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Background: Long-term outcomes of patients with severe stroke remain poorly documented. We aimed to characterize one-year outcomes of patients with stroke requiring mechanical ventilation in the intensive care unit (ICU)., Methods: We conducted a prospective multicenter cohort study in 33 ICUs in France (2017-2019) on patients with consecutive strokes requiring mechanical ventilation for at least 24 hours. Outcomes were collected via telephone interviews by an independent research assistant. The primary end point was poor functional outcome, defined by a modified Rankin Scale score of 4 to 6 at 1 year. Multivariable mixed models investigated variables associated with the primary end point. Secondary end points included quality of life, activities of daily living, and anxiety and depression in 1-year survivors., Results: Among the 364 patients included, 244 patients (66.5% [95% CI, 61.7%-71.3%]) had a poor functional outcome, including 190 deaths (52.2%). After adjustment for non-neurological organ failure, age ≥70 years (odds ratio [OR], 2.38 [95% CI, 1.26-4.49]), Charlson comorbidity index ≥2 (OR, 2.01 [95% CI, 1.16-3.49]), a score on the Glasgow Coma Scale <8 at ICU admission (OR, 3.43 [95% CI, 1.98-5.96]), stroke subtype (intracerebral hemorrhage: OR, 2.44 [95% CI, 1.29-4.63] versus ischemic stroke: OR, 2.06 [95% CI, 1.06-4.00] versus subarachnoid hemorrhage: reference) remained independently associated with poor functional outcome. In contrast, a time between stroke diagnosis and initiation of mechanical ventilation >1 day was protective (OR, 0.56 [95% CI, 0.33-0.94]). A sensitivity analysis conducted after exclusion of patients with early decisions of withholding/withdrawal of care yielded similar results. We observed persistent physical and psychological problems at 1 year in >50% of survivors., Conclusions: In patients with severe stroke requiring mechanical ventilation, several ICU admission variables may inform caregivers, patients, and their families on post-ICU trajectories and functional outcomes. The burden of persistent sequelae at 1 year reinforces the need for a personalized, multi-disciplinary, prolonged follow-up of these patients after ICU discharge., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03335995., Competing Interests: Disclosures Dr Sonneville reports grants from the French Ministry of Health, outside the submitted work. Dr Mazighi reports compensation from Novo Nordisk for consultant services; compensation from Boerhinger-Ingelheim for consultant services; and compensation from Acticor Biotech for consultant services. Dr Cortier reports employment by Foch. Dr Geri reports compensation from BARD for consultant services. Dr Demoule reports compensation from Agence Européenne Informatique for other services; compensation from Fisher and Paykel Healthcare Limited for other services; compensation from Baxter Healthcare for other services; compensation from Lowenstein for other services; compensation from Getinge for other services; travel support from Lowenstein; compensation from AstraZeneca for other services; compensation from Lungpacer for other services; compensation from Liberate Medical for other services; compensation from Respinor for other services; and compensation from Mindray DS USA Inc. for other services. Dr Timsit reports grants from Merck; compensation from BD Biosciences for consultant services; and grants from Pfizer. The other authors report no conflicts.

Interlayer excitons (ILXs) - electron-hole pairs bound across two atomically thin layered semiconductors - have emerged as attractive platforms to study exciton condensation 1-4 , single-photon emission and other quantum information applications 5-7 . Yet, despite extensive optical spectroscopic investigations 8-12 , critical information about their size, valley configuration and the influence of the moiré potential remains unknown. Here, in a WSe 2 /MoS 2 heterostructure, we captured images of the time-resolved and momentum-resolved distribution of both of the particles that bind to form the ILX: the electron and the hole. We thereby obtain a direct measurement of both the ILX diameter of around 5.2 nm, comparable with the moiré-unit-cell length of 6.1 nm, and the localization of its centre of mass. Surprisingly, this large ILX is found pinned to a region of only 1.8 nm diameter within the moiré cell, smaller than the size of the exciton itself. This high degree of localization of the ILX is backed by Bethe-Salpeter equation calculations and demonstrates that the ILX can be localized within small moiré unit cells. Unlike large moiré cells, these are uniform over large regions, allowing the formation of extended arrays of localized excitations for quantum technology., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Moiré superlattices formed by van der Waals materials can support a wide range of electronic phases, including Mott insulators 1-4 , superconductors 5-10 and generalized Wigner crystals 2 . When excitons are confined by a moiré superlattice, a new class of exciton emerges, which holds promise for realizing artificial excitonic crystals and quantum optical effects 11-16 . When such moiré excitons are coupled to charge carriers, correlated states may arise. However, no experimental evidence exists for charge-coupled moiré exciton states, nor have their properties been predicted by theory. Here we report the optical signatures of trions coupled to the moiré potential in tungsten diselenide/molybdenum diselenide heterobilayers. The moiré trions show multiple sharp emission lines with a complex charge-density dependence, in stark contrast to the behaviour of conventional trions. We infer distinct contributions to the trion emission from radiative decay in which the remaining carrier resides in different moiré minibands. Variation of the trion features is observed in different devices and sample areas, indicating high sensitivity to sample inhomogeneity and variability. The observation of these trion features motivates further theoretical and experimental studies of higher-order electron correlation effects in moiré superlattices.

Naturally occurring benzoxanthenones, which belong to the vast family of lignans, are promising biologically relevant targets. They are biosynthetically produced by the oxidative dimerization of 2-propenyl phenols. In this manuscript, we disclose a powerful automated flow-based strategy for identifying and optimizing a cobalt-catalyzed oxidizing system for the bioinspired dimerization of 2-propenyl phenols. We designed a reconfigurable flow reactor associating online monitoring and process control instrumentation. Our machine was first configured as an automated screening platform to evaluate a matrix of 4 catalysts (plus the blank) and 5 oxidants (plus the blank) at two different temperatures, resulting in an array of 50 reactions. The automated screening was conducted on micromole scale at a rate of one fully characterized reaction every 26 min. After having identified the most promising cobalt-catalyzed oxidizing system, the automated screening platform was straightforwardly reconfigured to an autonomous self-optimizing flow reactor by implementation of an optimization algorithm in the closed-loop system. The optimization campaign allowed the determination of very effective experimental conditions in a limited number of experiments, which allowed us to prepare the natural products carpanone and polemannone B as well as synthetic analogues.

A modular autonomous flow reactor combining monitoring technologies with a feedback algorithm is presented for the synthesis of the natural product carpanone. The autonomous self-optimizing system, controlled via MATLAB, was designed as a flexible platform enabling an adaptation of the experimental setup to the specificity of the chemical transformation to be optimized. The reaction monitoring uses either online high pressure liquid chromatography (HPLC) or in-line benchtop nuclear magnetic resonance (NMR) spectroscopy. The custom-made optimization algorithm derived from the Nelder-Mead and golden section search methods performs constrained optimizations of black-box functions in a multidimensional search domain, thereby assuming no a priori knowledge of the chemical reactions. This autonomous self-optimizing system allowed fast and efficient optimizations of the chemical steps leading to carpanone. This contribution is the first example of a multistep synthesis where all discrete steps were optimized with an autonomous flow reactor.

An emerging noninvasive approach to assess tissue proliferation uses the PET tracer 3'-deoxy-3'- 18 F-fluorothymidine ( 18 F-FLT). To evaluate the diagnostic value of this technique in myelofibrosis, 18 F-FLT PET imaging results were compared with bone marrow histology and bone marrow scintigraphy (BMS), the gold standard techniques in this clinical situation. Methods: Fifteen patients with histology-proven myelofibrosis were included consecutively in the study. Tracers' distributions were assessed using a visual grading assessment score of the uptake in the axial skeleton, proximal and distal limbs, liver, and spleen. This visual score was used to define patterns of tracer distribution and to compare the information provided either by PET or by BMS. A semiquantitative analysis with determination of SUV max in the same localizations was performed for 18 F-FLT PET. Results: The histology grade of fibrosis correlated with the SUV max in the axial skeleton (spine and iliac crests) and proximal limbs. 18 F-FLT uptake in these areas was much lower in patients with grade 3 fibrosis than in patients with grade 1 or 2 fibrosis. 18 F-FLT PET showed the same distribution of uptake as BMS in 13 of 14 patients (1 patient did not undergo BMS). In 1 patient, 18 F-FLT PET clearly showed an intense abnormal splenic uptake, whereas spleen uptake was inconclusive with BMS. Conclusion: 18 F-FLT PET appears to be a reliable and convenient technique to assess hematopoietic activity in bone marrow. It yields results close to those observed with BMS. In our study population, 18 F-FLT uptake in the axial skeleton and proximal limbs assessed by SUV max correlated with the grade of fibrosis. Thus, 18 F-FLT PET may be a useful tool to measure the severity of myelofibrosis, and to monitor noninvasively the patients' status during follow-up. Finally, 18 F-FLT PET may be foreseen as an alternative to BMS., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Objectives: To assess the safety and efficacy of intravenous (IV) abatacept plus methotrexate (MTX) over 7 years, the longest observational period to date, in patients with established rheumatoid arthritis (RA) and an inadequate response to MTX., Methods: Patients randomised to IV abatacept (10 or 2 mg/kg) or placebo, plus MTX, during the 1-year double-blind (DB) period of a Phase 2b study could enter the long-term extension (LTE) and receive IV abatacept 10 mg/kg monthly. Safety was assessed in patients who received ≥1 dose of abatacept; efficacy was assessed in patients originally randomised to 10 mg/kg abatacept (as-observed data)., Results: A total of 219 patients entered the LTE; 114 (52.1%) completed 7 years of treatment with abatacept plus MTX. Cumulative (DB + LTE) incidence rates of serious adverse events, serious infections, malignancies, and autoimmune events were 17.6, 3.2, 1.8, and 1.2/100 patient-years, respectively. Safety was consistent between the DB (n=220) and cumulative (n=287) periods. Improvements in American College of Rheumatology responses, disease activity, and normalisation of physical function and health-related quality of life were maintained over time. Approximately 80% of patients who achieved low disease activity or normalised modified Health Assessment Questionnaire scores at Year 1, and who remained in the study, sustained these responses in each subsequent year., Conclusions: IV abatacept in combination with MTX demonstrated consistent safety and sustained efficacy over 7 years in MTX inadequate responders with established RA. Furthermore, some patients demonstrated a normalisation of physical function and health-related quality of life that was sustained over time.

Trichomonads closely related to the bovid parasite Tritrichomonas foetus were identified in the bronchoalveolar lavage sample from a patient with AIDS in association with Pneumocystis pneumonia. This human case of T. foetus-like infection emphasizes the zoonotic potential of trichomonads, although the existence of a human-host-adapted T. foetus strain cannot be excluded.

Allosteric potentiation of acetylcholine nicotinic receptors is considered to be one of the most promising approaches for the treatment of Alzheimer's disease. However, the exact localization of the allosteric binding site and the potentiation mechanism at the molecular level are presently unknown. We have performed the "blind docking" of three known allosteric modulators (galanthamine, codeine and eserine) with the Acetylcholine Binding Protein and models of human alpha7, alpha3beta4 and alpha4beta2 nicotinic receptors, created by homology modeling. Three putative binding sites were identified in the channel pore, each one showing different affinities for the ligands. One of these sites is localized opposite to the agonist binding site and is probably implicated in the potentiation process. On the basis of these results, a possible mechanism for nicotinic acetylcholine receptor (nAChRs) activation is proposed. The present findings may represent an important advance for understanding the allosteric modulation mechanism of nAChRs. [Figure: see text].

The goal of this randomized study of high-risk surgical patients was to determine whether intraoperative thoracic epidural anesthesia in combination with light general anesthesia alters postoperative morbidity when compared to a standard technique of "balanced" general anesthesia. A total of 173 patients scheduled for abdominal aortic reconstruction were admitted to the study; 86 were to receive "balanced" general anesthesia (group 1) and 87 thoracic epidural anesthesia in combination with light general anesthesia (group 2). Preoperative evaluation included standard clinical tools, dipyridamole thallium gammatomography, and radionuclide angiography. In these patients, all of whom had peripheral artery disease, there were no significant differences in associated coronary artery disease, hypertension, and cardiovascular treatment. The distribution of left ventricular ejection fraction and the number of patients with thallium redistribution were not statistically different between the two groups. During the postoperative period, group 1 received analgesia of subcutaneous morphine (n = 35), epidural fentanyl (n = 30), or epidural bupivacaine (n = 21). In group 2, 6 patients with a nonfunctioning epidural catheter due to technical failure received a balanced general anesthesia and were eliminated from the study. During the postoperative period, group 2 received analgesia of subcutaneous morphine (n = 26), epidural fentanyl (n = 25), or epidural bupivacaine (n = 30). Cardiovascular morbidity did not differ between the two groups: 22 patients in group 1 and 19 patients in group 2 had a major postoperative cardiac event.(ABSTRACT TRUNCATED AT 250 WORDS)