INTRODUCTION: Multiple daily injection insulin regimen (MDI) represents the most intensive insulin regimen used in the management of people with type 2 diabetes (PwT2D). Its efficacy regarding glycaemic control is counterbalanced by the increased risk of hypoglycaemia, frequently observed tendency to weight gain and necessity for frequent glucose monitoring. Recent introduction of novel antidiabetic medications with pleiotropic effects reaching far beyond the reduction of glycaemia (HbA1c), such as the glucagon-like peptide 1 receptor agonist (GLP-1 RA), has significantly widened the therapeutic options available for management of T2D. Consequently, there is currently a substantial number of PwT2D for whom the MDI regimen was initiated at a time when no other options were available. Yet, in present times, these individuals could benefit from simplified insulin regimens ideally taking advantage of the beneficial effects of the novel classes of antidiabetic medications. iGlarLixi (Suliqua®) is a once-daily fixed-ratio combination of basal insulin analogue glargine 100 U/ml and a GLP-1 RA lixisenatide. METHODS: Insulin therapy DE-intensificAtion with iglarLixi (IDEAL) is a six-centre, open-label, parallel-group, active comparator, phase IV randomised controlled trial with a 24-week active treatment period examining the efficacy and safety of MDI regimen de-intensification with once-daily administration of iGlarLixi versus MDI regimen continuation in PwT2D on a backgroud therapy with metformin ± sodium-glucose cotransporter 2 inhibitor. PLANNED OUTCOMES: The primary objective is to compare the effects of MDI therapy de-intensification with iGlarLixi versus MDI regimen continuation regarding glycaemic control (HbA1c). Secondary objectives include detailed evaluation of the effects of MDI regimen de-intensification with iGlarLixi on glycaemic control using standardised continuous glucose monitoring (CGM) metrics and self-monitoring of plasma glucose. Furthermore, body weight and body composition analysis, quality of life and safety profile are evaluated. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT04945070.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The association between duration of smoking abstinence before non-small-cell lung cancer (NSCLC) diagnosis and subsequent survival can influence public health messaging delivered in lung-cancer screening. We aimed to assess whether the duration of smoking abstinence before diagnosis of NSCLC is associated with improved survival. METHODS: In this retrospective, pooled analysis of cohort studies, we used 26 cohorts participating in Clinical Outcomes Studies of the International Lung Cancer Consortium (COS-ILCCO) at 23 hospitals. 16 (62%) were from North America, six (23%) were from Europe, three (12%) were from Asia, and one (4%) was from South America. Patients enrolled were diagnosed between June 1, 1983, and Dec 31, 2019. Eligible patients had smoking data before NSCLC diagnosis, epidemiological data at diagnosis (obtained largely from patient questionnaires), and clinical information (retrieved from medical records). Kaplan-Meier curves and multivariable Cox models (ie, adjusted hazard ratios [aHRs]) were generated with individual, harmonised patient data from the consortium database. We estimated overall survival for all causes, measured in years from diagnosis date until the date of the last follow-up or death due to any cause and NSCLC-specific survival. FINDINGS: Of 42 087 patients with NSCLC in the COS-ILCCO database, 21 893 (52·0%) of whom were male and 20 194 (48·0%) of whom were female, we excluded 4474 (10·6%) with missing data. Compared with current smokers (15 036 [40·0%] of 37 613), patients with 1-3 years of smoking abstinence before NSCLC diagnosis (2890 [7·7%]) had an overall survival aHR of 0·92 (95% CI 0·87-0·97), patients with 3-5 years of smoking abstinence (1114 [3·0%]) had an overall survival aHR of 0·90 (0·83-0·97), and patients with more than 5 years of smoking abstinence (10 841 [28·8%]) had an overall survival aHR of 0·90 (0·87-0·93). Improved NSCLC-specific survival was observed in 4301 (44%) of 9727 patients who had quit cigarette smoking and was significant at abstinence durations of more than 5 years (aHR 0·87, 95% CI 0·81-0·93). Results were consistent across age, sex, histology, and disease-stage distributions. INTERPRETATION: In this large, pooled analysis of cohort studies across Asia, Europe, North America, and South America, overall survival was improved in patients with NSCLC whose duration of smoking abstinence before diagnosis was as short as 1 year. These findings suggest that quitting smoking can improve overall survival, even if NSCLC is diagnosed at a later lung-cancer screening visit. These findings also support the implementation of public health smoking cessation strategies at any time. FUNDING: The Alan B Brown Chair, The Posluns Family Fund, The Lusi Wong Fund, and the Princess Margaret Cancer Foundation.
- MeSH
- kohortové studie MeSH
- kouření epidemiologie MeSH
- lidé MeSH
- nádory plic * diagnóza MeSH
- nemalobuněčný karcinom plic * diagnóza MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND: Individuals initially diagnosed with type 2 diabetes (T2D) might exhibit positivity for diabetes-associated autoantibodies (DAA +). We investigated the prevalence of DAA positivity in a group of individuals with T2D who were referred to a tertiary diabetes centre within a pre-specified period of time. We aimed to identify characteristics linked with DAA positivity by comparing DAA + individuals with their DAA-negative counterparts. METHODS: This was a cross-sectional study into which all T2D patients referred to the National Institute of Endocrinology and Diabetology, Ľubochňa, Slovakia, between 1 January and 30 June 2016 were included. Data on > 70 participants' characteristics, including antibodies against glutamic acid decarboxylase (anti-GAD65), insulinoma-associated antigen IA-2 (IA-2A) and insulin (IAA), were collected. RESULTS: Six hundred and ninety-two individuals (387, 55.6% female) with a median (range) age of 62 (24-83) years, HbA1c of 8.9 (5.0-15.7)% [74 (31-148 mmol/mol)] and diabetes duration of 13.0 (0-42) years were analysed. One hundred and forty-five (145/692, 21.0%) tested positive for at least one DAA; 136/692 (19.7%) were positive for anti-GAD65, 21/692 (3.0%) were positive for IA-2A and 9/692 (1.3%) were positive for IAA. Only 84.9% of the DAA + individuals aged > 30 years at the time of diabetes diagnosis met the current diagnostic criteria for latent autoimmune diabetes of adults (LADA). DAA + differed from DAA - individuals in multiple characteristics, including the incidence of hypoglycaemia. CONCLUSION: Several pathological processes linked with distinct types of diabetes can develop in parallel, including insulin resistance and autoimmune insulitis. In this single-centre cross-sectional study from Slovakia, we report a higher than previously published prevalence of DAA positivity in a group of individuals with a formal diagnosis of T2D.
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Recent development of novel antidiabetic drugs with proven cardiovascular (CV) and renal benefit and positive effect on body weight enable to take a more complex approach toward the management of type 2 diabetes mellitus (T2DM). Fixed-ratio combinations of insulin-GLP-1 receptor agonist (FRC) utilize complementary mechanisms of action of their individual components and address multiple pathologies linked with T2DM at the same time. AREAS COVERED: There are currently three FRCs on the market: iGlarLixi (glargine and lixisenatide in 2 different formulations) and IDegLira (degludec and liraglutide). We provide an up-to-date review on the rationale for the use of FRCs and their current position in the management of T2DM. We discuss the available evidence from randomized controlled trials, post hoc analyses, indirect comparative studies and real-world data on their effect on glycemic control, risk of hypoglycemia, body weight, CV safety, and their safety profile. EXPERT OPINION: FRCs represent an efficacious option for treatment intensification from basal insulin or even the first insulin-based therapy in T2DM. Their excellent glucose-lowering efficacy is complemented with lower risk of hypoglycemia in comparison to basal insulin, neutral effect on body weight and the lower risk of gastrointestinal adverse effects in comparison to GLP-1 receptor agonists.
- MeSH
- diabetes mellitus 2. typu * farmakoterapie MeSH
- fixní kombinace léků MeSH
- glykovaný hemoglobin MeSH
- hypoglykemie * chemicky indukované MeSH
- hypoglykemika škodlivé účinky MeSH
- inzulin glargin terapeutické užití MeSH
- krevní glukóza MeSH
- lidé MeSH
- receptor pro glukagonu podobný peptid 1 agonisté MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
In 2016, guidelines for diagnostic Next Generation Sequencing (NGS) have been published by EuroGentest in order to assist laboratories in the implementation and accreditation of NGS in a diagnostic setting. These guidelines mainly focused on Whole Exome Sequencing (WES) and targeted (gene panels) sequencing detecting small germline variants (Single Nucleotide Variants (SNVs) and insertions/deletions (indels)). Since then, Whole Genome Sequencing (WGS) has been increasingly introduced in the diagnosis of rare diseases as WGS allows the simultaneous detection of SNVs, Structural Variants (SVs) and other types of variants such as repeat expansions. The use of WGS in diagnostics warrants the re-evaluation and update of previously published guidelines. This work was jointly initiated by EuroGentest and the Horizon2020 project Solve-RD. Statements from the 2016 guidelines have been reviewed in the context of WGS and updated where necessary. The aim of these recommendations is primarily to list the points to consider for clinical (laboratory) geneticists, bioinformaticians, and (non-)geneticists, to provide technical advice, aid clinical decision-making and the reporting of the results.
PURPOSE OF REVIEW: To review the currently available data on the effect of Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) on postprandial lipaemia. RECENT FINDINGS: Out of the available studies that examined the respective lipid parameter, exenatide reduced postprandial triacyglycerol (TAG) in 4/6, apolipoprotein B-48 in 3/3, non-esterified fatty acids in 2/2, and apolipoprotein C-III and very low-density lipoprotein cholesterol (VLDL-C) in 1/1 studies. Liraglutide reduced postprandial TAG in 2/2, apolipoprotein B-48 in 3/3 and apolipoprotein C-III, chylomicron-TAG and VLDL1-TAG in 1/1 studies. Lixisenatide reduced postprandial chylomicron-TAG and apolipoprotein B-48 in 1 study. Semaglutide reduced postprandial TAG, apolipoprotein B-48 and VLDL in 1 study. Dulaglutide reduced postprandial apolipoprotein B-48 in 1 study. GLP-1 RAs have consistent beneficial effects on postprandial lipaemia with most of the data coming from studies with exenatide and liraglutide. Reduction of postprandial lipaemia might be one of the mechanisms behind the pleiotropic effects of GLP-1 RAs.
- MeSH
- apolipoprotein B-48 MeSH
- apolipoprotein C-III MeSH
- chylomikrony MeSH
- diabetes mellitus 2. typu * MeSH
- exenatid terapeutické užití MeSH
- glukagonu podobný peptid 1 MeSH
- hyperlipidemie * farmakoterapie MeSH
- hypoglykemika MeSH
- lidé MeSH
- liraglutid farmakologie terapeutické užití MeSH
- receptor pro glukagonu podobný peptid 1 agonisté MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
INTRODUCTION: Obesity and atrial fibrillation (AF) pose a significant burden on healthcare systems worldwide. Reduction of body weight has been documented to reduce the risk of AF. Little is known about the effect of different weight-reducing interventions including bariatric surgery in obese individuals on the risk of arrhythmia recurrence following catheter ablation (CA) for AF, and about the pathophysiological mechanisms linking these two conditions. METHODS: The Effect of complex weigHt-reducing interventiOns on rhythm control in oBese subjects wITh Atrial Fibrillation (HOBIT-AF) is a single-blinded, parallel-group randomised controlled trial with 18-month follow-up to assess the effect of complex weight-reducing interventions supported by the use of smart technologies and bariatric surgery on the arrhythmia burden in obese individuals following CA for AF. One hundred and sixty individuals (age 18-70 years, body mass index ≥ 30 kg/m2) will be randomised in a 1:1 fashion to undergo a structured weight reduction programme and sleeve gastrectomy (when indicated and preferred by the patient) aiming to achieve greater than 10% weight reduction from baseline (intervention group) or standard post-ablation medical care (control group). Two-week continuous ECG monitoring will be used 3 and 18 months after CA to assess the arrhythmia burden. Other investigations will include transthoracic echocardiography with quantification of epicardial adipose tissue, and markers of low-grade inflammation and circulating adipokines. PLANNED OUTCOMES: The main objective is to assess the effect of complex weight-reducing interventions on the arrhythmia burden and quality of life. Subgroup analyses to identify patient subgroups preferentially benefiting from weight loss related to a decrease in arrhythmia burden will be performed. Exploratory objectives will include investigation of potential mechanisms linking weight reduction with amelioration of arrhythmia burden such as changes in markers of low-grade inflammation, circulating adipokines, cytokines, monocytes or reduction of epicardial adipose tissue volume. TRIAL REGISTRATION: NCT04560387.
- MeSH
- dospělí MeSH
- fibrilace síní * komplikace chirurgie MeSH
- hmotnostní úbytek MeSH
- katetrizační ablace * MeSH
- kvalita života MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- obezita komplikace chirurgie MeSH
- randomizované kontrolované studie jako téma MeSH
- recidiva MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- protokol klinické studie MeSH
Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.
- MeSH
- adenokarcinom genetika MeSH
- alely MeSH
- ATM protein genetika MeSH
- běloši genetika MeSH
- databáze genetické MeSH
- genetická predispozice k nemoci MeSH
- genotypizační techniky MeSH
- heterozygot MeSH
- lidé středního věku MeSH
- lidé MeSH
- missense mutace MeSH
- nádory plic genetika MeSH
- odds ratio MeSH
- rizikové faktory MeSH
- rodokmen MeSH
- sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
- sekvenování transkriptomu MeSH
- senioři MeSH
- zárodečné mutace MeSH
- židé genetika MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
