Pregnancy outcomes in women with Budd-Chiari syndrome or portal vein thrombosis - a multicentre retrospective cohort study.

OBJECTIVE: To evaluate current practice and outcomes of pregnancy in women previously diagnosed with Budd-Chiari syndrome and/or portal vein thrombosis, with and without concomitant portal hypertension. DESIGN AND SETTING: Multicentre retrospective cohort study between 2008 and 2021. POPULATION: Women who conceived in the predefined period after the diagnosis of Budd-Chiari syndrome and/or portal vein thrombosis. METHODS AND MAIN OUTCOME MEASURES: We collected data on diagnosis and clinical features. The primary outcomes were maternal mortality and live birth rate. Secondary outcomes included maternal, neonatal and obstetric complications. RESULTS: Forty-five women (12 Budd-Chiari syndrome, 33 portal vein thrombosis; 76 pregnancies) were included. Underlying prothrombotic disorders were present in 23 of the 45 women (51%). Thirty-eight women (84%) received low-molecular-weight heparin during pregnancy. Of 45 first pregnancies, 11 (24%) ended in pregnancy loss and 34 (76%) resulted in live birth of which 27 were at term (79% of live births and 60% of pregnancies). No maternal deaths were observed; one woman developed pulmonary embolism during pregnancy and two women (4%) had variceal bleeding requiring intervention. CONCLUSIONS: The high number of term live births (79%) and lower than expected risk of pregnancy-related maternal and neonatal morbidity in our cohort suggest that Budd-Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contraindication for pregnancy. Individualised, nuanced counselling and a multidisciplinary pregnancy surveillance approach are essential in this patient population. TWEETABLE ABSTRACT: Budd-Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contraindication for pregnancy.

Abnormal vaginal bleeding in women of reproductive age treated with edoxaban or warfarin for venous thromboembolism: a post hoc analysis of the Hokusai-VTE study.

OBJECTIVE: To investigate the characteristics and outcome of abnormal vaginal bleeding in women receiving edoxaban or warfarin for treatment of venous thromboembolism (VTE). DESIGN AND SETTING: Post hoc analysis of the Hokusai-VTE study, a multicentre, randomised, double-blind trial comparing edoxaban with warfarin for acute symptomatic VTE. POPULATION: Women below 50 years receiving edoxaban or warfarin for treatment of VTE. METHODS: We collected data on diagnostic measures, treatment, and clinical outcome of abnormal vaginal bleeding events. MAIN OUTCOME MEASURES: Occurrence of major and clinically relevant nonmajor (CRNM) abnormal vaginal bleeding events. RESULTS: In all, 628 women aged under 50 years were treated with edoxaban and 665 with warfarin. The rate of abnormal vaginal bleeding was 15/100 person-years (py) (95% CI 11-19) in women receiving edoxaban and 9/100 py (95% CI 6-12) in the warfarin group (hazard ratio: 1.7, 95% CI 1.1-2.5). Major abnormal vaginal bleeding occurred in eight (1.3%) women on edoxaban and in three (0.9%) women receiving warfarin [odds ratio (OR) 2.8; 95% CI 0.8-10.8], and CRNM abnormal vaginal bleeding occurred in 53 (8.4%) women treated with edoxaban and in 37 (5.6%) on warfarin therapy (OR 1.6, 95% CI 1.0-2.4). Over 85% of all vaginal bleeds were characterised by heavy menstrual bleeding. Major bleeds frequently required treatment, and in more than 75% of patients anticoagulant therapy was adjusted. The severity of clinical presentation and course of major and CRNM bleeds was mild in most patients. CONCLUSIONS: Abnormal vaginal bleeding occurred more frequently in women treated with edoxaban than with warfarin. Reassuringly, most events could be managed conservatively and had a mild outcome. TWEETABLE ABSTRACT: Abnormal vaginal bleeding occurred more frequently in women treated with edoxaban than with warfarin.

Biologics combined with conventional systemic agents or phototherapy for the treatment of psoriasis: real-life data from PSONET registries.

BACKGROUND: Biologics have greatly improved psoriasis management. However, primary and secondary non-response to treatment requires innovative strategies to optimize outcomes. OBJECTIVE: To describe the use of combined treatment of biologics with conventional systemic agents or phototherapy in daily clinical practice. METHODS: We collected data on frequency of use, demographics, treatment characteristics and drug survival of biologics combined with conventional systemic agents or phototherapy in five PSONET registries. RESULTS: Of 9922 biologic treatment cycles, 982 (9.9%) were identified as combination treatment. 72.9% of treatment cycles concerned concomitant use of methotrexate, 25.3% concerned concomitant UVB therapy, acitretin or cyclosporin and 1.8% concerned combined treatment with PUVA, fumaric acids or a second biologic. Substantial variation was detected in type and frequency of combination treatments prescribed across registries. Patients initiated on combined treatment had generally severe disease and were affected with psoriasis for many years. The extent to which patients had been priory treated with biologic monotherapy and the proportion of patients affected with psoriatic arthritis differed between registries. Survival rates for etanercept, adalimumab, infliximab and ustekinumab with methotrexate ranged between 43 and 92%, 28 and 83%, 65 and 87% and 53 and 77%, respectively, across registries after one year with no consistent superior survival for a particular biologic. Longest survival on a biologic combined with methotrexate, acitretin or cyclosporin was 103, 78 and 34 months, respectively. CONCLUSION: Methotrexate was the most commonly used concomitant treatment for patients on a biologic. Wide geographical variations in treatment selection and persistence of combination treatment exist. Data derived from ongoing studies may help to determine whether combined treatment is superior to biologic monotherapy.

Dissecting Kawasaki disease: a state-of-the-art review.

Kawasaki disease (KD) is a pediatric vasculitis with coronary artery aneurysms (CAA) as its main complication. The diagnosis is based on the presence of persistent fever and clinical features including exanthema, lymphadenopathy, conjunctival injection, and changes to the mucosae and extremities. Although the etiology remains unknown, the current consensus is that it is likely caused by an (infectious) trigger initiating an abnormal immune response in genetically predisposed children. Treatment consists of high dose intravenous immunoglobulin (IVIG) and is directed at preventing the development of CAA. Unfortunately, 10-20% of all patients fail to respond to IVIG and these children need additional anti-inflammatory treatment. Coronary artery lesions are diagnosed by echocardiography in the acute and subacute phases. Both absolute arterial diameters and z-scores, adjusted for height and weight, are used as criteria for CAA. Close monitoring of CAA is important as ischemic symptoms or myocardial infarction due to thrombosis or stenosis can occur. These complications are most likely to arise in the largest, so-called giant CAA. Apart from the presence of CAA, it is unclear whether KD causes an increased cardiovascular risk due to the vasculitis itself. CONCLUSION: Many aspects of KD remain unknown, although there is growing knowledge on the etiology, treatment, and development and classification of CAA. Since children with previous KD are entering adulthood, long-term follow-up is increasingly important. What is known: • Kawasaki disease (KD) is a pediatric vasculitis with coronary artery damage as its main complication. • Although KD approaches its 50th birthday since its first description, many aspects of the disease remain poorly understood. What is new: • In recent years, multiple genetic candidate pathways involved in KD have been identified, with recently promising information about the ITPKC pathway. • As increasing numbers of KD patients are reaching adulthood, increasing information is available about the long-term consequences of coronary artery damage and broader cardiovascular risk.

Regression and Complications of z-score-Based Giant Aneurysms in a Dutch Cohort of Kawasaki Disease Patients.

Kawasaki disease (KD) is a pediatric vasculitis. Its main complication is the development of coronary artery aneurysms (CAA), with giant CAA at the end of the spectrum. We evaluated regression and event-free rates in a non-Asian cohort of patients with giant CAA using the current z-scores adjusted for body surface area instead of absolute diameters. KD patients with giant CAA (z-score ≥10) visiting our outpatient clinic between January 1999 and September 2015 were included. Patient characteristics and clinical details were extracted from medical records. Regression was defined as all coronary arteries having a z-score of ≤3. A major adverse event was defined as cardiac death, myocardial infarction, cardiogenic shock, or any coronary intervention. Regression-free and event-free rates were calculated using the Kaplan-Meier method. We included 52 patients with giant CAA of which 45 had been monitored since the acute phase. The 1-, 2-, and 5-year regression-free rates were 0.86, 0.78, and 0.65, respectively. The 5-year, 10-year, and 15-year event-free rates were 0.79, 0.75, and 0.65, respectively. Four children, whose CAA would not have been classified as 'giant' based on absolute diameters instead of z-scores, had experienced an event during follow-up. CONCLUSION: We found a high percentage of children in whom the lumen of giant CAA completely normalized. Four children not classified as 'giant' based on absolute diameters with z-scores of ≥10 experienced a cardiac event. Hence, the use of z-scores seems to be justified.

Time to conception and time to live birth in women with unexplained recurrent miscarriage.

STUDY QUESTION: What is the time to conception in a cohort of women with unexplained recurrent miscarriage (RM). SUMMARY ANSWER: Median time to conception in women diagnosed with unexplained RM was 21 weeks (interquartile range (IQR) 8-55 weeks), with a cumulative incidence of conception of 74% after 12 months of trying to conceive. WHAT IS KNOWN ALREADY: There is no effective treatment in couples with unexplained RM. Adequate counselling about their prognosis, for example time to conception and time to a live birth, is therefore very important. So far, there are no studies that give insight on these issues. STUDY DESIGN, SIZE, DURATION: A nested prospective cohort study was performed from February 2004 through July 2009 within a multicentre randomized placebo-controlled trial (ALIFE trial) on anticoagulant treatment in 364 women with unexplained RM. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 251 women who were not pregnant at the time of diagnosis of unexplained RM were included in this study. Of these, 13% became pregnant with ART, and all other women conceived naturally. The primary outcome was time to conception in weeks, calculated from the moment of diagnosis until conception measured by a urinary HCG. Secondary outcome was time to a live birth in the subsequent pregnancy. The relative prognostic significance of female age, the number of preceding miscarriages, interventions within the trial and the presence or absence of a preceding late miscarriage, a previous live birth and factor V Leiden mutation, was evaluated by Cox regression for time to conception and by competing risk modelling for time to live birth, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: The cumulative incidence of conception was 56% after 6 months, 74% after 12 months and 86% after 24 months of which 65% resulted in a live birth. The median time to conception was 21 weeks (IQR 8-55 weeks). Of potential prognostic factors, the presence of the factor V Leiden mutation resulted in a significantly shorter median time to conception of 11 weeks for carriers versus 23 weeks for non-carriers (hazard ratio (HR) 1.94, 95% confidence interval (CI) 1.03-3.65). The cumulative incidence of a live birth of the subsequent pregnancy was 0% after 6 months, 23% after 12 months and 50% after 24 months. The median time to a live birth of the subsequent pregnancy was 102 weeks (IQR 82-115 weeks). The number of previous miscarriages was the only prognostic factor (HR 0.83, 95% CI 0.74-0.94) significantly associated with time to a live birth of the subsequent pregnancy. LIMITATIONS, REASONS FOR CAUTION: In our study only the subsequent pregnancy after diagnosing unexplained RM was included. A future collection of cumulative follow-up data of all the women included in this cohort may provide outcomes of all pregnancies following the diagnosis of unexplained RM. WIDER IMPLICATIONS OF THE FINDINGS: Time to conception in women diagnosed with unexplained RM appears to be comparable with time to conception in healthy fertile women, as reported in the literature. The interesting finding that women with Factor V Leiden mutation have a significant shorter time to conception may suggest a favourable embryo implantation process. Future research is needed to confirm these findings and unravel the biology of early implantation. STUDY FUNDING/COMPETING INTEREST(S): The RCT used for this nested cohort study was funded by a grant (945-27-003) from the Netherlands Organization for Health Research and Development and a grant from GlaxoSmithKline. Study drugs (aspirin and placebo) were packaged and donated by Meda Pharma. This analysis was supported by a VIDI innovative research grant from the Netherlands Organisation for Scientific Research (NWO) 016.126.364. There are no potential conflicts of interest to declare. TRIAL REGISTRATION NUMBER: This cohort study was nested in the randomized controlled trial; ALIFE study (Current Controlled Trials number, ISRCTN 58496168).

Lipoprotein(a) levels and carotid intima-media thickness in children: A 20-year follow-up study.

Elevated lipoprotein(a) [Lp(a)] is independently associated with cardiovascular disease (CVD). In a recent long-term follow-up study involving children with familial hypercholesterolemia, Lp(a) levels contributed significantly to early atherosclerosis, as measured by carotid intima-media thickness (cIMT). To determine if this holds true for children without FH, we conducted a 20-year follow-up study, examining 88 unaffected siblings (mean age: 12.9 years) of children with FH. No significant association was found between Lp(a) and cIMT during follow-up (ß-adjusted [95% CI] = 0.0001 [-0.008 to 0.008] mm per 50 nmol/L increase Lp(a), p = 0.97). In conclusion, our findings suggest that elevated levels of Lp(a) do not play a significant role in arterial wall thickening among children without FH during the 20-year follow-up period. This leads us to consider the possibility that cIMT may not be a suitable marker for detecting potential subtle changes in the arterial wall mediated by Lp(a) in the young, general population. However, it could also be that elevated Lp(a) is only a significant risk factor for atherosclerosis in the presence of other risk factors such as FH.

Plasma levels of PCSK9 and phenotypic variability in familial hypercholesterolemia.

The extent of hypercholesterolemia varies considerably in patients with familial hypercholesterolemia (FH). We hypothesized that the variability of the FH phenotype might be partly explained by variation in proprotein convertase subtilisin kexin type 9 (PCSK9) activity. Individuals between 18 and 53 years of age who had been tested for a pathogenic LDLR or APOB mutation were eligible. Mutation carriers with a LDL-C level below the 75(th) percentile (called "FH low") were selected, as well as those with LDL-C above the 90(th) percentile (called "FH high"). Relatives who tested negative for the mutation were the "controls." PCSK9 plasma levels were assessed in 267 individuals who did not receive cholesterol-lowering treatment at the time of the study. Mean PCSK9 plasma levels (95% CI) were lower in the FH-low group compared with the FH-high group [152 (137-167) ng/ml vs. 186 (165-207) ng/ml, P = 0.010] and the control group [177 (164-190) ng/ml, P = 0.013]. Mean PCSK9 levels did not statistically differ between the FH-high and control groups (P = 0.50). Plasma PCSK9 levels are positively associated with LDL-C levels in FH patients and might contribute to the phenotypic severity in this disorder. Therefore, the results of pharmaceutical inhibition of PCSK9 in FH patients are eagerly awaited.

Reduction of monocyte chemoattractant protein 1 and macrophage migration inhibitory factor by a polyphenol-rich extract in subjects with clustered cardiometabolic risk factors.

Inflammation is a hallmark of the metabolic syndrome, which also contributes to a pro-atherogenic state. NF-κB activation, a critical step in regulating inflammatory reactions, can be inhibited by polyphenol (PF) extracts, at least in vitro. In the present study, we set out to study whether a PF-rich extract could attenuate the chronic inflammatory state and/or an acute immune response in vivo in subjects with clustered metabolic risk factors. A commercially available, PF-rich extract (500 mg daily) or placebo was administered for 4 weeks to thirty-four subjects with two or more metabolic risk factors using a randomised, double-blind, cross-over design. During the final study visit, an acute inflammatory challenge (lipopolysaccharide (LPS) 1 ng/kg body weight) was administered to a random subgroup of subjects (PF-rich extract (n 12) and placebo (n 12)). The PF-rich extract modestly reduced the inflammatory chemokines monocyte chemoattractant protein 1 (MCP-1) and macrophage migration inhibitory factor (MIF) (MCP-1 - 6.5 % (PF, median 116 (interquartile range 97-136) pg/ml v. placebo, median 124 (interquartile range 105-153) pg/ml; P < 0.05); MIF - 10.8 % (PF, median 2512 (interquartile range 1898-3972) pg/ml v. placebo, median 2814.5 (interquartile range 2296-3852) pg/ml; P < 0.05); however, other measured markers of inflammation and cardiometabolic disease, such as C-reactive protein, IL-6, HDL-cholesterol, adiponectin and oxidised LDL, remained unaffected. Following the LPS challenge, we found a statistically significant 48 % reduction of MCP-1 production in the PF-rich extract group (n 12) v. placebo (n 12) over 6 h (PF 766 (sd 155) v. placebo 1466 (sd 989) ng/ml; P < 0.05, area under the curve). In conclusion, short-term oral administration of the PF-rich extract caused a modest anti-inflammatory effect in subjects with clustered metabolic risk factors. Further dose-ranging studies are needed to evaluate whether and to what extent PF-rich extracts can be used to reduce the pro-inflammatory state in subjects with metabolic diseases at increased cardiovascular risk.

Founder mutations in the Netherlands: geographical distribution of the most prevalent mutations in the low-density lipoprotein receptor and apolipoprotein B genes.

BACKGROUND: In the Netherlands, a screening programme was set up in 1994 in order to identify all patients with familial hypercholesterolaemia (FH). After 15 years of screening, we evaluated the geographical distribution, possible founder effects and clinical phenotype of the 12 most prevalent FH gene mutations. METHODS: Patients who carried one of the 12 most prevalent mutations, index cases and those identified between 1994 and 2009 through the screening programme and whose postal code was known were included in the study. Low-density lipoprotein cholesterol (LDL-C) levels at the time of screening were retrieved. The prevalence of identified FH patients in each postal code area was calculated and visualised in different maps. RESULTS: A total of 10,889 patients were included in the study. Mean untreated LDL-C levels ranged from 4.4 to 6.4 mmol/l. For almost all mutations, a region of high prevalence could be observed. In total, 51 homozygous patients were identified in the Netherlands, of which 13 true homozygous for one of the 12 most prevalent mutations. The majority of them were living in high-prevalence areas for that specific mutation. CONCLUSIONS: Phenotypes with regard to LDL-C levels varied between the 12 most prevalent FH mutations. For most of these mutations, a founder effect was observed. Our observations can have implications with regard to the efficiency of molecular screening and physician's perception of FH and to the understanding of the prevalence and distribution of homozygous patients in the Netherlands.

Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial.

Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDL-cholesterol (LDL-C) lowering and cholesterol absorption inhibition, in patients with familial hypercholesterolemia (FH). In a posthoc analysis of the two-year ENHANCE trial, we assessed baseline cholesterol-adjusted campesterol (campesterol/TC) and sitosterol/TC ratios in 591 FH patients. Associations with LDL-C changes and changes in cholesterol absorption markers were evaluated by multiple regression analysis. No association was observed between baseline markers of cholesterol absorption and the extent of LDL-C response to ezetimibe/simvastatin therapy (beta = 0.020, P = 0.587 for campesterol/TC and beta<0.001, P = 0.992 for sitosterol/TC). Ezetimibe/simvastatin treatment reduced campesterol levels by 68% and sitosterol levels by 62%; reductions were most pronounced in subjects with the highest cholesterol absorption markers at baseline, the so-called high absorbers (P < 0.001). Baseline cholesterol absorption status does not determine LDL-C lowering response to ezetimibe/simvastatin therapy in FH, despite more pronounced cholesterol absorption inhibition in high absorbers. Hence, these data do not support the use of baseline absorption markers as a tool to determine optimal cholesterol lowering strategy in FH patients. However, due to the exploratory nature of any posthoc analysis, these results warrant further prospective evaluation in different populations.

[Detection and treatment of familial hypercholesterolaemia; the earlier, the better?] / Opsporing en behandeling van erfelijk hoog cholesterol.

A recent Dutch study in patients with familial hypercholesterolaemia (FH), suggests that long-term statin treatment initiated at childhood reduces the risk for cardiovascular events in adulthood. None of the patients developed rhabdomyolysis or other serious adverse effects. Early detection of FH is crucial for early treatment initiation. However, the Dutch cascade screening program ended at the end of 2013, at which point approximately 40,000 FH patients had not yet been identified. In order to trace this cohort, in 2014 the 'LEEFH' foundation (National Expertise Centre for Genetic Testing for Familial Cardiovascular Diseases) was set up. Family members of index patients are no longer actively approached to be tested, and as a result the number of detected family members has decreased significantly. These study findings underline the importance of actively screening the family members of index patients, including children and adolescents.

A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia.

OBJECTIVE: Functional and morphological changes of the arterial wall already present in young children with heterozygous familial hypercholesterolemia (HeFH) suggest that treatment should be initiated early in life to prevent premature atherosclerotic cardiovascular disease. The purpose of this study was to assess the efficacy and particularly safety of statin therapy in children with HeFH. METHODS AND RESULTS: We performed a meta-analysis of randomized, double-blind, placebo-controlled trials evaluating statin therapy in children aged 8 to 18 years with HeFH. Six studies (n=798 children) with 12 to 104 weeks of treatment were included. Total cholesterol, LDL cholesterol, and apolipoprotein B were significantly reduced, whereas HDL cholesterol and apolipoprotein A1 were significantly increased by statin therapy. No statistically significant differences were found between statin- and placebo-treated children with respect to the occurrence of adverse events (RR 0.99; 95% CI: 0.79 to 1.25), sexual development (RR of advancing > or = 1 stage in Tanner classification 0.96; 95% CI: 0.79 to 1.17), muscle toxicity (RR of CK > or = 10 times the upper limit of normal [ULN] 1.38; 95% CI: 0.18 to 10.82), or liver toxicity (RR of > or = 3 times the ULN for ASAT 0.98; 95% CI: 0.23 to 4.26 and for ALAT 2.03; 95% CI: 0.24 to 16.95). We found a minimal difference in growth in favor of the statin group (0.33 cm; 95% CI: 0.03 cm to 0.63 cm). CONCLUSION: In addition to the fact that statin treatment is efficacious, our results support the notion that statin treatment in children with HeFH is safe. Thus, even though further studies are required to assess lifelong safety, statin treatment should be considered for all children aged 8 to 18 with HeFH.

Pediatric lipid reference values in the general population: The Dutch lifelines cohort study.

BACKGROUND: Atherosclerosis starts in childhood and its progression is influenced by lifelong low-density lipoprotein cholesterol (LDL-c) exposure, the so-called cholesterol burden. Early identification of children and adolescents with severely elevated LDL-c is thus of major clinical significance. This is especially true for children with familial hypercholesterolemia (FH), a frequent but undertreated genetic disorder. To identify children with possible FH, insight in the distribution of lipid levels in children is a prerequisite. OBJECTIVE: To provide health care professionals with contemporary age- and gender-based pediatric reference values for lipid and lipoprotein levels to help the identification of children with dyslipidemia, especially FH. METHODS: Lifelines is a large prospective population-based Dutch cohort study. Children from 8 till 18 years of age were included and fasting lipid levels were measured. Smoothed reference curves and percentiles (5th, 10th, 25th, 50th, 75th, 90th, and 95th) were generated using the Generalized Additive Models for Location, Scale and Shape package in the statistical software R. RESULTS: A total of 8071 children (3823 boys and 4248 girls) were included. In the total cohort we noted marked dynamic changes in lipid and lipoprotein levels over age, which were in part gender specific. Our data highlight a high and unexpected prevalence of severely elevated LDL-c (>190 mg/dL) in both boys and girls. CONCLUSION: Our cross-sectional data provide contemporary reference ranges for plasma lipids that can assist physicians in identifying children at increased risk of premature atherosclerosis, especially FH.

Classifying sepsis patients in the emergency department using SIRS, qSOFA or MEWS.

OBJECTIVE: To determine the effect of qSOFA and SOFA compared with the MEWS and SIRS criteria on the classification of emergency department (ED) patients with an infection as having sepsis. METHODS: A retrospective single-centre study was performed in a random sample of 600 medical patients who visited the ED of the Academic Medical Centre Amsterdam between 1 November 2015 and 1 November 2016. Data for the different sepsis scores, as well as general data and demographics were retrieved. Descriptive analytics and sensitivity/specificity analysis were used to evaluate the performance of the different sepsis tools. RESULTS: Of 577 evaluable medical patients, 198 patients (34.3%) had a probable infection. The SIRS sepsis criteria, severe sepsis criteria, MEWS ≥ 5 and qSOFA criteria classified 141/198 (71.2%), 55/198 (27.8%), 58/198 (29.3%) and 17/198 patients (8.6%) respectively, as septic. The in-hospital mortality of patients classified as septic by the SIRS and qSOFA score was 6.4% and 29.4%. The qSOFA and SIRS score of ≥ 2 had a specificity of 93.7% (95% CI: 91.3-95.6) and 56.9% (52.7-61.1) in predicting in-hospital mortality. CONCLUSION: No major differences in gender, age, comorbidity and site of infection between patients with sepsis or severe sepsis classified by the SIRS, qSOFA criteria or MEWS of ≥ 5 were found. The qSOFA criteria classifies a smaller group of patients as septic compared with the SIRS or MEWS. Due to this strict selection, the qSOFA score seems unsuitable as a bedside tool in the work-up and treatment of sepsis at the ED.

Reduced intima media thickness in adults after prenatal exposure to the Dutch famine.

BACKGROUND: Restricted prenatal growth is associated with an increased risk of coronary heart disease morbidity and mortality. We studied the effects of exposure to famine during gestation on intima media thickness (IMT) in later life. METHODS AND RESULTS: We studied 730 people aged 58 years who were born as term singletons around the time of the 1944-45 Dutch famine. Persons exposed to famine during gestation (n=293) had reduced carotid artery IMT compared to people who had not been exposed to famine in utero (n=437) (mean 0.71 mm, S.D. 0.16 mm compared to 0.75 mm, S.D. 0.15 mm, sex adjusted p=0.001). Femoral artery IMT was also thinner among people exposed to famine during gestation compared to people unexposed in utero (mean 0.64 mm, S.D. 0.20mm, compared to 0.68 mm, S.D. 0.24), although the difference did not achieve statistical significance. CONCLUSION: Exposure to famine in utero may reduce IMT. However, it does not reduce the risk of coronary heart disease among famine exposed people.

Surgical treatment of atrial fibrillation : a systematic review.

BACKGROUND: The recently published overwhelming number of publications on the surgical treatment of AF, using a wide variety of techniques, blurred any precise appreciation of the nowadays surgical treatment of AF. As a consequence, the "state of the art" of the surgical technique of AF is ill-defined. OBJECTIVES: In this review the efficacy of the alternative sources of energy (radiofrequency-microwave and cryoablation; (group I) and the classical "cut and sew" Cox-Maze III (group II), which claims a 97-99% sinus rhythm (SR) success rate, were evaluated in the surgical treatment of atrial fibrillation (AF). METHODS: A computerized search in the PubMed and Medline database was conducted. Only original, English written, clinical manuscripts on the surgical treatment of atrial fibrillation citing the clinical outcome, including the postoperative sinus rhythm, were included. The following data were registered: the absolute numbers and percentages of treated patients, gender (male versus female) distribution, the type of arrhythmia (permanent or paroxysmal AF), type of surgery (mitral or non-mitral valve or a lone AF surgical procedure), postoperative morbidity (bleeding, the use of an intra-aortic balloon pump, cerebral vascular accident), postoperative pacemaker implantations, 30-day mortality, survival and sinus rhythm conversion. The mean values for age (years), left atrial diameter (mm), preoperative duration of AF (years) and left ventricular ejection fraction (%) were also recorded. RESULTS: Forty-eight studies were included comprising 3832 patients: 2279 in group I and 1553 in group II. The mean duration of AF, left atrial diameter and LVEF were 5.4 versus 5.5 years (p=0.90), 55.5 versus 57.8 mm (p=0.23) and 57 versus 58% (p=0.63). The postoperative SR rates for group I and II were 78.3 versus 84.9% (p=0.03). However, the "cut and sew" Cox-Maze III was conducted in younger patients (55.0 versus 61.2 years; p=0.005), more often to treat paroxysmal (22.9 versus 8.0%) and lone AF (19.3 versus 1.6%). Alternative sources of energy were predominantly used to treat permanent AF (92.0%), almost always as a concomitant surgical procedure (98.4%) and increasingly in combination with non-mitral valve surgery (18.5%). After correction for these variations, the postoperative SR conversion rates for group I and II did not differ significantly anymore. CONCLUSIONS: We could not identify any significant difference in the postoperative SR conversion rates between the classical 'cut and sew' and the alternative sources of energy, which were used to treat atrial fibrillation.

Association between protein C levels and mortality in patients with advanced prostate, lung and pancreatic cancer.

INTRODUCTION: Procoagulant factors promote cancer progression and metastasis. Protein C is involved in hemostasis, inflammation and signal transduction, and has a protective effect on the endothelial barrier. In mice, administration of activated protein C reduced experimental metastasis. We assessed the association between protein C and mortality in patients with three types of cancer. METHODS: The study population consisted of patients with advanced prostate, non-small cell lung or pancreatic cancer, who participated in the INPACT trial (NCT00312013). The trial evaluated the addition of nadroparin to chemotherapy in patients with advanced malignancy. Patients were divided into tertiles based on protein C at baseline. The association between protein C levels and mortality was evaluated with Cox proportional hazard models. RESULTS: We analysed 477 patients (protein C tertiles: <97, 97-121 and ≥121%). Mean age was 65±9years; 390 (82%) were male; 191 patients (40%) had prostate cancer, 161 (34%) had lung cancer, and 125 (26%) pancreatic cancer. During a median follow-up of 10.4months, 291 patients (61%) died. Median protein C level was 107% (IQR 92-129). In the lowest tertile, 75 patients per 100 patient-years died, as compared to 60 and 54 in the middle and high tertile, respectively. Lower levels of protein C were associated with increased mortality (in tertiles: HR for trend 1.18, 95%CI 1.02-1.36, adjusted for age, sex and nadroparin use; as a continuous variable: HR 1.004, 95%CI 1.00-1.008, p=0.07). CONCLUSION: Protein C seems inversely associated with mortality in patients with advanced prostate, lung and pancreatic cancer. Further research should validate protein C as a biomarker for mortality, and explore the effects of protein C on progression of cancer.

Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial.

BACKGROUND: The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases. METHODS: This is an investigator-initiated, multicenter randomized controlled trial (RCT) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis. The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past. DISCUSSION: OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy. TRIAL REGISTRATION: NTR4499 . Registered on 7 April 2014.