Assessing real-world representativeness of prospective registry cohorts in oncology: insights from patients with esophagogastric cancer.

Objectives: This study aimed to explore the real-world representativeness of a prospective registry cohort with active accrual in oncology, applying a representativeness metric that is novel to health care.

Study Design And Setting: We used data from the Prospective Observational Cohort Study of Esophageal-Gastric Cancer Patients (POCOP) registry and from the population-based Netherlands Cancer Registry (NCR). We used Representativeness-indicators (R-indicators) and overall survival to investigate the degree to which the POCOP cohort and clinically relevant subgroups were a representative sample compared to the NCR database.

Exercise and Nutritional Interventions in Patients with Advanced Gastroesophageal Cancer: A Systematic Review.

Purpose: The quality of life and survival of patients with advanced gastroesophageal cancer can be improved. Positive effects of exercise and nutritional interventions on quality of life and potential effects on cancer outcomes are found in gastroesophageal cancer in the curative setting, as well as in other cancer types. We therefore systematically reviewed the current literature on the effect of exercise and nutritional interventions on various outcomes in patients with advanced gastroesophageal cancer.

Use of Palliative Chemotherapy and ICU Admissions in Gastric and Esophageal Cancer Patients in the Last Phase of Life: A Nationwide Observational Study.

Since intensive care unit (ICU) admission and chemotherapy use near death impair the quality of life, we studied the prevalence of both and their correlation with hospital volume in incurable gastroesophageal cancer patients as both impair the quality of life. We analyzed all Dutch patients with incurable gastroesophageal cancer who died in 2017-2018. National insurance claims data were used to determine the prevalence of ICU admission and chemotherapy use (stratified on previous chemotherapy treatment) at three and one month(s) before death.

A wake-active locomotion circuit depolarizes a sleep-active neuron to switch on sleep.

Sleep-active neurons depolarize during sleep to suppress wakefulness circuits. Wake-active wake-promoting neurons in turn shut down sleep-active neurons, thus forming a bipartite flip-flop switch. However, how sleep is switched on is unclear because it is not known how wakefulness is translated into sleep-active neuron depolarization when the system is set to sleep.

Achieved LDL cholesterol levels in patients with heterozygous familial hypercholesterolemia: A model that explores the efficacy of conventional and novel lipid-lowering therapy.

Background: A large proportion of patients with heterozygous familial hypercholesterolemia (heFH) do not reach low-density lipoprotein cholesterol (LDL-c) levels advocated by international guidelines (<70 mg/dL or <100 mg/dL).

Objective: We set out to model which proportion of patients reach targets using conventional and novel therapies.

Methods: We performed a cross-sectional analysis in a large cohort of genetically identified heFH patients and calculated the proportion reaching treatment targets in four scenarios: (1) after 50% LDL-c reduction (representing maximal dose statin); (2) after 70% LDL-c reduction (maximal dose statin + ezetimibe); (3) additional 40% LDL-c reduction representing cholesteryl ester transfer protein inhibitor (CETPi); and (4) 60% LDL-c reduction (proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK9i]), on top of scenario 2.

Engineered non-Mendelian inheritance of entire parental genomes in C. elegans.

The ability to rewrite the rules of genetic segregation would open new possibilities in diverse areas of biotechnology ranging from breeding to epigenetics. Here we engineer non-Mendelian inheritance of the entire maternal or paternal genome in Caenorhabditis elegans by changing the structure of the mitotic spindle during the first cell division of the zygote. Using germline-specific overexpression of a single protein, the conserved microtubule force regulator GPR-1, we increase forces that pull on spindle poles to convert the single bipolar mitotic spindle to two monopolar spindles.

Statins in Familial Hypercholesterolemia: Consequences for Coronary Artery Disease and All-Cause Mortality.

Background: A statin-induced reduction of coronary artery disease (CAD) events and mortality has not been adequately quantified in patients with heterozygous familial hypercholesterolemia (FH).

Objectives: This study estimated the relative risk reduction for CAD and mortality by statins in heterozygous FH patients.

Methods: The authors included all adult heterozygous FH patients, identified by the Dutch screening program for FH between 1994 and 2013, who were free of CAD at baseline.

Selection of individuals for genetic testing for familial hypercholesterolaemia: development and external validation of a prediction model for the presence of a mutation causing familial hypercholesterolaemia.

Aims: Familial hypercholesterolaemia (FH) is an autosomal dominant disease that warrants early diagnosis to prevent premature cardiovascular disease (CVD). However, genetic testing to make a definite diagnosis is costly, and careful selection of eligible subjects is important. Unfortunately, accuracy of current diagnostic criteria is poor, especially in young individuals.

Sleep-active neuron specification and sleep induction require FLP-11 neuropeptides to systemically induce sleep.

Sleep is an essential behavioral state. It is induced by conserved sleep-active neurons that express GABA. However, little is known about how sleep neuron function is determined and how sleep neurons change physiology and behavior systemically.

Automated analysis of sleep control via a single neuron active at sleep onset in C. elegans.

Longitudinal analyses are crucial for understanding long-term processes such as development and behavioral rhythms. For a complete understanding of such processes, both organism-level observations as well as single-cell observations are necessary. Sleep is an example for a long-term process that is under developmental control.

Clinical phenotype in relation to the distance-to-index-patient in familial hypercholesterolemia.

Background And Aim: We evaluated whether the severity of the familial hypercholesterolemia (FH) phenotype, i.e. increased levels of low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD) risk, decreases in more distantly related patients within one family.

Agarose Microchambers for Long-term Calcium Imaging of Caenorhabditis elegans.

Behavior is controlled by the nervous system. Calcium imaging is a straightforward method in the transparent nematode Caenorhabditis elegans to measure the activity of neurons during various behaviors. To correlate neural activity with behavior, the animal should not be immobilized but should be able to move.

Screening and treatment of familial hypercholesterolemia - Lessons from the past and opportunities for the future (based on the Anitschkow Lecture 2014).

In this review, we discuss the screening and treatment of familial hypercholesterolemia (FH), an autosomal dominant inherited disease, characterized by severely increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk for premature coronary heart disease (CHD). Genetic family based cascade screening for FH was shown to be cost-effective and a screening program with such an approach was carried out in the Netherlands from 1994 to 2014. Over 64,000 persons have participated in this program of whom 40.

The impact of LDLR function on fibroblast growth factor 21 levels.

Context: Fibroblast growth factor 21 (FGF21) has been described to have beneficial effects on glucose and lipid metabolism, and FGF21 analogs are currently evaluated in phase 1 trials. However, the complete spectrum of effects and regulators of FGF21 is yet partly elucidated. Recent studies have shown that FGF21 plays a role in transmembrane cholesterol transport.

Prevalence and management of familial hypercholesterolaemia in coronary patients: An analysis of EUROASPIRE IV, a study of the European Society of Cardiology.

Background: Familial hypercholesterolaemia (FH) is a hereditary disorder predisposing to premature coronary heart disease (CHD) and is until now mainly diagnosed clinically on the basis of a classical phenotype. Its prevalence varies and is estimated around 1 in 200-500; in patients with established CHD the prevalence is less well documented.

Methods And Results: In EUROASPIRE IV data were collected in coronary patients from 24 European countries by means of a standardized interview, bioclinical examination and venous blood sampling.

Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus.

Importance: Familial hypercholesterolemia is characterized by impaired uptake of cholesterol in peripheral tissues, including the liver and the pancreas. In contrast, statins increase the cellular cholesterol uptake and are associated with increased risk for type 2 diabetes mellitus. We hypothesize that transmembrane cholesterol transport is linked to the development of type 2 diabetes.

Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study.

Background: Present guidelines emphasise the importance of low concentrations of LDL cholesterol (LDL-C) in patients with familial hypercholesterolaemia. In most patients with the disease, however, these concentrations are not achieved with present treatments, so additional treatment is therefore warranted. Inhibition of cholesteryl ester transfer protein has been shown to reduce LDL-C concentrations in addition to regular statin treatment in patients with hypercholesterolaemia or at high risk of cardiovascular disease.

Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome.

Aims: Homozygous autosomal dominant hypercholesterolaemia (hoADH), an orphan disease caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9), is characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels and high risk for premature cardiovascular disease (CVD). The exact prevalence of molecularly defined hoADH is unknown. Therefore, we investigated the prevalence and phenotypical characteristics of this disease in an open society, i.

Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of 14,000 mutation carriers.

Background: Some recently emerged lipid-lowering therapies are currently restricted to patients with homozygous familial hypercholesterolemia (HoFH), and studies are underway to also assess these therapies in patients with 'severe heterozygous FH (HeFH)'. However, no uniform definition of 'severe HeFH' exists, although untreated low-density lipoprotein cholesterol (LDL-C) levels above 8 mmol/L (309 mg/dl) have been historically used to define this phenotype. Our aim was to define severe HeFH, to establish its prevalence and CVD risk, and to study the relative contribution of classical risk factors to CVD risk in HeFH patients.

Intestinal cholesterol secretion: future clinical implications.

Together with the liver, the intestine serves as a homeostatic organ in cholesterol metabolism. Recent evidence has substantiated the pivotal role of the intestine in reverse cholesterol transport (RCT). RCT is a fundamental antiatherogenic pathway, mediating the removal of cholesterol from tissues in the body to the faeces.

Antisense oligonucleotides in the treatment of lipid disorders: pitfalls and promises.

Dyslipidaemia is one of the pivotal risk factors for cardiovascular disease (CVD), and lipid-lowering therapy is therefore the cornerstone in cardiovascular risk management. With the currently available treatment options the relative risk reduction in CVD is approximately 30%, leaving a large residual risk. This calls for the development of additional therapeutic moieties and antisense oligonucleotides (ASOs) have proven to be such a new and effective treatment.

Efficacy and safety of mipomersen sodium (Kynamro).

Introduction: Mipomersen is a first-in-class drug indicated as an adjunct to lipid-lowering medications and diet to reduce low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB), total cholesterol (TC) and non-high density lipoprotein-cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).

Areas Covered: This article summarizes the efficacy and safety profile of mipomersen based on literature, public materials available from the Endocrinologic and Metabolic Drugs Advisory Committee meeting (FDA) in review of the New Drug Application (NDA 203568) and the recent product label.

Expert Opinion: Patients suffering from HoFH are characterized by elevated levels of LDL-C and are, therefore, at severely increased risk for cardiovascular disease (CVD).

CEP89 is required for mitochondrial metabolism and neuronal function in man and fly.

It is estimated that the human mitochondrial proteome consists of 1000-1500 distinct proteins. The majority of these support the various biochemical pathways that are active in these organelles. Individuals with an oxidative phosphorylation disorder of unknown cause provide a unique opportunity to identify novel genes implicated in mitochondrial biology.