Assessment of practical applicability and clinical relevance of a commonly used LDL-C polygenic score in patients with severe hypercholesterolemia

Background and aims: Low-density lipoprotein cholesterol (LDL-C) levels vary in patients with familial hypercholesterolemia (FH) and can be explained by a single deleterious genetic variant or by the aggregate effect of multiple, common small-effect variants that can be captured in a polygenic score (PS). We set out to investigate the contribution of a previously published PS to the inter-individual LDL-C variation and coronary artery disease (CAD) risk in patients with a clinical FH phenotype. Methods: First, in a cohort of 628 patients referred for genetic FH testing, we evaluated the distribution of a PS for LDL-C comprising 12 genetic variants. Next, we determined its association with coronary artery disease (CAD) risk using UK Biobank data. Results: The mean PS was higher in 533 FH-variant-negative patients (FH/M-) compared with 95 FH-variant carriers (1.02 vs 0.94, p < 0.001). 39% of all patients had a PS equal to the top 20% from a population-based reference cohort and these patients were less likely to carry an FH variant (OR 0.22, 95% CI 0.10–0.48) compared with patients in the lowest 20%. In UK Biobank data, the PS explained 7.4% of variance in LDL-C levels and was associated with incident CAD. Addition of PS to a prediction model using age and sex and LDL-C did not increase the c-statistic for predicting CAD risk. Conclusions: This 12-variant PS was higher in FH/M- patients and associated with incident CAD in UK Biobank data. However, the PS did not improve predictive accuracy when added to the readily available characteristics age, sex and LDL-C, suggesting limited discriminative value for CAD

An ABS control logic based on wheel force measurement

The paper presents an anti-lock braking system (ABS) control logic based on the measurement of the longitudinal forces at the hub bearings. The availability of force information allows to design a logic that does not rely on the estimation of the tyre-road friction coefficient, since it continuously tries to exploit the maximum longitudinal tyre force. The logic is designed by means of computer simulation and then tested on a specific hardware in the loop test bench: the experimental results confirm that measured wheel force can lead to a significant improvement of the ABS performances in terms of stopping distance also in the presence of road with variable friction coefficien

Mechanical thrombectomy versus intrasinus thrombolysis for cerebral venous sinus thrombosis: a non-randomized comparison.

Small retrospective studies have shown the benefit of endovascular treatment with intrasinus thrombolysis (IST) or mechanical thrombectomy (MT) with/without IST (MT ± IST) in cases of multifocal cerebral venous thrombosis (CVT). Our study compares the mortality, functional outcome and periprocedural complications among patients treated with MT ± IST versus IST alone. We reviewed clinical and angiographic findings of 63 patients with CVT who received endovascular treatment at three tertiary care centers. Primary outcome variables were discharge mortality and neurological dysfunction, and intermediate (three months) and long-term (\u3esix months) morbidity. The modified Rankin scale (mRS) was used to assess morbidity. mRS ≤ 1 was considered a good recovery. Neurological dysfunction was rated as neuroscore: 0, normal; 1, mild (ambulatory, communicative); 2, moderate (non-ambulatory, communicative); and 3, severe (non-ambulatory, non-communicative/comatose). In patients who received IST alone, presenting neurological deficits were comparatively minor (p\u3c0.001). When the two groups were adjusted for admission neuroscore, there was no statistical significance between discharge mortality [7(21%) versus 4(14%), p=0.228], neurological dysfunction (p=0.442), intermediate (p=0.336) and long-term morbidity (p=0.988). Patients who received MT ± IST had a higher percentage of periprocedural complications without reaching statistical significance. Compared to IST, MT was performed in severe cases with extensive sinus involvement. When adjusted for admission neurological dysfunction, both groups had similar mortality and discharge neurological dysfunction and similar intermediate and long-term morbidity

Glucose-Insulin Therapy, Plasma Substrate Levels and Cardiac Recovery After Cardiac Ischemic Events

INTRODUCTION: The potential usefulness of glucose-insulin therapy relies to a large extent on the premise that it prevents hyperglycemia and hyperlipidemia following cardiac ischemic events. METHODS: In this review we evaluate the literature concerning plasma glucose and free fatty acids levels during and following cardiac ischemic events. RESULTS: The data indicate that hyperlipidemia and hyperglycemia most likely occur during acute coronary ischemic syndromes in the conscious state (e.g. acute myocardial infarction) and less so during reperfusion following CABG reperfusion. This is in accordance with observations that glucose-insulin therapy during early reperfusion post CABG may actually cause hypolipidemia, because substantial hyperlipidemia does not appear to occur during that stage of cardiac surgery. DISCUSSION: Considering recent data indicating that hypolipidemia may be detrimental for cardiac function, we propose that free fatty acid levels during reperfusion post CABG with the adjunct glucose-insulin therapy need to be closely monitored. CONCLUSION: From a clinical point of view, a strategy directed at monitoring and thereafter maintaining plasma substrate levels in the normal range for both glucose (4-6 mM) and FFA (0.2-0.6 mM) as well as stimulation of glucose oxidation, promises to be the most optimal metabolic reperfusion treatment following cardiac ischemic episodes. Future (preclinical and subsequently clinical) investigations are required to investigate whether the combination of glucose-insulin therapy with concomitant lipid administration may be beneficial in the setting of reperfusion post CAB

Defining care products to finance health care in the Netherlands

A case-mix project started in the Netherlands with the primary goal to define a complete set of health care products for hospitals. The definition of the product structure was completed 4 years later. The results are currently being used for billing purposes. This paper focuses on the methodology and techniques that were developed and applied in order to define the casemix product structure. The central research question was how to develop a manageable product structure, i.e., a limited set of hospital products, with acceptable cost homogeneity. For this purpose, a data warehouse with approximately 1.5 million patient records from 27 hospitals was build up over a period of 3 years. The data associated with each patient consist of a large number of a priori independent parameters describing the resource utilization in different stages of the treatment process, e.g., activities in the operating theatre, the lab and the radiology department. Because of the complexity of the database, it was necessary to apply advanced data analysis techniques. The full analyses process that starts from the database and ends up with a product definition consists of four basic analyses steps. Each of these steps has revealed interesting insights. This paper describes each step in some detail and presents the major results of each step. The result consists of 687 product groups for 24 medical specialties used for billing purposes

Decompressive hemicraniectomy in severe cerebral venous thrombosis: a prospective case series

Small retrospective case series suggest that decompressive hemicraniectomy can be life saving in patients with cerebral venous thrombosis (CVT) and impending brain herniation. Prospective studies of consecutive cases are lacking. Thus, a single centre, prospective study was performed. In 2006 we adapted our protocol for CVT treatment to perform acute decompressive hemicraniectomy in patients with impending herniation, in whom the prognosis with conservative treatment was considered infaust. We included all consecutive patients with CVT between 2006 and 2010 who underwent hemicraniectomy. Outcome was assessed at 12 months with the modified Rankin Scale (mRS). Ten patients (8 women) with a median age of 41 years (range 26–52 years) were included. Before surgery 5 patients had GCS < 9, 9 patients had normal pupils, 1 patient had a unilaterally fixed and dilated pupil. All patients except one had space-occupying intracranial hemorrhagic infarcts. The median preoperative midline shift was 9 mm (range 3–14 mm). Unilateral hemicraniectomy was performed in 9 patients and bilateral hemicraniectomy in one. Two patients died from progressive cerebral edema and expansion of the hemorrhagic infarcts. Five patients recovered without disability at 12 months (mRS 0–1). Two patients had some residual handicap (one minor, mRS 2; one moderate, mRS 3). One patient was severely handicapped (mRS 5). Our prospective data show that decompressive hemicraniectomy in the most severe cases of cerebral venous thrombosis was probably life saving in 8/10 patients, with a good clinical outcome in six. In 2 patients death was caused by enlarging hemorrhagic infarcts

Does collaboration pay in agricultural supply chain? An empirical approach

This paper examines the effect of different types of collaboration on the level of Postharvest Food Losses (PHFL) and the proportion of low-quality peaches produced using a unique data-set of Greek peach producers. Quantile regression techniques are adopted to estimate the effects at different points of the conditional distribution of our variables of interest. The findings of this study suggest that high levels of collaboration between producers and cooperatives are associated with both low levels of PHFL and a low proportion of low-quality peaches. We also find that specific types of collaboration, such as ‘goal congruence’, can play a significant role in reducing PHFL and improving the quality of peach production at the extremes of the distribution. Important policy implications regarding collaborative practices and systems that can be implemented to reduce PHFL and boost a producer’s performance together with sustainability credentials are drawn from this study

Impact of complex NOTCH1 mutations on survival in paediatric T-cell leukaemia

<p>Abstract</p> <p>Background</p> <p>Molecular alterations occur frequently in T-ALL and the potential impact of those abnormalities on outcome is still controversial. The current study aimed to test whether <it>NOTCH1 </it>mutations and additional molecular abnormalities would impact T-ALL outcome in a series of 138 T-ALL paediatric cases.</p> <p>Methods</p> <p>T-ALL subtypes, status of <it>SIL-TAL1 </it>fusion, ectopic expression of <it>TLX3</it>, and mutations in <it>FBXW7</it>, <it>KRAS</it>, <it>PTEN </it>and <it>NOTCH1 </it>were assessed as overall survival (OS) and event-free survival (EFS) prognostic factors. OS and EFS were determined using the Kaplan-Meier method and compared using the log-rank test.</p> <p>Results</p> <p>The frequencies of mutations were 43.5% for <it>NOTCH1</it>, while <it>FBXW7</it>, <it>KRAS </it>and <it>PTEN </it>exhibited frequencies of 19.1%, 9.5% and 9.4%, respectively. In 78.3% of cases, the coexistence of <it>NOTCH1 </it>mutations and other molecular alterations was observed. In multivariate analysis no statistical association was revealed between <it>NOTCH1 </it>mutations and any other variable analyzed. The mean length of the follow-up was 68.4 months and the OS was 50.7%. <it>SIL-TAL1 </it>was identified as an adverse prognostic factor. <it>NOTCH1 </it>mutation status was not associated with outcome, while the presence of <it>NOTCH1 </it>complex mutations (indels) were associated with a longer overall survival (<it>p </it>= 0.031) than point mutations.</p> <p>Conclusion</p> <p><it>NOTCH1 </it>mutations alone or in combination with <it>FBXW7 </it>did not impact T-ALL prognosis. Nevertheless, complex <it>NOTCH1 </it>mutations appear to have a positive impact on OS and the <it>SIL-TAL1 </it>fusion was validated as a negative prognostic marker in our series of T-ALL.</p