequently in the early morning, suggesting that these hours are critical in terms of adequate platelet inhibition. This study therefore assed platelet function in the early morning-8.00 AM-in healthy volunteers, during a once-daily (OD) 80 mg morning in comparison with an OD evening regimen and a twice-daily (BID) 40 mg regimen. It was an open-label randomized cross-over study, comprising 12 healthy subjects. Subjects were allocated to three sequential dosage regimens: 80 mg OD at 8.00 AM, 80mg OD at 8.00 PM, and 40 mg BID at 8.00 AM and PM. Platelet function 12 and 24 hours after aspirin intake was measured by means of serum thromboxane B2 (sTxB2) levels, the collagen/epinephrine closure time (Platelet Function Analyzer(PFA)-200®) and the Aspirin Reaction Units (ARU, VerifyNow®). The results demonstrated that early morning sTxB2 concentrations were 5843pg in the morning regimen, 2877pg in the evening OD regimen, and 3343pg in the BID regimen (morning- vs evening regimen p = < 0.01; morning- vs BID regimen p = < 0.01). Early morning PFA-closure time (p = 0.12)) as well as VerifyNow ARU (p = 0.17) mean values were similar for all three regimens. In conclusion, the OD-morning regimen seems to acquire the lowest level of platelet inhibition during the critical early morning window. Switching to an OD-evening or BID intake seems prudent, although further research on clinical cardiovascular outcome in patients with stable cardiovascular disease is needed.

The effects of industry funding and positive outcomes in the interpretation of clinical trial results: a randomized trial among Dutch psychiatrists.

BACKGROUND: Most studies are inclined to report positive rather than negative or inconclusive results. It is currently unknown how clinicians appraise the results of a randomized clinical trial. For example, how does the study funding source influence the appraisal of an RCT, and do positive findings influence perceived credibility and clinical relevance? This study investigates whether psychiatrists' appraisal of a scientific abstract is influenced by industry funding disclosures and a positive outcome. METHODS: Dutch psychiatrists were randomized to evaluate a scientific abstract describing a fictitious RCT for a novel antipsychotic drug. Four different abstracts were created reporting either absence or presence of industry funding disclosure as well as a positive or a negative outcome. Primary outcomes were the perceived credibility and clinical relevance of the study results (10-point Likert scale). Secondary outcomes were the assessment of methodological quality and interest in reading the full article. RESULTS: Three hundred ninety-five psychiatrists completed the survey (completion rate 45%). Industry funding disclosure was found not to influence perceived credibility (Mean Difference MD 0.12; 95% CI - 0.28 to 0.47, p?) nor interpretation of its clinical relevance (MD 0.14; 95% CI - 0.54 to 0.27, p?). A negative outcome was perceived as more credible than a positive outcome (MD 0.81 points; 95% Confidence Interval (CI) 0.43 to 1.18, p?), but did not affect clinical relevance scores (MD -0.14; 95% CI - 0.54 to 0.27). CONCLUSIONS: In this study, industry funding disclosure was not associated with the perceived credibility nor judgement of clinical relevance of a fictional RCT by psychiatrists. Positive study outcomes were found to be less credible compared to negative outcomes, but industry funding had no significant effects. Psychiatrists may underestimate the influence of funding sources on research results. The fact that physicians indicated negative outcomes to be more credible may point to more awareness of existing publication bias in the scientific literature.

Hyperoxia does not affect oxygen delivery in healthy volunteers while causing a decrease in sublingual perfusion.

OBJECTIVE: To determine the human dose-response relationship between a stepwise increase in arterial oxygen tension and its associated changes in DO2 and sublingual microcirculatory perfusion. METHODS: Fifteen healthy volunteers breathed increasing oxygen fractions for 10 minutes to reach arterial oxygen tensions of baseline (breathing air), 20, 40, 60 kPa, and max kPa (breathing oxygen). Systemic hemodynamics were measured continuously by the volume-clamp method. At the end of each period, the sublingual microcirculation was assessed by SDF. RESULTS: Systemic DO2 was unchanged throughout the study (Pslope  = .8). PVD decreased in a sigmoidal fashion (max -15% while breathing oxygen, SD18, Pslope  = .001). CI decreased linearly (max -10%, SD10, Pslope  < .001) due to a reduction in HR (max -10%, SD7, Pslope  = .009). There were no changes in stroke volume or MAP. Most changes became apparent above an arterial oxygen tension of 20 kPa. CONCLUSIONS: In healthy volunteers, supraphysiological arterial oxygen tensions have no effect on systemic DO2 . Sublingual microcirculatory PVD decreased in a dose-dependent fashion. All hemodynamic changes appear negligible up to an arterial oxygen tension of 20 kPa.

Red wine polyphenols do not improve obesity-associated insulin resistance: A randomized controlled trial.

Preclinical studies have suggested that polyphenols extracted from red wine (RWPs) favourably affect insulin sensitivity, but there is controversy over whether RWPs exert similar effects in humans. The aim of the present study was to determine whether RWPs improve insulin sensitivity in obese volunteers. Obese (body mass index >30 kg/m2 ) volunteers were randomly allocated to RWPs 600 mg/d (n = 14) or matched placebo (n = 15) in a double-blind parallel-arm study for 8 weeks. The participants were investigated at baseline and at the end of the study. Insulin sensitivity was determined using a hyperinsulinaemic-euglycaemic clamp (M-value), a mixed-meal test (Matsuda index), and homeostatic model assessment of insulin resistance (HOMA-IR). RWPs elicited no significant changes in M-value (RWP group: median [interquartile range; IQR] baseline 3.0 [2.4; 3.6]; end of study 3.3 [2.4; 4.8] vs placebo group: median [IQR] baseline 3.4 [2.8; 4.4]; end of study 2.9 [2.8; 5.9] mg/kg/min; P = .65), in Matsuda index (RWP group: median [IQR] baseline 3.3 [2.2; 4.8]; end of study 3.6 [2.4; 4.8] vs placebo group: median [IQR] baseline 4.0 [3.0; 6.0]; end of study 4.0 [3.0; 5.2]; P = .88), or in HOMA-IR. This study showed that 8 weeks of RWP supplementation did not improve insulin sensitivity in 29 obese volunteers. Our findings were not consistent with the hypothesis that RWPs ameliorate insulin resistance in human obesity.

Association of HIV-infection, antiretroviral treatment and metabolic syndrome with large artery stiffness: a cross-sectional study.

BACKGROUND: Effective combined antiretroviral therapy (cART) has improved life expectancy among people living with HIV-1 infection. Treated HIV-1infection increases the prevalence of metabolic syndrome (MS). Despite sub-Saharan Africa having among the highest rates of HIV-1 infection, the effects of MS in HIV-1-infected individuals on cardiovascular risk is poorly explored. The aim of the study was to assess whether MS and/or HIV-1 treatment correlates with large elastic artery stiffness in HIV-1-infected patients treated with first-line cART. METHODS: The study sample comprised of 102 subjects free of cardiovascular disease and major risk factors divided into two groups based on HIV-1 infection, treatment, and MS status: HIV-1+/cART+/MS+ (n = 12); HIV-1+/cART-/MS+ (n = 16); HIV-1-/ MS+ (n = 10); HIV-1+/cART+/MS- (n = 42); HIV-1+/cART-/MS- (n = 32); HIV-1-/ MS- (n = 39). MS was established according the International Diabetes Federation definition. Large artery stiffness was measured using applanation tonometry to assess aortic pulse wave velocity (aPWV) and aortic augmentation index at heart rate of 75 bpm (AIx@HR75). cART included lamivudine/zidovudine and nevirapine or efavirenz. RESULTS: The prevalence of MS in the HIV-1-infected patients was 28%. There were no significant differences in aPWV in the non-MS groups. However, in subjects with MS, aPWV was significantly higher in the HIV-1 cART patients (9.0 ± 1.9 m/s) compared with both controls (7.5 ± 1.8 m/s; P = 0.018) and untreated HIV-1 patients (7.7 ± 1.3 m/s; P = 0.023), and these differences remained after adjustment for blood pressure and sex. Aortic PWV was significantly elevated (P = 0.009) in HIV-1 cART patients with MS compared to their counterparts without MS. Untreated HIV-1 patients with MS also demonstrated increased aPWV compared to their counterparts without MS (P = 0.05). Aortic AIx@HR75 was, on average, ~ 5% higher in HIV-1 cART patients with MS (28.3 ± 62% compared with untreated HIV-1 patients with MS (23.5 ± 9%; P = 0.075). Sub-group multivariate analysis identified MS as an independent predictor of increased aPWV in HIV-1 cART patients. CONCLUSIONS: Our study established that presence of MS in HIV-1 patients on treatment was associated with increased aPWV and hence increased arterial stiffness in sub-Saharan African HIV-1 patients on first-line cART.

Effects of hyperoxia on vascular tone in animal models: systematic review and meta-analysis.

BACKGROUND: Arterial hyperoxia may induce vasoconstriction and reduce cardiac output, which is particularly undesirable in patients who already have compromised perfusion of vital organs. Due to the inaccessibility of vital organs in humans, vasoconstrictive effects of hyperoxia have primarily been studied in animal models. However, the results of these studies vary substantially. Here, we investigate the variation in magnitude of the hyperoxia effect among studies and explore possible sources of heterogeneity, such as vascular region and animal species. METHOD: Pubmed and Embase were searched for eligible studies up to November 2017. In vivo and ex vivo animal studies reporting on vascular tone changes induced by local or systemic normobaric hyperoxia were included. Experiments with co-interventions (e.g. disease or endothelium removal) or studies focusing on lung, brain or fetal vasculature or the ductus arteriosus were not included. We extracted data pertaining to species, vascular region, blood vessel characteristics and method of hyperoxia induction. Overall effect sizes were estimated with a standardized mean difference (SMD) random effects model. RESULTS: We identified a total of 60 studies, which reported data on 67 in vivo and 18 ex vivo experiments. In the in vivo studies, hyperoxia caused vasoconstriction with an SMD of - 1.42 (95% CI - 1.65 to - 1.19). Ex vivo, the overall effect size was SMD - 0.56 (95% CI - 1.09 to - 0.03). Between-study heterogeneity (I2) was high for in vivo (72%, 95% CI 62 to 85%) and ex vivo studies (86%, 95% CI 78 to 98%). In vivo, in comparison to the overall effect size, hyperoxic vasoconstriction was less pronounced in the intestines and skin (P = 0.03) but enhanced in the cremaster muscle region (P < 0.001). Increased constriction was seen in vessels 15-25 µm in diameter. Hyperoxic constriction appeared to be directly proportional to oxygen concentration. For ex vivo studies, heterogeneity could not be explained with subgroup analysis. CONCLUSION: The effect of hyperoxia on vascular tone is substantially higher in vivo than ex vivo. The magnitude of the constriction is most pronounced in vessels ~ 15-25 µm in diameter and is proportional to the level of hyperoxia. Relatively increased constriction was seen in muscle vasculature, while reduced constriction was seen in the skin and intestines.

Hemodynamic effects of acute hyperoxia: systematic review and meta-analysis.

BACKGROUND: In clinical practice, oxygen is generally administered to patients with the intention of increasing oxygen delivery. Supplemental oxygen may, however, cause arterial hyperoxia, which is associated with hemodynamic alterations. We performed a systematic review and meta-analysis of the literature to determine the effect of hyperoxia on central hemodynamics and oxygen delivery in healthy volunteers and cardiovascular-compromised patients. METHODS: PubMed and EMBASE were searched up to March 2017. Studies with adult humans investigating changes in central hemodynamics or oxygen delivery induced by acute normobaric hyperoxia were included. Studies focusing on lung, retinal, or brain parameters were not included. We extracted subject and oxygen exposure characteristics, indexed and unindexed values for heart rate, stroke volume, cardiac output, mean arterial pressure (MAP), systemic vascular resistance, and oxygen delivery during normoxia and hyperoxia. For quantitative synthesis of the data, a random-effects ratio of means (RoM) model was used. RESULTS: We identified 33 studies with 42 datasets. Study categories included healthy volunteers (n = 22 datasets), patients with coronary artery disease (CAD; n = 6), heart failure (HF; n = 6), coronary artery bypass graft (CABG; n = 3) and sepsis (n = 5). Hyperoxia (arterial oxygen tension of 234-617 mmHg) reduced cardiac output (CO) by 10-15% in both healthy volunteers (-10.2%, 95% confidence interval (CI) -12.9% to -7.3%) and CAD (-9.6%, 95% CI -12.3% to -6.9%) or HF patients (-15.2%, 95% CI -21.7% to -8.2%). No significant changes in cardiac output were seen in CABG or septic patients (-3%). Systemic vascular resistance increased remarkably in patients with heart failure (24.6%, 95% CI 19.3% to 30.1%). In healthy volunteers, and those with CAD and CABG, the effect was smaller (11-16%) and was virtually absent in patients with sepsis (4.3%, 95% CI -3.2% to 12.3%). No notable effect on MAP was found in any group (2-3%). Oxygen delivery was not altered by hyperoxia. Considerable heterogeneity existed between study results, likely due to methodological differences. CONCLUSIONS: Hyperoxia may considerably decrease cardiac output and increase systemic vascular resistance, but effects differ between patient categories. Heart failure patients were the most sensitive while no hemodynamic effects were seen in septic patients. There is currently no evidence supporting the notion that oxygen supplementation increases oxygen delivery.

Cardiovascular risk management in rheumatoid arthritis patients still suboptimal: the Implementation of Cardiovascular Risk Management in Rheumatoid Arthritis project.

Objective: To assess the 10-year cardiovascular (CV) risk score and to identify treatment and undertreatment of CV risk factors in patients with established RA. Methods: Demographics, CV risk factors and prevalence of cardiovascular disease (CVD) were assessed by questionnaire. To calculate the 10-year CV risk score according to the Dutch CV risk management guideline, systolic blood pressure was measured and cholesterol levels were determined from fasting blood samples. Patients were categorized into four groups: indication for treatment but not treated; inadequately treated, so not meeting goals (systolic blood pressure ⩽140 mmHg and/or low-density lipoprotein ⩽2.5 mmol/l); adequately treated; or no treatment necessary. Results: A total of 720 consecutive RA patients were included, 375 from Reade and 345 from the Antonius Hospital. The mean age of patients was 59 years (s.d. 12) and 73% were female. Seventeen per cent of the patients had a low 10-year CV risk (<10%), 21% had an intermediate risk (10-19%), 53% a high risk (⩾20%) and 9% had CVD. In total, 69% had an indication for preventive treatment (cholesterol-lowering or antihypertensive drugs). Of those, 42% received inadequate treatment and 40% received no treatment at all. Conclusion: Optimal CV risk management remains a major challenge and better awareness and management are urgently needed to reduce the high risk of CVD in the RA population.