The platelet P2Y12 receptor (P2Y12R) for adenosine 5'diphosphate (ADP) plays a central role in platelet function, hemostasis, and thrombosis. Patients with inherited P2Y12R defects display ...mild-to-moderate bleeding diatheses. Defects of P2Y12R should be suspected when ADP, even at high concentrations (≥ 10 μm), is unable to induce full, irreversible platelet aggregation. P2Y12R also plays a role in inflammation: its role in the pathogenesis of allergic asthma has been well characterized. In addition, inhibition or genetic deficiency of P2Y12R has antitumor effects. Drugs inhibiting P2Y12R are potent antithrombotic drugs. Clopidogrel is the P2Y12R antagonist that is most widely used in the clinical setting. Its most important drawback is its inability to inhibit adequately P2Y12R-dependent platelet function in about one-third of patients. New drugs, such as prasugrel and ticagrelor, which effectively inhibit P2Y12R in the vast majority of patients, have proved to be more efficacious than clopdidogrel in preventing major adverse cardiovascular events.
This paper estimates the relationship between the strength of economic shocks and temporal recovery in the world air transport industry. Our results show that world recovery of passenger demand to ...pre-COVID-19 levels is estimated to take 2.4 years (recovery by late-2022), with the most optimistic estimate being 2 years (recovery by mid-2022), and the most pessimistic estimate 6 years (recovery in 2026). Large regional differences are detected, Asia Pacific has the shortest estimated average recovery time 2.2 years, followed by North America 2.5 years and Europe 2.7 years. For air freight the results show a shorter average world recovery time of 2.2 years compared to passenger demand. At the regional level, Europe and Asia Pacific are comparable with average recovery times of 2.2 years while North America is predicted to recover faster in 1.5 years. The results show that the strength of economic shocks of various origins impacts the linear growth of passenger and freight traffic and the temporal recovery of the industry in a predictable transitory way. Hence, the impact of the COVID-19 recession will represent a temporary, although long-lasting, correction to previous growth levels.
•We estimate relationship between economic shocks and recovery in air transport.•World recovery of passenger demand to pre-COVID-19 levels is estimated to take 2.4 years.•Asia pacific has the shortest estimated average recovery time of 2.2 years.•Air freight in Europe and Asia Pacific have average recovery times of 2.2 years while North Americarecovers faster or in 1.5 years.•The recession will represent a temporary correction to previous growth levels.
Clopidogrel is an antithrombotic prodrug, whose active metabolite inhibits platelet function by irreversibly binding to the platelet receptor for adenosine diphosphate, P2Y(12). Wide inter-individual ...variability of response to clopidogrel has been reported in several studies: a significant proportion of treated patients (about one-third) exhibit a suboptimal inhibition of platelet function. Genetic and environmental factors that influence the absorption and/or the extent of metabolism of clopidogrel to its active metabolite account for the observed variability of response. Tailored treatment based on the results of laboratory tests of platelet function has been proposed as a solution to this problem, which has important clinical implications. Although it is often considered a desirable evolution of modern medicine, tailored treatment based on laboratory tests is actually an old remedy (of yet unproven efficacy, in the case of antiplatelet therapy) for the problem of response variability to antithrombotic drugs with unpredictable bioavailability. When possible, the use of alternative drugs with more uniform and predictable bioavailability, and with favourable profiles in terms of risk/benefit and cost-benefit ratios should be preferred. Moreover, tailored treatment with laboratory tests must be validated in randomized clinical trials before its implementation can be recommended. We still need to identify and standardize the laboratory test for this purpose, as well as answer basic questions on its clinical utility and cost-effectiveness, before tailoring clopidogrel therapy based on laboratory tests can be recommended in clinical practise.
The definition 'resistance to antiplatelet drugs' should be limited to situations in which failure of the drug to hit its pharmacological target has been documented by specific laboratory tests. ...Aspirin resistance, as determined by specific tests (e.g. serum thromboxane B(2)), appears to be rare (1-2%) and, in most instances, is caused by poor compliance. In contrast to aspirin, studies that used specific tests to measure the pharmacological effect of thienopyridines e.g. vasodilator-stimulated phosphoprotein (VASP) showed a wide variability of responses to these drugs, with significant proportions of subjects (15-30%) who are very poor responders. Inter-individual differences in the extent of metabolism of thienopyridines to their active metabolites is the most plausible mechanism for the observed inter-individual variability in platelet inhibition. The demonstration that some patients may be 'resistant' or 'poor responders' to the pharmacological effect of antiplatelet drugs, has prompted the need of laboratory monitoring of antiplatelet therapy. However, many published studies have been performed using unspecific tests of platelet function, which identify patients on antiplatelet treatment with high residual platelet reactivity, which is not necessarily because of resistance to antiplatelet drugs. Despite this drawback, identification of patients with high residual platelet reactivity may be useful to predict their risk of atherothrombotic events. However, many studies still need to be carried out to identify the ideal laboratory test and to answer basic questions on its clinical utility and cost-effectiveness, before monitoring antiplatelet therapy can be recommended in the clinical practise. Until then, monitoring of antiplatelet therapy should be considered for investigational purposes only.
In the last decade, several studies revealed inter-patient response variability to antiplatelet agents: patients who display negligible or no responses to these drugs are considered poor responders, ...or "resistant" to treatment. In order to identify poor responders to an antiplatelet drug, laboratory tests of platelet function that specifically explore the platelet activation pathway that is targeted by the drug should be utilised. In addition, they should be performed both at baseline and during treatment: however, most studies explored platelet function during antiplatelet treatment, in order to identify those patients with "high on-treatment platelet reactivity" (HPR), which exposes them to increased risk of major adverse cardiovascular events (MACE). Many tests of platelet function have been used, most of which are able to identify patients at risk of MACE. Unfortunately, universal cut-off values for HPR have not been clearly established yet. In addition, the concordance among different tests in the identification of patients at risk is very poor and the most effective and safe treatment for patients at risk is still unknown.
The 2016–2017 Central Italy seismic sequence ruptured overlapping normal faults of the Apennines mountain chain, in nine earthquakes with magnitude Mw > 5 within a few months. Here we investigate the ...structure of the fault system using an extensive aftershock data set, from joint permanent and temporary seismic networks, and 3‐D Vp and Vp/Vs velocity models. We show that mainshocks nucleated on gently west dipping planes that we interpret as inverted steep ramps inherited from the late Pliocene compression. The two large shocks, the 24 August, Mw = 6.0 Amatrice and the 30 October, Mw = 6.5 Norcia occurred on distinct faults reactivated by high pore pressure at the footwall, as indicated by positive Vp/Vs anomalies. The lateral extent of the overpressurized volume includes the fault patch of the Norcia earthquake. The irregular geometry of normal faults together with the reactivated ramps leads to the kinematic complexity observed during the coseismic ruptures and the spatial distribution of aftershocks.
Plain Language Summary
In this study we present refined earthquake locations and tomographic images of the upper crust to investigate the mechanisms of the 2016 Amatrice and Norcia destructive earthquakes. We find that earthquakes ruptured distinct segments of the fault system, partially reutilizing preexisting faults inherited from the previous compressional phase. Overpressurized fluids within the carbonate rocks facilitate the reactivation of faults during the large ruptures.
Key Points
The two large shocks of Amatrice and Norcia nucleated on distinct and parallel faults reactivated by high pore pressure in the footwall
The irregular geometry of normal faults and reactivated ramps feeds in the complexity observed during coseismic ruptures and aftershocks
Rapid definition of overpressurized volumes along the fault system has implications for the a priori identification of nucleation locations
The presence of antibiotic resistant bacteria (ARB) in wastewater was investigated and the role of wastewater treatment plants (WWTPs) in promoting or limiting antibiotic resistance was assessed. ...Escherichia coli (E. coli) and total heterotrophic bacteria (THB) resistance to ampicillin, chloramphenicol and tetracycline was monitored in three WWTPs located in Milan urban area (Italy), differing among them for the operating parameters of biological process, for the disinfection processes (based on sodium hypochlorite, UV radiation, peracetic acid) and for the discharge limits to be met. Wastewater was collected from three sampling points along the treatment sequence (WWTP influent, effluent from sand filtration, WWTP effluent).
Antibiotic resistance to ampicillin was observed both for E. coli and for THB. Ampicillin resistant bacteria in the WWTP influents were 20–47% of E. coli and 16–25% of THB counts. A limited resistance to chloramphenicol was observed only for E. coli, while neither for E. coli nor for THB tetracycline resistance was observed. The biological treatment and sand filtration led to a decrease in the maximum percentage of ampicillin-resistant bacteria (20–29% for E. coli, 11–21% for THB). However, the conventionally adopted parameters did not seem adequate to support an interpretation of WWTP role in ARB spread. Peracetic acid was effective in selectively acting on antibiotic resistant THB, unlike UV radiation and sodium hypochlorite. The low counts of E. coli in WWTP final effluents in case of agricultural reuse did not allow to compare the effect of the different disinfection processes on antibiotic resistance.
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•Resistance to 3 antibiotics was assessed in 3 municipal wastewater treatment plants.•E. coli and total heterotrophic bacteria (THB) were selected as microbial indicators.•A relevant quote of resistant E. coli and THB was observed only for ampicillin.•Biological treatment and sand filtration influenced the presence of resistant bacteria.•Peracetic acid reduced resistant THB, unlike UV radiation and sodium hypochlorite.
Fluid overpressure is a primary mechanism behind fault interaction and earthquakes triggering. The Apennines section within the young Alpine mobile belt is a key locus to investigate the interplay ...between fluids and faults. Here, seismicity develops along the extending mountain belt and the key role of fluids has been invoked in past large earthquake sequences. In this study, we use seismological data to get improved images of the Apennines normal faulting system, trying to catch evidences for the involvement of fluids in the preparatory phase of large earthquakes. We observe that extension preferentially reutilizes inherited fragments of faults which were assembled during the Mio‐Pliocene contraction, with steep segments that floor on a regional‐scale gently east dipping plane. We find evidences for wide volumes of overpressured fluids at the base of the seismogenic layer, which are connected to the activation of the recent large earthquakes. The recognition of fluids compartments with overpressuring and diffusion molding seismicity is a key to understand faulting processes and possibly develop forecasts scenarios.
Plain Language Summary
We present the first full image of the deep structure of the paradigmatic normal faulting system of the Apennines, obtained by an impressive set of seismological data collected during seismic sequences originated in the past two decades. The synoptic view permits to explore the interaction between earthquakes and fluids within the crust. Such interaction is every day more important because fluid pressure changes in the subsurface (even created by human activities) might trigger large earthquakes even at a distance. The novelty of our results is the imaging of deep fluids at the base of the extensional fault system in the Apennines related to the development of all the large earthquakes that occurred over the two decades. This finding breaks through a persistent problem in earthquake preparation processes and has clear implications for tectonics of extensional systems, inversion tectonics, physics of earthquakes, and aftershock forecasting.
Key Points
The complex and diffuse fault segmentation of fault system derives from intense preexisting crustal heterogeneity
Large‐magnitude earthquakes along the system are related to broad high Vp/Vs overpressurized volumes at the base of the seismogenic layer
Monitoring of this target will help decipher the interaction between deep fluids and seismicity before and during major seismic sequences
Inherited platelet-based bleeding disorders include abnormalities of platelet number and function, and are generally classified based on the abnormal functions or responses. However, a clear ...distinction is problematic, and in this review, the classification has been based on abnormalities of platelet components that share common characteristics. Inherited thrombocytopenias are rare, but probably underdiagnosed. They are usually classified according to both platelet size and the presence or absence of clinical features other than those deriving from the platelet defect. Hereditary disorders of platelet function can be classified as resulting from: (i) abnormalities of the platelet receptors for adhesive proteins; (ii) abnormalities of the platelet receptors for soluble agonists; (iii) abnormalities of the platelet granules; (iv) abnormalities of the signal-transduction pathways; (v) abnormalities of the membrane phospholipids; and (vi) miscellaneous abnormalities of platelet function. The literature on these disorders is reviewed, and the underlying defects discussed.
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