Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.
- MeSH
- buněčná diferenciace genetika MeSH
- celogenomová asociační studie MeSH
- extracelulární matrix metabolismus patologie MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- genetické lokusy * MeSH
- hodnocení rizik MeSH
- jednonukleotidový polymorfismus * MeSH
- keratokonus diagnóza etnologie genetika metabolismus MeSH
- kolagen metabolismus MeSH
- lidé MeSH
- rizikové faktory MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Geografické názvy
- Austrálie MeSH
- Evropa MeSH
This ESC Council on Stroke/EAPCI/EBNI position paper summarizes recommendations for training of cardiologists in endovascular treatment of acute ischaemic stroke. Interventional cardiologists adequately trained to perform endovascular stroke interventions could complement stroke teams to provide the 24/7 on call duty and thus to increase timely access of stroke patients to endovascular treatment. The training requirements for interventional cardiologists to perform endovascular therapy are described in details and should be based on two main principles: (i) patient safety cannot be compromised, (ii) proper training of interventional cardiologists should be under supervision of and guaranteed by a qualified neurointerventionist and within the setting of a stroke team. Interdisciplinary cooperation based on common standards and professional consensus is the key to the quality improvement in stroke treatment.
The aim of this post hoc analysis of the VELOUR study (ClinicalTrials.gov NCT00561470) was to investigate the treatment effect of adding aflibercept to second-line infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) in patients with metastatic colorectal cancer (mCRC) who had failed any prior oxaliplatin-containing regimen. Adjuvant rapid relapsers (ARR), who were enrolled directly following relapse during or within 6 months of completion of oxaliplatin-containing adjuvant chemotherapy (N = 124, including 17 patients who also received bevacizumab as part of their adjuvant therapy), were excluded from the original VELOUR intention-to-treat (ITT) population (N = 1226). After exclusion of the ARR, overall survival (OS) in the ITT minus ARR (ITT-ARR) population (N = 1102) was longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm [hazard ratio (HR) 0.78, 95 % confidence interval (CI) 0.68-0.90; median survival difference 1.87 months]. In the subgroup of patients assigned to the prior bevacizumab stratum at randomization, OS was numerically longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm (HR 0.81; 95 % CI 0.63-1.04; median survival difference 2.14 months). Comparison of the post hoc analysis results with the primary analysis from VELOUR suggests that the inclusion of the directly enrolled ARR may have understated the aflibercept treatment benefit for both bevacizumab-pretreated and bevacizumab-naïve patients in the strictly second-line setting although no definitive conclusion may be inferred. The benefit associated with the addition of aflibercept to second-line FOLFIRI in patients with mCRC was observed whatever the timing of first-line disease progression. There were no unexpected safety concerns.
- MeSH
- analýza přežití MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- fluorouracil aplikace a dávkování farmakologie terapeutické užití MeSH
- kamptothecin aplikace a dávkování analogy a deriváty farmakologie terapeutické užití MeSH
- kolorektální nádory farmakoterapie mortalita MeSH
- leukovorin aplikace a dávkování farmakologie terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- organoplatinové sloučeniny aplikace a dávkování farmakologie terapeutické užití MeSH
- protokoly antitumorózní kombinované chemoterapie aplikace a dávkování farmakologie terapeutické užití MeSH
- receptory vaskulárního endoteliálního růstového faktoru aplikace a dávkování terapeutické užití MeSH
- rekombinantní fúzní proteiny aplikace a dávkování farmakologie terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: Patients with metastatic colorectal cancer (mCRC) previously-treated with oxaliplatin benefit significantly from the addition of aflibercept to FOLFIRI in relation to overall survival, progression-free survival and response rate. PATIENTS AND METHODS: The results for efficacy and safety over the time course of the VEGF Trap (aflibercept) with irinotecan in colorectal cancer after failure of oxaliplatin regimen trial were analysed based on data from 1226 patients randomised to receive FOLFIRI plus either aflibercept (n=612) or placebo (n=614). Hazard ratios (HR) by 6-month time period were estimated using a piecewise Cox proportional hazard model. Severity of adverse events (AEs) was graded using National Cancer Institute Common Terminology Criteria, version 3.0. RESULTS: The estimated probabilities of survival were 38.5% versus 30.9% at 18 months, 28.0% versus 18.7% at 24 months and 22.3% versus 12.0% at 30 months, for the aflibercept- and placebo-treated arms, respectively. The proportional improvement in the HR over time was consistent with the survival probability results; survival at 24 months was improved by 50% and almost doubled at 30 months. The majority of worst-grade AEs occurred within the first four cycles of treatment and in a small percent of treatment cycles and were mostly reversible. Common chemotherapy- and anti-vascular epithelial growth factor (VEGF)-associated AEs occurred rarely and in a small proportion of cycles with the majority being of single occurrence. CONCLUSIONS: The addition of aflibercept to FOLFIRI showed a continued and persistent improvement in overall survival over time in patients with mCRC. Although grade 3-4 AEs were more frequent in the aflibercept arm, they occurred in early treatment cycles and decreased sharply following initial presentation.
- MeSH
- biomarkery farmakologické MeSH
- fluorouracil škodlivé účinky farmakologie terapeutické užití MeSH
- kamptothecin škodlivé účinky analogy a deriváty farmakologie terapeutické užití MeSH
- kolorektální nádory patologie MeSH
- leukovorin škodlivé účinky farmakologie terapeutické užití MeSH
- lidé MeSH
- metastázy nádorů MeSH
- organoplatinové sloučeniny terapeutické užití MeSH
- přežití po terapii bez příznaků nemoci MeSH
- progrese nemoci MeSH
- proporcionální rizikové modely MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky farmakologie terapeutické užití MeSH
- receptory vaskulárního endoteliálního růstového faktoru škodlivé účinky farmakologie terapeutické užití MeSH
- rekombinantní fúzní proteiny škodlivé účinky terapeutické užití MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
OBJECTIVES: To evaluate the first experience of real-time instantaneous wave-free ratio (iFR) measurement by clinicians. BACKGROUND: The iFR is a new vasodilator-free index of coronary stenosis severity, calculated as a trans-lesion pressure ratio during a specific period of baseline diastole, when distal resistance is lowest and stable. Because all previous studies have calculated iFR offline, the feasibility of real-time iFR measurement has never been assessed. METHODS: Three hundred ninety-two stenoses with angiographically intermediate stenoses were included in this multicenter international analysis. Instantaneous wave-free ratio and fractional flow reserve (FFR) were performed in real time on commercially available consoles. The classification agreement of coronary stenoses between iFR and FFR was calculated. RESULTS: Instantaneous wave-free ratio and FFR maintain a close level of diagnostic agreement when both are measured by clinicians in real time (for a clinical 0.80 FFR cutoff: area under the receiver operating characteristic curve [ROC(AUC)] 0.87, classification match 80%, and optimal iFR cutoff 0.90; for a ischemic 0.75 FFR cutoff: iFR ROC(AUC) 0.90, classification match 88%, and optimal iFR cutoff 0.85; if the FFR 0.75-0.80 gray zone is accounted for: ROC(AUC) 0.93, classification match 92%). When iFR and FFR are evaluated together in a hybrid decision-making strategy, 61% of the population is spared from vasodilator while maintaining a 94% overall agreement with FFR lesion classification. CONCLUSION: When measured in real time, iFR maintains the close relationship to FFR reported in offline studies. These findings confirm the feasibility and reliability of real-time iFR calculation by clinicians.
- MeSH
- frakční průtoková rezerva myokardu MeSH
- koronární angiografie metody MeSH
- koronární cirkulace * MeSH
- koronární stenóza diagnóza MeSH
- lidé středního věku MeSH
- lidé MeSH
- plocha pod křivkou MeSH
- ROC křivka MeSH
- senioři MeSH
- senzitivita a specificita MeSH
- srdeční katetrizace metody MeSH
- studie případů a kontrol MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
