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La dermatophilose est une des maladies les plus importantes des ruminants domestiques des îles caraïbes, où la maladie clinique est associée à la présence de la tique Amblyomma variegatum. Des études séroépidémiologiques ont été effectuées afin d’éclaircir l’épidémiologie de la maladie dans la région, en faisant particulièrement attention au rôle d’A. variegatum. Une banque de 1300 sérums de bovins des Petites Antilles a été examinée par ELISA pour la présence d’anticorps contre Dermatophilus congolensis. Il s’est avéré que des animaux séropositifs existent dans des îles non infestées par A. variegatum, et où la dermatophilose n’est jamais ou rarement observée. De plus, il n’y avait pas de différence significative entre la prévalence d’animaux séropositifs des zones infestées par la tique et des zones non infestées de la Martinique et de Sainte-Lucie, deux îles partiellement infestées et où la dermatophilose n’est observée que dans les parties infestées par la tique. La prévalence était basse dans les petites îles ayant un climat sec. Ceci confirme les résultats expérimentaux indiquant qu’A. variegatum n’est pas indispensable pour la transmission de D. congolensis, qui est très répandu dans la plupart des îles. Les concentrations élevées de prostaglandine E2 (entre 151 et 377 ng/ml) et de prostacycline (entre 124 et 134 ng/ml) trouvées dans la salive des femelles d’A. variegatum, suggèrent fortement que la tique pourrait favoriser le développement des lésions par une activité immunomodulatrice de sa salive. Néanmoins, malgré un certain succès dans la reproduction de la dermatophilose chez des chèvres simultanément infestées avec des adultes d’A. variegatum et scarifiées avec Dermatophilus, on n’a pas observé de différence entre des bovins Créole naturellement résistants et des Brahman hautement sensibles, utilisant le même modèle. Les lésions de la dermatophilose sont restées très bénignes sur les animaux des deux races. Après cette expérience, les Brahman ont développé une dermatophilose généralisée après avoir été mis au pâturage, ce qui indique que le rôle respectif des facteurs de risque identifiés comme étant d’importance majeure pour l’expression de la dermatophilose clinique, n’est pas complètement clarifié et demande d’être étudié davantage.

Un foyer de dermatophilose grave est apparu en 1985 dans un troupeau de vaches Brahman importées de la Martinique en Guadeloupe en juillet 1983. La maladie était peu connue en Guadeloupe jusqu'alors, car la race zébu locale possède une résistance naturelle élevée aux maladies transmises par tiques ou associées à elles. Les conditions de l'apparition et du développement de la maladie ont été étudiées en rapport avec la gestion du troupeau, le climat et les traitements appliqués. les résultats ont démontré l'importance économique de cette maladie grave pour les bovins de la région, ainsi que la sensibilité des races exotiques.

Background: Intraoperative arterial hypotension (IOH) leads to increased postoperative morbidity. Norepinephrine is often use to treat IOH. The question regarding the mode of administration in either a bolus or continuous infusion remains unanswered. The aim of the present study was to describe and compare the effects on macrocirculation and microcirculation of a bolus and a continuous infusion of norepinephrine to treat IOH., Methods: We conducted a prospective observational study with adult patients who underwent neurosurgery. Patients with invasive arterial blood pressure and cardiac output (CO) monitoring were screened for inclusion. All patients underwent microcirculation monitoring by video-capillaroscopy, laser doppler, near-infrared spectroscopy technology, and tissular CO 2 . In case of IOH, the patient could receive either a bolus of 10 µg or a continuous infusion of 200 µg/h of norepinephrine. Time analysis for comparison between bolus and continuous infusion were at peak of MAP. The primary outcome was MFI by videocapillaroscopy., Results: Thirty-five patients were included, with 41 boluses and 33 continuous infusion. Bolus and continuous infusion induced an maximal increase in mean arterial pressure of +30[20-45] and +23[12-34] %, respectively (P=0,07). For macrocirculatory parameters, continuous infusion was associated with a smaller decrease in CO and stroke volume (p<0.05). For microcirculatory parameters, microvascular flow index (-0,1 vs. + 0,3, p=0,03), perfusion index (-12 vs. +12%, p=0,008), total vessel density (-0,2 vs. +2,3 mm2/mm2, p=0,002), showed significant opposite variations with bolus and continuous infusion, respectively., Conclusions: These results on macro and microcirculation enlighten the potential benefits of a continuous infusion of norepinephrine rather than a bolus to treat anaesthesia-induced hypotension., Trial Registration: (NOR-PHARM: 1-17-42 Clinical Trials: NCT03454204), 05/03/2018., (© 2023. The Author(s).)

Background: Preoperative abnormal cognitive status is a risk factor for postoperative complications yet remains underdiagnosed. During propofol general anesthesia, intraoperative electroencephalography (EEG) variables, such as alpha band power (α-BP), correlate with cognitive status. This relationship under sevoflurane is unclear. We investigated whether EEG biomarkers of poor cognitive status found under propofol could be extended to sevoflurane., Methods: In this monocentric prospective observational study, 106 patients with intraoperative EEG monitoring were included (propofol/sevoflurane = 55/51). We administered the Montreal Cognitive Assessment (MoCA) scale to identify abnormal cognition (low MoCA) 1 day before intervention. EEG variables included delta to beta frequency band powers. Results were adjusted to age and drug dosage. We assessed depth of anesthesia (DoA) using the spectral edge frequency (SEF 95 ) and maintained it within (8-13) Hz., Results: The difference in α-BP between low and normal MoCA patients was significantly larger among propofol patients (propofol: 4.3 ± 4.8 dB versus sevoflurane: 1.5 ± 3.4 dB, P = .022). SEF 95 and age were not statistically different between sevoflurane and propofol groups. After adjusting to age and dose, low α-BP was significantly associated with low MoCA under propofol (odds ratio [OR] [confidence interval {CI}] = 0.39 [0.16-0.94], P = .034), but not under sevoflurane, where theta-band power was significantly associated with low MoCA (OR [CI] = 0.31 [0.13-0.73], P = .007)., Conclusions: We suggest that intraoperative EEG biomarkers of abnormal cognition differ between propofol and sevoflurane under general anesthesia., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2023 International Anesthesia Research Society.)

Competing Interests: The authors have disclosed no conflicts of interest.

Background: Electroencephalography (EEG) is increasingly used for monitoring the depth of general anaesthesia, but EEG data from general anaesthesia monitoring are rarely reused for research. Here, we explored repurposing EEG monitoring from general anaesthesia for brain-age modelling using machine learning. We hypothesised that brain age estimated from EEG during general anaesthesia is associated with perioperative risk., Methods: We reanalysed four-electrode EEGs of 323 patients under stable propofol or sevoflurane anaesthesia to study four EEG signatures (95% of EEG power <8-13 Hz) for age prediction: total power, alpha-band power (8-13 Hz), power spectrum, and spatial patterns in frequency bands. We constructed age-prediction models from EEGs of a healthy reference group (ASA 1 or 2) during propofol anaesthesia. Although all signatures were informative, state-of-the-art age-prediction performance was unlocked by parsing spatial patterns across electrodes along the entire power spectrum (mean absolute error=8.2 yr; R 2 =0.65)., Results: Clinical exploration in ASA 1 or 2 patients revealed that brain age was positively correlated with intraoperative burst suppression, a risk factor for general anaesthesia complications. Surprisingly, brain age was negatively correlated with burst suppression in patients with higher ASA scores, suggesting hidden confounders. Secondary analyses revealed that age-related EEG signatures were specific to propofol anaesthesia, reflected by limited model generalisation to anaesthesia maintained with sevoflurane., Conclusions: Although EEG from general anaesthesia may enable state-of-the-art age prediction, differences between anaesthetic drugs can impact the effectiveness and validity of brain-age models. To unleash the dormant potential of EEG monitoring for clinical research, larger datasets from heterogeneous populations with precisely documented drug dosage will be essential., (© 2023 The Authors.)

Generation of ultra high frequency acoustic waves in water is key to nano resolution sensing, acoustic imaging and theranostics. In this context water immersed carbon nanotubes (CNTs) may act as an ideal optoacoustic source, due to their nanometric radial dimensions, peculiar thermal properties and broad band optical absorption. The generation mechanism of acoustic waves in water, upon excitation of both a single-wall (SW) and a multi-wall (MW) CNT with laser pulses of temporal width ranging from 5 ns down to ps, is theoretically investigated via a multiscale approach. We show that, depending on the combination of CNT size and laser pulse duration, the CNT can act as a thermophone or a mechanophone. As a thermophone, the CNT acts as a nanoheater for the surrounding water, which, upon thermal expansion, launches the pressure wave. As a mechanophone, the CNT acts as a nanopiston, its thermal expansion directly triggering the pressure wave in water. Activation of the mechanophone effect is sought to trigger few nanometers wavelength sound waves in water, matching the CNT acoustic frequencies. This is at variance with respect to the commonly addressed case of water-immersed single metallic nano-objects excited with ns laser pulses, where only the thermophone effect significantly contributes. The present findings might be of impact in fields ranging from nanoscale non-destructive testing to water dynamics at the meso to nanoscale., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background: Cerebral autoregulation actively maintains cerebral blood flow over a range of MAPs. During general anaesthesia, this mechanism may not compensate for reductions in MAP leading to brain hypoperfusion. Cerebral autoregulation can be assessed using the mean flow index derived from Doppler measurements of average blood velocity in the middle cerebral artery, but this is impractical for routine monitoring within the operating room. Here, we investigate the possibility of using the EEG as a proxy measure for a loss of cerebral autoregulation, determined by the mean flow index., Methods: Thirty-six patients (57.5 [44.25; 66.5] yr; 38.9% women, non-emergency neuroradiology surgery) anaesthetised using propofol were prospectively studied. Continuous recordings of MAP, average blood velocity in the middle cerebral artery, EEG, and regional cerebral oxygen saturation were made. Poor cerebral autoregulation was defined as a mean flow index greater than 0.3., Results: Eighteen patients had preserved cerebral autoregulation, and 18 had altered cerebral autoregulation. The two groups had similar ages, MAPs, and average blood velocities in the middle cerebral artery. Patients with altered cerebral autoregulation exhibited a significantly slower alpha peak frequency (9.4 [9.0, 9.9] Hz vs 10.5 [10.1, 10.9] Hz, P <0.001), which persisted after adjusting for age, norepinephrine infusion rate, and ASA class (odds ratio=0.038 [confidence interval, 0.004, 0.409]; P =0.007)., Conclusion: In this pilot study, we found that loss of cerebral autoregulation was associated with a slower alpha peak frequency, independent of age. This work suggests that impaired cerebral autoregulation could be monitored in the operating room using the existing EEG setup., Clinical Trial Registration: NCT03769142., (© 2022 The Author(s).)

Immune-mediated inflammatory diseases are characterized by variability in disease presentation and severity but studying it is a challenging task. Defining the limits of a healthy immune system is therefore a prior step to capture variability in disease conditions. The goal of this study is to characterize the global immune cell composition along with their influencing factors. Blood samples were collected from 2 independent cohorts of respectively 389 (exploratory) and 208 (replication) healthy subjects. Twelve immune cells were measured in blood together with biological parameters. Three complementary clustering approaches were used to evaluate if variability related to the immune cells could be characterized as clusters or as a continuum. Large coefficients of variation confirmed the inter-individual variability of immune cells. Considering all subset variations in an overall analysis, it appeared that the immune makeup was organized as a continuum through the two cohorts. Some intrinsic and environmental factors affected the inter-individual variability of cells but without unveiling separable groups with similar features. This study provides a framework based on complementary clustering approach for analyzing inter-individual variability of immune cells. Our analyses support the absence of clusters in our two healthy cohorts. Also, our study reports some influence of age, gender, BMI, cortisol, season and CMV infection on immune variability.

Background: Although cognitive decline (CD) is associated with increased post-operative morbidity and mortality, routinely screening patients remains difficult. The main objective of this prospective study is to use the EEG response to a Propofol-based general anesthesia (GA) to reveal CD. Methods: 42 patients with collected EEG and Propofol target concentration infusion (TCI) during GA had a preoperative cognitive assessment using MoCA. We evaluated the performance of three variables to detect CD (MoCA < 25 points): age, Propofol requirement to induce unconsciousness (TCI at SEF 95 : 8-13 Hz) and the frontal alpha band power (AP at SEF 95 : 8-13 Hz). Results: The 17 patients (40%) with CD were significantly older ( p < 0.001), had lower TCI ( p < 0.001), and AP ( p < 0.001). We found using logistic models that TCI and AP were the best set of variables associated with CD (AUC: 0.89) and performed better than age ( p < 0.05). Propofol TCI had a greater impact on CD probability compared to AP, although both were complementary in detecting CD. Conclusion: TCI and AP contribute additively to reveal patient with preoperative cognitive decline. Further research on post-operative cognitive trajectory are necessary to confirm the interest of intra operative variables in addition or as a substitute to cognitive evaluation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Touchard, Cartailler, Levé, Serrano, Sabbagh, Manquat, Joachim, Mateo, Gayat, Engemann and Vallée.)

Background: Awake surgery has become a key treatment of diffuse low-grade gliomas (DLGG) and is divided in three main phases: opening, tumor resection - during which the patient needs to be fully awake - and closure. The anesthetic management of awake neurosurgery is a challenge, and there are currently no guidelines., Objective: The objective of the survey was to explore differences and commonalities regarding the anesthetic management of awake DLGG surgery within the European Low-Grade Glioma Network (ELGGN) centers., Methods: A form that contained 14 questions about the anesthetic management was sent to 28 centers in May 2015., Results: Twenty centers responded. During the opening and closing non-awake periods, 56% of teams chose general anesthesia with mechanical ventilation for at least one period (asleep-awake-asleep, SAS protocol), and 44% monitored anesthesia care including sedation without mechanical ventilation (MAC protocol). In case of SAS, all the teams chose intravenous anesthesia, 82% used laryngeal mask instead of endotracheal intubation during the opening sequence, and 71% during closure. Local and regional anesthesia was practiced by all the teams. The most frequently reported cause of pain was dural and cerebral vessels manipulation (77%). Pain management was mostly based on paracetamol (70%) and remifentanil (55%)., Conclusion: Our survey showed that there was an equivalent proportion of centers using SAS or MAC protocols in the anesthetic management of awake surgery in ELGGN centers. The advantages and disadvantages of each anesthesia protocol were reviewed.

During general anesthesia (GA), direct analysis of arterial pressure or aortic flow waveforms may be inconclusive in complex situations. Patient-specific biomechanical models, based on data obtained during GA and capable to perform fast simulations of cardiac cycles, have the potential to augment hemodynamic monitoring. Such models allow to simulate Pressure-Volume (PV) loops and estimate functional indicators of cardiovascular (CV) system, e.g. ventricular-arterial coupling (Vva), cardiac efficiency (CE) or myocardial contractility, evolving throughout GA. In this prospective observational study, we created patient-specific biomechanical models of heart and vasculature of a reduced geometric complexity for n = 45 patients undergoing GA, while using transthoracic echocardiography and aortic pressure and flow signals acquired in the beginning of GA (baseline condition). If intraoperative hypotension (IOH) appeared, diluted norepinephrine (NOR) was administered and the model readjusted according to the measured aortic pressure and flow signals. Such patients were a posteriori assigned into a so-called hypotensive group. The accuracy of simulated mean aortic pressure (MAP) and stroke volume (SV) at baseline were in accordance with the guidelines for the validation of new devices or reference measurement methods in all patients. After NOR administration in the hypotensive group, the percentage of concordance with 10% exclusion zone between measurement and simulation was >95% for both MAP and SV. The modeling results showed a decreased Vva (0.64±0.37 vs 0.88±0.43; p = 0.039) and an increased CE (0.8±0.1 vs 0.73±0.11; p = 0.042) in hypotensive vs normotensive patients. Furthermore, Vva increased by 92±101%, CE decreased by 13±11% (p < 0.001 for both) and contractility increased by 14±11% (p = 0.002) in the hypotensive group post-NOR administration. In this work we demonstrated the application of fast-running patient-specific biophysical models to estimate PV loops and functional indicators of CV system using clinical data available during GA. The work paves the way for model-augmented hemodynamic monitoring at operating theatres or intensive care units to enhance the information on patient-specific physiology., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: A.L.G., F.V., D.C. and R.C. are co-owners of the patent entitled "Dispositif cardiaque" (number 1758006, 2017). A research license agreement is currently ongoing between the Anesthesiology and intensive care department of Lariboisière hospital, Paris, France and Deltex Medical, Chichester, UK. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Cardiac afterload is usually assessed in the ascending aorta and can be defined by the association of peripheral vascular resistance (PVR), total arterial compliance (Ctot), and aortic wave reflection (WR). We recently proposed the global afterload angle (GALA) and β-angle derived from the aortic velocity-pressure (VP) loop as continuous cardiac afterload monitoring in the descending thoracic aorta. The aim of this study was to 1 ) describe the arterial mechanic properties by studying the velocity-pressure relations according to cardiovascular risk (low-risk and high-risk patients) in the ascending and descending thoracic aorta and 2 ) analyze the association between the VP loop (GALA and β-angle) and cardiac afterload parameters (PVR, Ctot, and WR). PVR, Ctot, WR, and VP loop parameters were measured in the ascending and descending thoracic aorta in 50 anesthetized patients. At each aortic level, the mean arterial pressure (MAP), cardiac output (CO), and PVR were similar between low-risk and high-risk patients. In contrast, Ctot, WR, GALA, and β-angle were strongly influenced by cardiovascular risk factors regardless of the site of measurement along the aorta. The GALA angle was inversely related to aortic compliance, and the β-angle reflected the magnitude of wave reflection in both the ascending and descending aortas ( P < 0.001). Under general anesthesia, the VP loop can provide new visual insights into arterial mechanical properties compared with the traditional MAP and CO for the assessment of cardiac afterload. Further studies are necessary to demonstrate the clinical utility of the VP loop in the operating room. NEW & NOTEWORTHY Our team recently proposed the global afterload angle (GALA) and β-angle derived from the aortic velocity-pressure (VP) loop as continuous cardiac afterload monitoring in the descending thoracic aorta under general anesthesia. However, the evaluation of cardiac afterload at this location is unusual. The present study shows that VP loop parameters can describe the components of cardiac afterload both in the ascending and descending thoracic aorta in the operating room. Aging and cardiovascular risk factors strongly influence VP loop parameters. The VP loop could provide continuous visual additional information on the arterial system than the traditional mean arterial pressure and cardiac output during the general anesthesia.

Could an overly deep sedation be anticipated from ElectroEncephaloGram (EEG) patterns? We report here motifs hidden in the EEG signal that predict the appearance of Iso-Electric Suppressions (IES), observed during epileptic encephalopathies, drug intoxications, comatose, brain death or during anesthetic over-dosage that are considered to be detrimental. To show that IES occurrences can be predicted from EEG traces dynamics, we focus on transient suppression of the alpha rhythm (8-14 Hz) recorded for 80 patients, that had a Propofol target controlled infusion of 5 μg/ml during a general anesthesia. We found that the first time of appearance as well as changes in duration of these Alpha-Suppressions ( α S) are two parameters that anticipate the appearance of IES. Using machine learning, we predicted IES appearance from the first 10 min of EEG (AUC of 0.93). To conclude, transient motifs in the alpha rhythm predict IES during anesthesia and can be used to identify patients, with higher risks of post-operative complications., Competing Interests: Competing interestsThe authors declare no competing financial interests but the competing non-financial interests: J.C., P.P., C.T., F.V. and D.H. have filled a patent for the prediction of anesthesia (French declaration d’invention 62/55/134, titled “Outil predictif pour l’apparition de suppression isoelectrique pendant l’anesthesie générale”).

The physiology of venous and tissue CO 2 monitoring has a long and well-established physiological background, leading to the technological development of different tissue capnometric devices, such as transcutaneous capnometry monitoring (TCM). To outline briefly, measuring transcutaneous PCO 2 (tcPCO 2 ) depends on at least three main phenomena: (I) the production of CO 2 by tissues (VCO 2 ), (II) the removal of CO 2 from the tissues by perfusion (wash-out phenomenon), and (III) the reference value of CO 2 at tissue inlet represented by arterial CO 2 content (approximated by arterial PCO 2 , or artPCO 2 ). For this reason, there are, at present, roughly two clinical uses for tcPCO 2 measurement: a respiratory approach where tcPCO 2 is likely to estimate and non-invasively track artPCO 2 ; and a hemodynamic under-estimate use where tcPCO 2 can reflect tissue perfusion, summarized by a so-called "tc-art PCO 2 gap". Recent research shows that these two uses are not incompatible and could be combined. The spectrum of indications and validation studies in ICUs is summarized in this review to give a survey of the potential applications of TCM in critically ill patients, focusing mainly on its potential (micro)circulatory monitoring contribution. We strongly believe that the greatest benefit of measuring tcPCO 2 is not to only to estimate artPCO 2 , but also to quantify the gap between these two values, which can then help clinicians continuously and noninvasively assess both respiratory and hemodynamic failures in critically ill patients., Competing Interests: Conflicts of Interest: A patent application (n° PCT IB2009/006903) is pending on variations of PcCO2 and PI during Heating Challenge. The patent belongs to the Assistance Publique-Hôpitaux de Paris (France). F Vallée and H Nougue received consultant fees from Radiometer. The other authors have no conflicts of interest to declare.

Introduction: In shock, the increase in cutaneous-to-arterial carbon dioxide partial pressure (Pc-aCO2) and the decrease in the perfusion index (PI) are related to macrovascular or microvascular alterations. We hypothesized that inducing cutaneous vasodilation and local perfusion with heat could provide a noninvasive tool to monitor microvascular reactivity., Objectives: This study aimed to develop a noninvasive approach, the heating challenge (HC), to monitor the microvascular reactivity of patients with shock and to evaluate the potential relationship with outcome., Methods: After ethics committee agreement was obtained, 59 shock patients, including 37 septic shock, 22 non-septic shock (14 cardiogenic and eight hemorrhagic), 10 intensive care unit (ICU)-controls and 12 healthy volunteers, were included in this study. The HC consisted of heating the ear lobe PcCO2 sensor from 37° to 45° over 5 min and recording PcCO2 and PI variations (ΔPcCO2 and PImax/min). HC was performed on admission and during the first 48 h of hospitalization., Results: Pc-aCO2 was significantly higher in shock patients than ICU-controls at baseline (P < 0.05). HC led to a decrease in PcCO2 and an increase in PI in the healthy volunteers (ΔPcCO2 = -9.0 ± 4.6% and PImax/min = 5.5 ± 1.9). On admission, non-septic shock patients (cardiogenic and hemorrhagic shocks) had an HC response profile identical to that of healthy volunteers and ICU-controls. In contrast, septic shock patients had a lower ΔPcCO 2 and PImax/min compared to healthy volunteers and all other groups (P < 0.05). After the first day, the combination of a Pc-aCO2 >17 mm Hg with a positive ΔPcCO2 could predict mortality with a specificity of 82% and a sensitivity of 93%., Conclusions: HC appears to be a dynamic test to classify vascular reactivity alterations in shock. At baseline, HC results were impaired in septic patients and conserved in non-septic patients. After the first day, the association between Pc-aCO2 and ΔPcCO2 was strongly related to prognosis in shock patients.

Background: During general anaesthesia, intraoperative hypotension (IOH), defined as a mean arterial pressure (MAP) reduction of > 20%, is frequent and may lead to complications. Pulse oximetry is mandatory in the operating room, making the photoplethysmographic signal and parameters, such as relative dicrotic notch height (Dic pleth ) or perfusion index (PI), readily available. The purpose of this study was to investigate whether relative variations of Dic pleth and PI could detect IOH during anaesthesia induction, and to follow their variations during vasopressor boluses., Methods: MAP, Dic pleth , and PI were monitored at 1-min intervals during target control induction of anaesthesia with propofol and remifentanil in 61 subjects. Vasopressor infusion (norepinephrine or phenylephrine) was performed when hypotension occurred according to the decision of the physician., Results: The delta in Dic pleth and PI accurately detected IOH, with areas under the receiver operating characteristic curves (AUC) of 0.86 and 0.83, respectively. The optimal thresholds were -19% (sensitivity 79%; specificity 84%) and 51% (sensitivity 82%; specificity 74%) for ΔDic pleth and ΔPI, respectively. There was no difference between the ROC of ΔDic pleth and ΔPI (P=0.22). Combining both ΔDic pleth and ΔPI further improved the hypotension detection power (AUC=0.91) with a sensitivity and specificity of 84%. MAP variations were correlated with ΔDic pleth and ΔPI during vasopressor infusion (r=0.73 and -0.62, respectively; P<0.001)., Conclusions: The relative variation in Dic pleth and PI derived from the photoplethysmographic signal can be used as a non invasive, continuous, and simple tool to detect intraoperative hypotension, and to track the vascular response to vasoconstrictor drugs during induction of general anaesthesia., Clinical Trial Registration: NCT03756935., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

We report the use of XtalFluor-E ([Et 2 NSF 2 ]BF 4 ) as an alternative to POCl 3 in the Vilsmeier-Haack formylation reaction of C-2-glycals. Employing a XtalFluor-E/DMF combination allowed the desired C-2-formyl glycals to be isolated in 11-90% yield. This method was extended to the synthesis of a C-2 -formylated disaccharide glycal.

Objectives: To evaluate the interchangeability of oxygen consumption variations measured with the Fick equation (ΔVO2Fick) and indirect calorimetry (ΔVO2Haldane) in critically ill burns patients., Methods: Prospective observational single-center study conducted in a university hospital. Twenty-two consecutive burns patients with circulatory insufficiency and hyperlactatemia (>2 mmol/L) who required a fluid challenge (FC) were included. All patients had cardiac output monitoring (transpulmonary thermodilution technique) and were ventilated and sedated. Simultaneous measurements of VO2Fick and VO2Haldane were performed before and immediately after the FC, at rest, and in hemodynamic conditions stabilized for at least 1 h. VO2Fick and VO2Haldane were measured, respectively, with the standard formulae (using arterial and central venous saturation measured with a blood gas analyzer) and with a metabolic monitor., Results: Forty-four paired measurements of VO2 were obtained. At each timepoint, the median (interquartile range, 25-75) VO2Haldane values were significantly higher than the median VO2Fick values (126 (103-192) vs. 90 (66-149) mL O2/min/m (P = 0.004) before FC and 129 (105-189) vs. 80 (54-119) mL O2/min/m (P = 0.001) after FC). Correlation between the ΔVO2Fick and the ΔVO2Haldane (%) measurements was poor, with an r = 0.06, (P = 0.77). The mean bias was 8.6% [limits of agreement (LOA): -75.7%, 92.9%]., Conclusions: Analysis of agreement showed poor concordance for the ΔVO2Haldane and the ΔVO2Fick (%) with a low mean bias but large and clinically unacceptable LOA. ΔVO2Haldane and ΔVO2Fick (%) are not interchangeable in these conditions.

Archaeology, linguistics, and increasingly genetics are clarifying how populations moved from mainland Asia, through Island Southeast Asia, and out into the Pacific during the farming revolution. Yet key features of this process remain poorly understood, particularly how social behaviors intersected with demographic drivers to create the patterns of genomic diversity observed across Island Southeast Asia today. Such questions are ripe for computer modeling. Here, we construct an agent-based model to simulate human mobility across Island Southeast Asia from the Neolithic period to the present, with a special focus on interactions between individuals with Asian, Papuan, and mixed Asian-Papuan ancestry. Incorporating key features of the region, including its complex geography (islands and sea), demographic drivers (fecundity and migration), and social behaviors (marriage preferences), the model simultaneously tracks a full suite of genomic markers (autosomes, X chromosome, mitochondrial DNA, and Y chromosome). Using Bayesian inference, model parameters were determined that produce simulations that closely resemble the admixture profiles of 2299 individuals from 84 populations across Island Southeast Asia. The results highlight that greater propensity to migrate and elevated birth rates are related drivers behind the expansion of individuals with Asian ancestry relative to individuals with Papuan ancestry, that offspring preferentially resulted from marriages between Asian women and Papuan men, and that in contrast to current thinking, individuals with Asian ancestry were likely distributed across large parts of western Island Southeast Asia before the Neolithic expansion., (Copyright © 2016 Vallée et al.)

Bispecific immunoglobulins (Igs) typically contain at least two distinct variable domains (Fv) that bind to two different target proteins. They are conceived to facilitate clinical development of biotherapeutic agents for diseases where improved clinical outcome is obtained or expected by combination therapy compared to treatment by single agents. Almost all existing formats are linear in their concept and differ widely in drug-like and manufacture-related properties. To overcome their major limitations, we designed cross-over dual variable Ig-like proteins (CODV-Ig). Their design is akin to the design of circularly closed repeat architectures. Indeed, initial results showed that the traditional approach of utilizing (G4S)x linkers for biotherapeutics design does not identify functional CODV-Igs. Therefore, we applied an unprecedented molecular modeling strategy for linker design that consistently results in CODV-Igs with excellent biochemical and biophysical properties. CODV architecture results in a circular self-contained structure functioning as a self-supporting truss that maintains the parental antibody affinities for both antigens without positional effects. The format is universally suitable for therapeutic applications targeting both circulating and membrane-localized proteins. Due to the full functionality of the Fc domains, serum half-life extension as well as antibody- or complement-dependent cytotoxicity may support biological efficiency of CODV-Igs. We show that judicious choice in combination of epitopes and paratope orientations of bispecific biotherapeutics is anticipated to be critical for clinical outcome. Uniting the major advantages of alternative bispecific biotherapeutics, CODV-Igs are applicable in a wide range of disease areas for fast-track multi-parametric drug optimization.

Doing long sums in the absence of complementary actions or artefacts is a multistep procedure that quickly taxes working memory; congesting the phonological loop further handicaps performance. In the experiment reported here, participants completed long sums either with hands down - the low interactivity condition - or by moving numbered tokens - the high interactivity condition - while they repeated "the" continuously, loading the phonological loop, or not. As expected, interactivity and articulatory suppression substantially affected performance; critically, the effect of articulatory suppression was stronger in the low than in the high interactivity condition. In addition, an independent measure of mathematics anxiety predicted the impact of articulatory suppression on performance only in the low (not high) interactivity condition. These findings suggest that interactivity augmented overall or systemic working memory resources and diminished the effect of mathematics anxiety, underscoring the importance of characterizing the properties of the system as it is configured by the dynamic agent-environment coupling.

Background: Maintaining adequate organ perfusion during high-risk surgery requires continuous monitoring of cardiac output to optimise haemodynamics. Oesophageal Doppler Cardiac Output monitoring (DCO) is commonly used in this context, but has some limitations. Recently, the cardiac output estimated by pulse pressure analysis- (PPCO) was developed. This study evaluated the agreement of cardiac output variations estimated with 9 non-commercial algorithms of PPCO compared with those obtained with DCO., Methods: High-risk patients undergoing neurosurgery were monitored with invasive blood pressure and DCO. For each patient, 9 PPCO algorithms and DCO were recorded before and at the peak effect for every haemodynamic challenge., Results: Sixty-two subjects were enrolled; 284 events were recorded, including 134 volume expansions and 150 vasopressor boluses. Among the 9 algorithms tested, the Liljestrand-Zander model led to the smallest bias (0.03 litre min(-1) [-1.31, +1.38] (0.21 litre min(-1) [-1.13; 1.54] after volume expansion and -0.13 litre min(-1) [-1.41, 1.15] after vasopressor use). The corresponding percentage of the concordance was 91% (86% after volume expansion and 94% after vasopressor use). The other algorithms, especially those using the Winkessel concept and the area under the pressure wave, were profoundly affected by the vasopressor., Conclusions: Among the 9 PPCO algorithms examined, the Liljestrand-Zander model demonstrated the least bias and best limits of agreement, especially after vasopressor use. Using this particular algorithm in association with DCO calibration could represent a valuable option for continuous cardiac output monitoring of high risk patients., Clinical Trial Registration: Comité d'éthique de la Société de Réanimation de Langue Française No. 11-356., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents.

Introduction: The occurrence of cardiac dysfunction is common after subarachnoid hemorrhage (SAH) and was hypothesized to be related to the release of endogenous catecholamines. The aim of this prospective study was to evaluate the relationship between endogenous catecholamine and cardiac dysfunction at the onset and during the first week after SAH., Methods: Forty consecutive patients admitted for acute SAH without known heart disease were included. Catecholamine plasma concentrations and transthoracic echocardiography (TTE) were documented on admission, on day 1 (D1), and day 7 (D7)., Results: At baseline, 24 patients had a World Federation of Neurosurgical Societies score (WFNS) of one or two; the remaining 16 had a WFNS between three and five. Twenty patients showed signs of cardiac dysfunction on admission, including six with left ventricle (LV) systolodiastolic dysfunction and 14 with pure LV diastolic dysfunction. On admission, norepinephrine, epinephrine, dopamine, B-type Natriuretic Peptide (BNP) and Troponin Ic (cTnI) plasmatic levels were higher in patients with the higher WFNS score and in patients with altered cardiac function (all P <0.05). Among patients with cardiac injury, heart function was restored within one week in 13 patients, while seven showed persistent LV diastolic dysfunction (P = 0.002). Plasma BNP, cTnI, and catecholamine levels exerted a decrease towards normal values between D1 and D7., Conclusion: Our findings show that cardiac dysfunction seen early after SAH was associated with both a rapid and sustained endogenous catecholamine release and WFNS score. SAH-induced cardiac dysfunction was regressive over the first week and paralleled the normalization of catecholamine concentration.

Purpose: The CD38 cell surface antigen is expressed in diverse hematologic malignancies including multiple myeloma, B-cell non-Hodgkin lymphoma (NHL), B-cell chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), and T-cell ALL. Here, we assessed the antitumor activity of the anti-CD38 antibody SAR650984., Experimental Design: Activity of SAR650984 was examined on lymphoma, leukemia and multiple myeloma cell lines, primary multiple myeloma samples, and multiple myeloma xenograft models in immunodeficient mice., Results: We identified a humanized anti-CD38 antibody with strong proapoptotic activity independent of cross-linking agents, and potent effector functions including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis (ADCP), equivalent in vitro to rituximab in CD20+ and CD38+ models. This unique antibody, termed SAR650984, inhibited the ADP-ribosyl cyclase activity of CD38, likely through an allosteric antagonism as suggested by 3D structure analysis of the complex. In vivo, SAR650984 was active in diverse NHL, ALL, and multiple myeloma CD38+ tumor xenograft models. SAR650984 demonstrated single-agent activity comparable with rituximab or cyclophosphamide in Daudi or SU-DHL-8 lymphoma xenograft models with induction of the proapoptotic marker cleaved capase-7. In addition, SAR650984 had more potent antitumor activity than bortezomib in NCI-H929 and Molp-8 multiple myeloma xenograft studies. Consistent with its mode of action, SAR650984 demonstrated potent proapoptotic activity against CD38+ human primary multiple myeloma cells., Conclusion: These results validate CD38 as a therapeutic target and support the current evaluation of this unique CD38-targeting functional antibody in phase I clinical trials in patients with CD38+ B-cell malignancies., (©2014 American Association for Cancer Research.)

Dissolved oxygen (i.e., unbound to hemoglobin) is often neglected as a determinant of central venous oxygen saturation (ScvO2) in review articles and textbooks. These statements may lead to potential misinterpretation of SCvO2 value across FiO2 changes. In this study, we aimed to explore the influence of PaO2 and FiO2 on ScvO2 in ventilated critically ill patients. This was a prospective observational study in two surgical intensive care units. Mechanically ventilated and sedated patients with cardiac output and ScvO2 monitoring and PaO2/FiO2 > 200 with inspiratory oxygen (FiO2) ≤ 0.5 were enrolled (cohort [ScvO2]). A second cohort of brain-injured patients with jugular venous oxygen saturation monitoring was studied to assess the application of the results to regional circulation (cohort [SjvO2]). Central venous oxygen saturation was measured at baseline FiO2 and at FiO2 = 1. We finally estimated the participation of the dissolved oxygen (PadissolvO2) to the ScvO2 variations. Twenty patients formed the cohort ScvO2 and eight formed the cohort SjvO2. Central venous oxygen saturation rose from 71% (69%-76%) to 84% (78%-88%) after increasing FiO2, whereas PaO2 rose from 100 (85-124) mmHg to 387 (360-449) mmHg. The rise of ScvO2 was mostly ascribable to the dissolved oxygen. The increase of ScvO2 was not explained by changes in cardiac output or hemoglobin levels. Jugular venous oxygen saturation rose from 71% (58%-78%) to 83% (78%-89%) after increasing FiO2. Arterial dissolved oxygen level can significantly influence the ScvO2 value. Therefore, PaO2 should not be overlooked while considering the ScvO2 value as a therapeutic goal. Interpretation of ScvO2 variations in response to a therapeutic challenge (i.e., fluid challenge, inotropic drug initiation) should be performed at constant FiO2.

Transcutaneous oxygen pressure (PtcO2) value in response to an increase of FiO2 or oxygen challenge test (OCT) in ventilated patients has been reported to be related to peripheral perfusion and outcome during septic shock. However, patients with sepsis-related acute respiratory distress syndrome could demonstrate compromised arterial oxygenation with OCT impairment decoupled to circulatory failure. The aims of this study were to confirm the prognostic value of OCT and to explore the influence of respiratory status on OCT results. This was a prospective study set in an intensive care unit of a tertiary teaching hospital. Fifty-six mechanically ventilated patients with septic shock criteria were studied. Transcutaneous oxygen pressure was measured at baseline and after OCT, at intensive care unit admittance (T0), and 24 h later (T24). Survival at day 28 and hemodynamic and respiratory parameters were analyzed and compared according to outcome and respiratory status. Central hemodynamic parameters or static transcutaneous data did not differ between survivors and nonsurvivors at enrollment. The OCT was statistically different at T24 according to outcome (P < 0.001), but sensitivity was low (53%). Moreover, patients with low OCT results at T24 exhibited more severe respiratory failure (P < 0.01). The OCT at T24 is related to outcome but is influenced by the severity of respiratory failure. Our results suggest considering with caution hemodynamic management based on OCT in septic shock patients with altered pulmonary function.

Background: This study was design to investigate the prognostic value for death at day-28 of lactate course and lactate clearance during the first 24 hours in Intensive Care Unit (ICU), after initial resuscitation., Methods: Prospective, observational study in one surgical ICU in a university hospital. Ninety-four patients hospitalized in the ICU for severe sepsis or septic shock were included. In this septic cohort, we measured blood lactate concentration at ICU admission (H0) and at H6, H12, and H24. Lactate clearance was calculated as followed: [(lactateinitial - lactatedelayed)/ lactateinitial] x 100%]., Results: The mean time between severe sepsis diagnosis and H0 (ICU admission) was 8.0 ± 4.5 hours. Forty-two (45%) patients died at day 28. Lactate clearance was higher in survivors than in nonsurvivors patients for H0-H6 period (13 ± 38% and -13 ± 7% respectively, p = 0.021) and for the H0-H24 period (42 ± 33% and -17 ± 76% respectively, p < 0.001). The best predictor of death at day 28 was lactate clearance for the H0-H24 period (AUC = 0.791; 95% CI 0.6-0.85). Logistic regression found that H0-H24 lactate clearance was independently correlated to a survival status with a p = 0.047 [odds ratio = 0.35 (95% CI 0.01-0.76)]., Conclusions: During the first 24 hr in the ICU, lactate clearance was the best parameter associated with 28-day mortality rate in septic patients. Protocol of lactate clearance-directed therapy should be considered in septic patients, even after the golden hours.