Multidimensional auctions for long-term procurement contracts under the threat of early exit

In this paper we study how early-exit options, embedded in long-term procurement contracts which do not provide for sufficiently strong incentives against contract breach, can affect bidding behaviors in multidimensional procurement auctions and the parties' expected payoffs. We show first that bidders' payoff is lower when competing for contracts with unenforceable contract terms. Secondly, that neglecting the risk of opportunistic behavior by sellers can lead to contract awards that do not maximize the buyer's potential payoff. Finally, we make suggestions about how to mitigate potential misallocations, by pointing out the role of eligibility rules and competition among bidders

Pharmacokinetics of ketamine and norketamine following intramuscular administration combined with dexmedetomidine in tigers (Panthera tigris)

In zoo practice, for physical examination or medical procedure in captive tigers, chemical immobilization is needed and ketamine (KET) in association with sedatives is an option frequently used (Clark-Price et al., 2015). Aims of the study is the assessment of the pharmacokinetics of KET and its main metabolite, norketamine (NORKET), after its intramuscular administration in combination with dexmedetomidine in tigers.Nineteen adult captive tigers, from different zoos, were scheduled for periodic physical examination or diagnostic procedures at the Milan University facilities. All animals were administered with a combination of KET at 2 mg/kg and dexmedetomidine at 10 µg/kg, given intramuscularly through blowpipe darts. If necessary, tigers where re-administered with variable doses of KET and dexmedetomidine or other drugs. When animals were sufficiently sedated, blood samples were collected every 5-10 min for the time tigers were safely approachable. Nine animals were assigned to standard protocol group (KET 2 mg/kg and dexmedetomidine 10 µg/kg) and ten animals to non-standard protocol group (tigers administered with different doses of KET, 2 – 2.5 mg/kg, and dexmedetomidine 10 – 30 µg/kg or with any other necessary drug, such as titrate-to-effect propofol and isoflurane, respectively for anaesthesia induction and maintenance). Ketamine and NORKET were extracted from plasma according to a validated HPLC-UV method (Zonca et al., 2012). For pharmacokinetic assessment, KET and NORKET concentrations were analysed with a noncompartmental approach (Phoenix® 7.0, Pharsight). Differences in the pharmacokinetic parameters between groups were statistically analysed (SPSS 25.0, SPSS Inc.).This is the first study that evaluates the pharmacokinetics of KET and NORKET in tigers. Due to the harmful attitude of these animals, samples collection was limited to the period of sedation, a short time for a complete pharmacokinetic evaluation. Nevertheless, we observed a favorable kinetic profile of KET and NORKET and, from a clinical point of view, all animals showed a good recovery, no adverse effects and a good level of sedation.     Standard Protocol              (mean ± s.d.)Non-Standard protocol             (mean ± s.d.)     KetamineHL_Lambda_zmin77.62 ± 54.5076.14 ± 67.32 Tmaxmin27.78 ± 7.9049.70 ± 29.64 Cmaxug/mL0.63 ± 0.170.67 ± 0.19 AUClastmin*ug/mL23.84 ±6.40*35.97 ± 12.84* AUMClastmin*min*ug/mL802.24 ± 331.03*2054.97 ± 1018.88* MRTlastmin32.88 ± 5.71*54.38 ± 19.71*     NorketamineTmaxmin51.89 ± 8.95*77.10 ± 24.41* Cmaxug/mL0.24 ± 0.070.23 ± 0.09 AUClastmin*ug/mL7.30 ± 3.9811.07 ± 5.46 AUMClastmin*min*ug/mL291.94 ± 227.01*701.87 ± 424.80* MRTlastmin36.95 ± 7.32*58.65 ± 19.58*HL_Lambda_z = Elimination Half-Life; Tmax = Time to Maximum concentration; Cmax = Maximum Concentration; AUClast = Area Under the Curve to the last concentration; AUMClast = Area under the first Moment Curve to the last concentration ;MRTlast = Mean Residence Time to the last concentration  Tab.1: Pharmacokinetic parameters of ketamine and norketamine in nineteen adult captive tigers after intramuscular administration of 2 mg/kg of ketamine, with or without variation from the standard protocol, in combination with dexmedetomidine (with * are indicated results with p < 0.05)

Collaboration in Planning: the Geodesign approach

After proposing Geodesign as a novel approach to spatial planning and design, the paper presents the workflow and the results of a collaborative Geodesign workshop held in May 2016 to design the future development plan of the Cagliari Metropolitan Area in Italy. The workshop results demonstrate how it is possible to involve teams of members of the community in what is perhaps the most critical (and least understood in its dynamics) phase of a spatial planning process, that is putting knowledge into action through the design of future change alternatives. The participatory creation of design alternative is explained with reference to the case study, as well as the negotiation process which through impact assessment converges towards consensus on a final design solution

Prevalence and characteristics of Alice in Wonderland Syndrome in adult migraineurs: Perspectives from a tertiary referral headache unit

Background: Migraine affects how the brain processes sensory information at multiple levels. The aberrant integration of visual and somatosensory stimuli is thought to underlie Alice in Wonderland Syndrome, a disorder often reported as being associated with migraine. However, there is still a lack of knowledge about the epidemiology of this syndrome in migraineurs and the association between Alice in Wonderland Syndrome episodes and migraine attacks. Therefore, we conducted a prospective cohort study to systematically evaluate the prevalence and the clinical features of Alice in Wonderland Syndrome in a large sample of patients with migraine. Methods: All the patients attending for the first time a tertiary-level headache clinic were consecutively screened for Alice in Wonderland Syndrome symptoms by means of an ad hoc questionnaire and detailed clinical interview, over a period of 1.5 years. Patients experiencing Alice in Wonderland Syndrome symptoms were contacted for a follow-up after 8–12 months. Results: Two hundred and ten patients were recruited: 40 patients (19%) reported lifetime occurrence of Alice in Wonderland Syndrome, 90% of whom (38/40) had migraine with aura. Thirty-one patients experienced episodes of Alice in Wonderland Syndrome within 1 h from the start of migraine headache. Patients reported either visual or visual and somatosensory symptoms (i.e. somatosensory symptoms never presented alone). We collected the follow-up details of 30 patients with Alice in Wonderland Syndrome, 18 of whom had been prescribed a preventive treatment for migraine. After 8–12 months, 5 of the treated patients reported a decrease, while 13 reported no episodes of Alice in Wonderland Syndrome. Conclusion: Alice in Wonderland Syndrome prevalence in migraineurs was found to be higher than expected. Alice in Wonderland Syndrome was mostly associated with migraine with aura and tended to occur close to the migraine attack, suggesting the existence of a common pathophysiological mechanism. Patients treated with migraine preventive treat- ments had a higher chance of decreasing or even resolving Alice in Wonderland Syndrome episodes

To See or Not to See a z∼13z\sim13 Galaxy? That is the Question

``When did the first galaxies form?'' is still one of the greatest unanswered questions in astronomy. Theory and current stellar population models imply that the first galaxies formed at least at z=14-15. Yet, the highest redshift galaxy to have been securely confirmed remains GN-z11, at z$\sim$11. The galaxy ``HD1'' was recently proposed to be a z=13.27 galaxy based on its potential Lyman break and tentative [O III] 88 {\mu}m detection with ALMA. We hereby aim to test this scenario with new ALMA Band 4, DDT observations of what would be the [C II] 158 {\mu}m emission, if HD1 is at z$\sim$13.27. We carefully analyse the new ALMA Band 4 observations as well as re-analysing the existing ALMA Band 6 data on the source to determine the proposed redshift. We find a tentative $4\sigma$ feature in the Band 4 data that is spatially offset by 1.7" and spectrally offset by 190 km s-1 from the previously-reported $3.8\sigma$ ``[O III] 88 {\mu}m'' feature. Through various statistical tests, we demonstrate that these tentative features are fully consistent with being random noise features. The chances of finding a noise peak of the same significance as the tentative [C II] and [O III] features are 50\% and 100\%, respectively. Given the noise properties of the ALMA data, we recover at least a 50\% chance of finding two, matched $\geq3.8\sigma$ noise peaks that are spatially and spectrally offset by $\leq$10 kpc and 1000 km s-1. We conclude that we are more likely to be recovering noise features than both [O III] and [C II] emission from a source at $z\sim 13.27$. Although we find no evidence of a $z\sim 13.27$ galaxy, we cannot entirely rule out this scenario. Non-detections are also possible for a $z\sim 13$ source with a low interstellar gas-phase metallicity and density. Determining where and exactly what type of galaxy HD1 is, will now likely require JWST/NIRSpec spectroscopy.Comment: Submitted to A&A, 9 pages, 6 figures

Efficacy of milbemycin oxime/afoxolaner chewable tablets (NEXGARD SPECTRA®) against Capillaria aerophila and Capillaria boehmi in naturally infected dogs

BACKGROUND: Capillaria aerophila and Capillaria boehmi parasitize the respiratory system of wild and domestic carnivores. Capillaria aerophila inhabits the trachea and bronchi of dogs and cats, while C. boehmi affects the nasal cavities and sinuses of dogs. In dogs the infection may be subclinical or characterized by varying respiratory distress.METHODS: The present study evaluated the efficacyof an oral formulation containing milbemycin oxime and afoxolaner (NEXGARD SPECTRA) in dogs naturally infected with C. aerophila and/or C. boehmi from three enzootic areas of Italy. Dogs were enrolled pending fecal examination and molecular confirmation of respiratory capillarioses. Dogs were allocated in two groups: Group 1 (G1, 25 dogs), treated with a negative control product with no anthelmintic activity (afoxolaner, NEXGARD), and Group 2 (G2, 26 dogs), treated with NEXGARD SPECTRA. At the day of treatment administration (Day 0), all dogs were clinically examined. Dogs were again subjected to clinical and fecal examinations at Days 28 (±4) and 56 (±2). The primary criterion for treatment efficacy was the reduction of fecal Capillaria egg counts in G2 compared with G1. The regression of/recovery from baseline clinical signs was considered as a further efficacy criterion.RESULTS: Percentage reduction of fecal Capillaria egg counts in the NEXGARD SPECTRA group compared to the control group was >97% on Day 28 and 100% on Day 56, respectively (p<0.05 for both time points). Twelve of the 13 dogs in the NEXGARD SPECTRA group with respiratory signs prior to treatment were free of clinical signs at the end of the study. Conversely, the six control group dogs with respiratory signs prior to treatment remained symptomatic.CONCLUSIONS: Results of the present study showed that NEXGARD SPECTRA was safe and highly efficacious in the reduction of C. aerophila and C. boehmi eggs after one treatment with a complete reduction of the egg output after the second administration associated with a recovery from respiratory signs

N-Acylethanolamine Acid Amidase Inhibition Potentiates Morphine Analgesia and Delays the Development of Tolerance

Opioids are essential drugs for pain management, although long-term use is accompanied by tolerance, necessitating dose escalation, and dependence. Pharmacological treatments that enhance opioid analgesic effects and/or attenuate the development of tolerance (with a desirable opioid-sparing effect in treating pain) are actively sought. Among them, N-palmitoylethanolamide (PEA), an endogenous lipid neuromodulator with anti-inflammatory and neuroprotective properties, was shown to exert anti-hyperalgesic effects and to delay the emergence of morphine tolerance. A selective augmentation in endogenous PEA levels can be achieved by inhibiting N-acylethanolamine acid amidase (NAAA), one of its primary hydrolyzing enzymes. This study aimed to test the hypothesis that NAAA inhibition, with the novel brain permeable NAAA inhibitor AM11095, modulates morphine’s antinociceptive effects and attenuates the development of morphine tolerance in rats. We tested this hypothesis by measuring the pain threshold to noxious mechanical stimuli and, as a neural correlate, we conducted in vivo electrophysiological recordings from pain-sensitive locus coeruleus (LC) noradrenergic neurons in anesthetized rats. AM11095 dose-dependently (3–30 mg/kg) enhanced the antinociceptive effects of morphine and delayed the development of tolerance to chronic morphine in behaving rats. Consistently, AM11095 enhanced morphine-induced attenuation of the response of LC neurons to foot-shocks and prevented the attenuation of morphine effects following chronic treatment. Behavioral and electrophysiological effects of AM11095 on chronic morphine were paralleled by a decrease in glial activation in the spinal cord, an index of opioid-induced neuroinflammation. NAAA inhibition might represent a potential novel therapeutic approach to increase the analgesic effects of opioids and delay the development of tolerance

Increased demand for FAD synthesis in differentiated and stem pancreatic cancer cells is accomplished by modulating FLAD1 gene expression: the inhibitory effect of Chicago Sky Blue

FLAD1, along with its FAD synthase (FADS, EC 2.7.7.2) product, is crucial for flavin homeostasis and, due to its role in the mitochondrial respiratory chain and nuclear epigenetics, is closely related to cellular metabolism. Therefore, it is not surprising that it could be correlated with cancer. To our knowledge, no previous study has investigated FLAD1 prognostic significance in pancreatic ductal adenocarcinoma (PDAC). Thus, in the present work, the FAD synthesis process was evaluated in two PDAC cell lines: (a) PANC‐1‐ and PANC‐1‐derived cancer stem cells (CSCs), presenting the R273H mutation in the oncosuppressor p53, and (b) MiaPaca2 and MiaPaca2‐derived CSCs, presenting the R248W mutation in p53. As a control, HPDE cells expressing wt‐p53 were used. FADS expression/activity increase was found with malignancy and even more with stemness. An increased FAD synthesis rate in cancer cell lines is presumably demanded by the increase in the FAD‐dependent lysine demethylase 1 protein amount as well as by the increased expression levels of the flavoprotein subunit of complex II of the mitochondrial respiratory chain, namely succinate dehydrogenase. With the aim of proposing FADS as a novel target for cancer therapy, the inhibitory effect of Chicago Sky Blue on FADS enzymatic activity was tested on the recombinant 6His‐hFADS2 (IC50 = 1.2 μm) and PANC‐1‐derived CSCs' lysate (IC50 = 2–10 μm). This molecule was found effective in inhibiting the growth of PANC‐1 and even more of its derived CSC line, thus assessing its role as a potential chemotherapeutic drug

Correction: miRNAs in the vitreous humor of patients affected by idiopathic epiretinal membrane and macular hole

[This corrects the article DOI: 10.1371/journal.pone.0174297.]