Paradigm change
Dotaz
Zobrazit nápovědu
Traditional transvenous approach for permanent cardiac pacing can be associated with significant acute and chronic complications related partly to either the insertion of transvenous lead or subcutaneous placement of pacemaker device. We summarize the current status of a novel self-contained leadless cardiac pacemaker in the first-in-human and subsequent series of feasibility studies in patients indicated for ventricular rate-responsive pacing (VVI). Using a femoral venous approach, the device is implanted at the right ventricular apical septum region. We describe the technical and clinical characterization of this innovative technology. Two different systems of leadless pacemakers are currently implanted to the patients. Up to now, the electrical parameters, such as pacing thresholds, sensing parameters, and pacing impedances, either improved or remained stable within the accepted range. In this chapter, we also discuss the potential benefit for the future, but in summary, all available data demonstrate the feasibility of leadless cardiac pacing.
Chronic heart failure is a crucial problem of current cardiology. Despite that, no major development has occurred in the therapy in recent years. In this regard, first results of studies with ARNI inhibitors (angiotensin-receptor neprilysin inhibitors) may be considered hopeful. Dual inhibition of AT1 receptors and neprilysin blocks renin-angiotensin-aldosteron (RAS) axis and concurrently supports natural vasodilatory and diuretic effect of natriuretic peptides. Large-scale prospective randomized multicenter trial PARADIGM-HF with more than 8000 individuals with stabilized chronic heart failure with systolic dysfunction (LV EF 40%, later 35%), mostly in functional class NYHA II-III with elevated BNP/NT-pro BNP has shown 20% decrease in primary endpoint (cardiovascular death or hospitalization for heart failure) in a group treated by ARNI (LCZ696; sacubiltril - valsartan). Beneficial effect of ARNI was consistent also for total and cardiovascular mortality, for hospitalization for heart failure and in other pre-specified subgroup analyses, including quality of life. The treatment was safe, typical adverse event was hypotension, however without a need to interrupt the treatment. Dual RAS and neprilysin inhibition might thus after long time become a change in stable chronic heart failure with systolic dysfunction treatment "paradigm". Czech Republic significantly contributed to this study and all study sites should be congratulated and thanked for their high-quality work provided.
- Klíčová slova
- chronic heart failure - neprilysin - angiotensin-receptor inhibitors.,
- MeSH
- aminobutyráty škodlivé účinky terapeutické užití MeSH
- bifenylové sloučeniny MeSH
- blokátory receptorů AT1 pro angiotensin II škodlivé účinky terapeutické užití MeSH
- chronická nemoc MeSH
- dysfunkce levé srdeční komory farmakoterapie mortalita patofyziologie MeSH
- fixní kombinace léků MeSH
- kardiotonika škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- míra přežití MeSH
- natriuretický peptid typu B krev MeSH
- neprilysin antagonisté a inhibitory MeSH
- peptidové fragmenty krev MeSH
- prospektivní studie MeSH
- tetrazoly škodlivé účinky terapeutické užití MeSH
- valsartan MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- Geografické názvy
- Česká republika MeSH
- Názvy látek
- aminobutyráty MeSH
- bifenylové sloučeniny MeSH
- blokátory receptorů AT1 pro angiotensin II MeSH
- fixní kombinace léků MeSH
- kardiotonika MeSH
- natriuretický peptid typu B MeSH
- neprilysin MeSH
- peptidové fragmenty MeSH
- pro-brain natriuretic peptide (1-76) MeSH Prohlížeč
- sacubitril and valsartan sodium hydrate drug combination MeSH Prohlížeč
- tetrazoly MeSH
- valsartan MeSH
The still valid method of defining obesity by the current body mass index (BMI) value does not adequately reflect the severity or health risks of individuals and does not meet the requirements of evidence-based medicine. This definition of obesity has, among other things, led in the past to proposals for such problematic categories as metabolically healthy obesity or obesity with normal weight, and it also contributes to the so-called obesity paradox. The definition of clinical obesity according to The Lancet Diabetes & Endocrinology Commission addresses these shortcomings and characterizes obesity as a chronic, systemic disease characterized by changes in the function of tissues, organs, the whole individual, or their combinations due to excessive fat accumulation. Conditions with increased amounts of fat tissue without such changes are referred to as preclinical obesity; the recommendations for the care of individuals with preclinical obesity are somewhat problematic.
- Klíčová slova
- body mass index, obesity, clinical obesity, preclinical obesity, obesity paradox,
- MeSH
- chronická nemoc MeSH
- index tělesné hmotnosti * MeSH
- lidé MeSH
- obezita * diagnóza komplikace klasifikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Sequential administration of single targeted agents has been challenged as the dominant treatment paradigm in patients with metastatic renal cell carcinoma by improved outcomes obtained with combination regimens based on immune checkpoint inhibitors. Most patients treated with sequential monotherapy eventually develop drug resistance and succumb to progressive disease, leading to the search for therapies that would overcome drug resistance and result in a more durable treatment response. Improved outcomes have been demonstrated in Phase III trials in comparison with sunitinib for the combinations of axitinib plus pembrolizumab, axitinib plus avelumab, bevacizumab plus atezolizumab and ipilimumab plus nivolumab. A statistically significant improvement of both progression-free and overall survival has been demonstrated for the axitinib plus pembrolizumab combination.
- Klíčová slova
- axitinib, immune checkpoint inhibitors, immunotherapy, metastatic renal cell carcinoma, multiple tyrosine kinase inhibitors, pembrolizumab,
- MeSH
- axitinib farmakologie terapeutické užití MeSH
- bezpečnost MeSH
- doba přežití bez progrese choroby MeSH
- humanizované monoklonální protilátky farmakologie terapeutické užití MeSH
- inhibitory kontrolních bodů farmakologie terapeutické užití MeSH
- inhibitory proteinkinas farmakologie terapeutické užití MeSH
- karcinom z renálních buněk farmakoterapie mortalita patologie MeSH
- klinické zkoušky, fáze III jako téma MeSH
- lidé MeSH
- míra přežití MeSH
- nádory ledvin farmakoterapie mortalita patologie MeSH
- protokoly protinádorové kombinované chemoterapie farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- axitinib MeSH
- humanizované monoklonální protilátky MeSH
- inhibitory kontrolních bodů MeSH
- inhibitory proteinkinas MeSH
- pembrolizumab MeSH Prohlížeč
Cancer cells can escape the effects of chemotherapy through mutations and upregulation of a tyrosine kinase protein called the epidermal growth factor receptor (EGFR). In the past two decades, four generations of tyrosine kinase inhibitors targeting EGFR have been developed. Using comparative structure analysis of 116 EGFR-drug complex crystal structures, cluster analysis produces two clans of 73 and 43 structures, respectively. The first clan of 73 structures is larger and is comprised mostly of the C-helix-IN conformation while the second clan of 43 structures correlates with the C-helix-OUT conformation. A deep rotamer analysis identifies 43 residues (18%) of the total of 237 residues spanning the kinase structures under investigation with significant rotamer variations between the C-helix-IN and C-helix-OUT clans. The locations of these rotamer variations take on the appearance of side chain conformational relays extending out from points of EGFR mutation to different regions of the EGFR kinase. Accordingly, we propose that key EGFR mutations act singly or together to induce drug resistant conformational changes in EGFR that are communicated via these side chain conformational relays. Accordingly, these side chain conformational relays appear to play a significant role in the development of tumour resistance. This phenomenon also suggests a new paradigm in protein conformational change that is mediated by supportive relays of rotamers on the protein surface, rather than through conventional backbone movements.
- Klíčová slova
- EGFR, NSCLC, Protein folding, Protein structure, Rotamer, Tumour resistance, Tyrosine kinase inhibitor,
- Publikační typ
- časopisecké články MeSH
Evolutionary arms-races between avian brood parasites and their hosts have typically resulted in some spectacular adaptations, namely remarkable host ability to recognize and reject alien eggs and, in turn, sophisticated parasite egg mimicry. In a striking contrast to hosts sometimes rejecting even highly mimetic eggs, the same species typically fail to discriminate against highly dissimilar parasite chicks. Understanding of this enigma is still hampered by the rarity of empirical tests - and consequently evidence - for chick discrimination. Recent work on Australian host-parasite systems (Gerygone hosts vs. Chalcites parasites), increased not only the diversity of hosts showing chick discrimination, but also discovered an entirely novel host behavioural adaptation. The hosts do not desert parasite chicks (as in all previously reported empirical work) but physically remove living parasites from their nests. Here, I briefly discuss these exciting findings and put them in the context of recent empirical and theoretical work on parasite chick discrimination. Finally, I review factors responsible for a relatively slow progress in this research area and suggest most promising avenues for future research.
The predominant research publishing system is not equitable by design, nor optimised to advance research to create knowledge and ultimately to benefit society. Open Research Central (ORC) was created to foster the re-imagination of the research dissemination system to facilitate trust, transparency and equitable participation. In five years of operation, before dissolving, the non-profit organisation produced outputs and learnings valuable to the development of a responsible research dissemination system. We are sharing our experience in the hope that it will provide others who share the same vision and goals with useful materials to build on. We think that there remains a need for global, cross-stakeholder exploration to build collective understanding of research validation and dissemination and to pilot solutions. However, as this article will explore, enabling and supporting the development of such a collective voice and consequent action is a challenging endeavour in the current landscape and funding environment.
- Klíčová slova
- Open research, cross-stakeholder, funding., research dissemination, research validation, scholarly infrastructure,
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: The aim of this work was to study the oscillatory changes during target and distractor stimuli processing. We focused mainly on responses after distractor stimuli in the prefrontal cortex and their possible relation to our previous results from the basal ganglia. METHODS: Five epilepsy surgery candidates with implanted depth electrodes performed a three-stimulus paradigm. The frequent stimulus (70%; without required response) was a small blue circle, the target stimulus (15%; with motor response) was a larger blue circle, and the distractor stimulus (15%; without required response) was a checkerboard. The SEEG signals from 404 electrode contacts were analysed using event-related de/synchronization (ERD/S) methodology. RESULTS: The main response to the target stimuli was ERD in the alpha and low beta bands, predominantly in the motor control areas, parietal cortex and hippocampus. The distractor stimuli were generally accompanied by an early theta frequency band power increase most markedly in the prefrontal cortex. CONCLUSIONS: Different ERD/S patterns underline attentional shifting to rare target ("go") and distractor ("no-go") stimuli. SIGNIFICANCE: As an increase in lower frequency band power is considered to be a correlate of active inhibition, the prefrontal structures seem to be essential for inhibition of non-required movements.
- MeSH
- alfa rytmus EEG fyziologie MeSH
- beta rytmus EEG fyziologie MeSH
- biologické hodiny fyziologie MeSH
- dospělí MeSH
- elektroencefalografie * MeSH
- epilepsie patofyziologie MeSH
- evokované potenciály fyziologie MeSH
- kognice fyziologie MeSH
- korová synchronizace fyziologie MeSH
- lidé MeSH
- mladiství MeSH
- modely neurologické * MeSH
- prefrontální mozková kůra fyziologie MeSH
- psychomotorický výkon fyziologie MeSH
- světelná stimulace metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Worldwide stroke is the second leading cause of death and the third leading cause of death and disability combined. The estimated global economic burden by stroke is over US$891 billion per year. Within three decades (1990-2019), the incidence increased by 70%, deaths by 43%, prevalence by 102%, and DALYs by 143%. Of over 100 million people affected by stroke, about 76% are ischemic stroke (IS) patients recorded worldwide. Contextually, ischemic stroke moves into particular focus of multi-professional groups including researchers, healthcare industry, economists, and policy-makers. Risk factors of ischemic stroke demonstrate sufficient space for cost-effective prevention interventions in primary (suboptimal health) and secondary (clinically manifested collateral disorders contributing to stroke risks) care. These risks are interrelated. For example, sedentary lifestyle and toxic environment both cause mitochondrial stress, systemic low-grade inflammation and accelerated ageing; inflammageing is a low-grade inflammation associated with accelerated ageing and poor stroke outcomes. Stress overload, decreased mitochondrial bioenergetics and hypomagnesaemia are associated with systemic vasospasm and ischemic lesions in heart and brain of all age groups including teenagers. Imbalanced dietary patterns poor in folate but rich in red and processed meat, refined grains, and sugary beverages are associated with hyperhomocysteinaemia, systemic inflammation, small vessel disease, and increased IS risks. Ongoing 3PM research towards vulnerable groups in the population promoted by the European Association for Predictive, Preventive and Personalised Medicine (EPMA) demonstrates promising results for the holistic patient-friendly non-invasive approach utilising tear fluid-based health risk assessment, mitochondria as a vital biosensor and AI-based multi-professional data interpretation as reported here by the EPMA expert group. Collected data demonstrate that IS-relevant risks and corresponding molecular pathways are interrelated. For examples, there is an evident overlap between molecular patterns involved in IS and diabetic retinopathy as an early indicator of IS risk in diabetic patients. Just to exemplify some of them such as the 5-aminolevulinic acid/pathway, which are also characteristic for an altered mitophagy patterns, insomnia, stress regulation and modulation of microbiota-gut-brain crosstalk. Further, ceramides are considered mediators of oxidative stress and inflammation in cardiometabolic disease, negatively affecting mitochondrial respiratory chain function and fission/fusion activity, altered sleep-wake behaviour, vascular stiffness and remodelling. Xanthine/pathway regulation is involved in mitochondrial homeostasis and stress-driven anxiety-like behaviour as well as molecular mechanisms of arterial stiffness. In order to assess individual health risks, an application of machine learning (AI tool) is essential for an accurate data interpretation performed by the multiparametric analysis. Aspects presented in the paper include the needs of young populations and elderly, personalised risk assessment in primary and secondary care, cost-efficacy, application of innovative technologies and screening programmes, advanced education measures for professionals and general population-all are essential pillars for the paradigm change from reactive medical services to 3PM in the overall IS management promoted by the EPMA.
- Klíčová slova
- Artificial intelligence, Behavioural patterns, Cytokine storm (COVID-19), Diabetes mellitus, Diabetic retinopathy, Expert recommendations, Flammer syndrome, Health policy, Health risk assessment, Health-to-disease transition, Healthcare economy, Individualised patient profile, Inflammation, Ischemic stroke, Mitochondrial health, Mitophagy, Patient-friendly non-invasive approach, Population screening, Predictive preventive personalised medicine (PPPM / 3PM), Primary and secondary care, Sleep medicine, Suboptimal health, Sudden cardiac arrest/death, Tear fluid analysis, Viromics and metabolomics,
- Publikační typ
- časopisecké články MeSH
