In this trial, bedside platelet-function monitoring to adjust antiplatelet therapy after coronary stent implantation did not reduce the rate of subsequent cardiovascular events, a finding that calls ...into question the clinical value of this type of testing.
Clopidogrel and aspirin play a central role in the treatment of patients undergoing percutaneous coronary intervention.
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Up to one third of patients have inadequate platelet inhibition, with an increased risk of events.
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Platelet-function testing can determine the degree of platelet reactivity during treatment at the bedside and potentially identify patients in whom adjustment of antiplatelet therapy is warranted to minimize the risks of both ischemic and bleeding complications.
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Cohort studies and meta-analyses have largely shown the prognostic value of high platelet reactivity during antiplatelet therapy in patients undergoing coronary stenting.
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Randomized clinical trials have also shown that stronger . . .
The development of ultra-intense and ultra-short light sources is currently a subject of intense research driven by the discovery of novel phenomena in the realm of relativistic optics, such as the ...production of ultrafast energetic particle and radiation beams for applications. It has been a long-standing challenge to unite two hitherto distinct classes of light sources: those achieving relativistic intensity and those with pulse durations approaching a single light cycle. While the former class traditionally involves large-scale amplification chains, the latter class places high demand on the spatiotemporal control of the electromagnetic laser field. Here, we present a light source producing waveform-controlled 1.5-cycle pulses with a 719 nm central wavelength that can be focused to relativistic intensity at a 1 kHz repetition rate based on nonlinear post-compression in a long hollow-core fiber. The unique capabilities of this source allow us to observe the first experimental indications of light waveform effects in laser wakefield acceleration of relativistic energy electrons.
Summary Background Carotid stenting is a potential alternative to carotid endarterectomy but whether this technique is as safe as surgery and whether the long-term protection against stroke is ...similar to that of surgery are unclear. We previously reported that in patients in the Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial, the rate of any stroke or death within 30 days after the procedure was higher with stenting than with endarterectomy. We now report the results up to 4 years. Methods In this follow-up study of a multicentre, randomised, open, assessor-blinded, non-inferiority trial, we compared outcome after stenting with outcome after endarterectomy in 527 patients who had carotid stenosis of at least 60% that had recently become symptomatic. The primary endpoint of the EVA-3S trial was the rate of any periprocedural stroke or death (ie, within 30 days after the procedure). The prespecified main secondary endpoint was a composite of any periprocedural stroke or death and any non-procedural ipsilateral stroke during up to 4 years of follow-up. Other trial outcomes were any stroke or periprocedural death, any stroke or death, and the above endpoints restricted to disabling or fatal strokes. This trial is registered with ClinicalTrials.gov , number NCT00190398. Findings 262 patients were randomly assigned to endarterectomy and 265 to stenting. The cumulative probability of periprocedural stroke or death and non-procedural ipsilateral stroke after 4 years of follow-up was higher with stenting than with endarterectomy (11·1% vs 6·2%, hazard ratio HR 1·97, 95% CI 1·06–3·67; p=0·03). The HR for periprocedural disabling stroke or death and non-procedural fatal or disabling ipsilateral stroke was 2·00 (0·75–5·33; p=0·17). A hazard function analysis showed the 4-year differences in the cumulative probabilities of outcomes between stenting and endarterectomy were largely accounted for by the higher periprocedural (within 30 days of the procedure) risk of stenting compared with endarterectomy. After the periprocedural period, the risk of ipsilateral stroke was low and similar in both treatment groups. For any stroke or periprocedural death, the HR was 1·77 (1·03–3·02; p=0·04). For any stroke or death, the HR was 1·39 (0·96–2·00; p=0·08). Interpretation The results of this study suggest that carotid stenting is as effective as carotid endarterectomy for middle-term prevention of ipsilateral stroke, but the safety of carotid stenting needs to be improved before it can be used as an alternative to carotid endarterectomy in patients with symptomatic carotid stenosis. Funding French Ministry of Health.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Optimum duration of dual antiplatelet treatment (DAPT) after coronary stenting remains uncertain, with an unknown efficacy to safety ratio of extended treatment leading to ...discrepancies between international guidelines and clinical practice. We assessed whether DAPT continuation beyond 1 year after coronary stenting is beneficial. Methods This analysis was a planned extension of the previously published ARCTIC-Monitoring trial, in which we randomly allocated 2440 patients to a strategy of platelet function testing with antiplatelet treatment adjustment or a conventional strategy after coronary stenting with drug-eluting stent (DES). We recruited patients (aged 18 years or older) scheduled for planned DES implantation at 38 centres in France. After 1 year of follow-up, patients without contraindication to interruption of DAPT were eligible for a second randomisation to this second phase of the study (ARCTIC-Interruption). Using a computer-generated randomisation sequence (1:1; stratified by centre), we allocated patients to a strategy of interruption of DAPT where the thienopyridine was interrupted and single aspirin antiplatelet treatment was maintained (interruption group) or a strategy of DAPT continuation for 6–18 months (continuation group). The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularisation, analysed by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00827411. Findings Between Jan 4, 2011, and March 3, 2012, 1259 eligible patients were randomly allocated to treatment in ARCTIC-Interruption: 624 to the interruption group and 635 to the continuation group. After a median follow-up of 17 months (IQR 15–18), the primary endpoint occurred in 27 (4%) patients in the interruption group and 24 (4%) patients in the continuation group (hazard ratio HR 1·17 95% CI 0·68–2·03; p=0·58). STEEPLE major bleeding events occurred more often in the continuation group (seven 1% patients) compared with the interruption group (one <0·5% patient; HR 0·15 0·02–1·20; p=0·073). Major or minor bleedings were also more common in the continuation group compared with the interruption group (12 2% patients vs three 1% patients; HR 0·26 0·07–0·91; p=0·04). Interpretation Our finding suggests no apparent benefit but instead harm with extension of DAPT beyond 1 year after stenting with DES when no event has occurred within the first year after stenting. No conclusion can be drawn for high-risk patients who could not be randomised. The consistency between findings from all trials of such interruption suggests the need for a reappraisal of guidelines for DAPT after coronary stenting towards shorter duration of treatment. Funding Allies in Cardiovascular Trials Initiatives and Organized Networks (ACTION Study Group), Fondation de France, Sanofi-Aventis, Cordis, Medtronic, Boston Scientific, Fondation SGAM.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background
Minor burns could be associated with moderate hypermetabolism. In this study, the primary outcome was measured energy expenditure (mEE) determined by indirect calorimetry in patients with ...minor burns. We also compared mEE with predictive values and actual energy intakes.
Methods
Adults with minor burns exclusively treated on an outpatient basis were included. During the week following injury, a dietitian performed indirect calorimetry (Q‐NRG in canopy mode), calculated the estimated energy expenditure (eEE) based on the Harris‐Benedict (HB) and Henry formulas, and evaluated daily energy intakes using a food anamnesis.
Results
Forty‐nine patients (59.2% male; median age: 35 interquartile range: 29–46.5 years; body mass index BMI: 26.2 22.3–29.6 kg/m2; burn surface area BSA: 1.5% 1%–2%) were included 4 (2–6) days after injury. The mEE was 1863 (1568–2199) kcal or 25 (22.4–28.5) kcal/kg and 1838 (1686–2026) kcal or 26.1 (23.7–27.7) kcal/kg in patients who were respectively fasting for >10 h or not (P = 0.991 or P = 0.805). The total mEE was 104% (95%–116%) and 108% (99%–122%) of the total eEE using the HB and Henry formulas, respectively, with diet‐induced thermogenesis and physical activity level. Hypermetabolism (ie, oxygen consumption at rest ≥3.5 ml/kg/min) was observed in 21/49 (42.9%) patients. Energy intakes corresponded to 71% (60%–86%) of the total mEE.
Conclusion
Performing indirect calorimetry in adults with minor burns revealed that ≥40% of the tested adults presented a hypermetabolism and that their mEE was not covered by their energy intakes.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
During gestation, the mother is the main source of thyroid hormones for the foetus. Thus, hypothyroidism during pregnancy and/or preterm birth compromise thyroid hormone supply for the foetus. ...Maternal hypothyroidism increases risk of preterm birth and both conditions are associated with respiratory distress in infants. Since thyroid hormones are essential for normal brain development, it is plausible that maternal thyroid hormone deficiency plays a role in respiratory disorders related to neurological immaturity in the newborn; however, this hypothesis is yet to be tested. Here, we used methimazole treatment (MMI; 0.05% v/w) from the onset of pregnancy until two weeks postpartum to induce thyroid hormone deficiency in rat pups. At 14–15 days of age, we used plethysmography to measure breathing at rest and in response to hypoxia (12% O2, 20 min) in intact pups. We then used a urethane/chloralose anesthetised preparation to measure cardiorespiratory inhibition induced by laryngeal chemoreflex stimulation. In intact pups, basal breathing did not differ between groups but the breathing frequency response to hypoxia of MMI-treated pups was lower than controls. Following anesthesia, breathing frequency of MMI pups was 60% lower than controls; following laryngeal chemoreflex stimulation, the drop in O2 saturation that was 82% greater in MMI-treated pups than controls. Inactivation of GABAA receptors (bicuculline; 0.5 mg/kg) raised the frequency of anesthetised MMI pups but not control. We conclude that gestational thyroid hormone deficiency interferes with the respiratory and autonomic control systems of the offspring. Thyroid hormone supplementation could alleviate cardiorespiratory disorders in newborn, especially those born preterm.
•Thyroid hormones are crucial for normal brain development.•Maternal hypothyroidism during pregnancy reduces thyroid hormone access for the foetus•Respiratory disorders due to neurological immaturity are clinically significant.•We determined if thyroid hormone deficiency induces respiratory disorders in rat pups.•Thyroid hormone deficient pups show abnormal reflexes that predispose to respiratory disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Rhythmic breathing is generated by neural circuits located in the brainstem. At its core is the preBötzinger Complex (preBötC), a region of the medulla, necessary for the generation of rhythmic ...breathing in mammals. The preBötC is comprised of various neuronal populations expressing neurokinin-1 receptors, the cognate G-protein-coupled receptor of the neuropeptide substance P (encoded by the tachykinin precursor 1 or
). Neurokinin-1 receptors are highly expressed in the preBötC and destruction or deletion of neurokinin-1 receptor-expressing preBötC neurons severely impairs rhythmic breathing. Although application of substance P to the preBötC stimulates breathing in rodents, substance P is also involved in nociception and locomotion in various brain regions, suggesting that
neurons found in the preBötC may have diverse functional roles. Here, we characterized the role of
-expressing preBötC neurons in the generation of rhythmic breathing
, as well as motor behaviors. Using a cre‑lox recombination approach, we injected adeno-associated virus containing the excitatory channelrhodopsin-2 ChETA in the preBötC region of
-cre mice. Employing a combination of histological, optogenetics, respiratory, and behavioral assays, we showed that stimulation of glutamatergic or
preBötC neurons promoted rhythmic breathing in both anesthetized and freely moving animals, but also triggered locomotion and overcame respiratory depression by opioid drugs. Overall, our study identified a population of excitatory preBötC with major roles in rhythmic breathing and behaviors.
Rational
Opioids are extensively used for their analgesic properties but present a variety of unwanted side effects, including tolerance, dependence and respiratory depression. The analgesic effect ...of opioids is due to activation of µ‐opioid receptors (MOR) in the central nervous system and no treatments are currently available to prevent respiratory depression without reducing their analgesic properties. The neural circuits and mechanisms regulating respiratory depression, sedation, and analgesia by opioids often overlap, therefore making challenging the identification of the mechanisms regulating respiratory depression. Neurons expressing tachykinin precursor 1 peptide (Tac1) located in the pre‐Bötzinger complex (preBötC) also co‐express neurokinin‐1 receptors (NK1R) and MORs. NK1R neurons are preferentially inhibited by opioids and play an essential role in mediating opioid‐induced respiratory depression.
Objective
Here, we tested the hypothesis that optogenetic activation of Tac1‐expressing preBötC cells in freely behaving mice will modulate breathing and prevent respiratory depression by opioids.
Methods
Using a Cre‐loxP recombination approach, we injected in Tac1 Cre recombinase mice the adeno‐associated virus containing the gene cassette of the excitatory channelrhodopsin‐2 ChETA flanked between loxP sites. A 200 µm optical fiber was then fixed above the preBötC for laser stimulation with blue light (wavelength: 480 nm). After a four weeks period to allow ChETA expression in targeted cells, the mouse was placed in a plethysmographic chamber and breathing was measured while laser stimulations were performed under baseline conditions (30 Hz). Following baseline measurements, the clinically relevant µ‐opioid drug fentanyl was administered by intraperitoneal injection (0.3 mg/Kg). About 5 minutes after fentanyl injection, targeted preBötC cells were activated using laser stimulations (30 Hz).
Results
Data show that stimulation of Tac1‐expressing cells increased respiratory frequency under baseline conditions. Fentanyl depressed breathing in 5 minutes and stimulation of Tac1 cells prevented opioid‐induced respiratory depression; an effect that was reversible.
Conclusion
Tac1‐expressing preBötC cells may constitute a target to prevent depression of breathing by opioids. These results will help identify the cells mediating opioid‐induced respiratory depression, an essential step toward the development of therapeutic targets to reduce the risk of opioids overdose and associated mortality.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
•Thyroid hormones are crucial for normal brain development.•Thyroid hormones are effectors on microglia during development.•Microglial functions in lower brain regions (brainstem) are unknown.•Effect ...of T3 on microglial functions differs between brain areas.•Neurons are necessary for T3-induced microglial motility in the brainstem.
Microglia are critical for the refinement of neural networks that takes place during the perinatal period. Their phenotype and actions are guided by the signals produced by neighbouring cells and hormones present in their surrounding milieu. Cell populations and the signals they produce differ between regions. The fact that thyroid hormones (THs) promote the growth and morphological differentiation of microglia within the cortex contributes to the TH’s powerful actions on the developing brain. The brainstem is especially active during early life owing to its role in generation of the rhythmic respiratory motor command. Despite evidences indicating that THs are necessary to proper development of the neural networks regulating this vital homeostatic function, their actions on microglia originating from the brainstem remain unknown. Using primary cultured microglia from newborn mice (C57BL/6J), we first report that regulation of microglial motility by THs is different between cortex and brainstem. Microglial motility (μm traveled over 3 h) was monitored with or without triiodothyronine (T3, 1μM). Exposure to T3 did not stimulate microglial motility from brainstem, but significantly stimulated (316 %) when they were co-cultured with neurons. Motility of cortex microglia was stimulated to the similar extent either with or without neurons. These data suggest that the microglial function in different regions of the brain is determined by the surrounding environment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The objective of this observational cross-sectional study was to describe the cleanliness of various equipment used for colostrum harvest and calf feeding procedures on dairy farms in Québec, Canada. ...The study was performed on 42 commercial dairy herds also enrolled in another study aiming to determine the transfer of passive immunity over a 14-mo period. Information on colostrum quality (using Brix value) and cleanliness (total aerobic and total coliform count) were recorded as well as various practices focused on colostrum-feeding equipment and preweaning period using a standard questionnaire. During the study period, colostrum and milk-feeding equipment cleanliness was assessed using direct surface swabbing with Hygiena Ultrasnap swabs. A total of 155 swab samples were obtained from 6 pieces of equipment. Adenosine triphosphate collected from the swabbed surface reacts with the luciferase solution present in the swab by bioluminescence, which is proportional to the quantity of ATP present and quantified as relative light units (RLU). The description of feed equipment cleanliness (defined as the maximal RLU found for a specific herd, dichotomized as <1,000 RLU vs. ≥1,000 RLU) was compared with the herds' descriptive characteristics, focusing on the first 2 components of a multiple correspondence analysis. The median (range) RLU for buckets used for colostrum harvest, bucket or bottle used for feeding, tube feeders, milking colostrum line, and internal surface of the nipples were 41 RLU (3–1,625 RLU), 78 RLU (<1–3,765 RLU), 29 RLU (<1–2,177 RLU), 83 RLU (<1–9,968 RLU), and 1,101 RLU (2–9,546 RLU), respectively. The first 2 components of multiple correspondence analysis explained 24.7% of data variances and were related to the farms' hygiene and health (13.0%) and feeding practices (11.7% of data variance). The maximal dichotomized luminometry value (<1,000 RLU or ≥1,000 RLU) was associated with hygiene and health dimension. This study gave promising results concerning the potential application of ATP luminometry for calf rearing practices assessment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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