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We compared the effects of Heat-not-Burn cigarette (HNBC) to those of tobacco cigarette (Tcig), on myocardial, coronary and arterial function as well as on oxidative stress and platelet activation in 75 smokers. In the acute study, 50 smokers were randomised into smoking a single Tcig or a HNBC and after 60 min were crossed-over to the alternate smoking. For chronic phase, 50 smokers were switched to HNBC and were compared with an external group of 25 Tcig smokers before and after 1 month. Exhaled carbon monoxide (CO), pulse wave velocity (PWV), malondialdehyde (MDA) and thromboxane B2 (TxB2) were assessed in the acute and chronic study. Global longitudinal strain (GLS), myocardial work index (GWI), wasted myocardial work (GWW), coronary flow reserve (CFR), total arterial compliance (TAC) and flow-mediated dilation (FMD) were assessed in the chronic study. Acute HNBC smoking caused a smaller increase of PWV than Tcig (change 1.1 vs 0.54 m/s, p < 0.05) without change in CO and biomarkers in contrast to Tcig. Compared to Tcig, switching to HNBC for 1-month improved CO, FMD, CFR, TAC, GLS, GWW, MDA, TxB2 (differences 10.42 ppm, 4.3%, 0.98, 1.8 mL/mmHg, 2.35%, 19.72 mmHg%, 0.38 nmol/L and 45 pg/mL respectively, p < 0.05). HNBCs exert a less detrimental effect on vascular and cardiac function than tobacco cigarettes. Trial registration Registered on https://clinicaltrials.gov/ (NCT03452124, 02/03/2018).

The P2Y 12 receptor plays a pivotal role in platelet activation and aggregation through a complex cascade of actions. Laboratory and clinical data have convincingly shown the benefit of P2Y 12 inhibition combined with aspirin in patients with acute coronary syndrome (ACS)/undergoing percutaneous coronary intervention (PCI). Newer agents - like prasugrel, ticagrelor, and cangrelor - provide more consistent, faster, and stronger platelet inhibition than clopidogrel. In large clinical trials newer agents have resulted in fewer ischemic complications (though with increased bleeding potential) than clopidogrel. High-risk subpopulations like ST-segment elevation myocardial infarction, diabetes, chronic kidney disease, elderly, and low body weight patients have been identified. A ‘return to the laboratory' has been observed recently, with several pharmacodynamic studies being performed particularly in these cohorts. This interplay between research laboratory and clinical data may lead to a more efficient and safer use of P2Y 12 inhibitors.

BackgroundSeizures are underrecognized in preterm infants, and little is known about their impact on brain growth. We aimed to define the association between early seizures and subsequent brain growth.MethodsInfants <30 weeks gestation underwent 72 h of prospective amplitude-integrated electroencephalography (aEEG) monitoring, term-equivalent age (TEA) magnetic resonance imaging (MRI), and 2-year neurodevelopmental testing. Seizures were defined as trains of sharp waves >10 s, evolving in frequency/amplitude/morphology, and identified using automated algorithms with manual review. Using T2-weighted images, cortical surface area (CSA) and gyrification index (GI) were calculated and volumes were segmented into five tissue classes: cerebrospinal fluid, gray matter, white matter (WM), deep nuclear gray matter, and cerebellum. Correlations between total seizure burden and tissue-specific volumes were evaluated, controlling for clinical variables of interest.ResultsNinety-nine infants underwent aEEG/MRI assessments (mean GA = 26.3 weeks, birthweight = 899 g). Seizure incidence was 55% with a median of two events; median length = 66 s and mean burden = 285 s. Greater seizure burden was associated with smaller CSA and volumes across all tissue types, most prominently in WM (R2 = −0.603, p < 0.01), even after controlling for confounders. There was no association with GI.ConclusionsSeizures in preterm infants are common and associated with smaller TEA brain volumes. This relationship was strongest for WM and independent of clinical factors.ImpactSeizures in preterm infants are common.Little is known about the association between early seizures and later brain growth.Greater seizure burden is linked with smaller volumes of all brain tissue types, most prominently the WM.This relationship is true even controlling for other factors.Additional study is needed to identify the optimal EEG monitoring and seizure treatment strategy for improved brain growth and neurodevelopmental outcomes.

AimsRemote ischemic conditioning (RIC) alleviates ischemia–reperfusion injury via several pathways, including micro-RNAs (miRs) expression and oxidative stress modulation. We investigated the effects of RIC on endothelial glycocalyx, arterial stiffness, LV remodelling, and the underlying mediators within the vasculature as a target for protection.Methods and resultsWe block-randomised 270 patients within 48 h of STEMI post-PCI to either one or two cycles of bilateral brachial cuff inflation, and a control group without RIC. We measured: (a) the perfusion boundary region (PBR) of the sublingual arterial microvessels to assess glycocalyx integrity; (b) the carotid-femoral pulse wave velocity (PWV); (c) miR-144,-150,-21,-208, nitrate-nitrite (NOx) and malondialdehyde (MDA) plasma levels at baseline (T0) and 40 min after RIC onset (T3); and (d) LV volumes at baseline and after one year. Compared to baseline, there was a greater PBR and PWV decrease, miR-144 and NOx levels increase (p < 0.05) at T3 following single- than double-cycle inflation (PBR:ΔT0–T3 = 0.249 ± 0.033 vs 0.126 ± 0.034 μm, p = 0.03 and PWV:0.4 ± 0.21 vs −1.02 ± 0.24 m/s, p = 0.03). Increased miR-150,-21,-208 (p < 0.05) and reduced MDA was observed after both protocols. Increased miR-144 was related to PWV reduction (r = 0.763, p < 0.001) after the first-cycle inflation in both protocols. After one year, single-cycle RIC was associated with LV end-systolic volume reduction (LVESV) > 15% (odds-ratio of 3.75, p = 0.029). MiR-144 and PWV changes post-RIC were interrelated and associated with LVESV reduction at follow-up (r = 0.40 and 0.37, p < 0.05), in the single-cycle RIC.ConclusionRIC evokes “vascular conditioning” likely by upregulation of cardio-protective microRNAs, NOx production, and oxidative stress reduction, facilitating reverse LV remodelling.Clinical Trial Registrationhttp://www.clinicaltrials.gov. Unique identifier: NCT03984123.

We evaluated 22 measures of cortical folding, 20 derived from local curvature (curvature-based measures) and two based on other features (sulcal depth and gyrification index), for their capacity to distinguish between normal and aberrant cortical development. Cortical surfaces were reconstructed from 12 term-born control and 63 prematurely-born infants. Preterm infants underwent 2–4 MR imaging sessions between 27 and 42weeks postmenstrual age (PMA). Term infants underwent a single MR imaging session during the first postnatal week. Preterm infants were divided into two groups. One group (38 infants) had no/minimal abnormalities on qualitative assessment of conventional MR images. The second group (25 infants) consisted of infants with injury on conventional MRI at term equivalent PMA. For both preterm infant groups, all folding measures increased or decreased monotonically with increasing PMA, but only sulcal depth and gyrification index differentiated preterm infants with brain injury from those without. We also compared scans obtained at term equivalent PMA (36–42weeks) for all three groups. No curvature-based measured distinguished between the groups, whereas sulcal depth distinguished term control from injured preterm infants and gyrification index distinguished all three groups. When incorporating total cerebral volume into the statistical model, sulcal depth no longer distinguished between the groups, though gyrification index distinguished between all three groups and positive shape index distinguished between the term control and uninjured preterm groups. We also analyzed folding measures averaged over brain lobes separately. These results demonstrated similar patterns to those obtained from the whole brain analyses. Overall, though the curvature-based measures changed during this period of rapid cerebral development, they were not sensitive for detecting the differences in folding associated with brain injury and/or preterm birth. In contrast, gyrification index was effective in differentiating these groups. •We compared 20 measures of cortical curvature in term and prematurely born infants•Data were collected throughout the neonatal intensive care unit stay•All of the measures changed markedly with brain development•No curvature-based measure distinguished injured from uninjured premature infants•Gyrification index, a non-curvature based measure, consistently differentiated groups

Cardiogenic shock (CS) in the setting of severe aortic stenosis (AS) presents a critical and high-risk scenario with limited therapeutic options and poor prognosis. Transcatheter aortic valve implantation (TAVI), initially reserved for inoperable or high-risk surgical candidates, is increasingly being considered in patients with CS due to improvements in device technology, operator experience, and supportive care. This review synthesizes current evidence from large registries, observational studies, and meta-analyses that support the feasibility, safety, and potential survival benefit of urgent or emergent TAVI in selected CS patients. Procedural success is high, and early intervention appears to confer improved short-term and mid-term outcomes compared to balloon aortic valvuloplasty or medical therapy alone. Critical factors influencing prognosis include lactate levels, left ventricular ejection fraction, renal function, and timing of intervention. The absence of formal guidelines, logistical constraints, and ethical concerns complicate decision-making in this unstable population. A multidisciplinary Heart Team/Shock Team approach is essential to identify appropriate candidates, manage procedural risk, and guide post-intervention care. Further studies and the development of TAVI-specific risk models in CS are anticipated to refine patient selection and therapeutic strategies. TAVI may represent a transformative option for stabilizing hemodynamics and improving outcomes in this otherwise high-mortality group.

Environmental influences on brain structure and function during early development have been well-characterized, but whether early environments are associated with the pace of brain development is not clear. In pre-registered analyses, we use flexible non-linear models to test the theory that prenatal disadvantage is associated with differences in trajectories of intrinsic brain network development from birth to three years ( n  = 261). Prenatal disadvantage was assessed using a latent factor of socioeconomic disadvantage that included measures of mother’s income-to-needs ratio, educational attainment, area deprivation index, insurance status, and nutrition. We find that prenatal disadvantage is associated with developmental increases in cortical network segregation, with neonates and toddlers with greater exposure to prenatal disadvantage showing a steeper increase in cortical network segregation with age, consistent with accelerated network development. Associations between prenatal disadvantage and cortical network segregation occur at the local scale and conform to a sensorimotor-association hierarchy of cortical organization. Disadvantage-associated differences in cortical network segregation are associated with language abilities at two years, such that lower segregation is associated with improved language abilities. These results shed light on associations between the early environment and trajectories of cortical development. Early environmental factors, like disadvantage, are associated with neurocognitive development. Here, the authors find that neonates and toddlers from economically disadvantaged backgrounds show accelerated brain development, with implications for language abilities in toddlerhood.

Objective The objective of this study was to assess the pharmacokinetic and pharmacodynamic behavior of ticagrelor administered either as crushed (in the semi-upright sitting position) or as integral (in the supine position) tablets in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). Methods We randomized 20 patients to ticagrelor 180 mg either as 2 integral tablets administered in the supine position (standard administration) or as 2 tablets crushed and dispersed, administered in the semi-upright sitting position. Blood samples were drawn for pharmacokinetic and pharmacodynamic assessment at randomization (0 h) and at 0.5, 1, 2, and 4 h. Results At 1 h, ticagrelor plasma exposure and area under the plasma concentration–time curve from time zero to 1 h (AUC 1 ) (co-primary endpoints) were higher in the crushed versus integral tablets group (median 586 vs. 70.1 ng/mL and 234 vs. 24.4 ng·h/mL, respectively), with a ratio of adjusted geometric means (95 % confidence interval [CI]) of 12.67 (2.34–68.51) [ p  = 0.005] and 19.28 (3.51–106.06) [ p  = 0.002], respectively. Time to maximum plasma concentration was shorter in the crushed versus integral tablets group (median 2 vs. 4 h), with a ratio of adjusted geometric means (95 % CI) of 0.69 (0.49–0.97) [ p  = 0.035]. Parallel findings were observed with AR-C124910XX (active metabolite). Platelet reactivity (VerifyNow ® ) at 1 h was lower with crushed versus standard administration with least squares estimates mean difference (95 % CI) of 92 (−158.4 to 26.6) P2Y 12 reaction units ( p  = 0.009). Conclusions In patients with STEMI undergoing primary PCI, ticagrelor crushed tablets administered in the semi-upright sitting position seems to lead to a faster—compared with standard administration—absorption, with stronger antiplatelet activity within the first hour. Trial registration: ClinicalTrials.gov identifier: NCT02046486.

In the current era of percutaneous coronary intervention (PCI), with the use of contemporary drug-eluting stents, refined techniques, and adjunctive pharmacotherapy, the role of aspirin peri-PCI remains undisputable. Beyond the initial period, dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 receptor inhibitor for 6 months in stable coronary artery disease and 12 months in acute coronary syndromes is the standard of care. However, concerns regarding bleeding adverse events caused by aspirin have led to shortened DAPT duration or even omission of aspirin. Aspirin free-strategies have been increasingly encountered in several studies and showed a significant reduction in bleeding events, without any sign of increased ischemic risk. Individualization of DAPT duration particularly in high bleeding risk patients appears therefore mandatory, making aspirin not necessary in several cases. Moreover, recent randomized trials have shed light on how to treat PCI patients in the presence of concomitant anticoagulant treatment with P2Y12 monotherapy and excluding aspirin. These aspirin-free strategies have been proved safer than the “older” standard triple antithrombotic treatment, without compromising safety. Ongoing studies may further dispel the myths and establish real facts regarding post-PCI-tailored treatment with or without aspirin.

Factors associated with platelet reactivity (PR) during ticagrelor maintenance dose (MD) are not well defined. We aimed to examine factors that influence levels of PR during chronic ticagrelor therapy. We performed individual participant data meta-analysis of 445 patients from 8 studies who had PR assessment with the VerifyNow P2Y12 assay (Accumetrics, Inc, San Diego, CA) while on ticagrelor 90 mg twice a day MD for at least 14 days. Distribution of PR during ticagrelor MD was highly skewed toward lower values. No case of high PR (≥230 P2Y12 reaction units [PRU]) was observed. Age and body mass index (BMI) positively affected PR, with every increase in decade and 5 units of BMI resulting in 7.9% and 4.1% increase in PR, respectively. Current smoking status negatively affected PR with 13.7% decrease in PR in current smokers, compared with nonsmokers. Low PR (LPR) was defined as the lowest quartile of PR values (<10 PRU). In multivariate analysis, diabetes mellitus and age >70 years were independently associated with lower probability for LPR with a relative risk (95% CIs) of 0.570 (0.361-0.899) and 0.554 (0.325-0.944), P = .016 and P = .030, respectively. Age, BMI, and current smoking status affect PR during ticagrelor MD. Diabetes mellitus and age >70 years were found to be associated with lower probability for LPR. Further research is required to assess the clinical implications of these findings in ticagrelor-treated patients.