Correcting for serial dependence in studies of respiratory dynamics

Understanding the physiological impact of drug treatments on patients is important in assessing their performance and determining possible side effects. While this effect might be best determined in individual subjects, conventional methods assess treatment performance by averaging a physiological measure of interest before and after drug administration for n subjects. Summarizing large numbers of time-series observations in two means for each subject in this way results in significant information loss. Treatment effect can instead be analyzed in individual subjects. Because serial dependence of observations from the same animal must then be considered, methods that assume independence of observations, such as the t-test and z-test, cannot be used. We address this issue in the case of respiratory data collected from anesthetized rats that were injected with a dopamine agonist. In order to accurately assess treatment effect in time-series data, we begin by formulating a method of conditional likelihood maximization to estimate the parameters of a first-order autoregressive (AR) process. We show that treatment effect of a dopamine agonist can be determined while incorporating serial effect into the analysis. In addition, while maximum likelihood estimators of a large sample with independent observations may converge to an asymptotically normal distribution, this result of large sample theory may not hold when observations are serially dependent. In this case, a parametric bootstrap comparison can be used to approximate an appropriate measure of uncertainty.National Institutes of Health (U.S.) (Grant DP1-OD003646)National Institutes of Health (U.S.) (Grant K08-GM094394)National Institutes of Health (U.S.) (Grant K08-GM083216

Triassic alkaline magmatism of the Hawasina Nappes: Post-breakup melting of the Oman lithospheric mantle modified by the Permian Neotethyan Plume

International audienceMiddle to Late Triassic lavas were sampled within three tectonostratigraphic groups of the Hawasina Nappes in the Oman Mountains. They are predominantly alkali basalts and trachybasalts, associated with minor sub-alkaline basalts, trachyandesites, trachytes and rhyolites. Their major, trace elements and Nd-Pb isotopic compositions are very similar to those of the Permian plume-related high-Ti basalts which also occur in the Hawasina Nappes. The Triassic lavas derive from low-degree melting of an enriched OIB-type mantle source, characterized by εNdi = 0.3-5.3 and (206Pb/204Pb)i = 16.96-19.31 (for t = 230 My). With time, melting depths decreased from the garnet + spinel to the spinel lherzolite facies and the degree of melting increased. The oldest are distinguished from the others by unradiogenic Nd and Pb signatures, with εNdi = − 4.5 to − 1.2 and (206Pb/204Pb)i = 16.35-17.08, which we attribute to their contamination by Arabo-Nubian lower crust. The lavas likely derived from the Oman lithospheric mantle, the original DMM-HIMU signature of which was overprinted during its pervasive metasomatism by the Permian plume-related melts. We suggest that these lavas were emplaced during post-breakup decompression-triggered melting in the Middle Triassic during global kinematic reorganization of the Tethyan realm

Methylphenidate Actively Induces Emergence from General Anesthesia

Background: Although accumulating evidence suggests that arousal pathways in the brain play important roles in emergence from general anesthesia, the roles of monoaminergic arousal circuits are unclear. In this study, the authors tested the hypothesis that methylphenidate (an inhibitor of dopamine and norepinephrine transporters) induces emergence from isoflurane general anesthesia. Methods: Using adult rats, the authors tested the effect of intravenous methylphenidate on time to emergence from isoflurane general anesthesia. They then performed experiments to test separately for methylphenidate-induced changes in arousal and changes in minute ventilation. A dose–response study was performed to test for methylphenidate-induced restoration of righting during continuous isoflurane general anesthesia. Surface electroencephalogram recordings were performed to observe neurophysiological changes. Plethysmography recordings and arterial blood gas analysis were performed to assess methylphenidate-induced changes in respiratory function. Intravenous droperidol was administered to test for inhibition of methylphenidate's actions. Results: Methylphenidate decreased median time to emergence from 280 to 91 s. The median difference in time to emergence without methylphenidate compared with administration of methylphenidate was 200 [155–331] s (median, [95% CI]). During continuous inhalation of isoflurane, methylphenidate induced return of righting in a dose-dependent manner, induced a shift in electroencephalogram power from delta (less than 4 Hz) to theta (4–8 Hz), and induced an increase in minute ventilation. Administration of intravenous droperidol (0.5 mg/kg) before intravenous methylphenidate (5 mg/kg) largely inhibited methylphenidate-induced emergence behavior, electroencephalogram changes, and changes in minute ventilation. Conclusions: Methylphenidate actively induces emergence from isoflurane general anesthesia by increasing arousal and respiratory drive, possibly through activation of dopaminergic and adrenergic arousal circuits. The authors' findings suggest that methylphenidate may be useful clinically as an agent to reverse general anesthetic-induced unconsciousness and respiratory depression at the end of surgery.National Institutes of Health (U.S.) (Grant DP1-OD003646)National Institutes of Health (U.S.) (Grant K08-GM094394)National Institutes of Health (U.S.) (Grant K08-GM083216)Massachusetts General Hospital. Dept. of Anesthesia and Critical Car

Petrology, geochemistry, and cosmic-ray exposure age of lherzolitic shergottite Northwest Africa 1950

Northwest Africa (NWA) 1950 is a new member of the lherzolitic shergottite clan of the Martian meteorites recently found in the Atlas Mountains. The petrological, mineralogical, and geochemical data are very close to those of the other known lherzolitic shergottites. The meteorite has a cumulate gabbroic texture and its mineralogy consists of olivine (Fo66 to Fo75), low and high-Ca pyroxenes (En78Fs19Wo2- En60Fs26W14; En53Fs16Wo31-En45Fs14Wo41), and plagioclase (An57Ab41Or1 to An40Ab57Or3; entirely converted into maskelynite during intense shock metamorphism). Accessory minerals include phosphates (merrillite), chromite and spinels, sulfides, and a glass rich in potassium. The oxygen isotopic values lie on the fractional line defined by the other SNC meteorites (Δ17O = 0.312 ‰). The composition of NWA 1950 is very similar to the other lherzolitic shergottites and suggests an origin from the same magmatic system, or at least crystallization from a close parental melt. Cosmogenic ages indicate an ejection age similar to those of the other lherzolitic shergottites. The intensity of the shock is similar to that observed in other shergottites, as shown by the occurrence of small melt pockets containing glass interwoven with stishovite

Offshore Oligo-Miocene volcanic fields within the Corsica-Liguria Basin: Magmatic diversity and slab evolution in the western Mediterranean Sea

International audienceThe European and Corsica-Sardinia margins of the Ligurian Sea (western Mediterranean) have been affected by a geochemically diverse igneous activity, offshore and onshore, since the Eocene. This magmatism occurred in a global subduction-related framework. On the European side, the oldest Tertiary magmatism dated at ca. 35 Ma was mainly calc-alkaline. It included the emplacement of plutonic bodies of adakitic affinity, such as the quartz microdiorite laccolith locally referred to as "esterellite". Younger magmatic events on-land within the whole Ligurian domain were mostly medium-K or K-rich calc-alkaline. Miocene volcanic activity was important in Sardinia, where andesites and ignimbrites were erupted during several magmatic cycles. In Corsica, it was minor although it emplaced lamprophyres near Sisco at 15 Ma. Dredging and diving cruises conducted in the Ligurian Sea during the last thirty years allowed us to collect a number of submarine samples. We discuss here their geochemistry (major and trace elements) and their whole-rock K-Ar ages and mineral 40Ar-39Ar plateau ages. Around 15 Ma, minor amounts of adakitic lavas were emplaced off southwestern Corsica, in the deepest part of the Liguria-Corsica Basin. They rested over the thinnest southwestern Corsica Hercynian continental crust. Closer to the coast, contemporaneous calc-alkaline rocks erupted on a less thinned crust. The adakitic events could be indicative of either the final stages of active subduction, or alternatively of a slab tearing linked to the southeastern retreat and steepening of the slab. The latter event could be connected with the end of the Corsica-Sardinia block drifting and its correlative eastern collision. Younger volcanic effusions, dated at 14-6 Ma, occurred mostly northwest and north of Corsica. K-rich calc-alkaline basalts, shoshonites and K-rich trachytes were emplaced during this period, and alkali basalts erupted as early as 12 Ma in Sardinia. In the Toulon area, alkali basalts dated at 7-6 Ma represent the last onshore activity just before the Messinian crisis, and the Pliocene alkali basaltic outpouring in Sardinia. We propose to link these latter volcanic events to the development of a slab window in a post-collisional tectonic framework

Hydroxyl as a Tracer of H2 in the Envelope of MBM40

We observed 51 positions in the OH 1667 MHz main line transitions in the translucent, high latitude cloud MBM40. We detected OH emission in 8 out of 8 positions in the molecular core of the cloud and 24 out of 43 in the surrounding, lower extinction envelope and periphery of the cloud. Using a linear relationship between the integrated OH line intensity and E(B-V), we estimate the mass in the core, the envelope, and the periphery of the cloud to be 4, 8, and 5 solar masses. As much as a third of the total cloud mass may be found in the in the periphery (E(B-V) $<$ 0.12 mag) and about a half in the envelope (0.12 $\le$ E(B-V) $\le$ 0.17 mag). If these results are applicable to other translucent clouds the OH 1667 MHz line is an excellent tracer of gas in very low extinction regions and high-sensitivity mapping of the envelopes of molecular clouds may reveal the presence of significant quantities of molecular mass.Comment: 26 pages, 3 figures, and 5 table

Physostigmine and Methylphenidate Induce Distinct Arousal States During Isoflurane General Anesthesia in Rats

BACKGROUND: Although emergence from general anesthesia is clinically treated as a passive process driven by the pharmacokinetics of drug clearance, agents that hasten recovery from general anesthesia may be useful for treating delayed emergence, emergence delirium, and postoperative cognitive dysfunction. Activation of central monoaminergic neurotransmission with methylphenidate has been shown to induce reanimation (active emergence) from general anesthesia. Cholinergic neurons in the brainstem and basal forebrain are also known to promote arousal. The objective of this study was to test the hypothesis that physostigmine, a centrally acting cholinesterase inhibitor, induces reanimation from isoflurane anesthesia in adult rats. METHODS: The dose-dependent effects of physostigmine on time to emergence from a standardized isoflurane general anesthetic were tested. It was then determined whether physostigmine restores righting during continuous isoflurane anesthesia. In a separate group of rats with implanted extradural electrodes, physostigmine was administered during continuous inhalation of 1.0% isoflurane, and the electroencephalogram changes were recorded. Finally, 2.0% isoflurane was used to induce burst suppression, and the effects of physostigmine and methylphenidate on burst suppression probability (BSP) were tested. RESULTS: Physostigmine delayed time to emergence from isoflurane anesthesia at doses ≥0.2 mg/kg (n = 9). During continuous isoflurane anesthesia (0.9% ± 0.1%), physostigmine did not restore righting (n = 9). Blocking the peripheral side effects of physostigmine with the coadministration of glycopyrrolate (a muscarinic antagonist that does not cross the blood-brain barrier) produced similar results (n = 9 each). However, during inhalation of 1.0% isoflurane, physostigmine shifted peak electroencephalogram power from δ ( < 4 Hz) to θ (4-8 Hz) in 6 of 6 rats. During continuous 2.0% isoflurane anesthesia, physostigmine induced large, statistically significant decreases in BSP in 6 of 6 rats, whereas methylphenidate did not. CONCLUSIONS: Unlike methylphenidate, physostigmine does not accelerate time to emergence from isoflurane anesthesia and does not restore righting during continuous isoflurane anesthesia. However, physostigmine consistently decreases BSP during deep isoflurane anesthesia, whereas methylphenidate does not. These findings suggest that activation of cholinergic neurotransmission during isoflurane anesthesia produces arousal states that are distinct from those induced by monoaminergic activation.National Institutes of Health (U.S.) (Grant TR01-GM104948)National Institutes of Health (U.S.) (Grant DP1-OD003646)National Institutes of Health (U.S.) (Grant K08-GM094394

In Vivo and In Vitro Pharmacological Studies of Methoxycarbonyl-Carboetomidate

Background—We previously developed two etomidate analogs that retain etomidate’s favorable hemodynamic properties, but whose adrenocortical effects are reduced in duration or magnitude. Methoxycarbonyl-etomidate (MOC-etomidate) is rapidly metabolized and ultra-short acting whereas (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) does not potently inhibit 11?-hydroxylase. We hypothesized that MOC-etomidate’s labile ester could be incorporated into carboetomidate to produce a new agent that possesses favorable properties individually found in each agent. We describe the synthesis and pharmacology of methoxycarbonyl-(R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (MOC-carboetomidate), a “soft” analog of carboetomidate. Methods—MOC-carboetomidate’s octanol:water partition coefficient was determined chromatographically and compared with those of etomidate, carboetomidate, and MOC-etomidate. MOC-carboetomidate’s EC50 and ED50 for loss of righting reflexes (LORR) were measured in tadpoles and rats, respectively. Its effect on gamma-aminobutyric acid A (GABAA) receptor function was assessed using two-microelectrode voltage clamp electrophysiological techniques and its metabolic stability was determined in pooled rat blood using high performance liquid chromatography. Its duration of action and effects on arterial blood pressure and adrenocortical function were assessed in rats. Results—MOC-carboetomidate’s octanol:water partition coefficient was 3300 ± 280, whereas those for etomidate, carboetomidate, and MOC-etomidate were 800 ± 180, 15000 ± 3700, and 190 ± 25, respectively. MOC-carboetomidate’s EC50 for LORR in tadpoles was 9 ± 1 µM and its EC50 for LORR in rats was 13 ± 5 mg/kg. At 13 µM, MOC-carboetomidate enhanced GABAA receptor currents by 400 ± 100%. Its metabolic half-life in pooled rat blood was 1.3 minutes. The slope of a plot of the duration of LORR in rats versus the logarithm of the hypnotic dose was significantly shallower for MOC-carboetomidate than for carboetomidate (4 ± 1 vs. 15 ± 3, respectively; p = 0. 0004123). At hypnotic doses, the effects of MOC-carboetomidate on arterial blood pressure and adrenocortical function were not significantly different from those of vehicle alone. Conclusions—MOC-carboetomidate is a GABAA receptor modulator with potent hypnotic activity that is more rapidly metabolized and cleared from the brain than carboetomidate, maintains hemodynamic stability similar to carboetomidate, and does not suppress adrenocortical function

The Gemini Planet Imager View of the HD 32297 Debris Disk

We present new H-band scattered light images of the HD 32297 edge-on debris disk obtained with the Gemini Planet Imager. The disk is detected in total and polarized intensity down to a projected angular separation of 0.?15, or 20 au. On the other hand, the large-scale swept-back halo remains undetected, likely a consequence of its markedly blue color relative to the parent body belt. We analyze the curvature of the disk spine and estimate a radius of ?100 au for the parent body belt, smaller than past scattered light studies but consistent with thermal emission maps of the system. We employ three different flux-preserving post-processing methods to suppress the residual starlight and evaluate the surface brightness and polarization profile along the disk spine. Unlike past studies of the system, our high-fidelity images reveal the disk to be highly symmetric and devoid of morphological and surface brightness perturbations. We find the dust scattering properties of the system to be consistent with those observed in other debris disks, with the exception of HR 4796. Finally, we find no direct evidence for the presence of a planetary-mass object in the system

SARS-CoV-2 Variants, South Sudan, January-March 2021.

As the coronavirus pandemic continues, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequence data are required to inform vaccine efforts. We provide SARS-CoV-2 sequence data from South Sudan and document the dominance of SARS-CoV-2 lineage B.1.525 (Eta variant) during the country's second wave of infection