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To systematically review the literature comparing the efficacy and safety of dexmedetomidine and midazolam when used for procedural sedation. We searched MEDLINE, EMBASE and COCHRANE for clinical trials comparing dexmedetomidine and midazolam for procedural sedation up to June 20, 2016. Inclusion criteria: clinical trial, human subjects, adult subjects (≥18 years), article written in English, German, French or Dutch, use of study medication for conscious sedation and at least one group receiving dexmedetomidine and one group receiving midazolam. Exclusion criteria: patients in intensive care, pediatric subjects and per protocol use of additional sedative medication other than rescue medication. Outcome measures for efficacy comparison were patient and clinician satisfaction scores and pain scores; outcome measures for safety comparison were hypotension, hypoxia, and circulatory and respiratory complications. We identified 89 papers, of which 12 satisfied the inclusion and exclusion criteria; 883 patients were included in these studies. Dexmedetomidine was associated with higher patient and operator satisfaction than midazolam. Patients receiving dexmedetomidine experienced less pain and had lower analgesic requirements. Respiratory and hemodynamic safety were similar. Dexmedetomidine is a promising alternative to midazolam for use in procedural sedation. Dexmedetomidine provides more comfort during the procedure for the patient and clinician. If carefully titrated, the safety profiles are similar.

Dexmedetomidine is an α 2 -adrenoceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic-sparing effects, and minimal depression of respiratory function. It is potent and highly selective for α 2 -receptors with an α 2 :α 1 ratio of 1620:1. Hemodynamic effects, which include transient hypertension, bradycardia, and hypotension, result from the drug’s peripheral vasoconstrictive and sympatholytic properties. Dexmedetomidine exerts its hypnotic action through activation of central pre- and postsynaptic α 2 -receptors in the locus coeruleus, thereby inducting a state of unconsciousness similar to natural sleep, with the unique aspect that patients remain easily rousable and cooperative. Dexmedetomidine is rapidly distributed and is mainly hepatically metabolized into inactive metabolites by glucuronidation and hydroxylation. A high inter-individual variability in dexmedetomidine pharmacokinetics has been described, especially in the intensive care unit population. In recent years, multiple pharmacokinetic non-compartmental analyses as well as population pharmacokinetic studies have been performed. Body size, hepatic impairment, and presumably plasma albumin and cardiac output have a significant impact on dexmedetomidine pharmacokinetics. Results regarding other covariates remain inconclusive and warrant further research. Although initially approved for intravenous use for up to 24 h in the adult intensive care unit population only, applications of dexmedetomidine in clinical practice have been widened over the past few years. Procedural sedation with dexmedetomidine was additionally approved by the US Food and Drug Administration in 2003 and dexmedetomidine has appeared useful in multiple off-label applications such as pediatric sedation, intranasal or buccal administration, and use as an adjuvant to local analgesia techniques.

Femtosecond crystallography with an X-ray free-electron laser is used to analyse micrometre-sized protein crystals, generating a high-resolution structure of the protein without previous knowledge of what it looks like. Protein structures from smaller crystals X-ray crystallographers typically spend a great deal of time optimizing crystallization conditions to obtain the large, well-ordered crystals needed to generate high-quality data sets. It was shown recently that extremely short and intense pulses of X-rays from X-ray free-electron lasers can be used to obtain diffraction data on nano-to-micrometre-sized protein crystals before radiation damage to the crystal occurs. The hope is that this approach — called serial femtosecond crystallography — will produce structures of proteins and protein complexes that do not yield macroscopic, well-ordered crystals. One of the major limitations of serial femtosecond crystallography is that it has not been possible to solve the structure of a protein without prior knowledge of related, known structures. In this paper, the authors show how serial femtosecond crystallography with an X-ray free-electron laser can be used to experimentally solve the 'phase problem', generating a high-resolution structure of a protein without a priori knowledge of what the protein looks like. The determination of protein crystal structures is hampered by the need for macroscopic crystals. X-ray free-electron lasers (FELs) provide extremely intense pulses of femtosecond duration, which allow data collection from nanometre- to micrometre-sized crystals 1 , 2 , 3 , 4 in a ‘diffraction-before-destruction’ approach. So far, all protein structure determinations carried out using FELs have been based on previous knowledge of related, known structures 1 , 2 , 3 , 4 , 5 . Here we show that X-ray FEL data can be used for de novo protein structure determination, that is, without previous knowledge about the structure. Using the emerging technique of serial femtosecond crystallography 1 , 2 , 3 , 4 , 6 , we performed single-wavelength anomalous scattering measurements on microcrystals of the well-established model system lysozyme, in complex with a lanthanide compound. Using Monte-Carlo integration 6 , 7 , we obtained high-quality diffraction intensities from which experimental phases could be determined, resulting in an experimental electron density map good enough for automated building of the protein structure. This demonstrates the feasibility of determining novel protein structures using FELs. We anticipate that serial femtosecond crystallography will become an important tool for the structure determination of proteins that are difficult to crystallize, such as membrane proteins 1 , 2 , 8 .

The intriguing many-body phases of quantum matter arise from the interplay of particle interactions, spatial symmetries, and external fields. Generating these phases in an engineered system could provide deeper insight into their nature. Using superconducting qubits, we simultaneously realize synthetic magnetic fields and strong particle interactions, which are among the essential elements for studying quantum magnetism and fractional quantum Hall phenomena. The artificial magnetic fields are synthesized by sinusoidally modulating the qubit couplings. In a closed loop formed by the three qubits, we observe the directional circulation of photons, a signature of broken time-reversal symmetry. We demonstrate strong interactions through the creation of photon vacancies, or ‘holes’, which circulate in the opposite direction. The combination of these key elements results in chiral ground-state currents. Our work introduces an experimental platform for engineering quantum phases of strongly interacting photons. Superconducting circuits, coupled to form a ring in which a photonic excitation can circulate between sites, are established as a versatile platform for studying the interplay of strong particle interactions and external fields.

With the advent of X-ray Free Electron Lasers (XFELs), new, high-throughput serial crystallography techniques for macromolecular structure determination have emerged. Serial femtosecond crystallography (SFX) and related methods provide possibilities beyond canonical, single-crystal rotation crystallography by mitigating radiation damage and allowing time-resolved studies with unprecedented temporal resolution. This primer aims to assist structural biology groups with little or no experience in serial crystallography planning and carrying out a successful SFX experiment. It discusses the background of serial crystallography and its possibilities. Microcrystal growth and characterization methods are discussed, alongside techniques for sample delivery and data processing. Moreover, it gives practical tips for preparing an experiment, what to consider and do during a beamtime and how to conduct the final data analysis. Finally, the Primer looks at various applications of SFX, including structure determination of membrane proteins, investigation of radiation damage-prone systems and time-resolved studies.

X-ray free-electron lasers (XFELs) enable crystallographic structure determination beyond the limitations imposed upon synchrotron measurements by radiation damage. The need for very short XFEL pulses is relieved through gating of Bragg diffraction by loss of crystalline order as damage progresses, but not if ionization events are spatially non-uniform due to underlying elemental distributions, as in biological samples. Indeed, correlated movements of iron and sulfur ions were observed in XFEL-irradiated ferredoxin microcrystals using unusually long pulses of 80 fs. Here, we report a femtosecond time-resolved X-ray pump/X-ray probe experiment on protein nanocrystals. We observe changes in the protein backbone and aromatic residues as well as disulfide bridges. Simulations show that the latter’s correlated structural dynamics are much slower than expected for the predicted high atomic charge states due to significant impact of ion caging and plasma electron screening. This indicates that dense-environment effects can strongly affect local radiation damage-induced structural dynamics. The local X-ray-induced dynamics that occur in protein crystals during serial femtosecond crystallography (SFX) measurements at XFELs are not well understood. Here the authors performed a time-resolved X-ray pump X-ray probe SFX experiment, and they observe distinct structural changes in the disulfide bridges and peptide backbone of proteins; complementing theoretical approaches allow them to further characterize the details of the X-ray induced ionization and local structural dynamics.

Quantum computing can become scalable through error correction, but logical error rates only decrease with system size when physical errors are sufficiently uncorrelated. During computation, unused high energy levels of the qubits can become excited, creating leakage states that are long-lived and mobile. Particularly for superconducting transmon qubits, this leakage opens a path to errors that are correlated in space and time. Here, we report a reset protocol that returns a qubit to the ground state from all relevant higher level states. We test its performance with the bit-flip stabilizer code, a simplified version of the surface code for quantum error correction. We investigate the accumulation and dynamics of leakage during error correction. Using this protocol, we find lower rates of logical errors and an improved scaling and stability of error suppression with increasing qubit number. This demonstration provides a key step on the path towards scalable quantum computing. Correlated errors coming from leakage out of the computational subspace are an obstacle to fault-tolerant superconducting circuits. Here, the authors use a multi-level reset protocol to improve the performances of a bit-flip error correcting code by reducing the magnitude of correlations.

Hydrazine is an intermediate in the process of anaerobic ammonium oxidation which has a major role in the Earth’s nitrogen cycle; the crystal structure of a hydrazine synthase enzyme provides insights into the mechanism of hydrazine synthesis. Biological hydrazine synthesis Hydrazine is an intermediate in the process of anaerobic ammonium oxidation, or anammox, which has a major role in the Earth's nitrogen cycle. These authors report a 2.7 Å resolution crystal structure of a hydrazine synthase multiprotein complex isolated from the anammox organism Kuenenia stuttgartiensis . The structure provides insights into the mechanism of hydrazine synthesis. Anaerobic ammonium oxidation (anammox) has a major role in the Earth’s nitrogen cycle 1 , 2 and is used in energy-efficient wastewater treatment 3 . This bacterial process combines nitrite and ammonium to form dinitrogen (N 2 ) gas, and has been estimated to synthesize up to 50% of the dinitrogen gas emitted into our atmosphere from the oceans 2 . Strikingly, the anammox process relies on the highly unusual, extremely reactive intermediate hydrazine 4 , a compound also used as a rocket fuel because of its high reducing power. So far, the enzymatic mechanism by which hydrazine is synthesized is unknown. Here we report the 2.7 Å resolution crystal structure, as well as biophysical and spectroscopic studies, of a hydrazine synthase multiprotein complex isolated from the anammox organism Kuenenia stuttgartiensis . The structure shows an elongated dimer of heterotrimers, each of which has two unique c -type haem-containing active sites, as well as an interaction point for a redox partner. Furthermore, a system of tunnels connects these active sites. The crystal structure implies a two-step mechanism for hydrazine synthesis: a three-electron reduction of nitric oxide to hydroxylamine at the active site of the γ-subunit and its subsequent condensation with ammonia, yielding hydrazine in the active centre of the α-subunit. Our results provide the first, to our knowledge, detailed structural insight into the mechanism of biological hydrazine synthesis, which is of major significance for our understanding of the conversion of nitrogenous compounds in nature.

The realization of a quantum kicked top provides evidence for ergodic dynamics and thermalization in a small quantum system consisting of three superconducting qubits. Statistical mechanics is founded on the assumption that all accessible configurations of a system are equally likely. This requires dynamics that explore all states over time, known as ergodic dynamics. In isolated quantum systems, however, the occurrence of ergodic behaviour has remained an outstanding question 1 , 2 , 3 , 4 . Here, we demonstrate ergodic dynamics in a small quantum system consisting of only three superconducting qubits. The qubits undergo a sequence of rotations and interactions and we measure the evolution of the density matrix. Maps of the entanglement entropy show that the full system can act like a reservoir for individual qubits, increasing their entropy through entanglement. Surprisingly, these maps bear a strong resemblance to the phase space dynamics in the classical limit; classically, chaotic motion coincides with higher entanglement entropy. We further show that in regions of high entropy the full multi-qubit system undergoes ergodic dynamics. Our work illustrates how controllable quantum systems can investigate fundamental questions in non-equilibrium thermodynamics.

The hemoprotein myoglobin is a model system for the study of protein dynamics. We used time-resolved serial femtosecond crystallography at an x-ray free-electron laser to resolve the ultrafast structural changes in the carbonmonoxy myoglobin complex upon photolysis of the Fe-CO bond. Structural changes appear throughout the protein within 500 femtoseconds, with the C, F, and H helices moving away from the heme cofactor and the E and A helices moving toward it. These collective movements are predicted by hybrid quantum mechanics/molecular mechanics simulations. Together with the observed oscillations of residues contacting the heme, our calculations support the prediction that an immediate collective response of the protein occurs upon ligand dissociation, as a result of heme vibrational modes coupling to global modes of the protein.