Systematic reviews and consensus definitions for the Standardised Endpoints in Perioperative Medicine (StEP) initiative: mortality, morbidity, and organ failure.

BACKGROUND: Mortality, morbidity, and organ failure are important and common serious harms after surgery. However, there are many candidate measures to describe these outcome domains. Definitions of these measures are highly variable, and validity is often unclear. As part of the International Standardised Endpoints in Perioperative Medicine (StEP) initiative, this study aimed to derive a set of standardised and valid measures of mortality, morbidity, and organ failure for use in perioperative clinical trials. METHODS: Three domains of endpoints (mortality, morbidity, and organ failure) were explored through systematic literature review and a three-stage Delphi consensus process using methods consistently applied across the StEP initiative. Reliability, feasibility, and patient-centredness were assessed in round 3 of the consensus process. RESULTS: A high level of consensus was achieved for two mortality time points, 30-day and 1-yr mortality, and these two measures are recommended. No organ failure endpoints achieved threshold criteria for consensus recommendation. The Clavien-Dindo classification of complications achieved threshold criteria for consensus in round 2 of the Delphi process but did not achieve the threshold criteria in round 3 where it scored equivalently to the Post Operative Morbidity Survey. Clavien-Dindo therefore received conditional endorsement as the most widely used measure. No composite measures of organ failure achieved an acceptable level of consensus. CONCLUSIONS: Both 30-day and 1-yr mortality measures are recommended. No measure is recommended for organ failure. One measure (Clavien-Dindo) is conditionally endorsed for postoperative morbidity, but our findings suggest that no single endpoint offers a reliable and valid measure to describe perioperative morbidity that is not dependent on the quality of deli-vered care. Further refinement of current measures, or development of novel measures, of postoperative morbidity might improve consensus in this area.

Neurokinin B-Expressing Neurons of the Central Extended Amygdala Mediate Inhibitory Synaptic Input onto Melanin-Concentrating Hormone Neuron Subpopulations.

The lateral hypothalamic area (LHA) is a highly conserved brain region critical for maintaining physiological homeostasis and goal-directed behavior. LHA neurons that express melanin-concentrating hormone (MCH) are key regulators of arousal, energy balance, and motivated behavior. However, cellular and functional diversity among LHAMCH neurons is not well understood. Previous anatomic and molecular data suggest that LHAMCH neurons may be parsed into at least two distinct subpopulations, one of which is enriched in neurokinin-3 receptor (NK3R), the receptor for neurokinin B (NKB), encoded by the Tac2 gene. This tachykininergic ligand-receptor system has been implicated in reproduction, fear memory, and stress in other brain regions, but NKB interactions with LHAMCH neurons are poorly understood. We first identified how LHAMCH subpopulations may be distinguished anatomically and electrophysiologically. To dissect functional connectivity between NKB-expressing neurons and LHAMCH neurons, we used Cre-dependent retrograde and anterograde viral tracing in male Tac2-Cre mice and identified Tac2/EYFP+ neurons in the bed nucleus of the stria terminalis and central nucleus of the amygdala, the central extended amygdala, as major sources of NKB input onto LHAMCH neurons. In addition to innervating the LHA, these limbic forebrain NKB neurons also project to midbrain and brainstem targets. Finally, using a dual-virus approach, we found that optogenetic activation of these inputs in slices evokes GABA release onto a subset of LHAMCH neurons but lacked specificity for the NK3R+ subpopulation. Overall, these data define parallel tachykininergic/GABAergic limbic forebrain projections that are positioned to modulate multiple nodes of homeostatic and behavioral control.SIGNIFICANCE STATEMENT The LHA orchestrates fundamental behavioral states in the mammalian hypothalamus, including arousal, energy balance, memory, stress, and motivated behavior. The neuropeptide MCH defines one prominent population of LHA neurons, with multiple roles in the regulation of homeostatic behavior. Outstanding questions remain concerning the upstream inputs that control MCH neurons. We sought to define neurochemically distinct pathways in the mouse brain that may communicate with specific MCH neuron subpopulations using viral-based retrograde and anterograde neural pathway tracing and optogenetics in brain slices. Here, we identify a specific neuropeptide-defined forebrain circuit that makes functional synaptic connections with MCH neuron subpopulations. This work lays the foundation for further manipulating molecularly distinct neural circuits that modulate innate behavioral states.

Biochemical Characterization of Yeast Xrn1.

Messenger RNA degradation is an important component of overall gene expression. During the final step of eukaryotic mRNA degradation, exoribonuclease 1 (Xrn1) carries out 5' → 3' processive, hydrolytic degradation of RNA molecules using divalent metal ion catalysis. To initiate studies of the 5' → 3' RNA decay machinery in our lab, we expressed a C-terminally truncated version of Saccharomyces cerevisiae Xrn1 and explored its enzymology using a second-generation, time-resolved fluorescence RNA degradation assay. Using this system, we quantitatively explored Xrn1's preference for 5'-monophosphorylated RNA substrates, its pH dependence, and the importance of active site mutations in the molecule's conserved catalytic core. Furthermore, we explore Xrn1's preference for RNAs containing a 5' single-stranded region both in an intermolecular hairpin structure and in an RNA-DNA hybrid duplex system. These results both expand and solidify our understanding of Xrn1, a centrally important enzyme whose biochemical properties have implications in numerous RNA degradation and processing pathways.

Hypothalamic Tuberomammillary Nucleus Neurons: Electrophysiological Diversity and Essential Role in Arousal Stability.

Histaminergic (HA) neurons, found in the posterior hypothalamic tuberomammillary nucleus (TMN), extend fibers throughout the brain and exert modulatory influence over numerous physiological systems. Multiple lines of evidence suggest that the activity of HA neurons is important in the regulation of vigilance despite the lack of direct, causal evidence demonstrating its requirement for the maintenance of arousal during wakefulness. Given the strong correlation between HA neuron excitability and behavioral arousal, we investigated both the electrophysiological diversity of HA neurons in brain slices and the effect of their acute silencing in vivo in male mice. For this purpose, we first validated a transgenic mouse line expressing cre recombinase in histidine decarboxylase-expressing neurons (Hdc-Cre) followed by a systematic census of the membrane properties of both HA and non-HA neurons in the ventral TMN (TMNv) region. Through unsupervised hierarchical cluster analysis, we found electrophysiological diversity both between TMNv HA and non-HA neurons, and among HA neurons. To directly determine the impact of acute cessation of HA neuron activity on sleep-wake states in awake and behaving mice, we examined the effects of optogenetic silencing of TMNv HA neurons in vivo We found that acute silencing of HA neurons during wakefulness promotes slow-wave sleep, but not rapid eye movement sleep, during a period of low sleep pressure. Together, these data suggest that the tonic firing of HA neurons is necessary for the maintenance of wakefulness, and their silencing not only impairs arousal but is sufficient to rapidly and selectively induce slow-wave sleep.SIGNIFICANCE STATEMENT The function of monoaminergic systems and circuits that regulate sleep and wakefulness is often disrupted as part of the pathophysiology of many neuropsychiatric disorders. One such circuit is the posterior hypothalamic histamine (HA) system, implicated in supporting wakefulness and higher brain function, but has been difficult to selectively manipulate owing to cellular heterogeneity in this region. Here we use a transgenic mouse to interrogate both the characteristic firing properties of HA neurons and their specific role in maintaining wakefulness. Our results demonstrate that the acute, cell type-specific silencing of HA neurons during wakefulness is sufficient to not only impair arousal but to rapidly and selectively induce slow-wave sleep. This work furthers our understanding of HA-mediated mechanisms that regulate behavioral arousal.

Relative contribution of TARPs γ-2 and γ-7 to cerebellar excitatory synaptic transmission and motor behavior.

Transmembrane AMPA receptor regulatory proteins (TARPs) play an essential role in excitatory synaptic transmission throughout the central nervous system (CNS) and exhibit subtype-specific effects on AMPA receptor (AMPAR) trafficking, gating, and pharmacology. The function of TARPs has largely been determined through work on canonical type I TARPs such as stargazin (TARP γ-2), absent in the ataxic stargazer mouse. Little is known about the function of atypical type II TARPs, such as TARP γ-7, which exhibits variable effects on AMPAR function. Because γ-2 and γ-7 are both strongly expressed in multiple cell types in the cerebellum, we examined the relative contribution of γ-2 and γ-7 to both synaptic transmission in the cerebellum and motor behavior by using both the stargazer mouse and a γ-7 knockout (KO) mouse. We found that the loss of γ-7 alone had little effect on climbing fiber (cf) responses in Purkinje neurons (PCs), yet the additional loss of γ-2 all but abolished cf responses. In contrast, γ-7 failed to make a significant contribution to excitatory transmission in stellate cells and granule cells. In addition, we generated a PC-specific deletion of γ-2, with and without γ-7 KO background, to examine the relative contribution of γ-2 and γ-7 to PC-dependent motor behavior. Selective deletion of γ-2 in PCs had little effect on motor behavior, yet the additional loss of γ-7 resulted in a severe disruption in motor behavior. Thus, γ-7 is capable of supporting a component of excitatory transmission in PCs, sufficient to maintain essentially normal motor behavior, in the absence of γ-2.

Totally percutaneous versus surgical cut-down femoral artery access for elective bifurcated abdominal endovascular aneurysm repair.

BACKGROUND: Abdominal aortic aneurysms (AAAs) are a vascular condition with significant risk attached, particularly if they rupture. It is, therefore, critical to identify and repair these as an elective procedure before they rupture and require emergency surgery. Repair has traditionally been an open surgical technique that required a large incision across the abdomen. Endovascular abdominal aortic aneurysm repairs (EVARs) are now a common alternative. In this procedure, the common femoral artery is exposed via a cut-down approach and a graft introduced to the aneurysm in this way. This review examines a totally percutaneous approach to EVAR. This technique gives a minimally invasive approach to femoral artery access that may reduce groin wound complication rates and improve recovery time. The technique may, however, be less applicable in people with, for example, groin scarring or arterial calcification. This is an update of the review first published in 2014. OBJECTIVES: This review aims to compare the clinical outcomes of percutaneous access with surgical cut-down femoral artery access in elective bifurcated abdominal endovascular aneurysm repair (EVAR). SEARCH METHODS: For this update the Cochrane Vascular Information Specialist (CIS) searched their Specialised Register (last searched October 2016) and CENTRAL (2016, Issue 9). We also searched clinical trials registries and checked the reference lists of relevant retrieved articles. SELECTION CRITERIA: We considered only randomised controlled trials. The primary intervention was a totally percutaneous endovascular repair. We considered all device types. We compared this against surgical cut-down femoral artery access endovascular repair. We only considered studies investigating elective repairs. We excluded studies reporting emergency surgery for a ruptured abdominal aortic aneurysm and those reporting aorto-uni-iliac repairs. DATA COLLECTION AND ANALYSIS: Two review authors independently collected all data. Owing to the small number of trials identified we did not conduct any formal sensitivity analysis. Heterogeneity was not significant for any outcome. MAIN RESULTS: Two studies with a total of 181 participants met the inclusion criteria, 116 undergoing the percutaneous technique and 65 treated by cut-down femoral artery access. One study had a small sample size and did not adequately report method of randomisation, allocation concealment or pre-selected outcomes. The second study was a larger study with few sources of bias and good methodology.We observed no significant difference in mortality between groups, with only one mortality occurring overall, in the totally percutaneous group (risk ratio (RR) 1.50; 95% confidence interval (CI) 0.06 to 36.18; 181 participants; moderate-quality evidence). Only one study reported aneurysm exclusion. In this study we observed only one failure of aneurysm exclusion in the surgical cut-down femoral artery access group (RR 0.17, 95% CI 0.01 to 4.02; 151 participants; moderate-quality evidence). No wound infections occurred in the cut-down femoral artery access group or the percutaneous group across either study (moderate-quality evidence).There was no difference in major complication rate between cut-down femoral artery access and percutaneous groups (RR 0.91, 95% CI 0.20 to 1.68; 181 participants; moderate-quality evidence); or in bleeding complications and haematoma (RR 0.94, 95% CI 0.31 to 2.82; 181 participants; high-quality evidence).Only one study reported long-term complication rates at six months, with no differences between the percutaneous and cut-down femoral artery access group (RR 1.03, 95% CI 0.34 to 3.15; 134 participants; moderate-quality evidence).We detected differences in surgery time, with percutaneous approach being significantly faster than cut-down femoral artery access (mean difference (MD) -31.46 minutes; 95% CI -47.51 minutes to -15.42 minutes; 181 participants; moderate-quality evidence). Only one study reported duration of ITU (intensive treatment unit) and hospital stay, with no difference found between groups. AUTHORS' CONCLUSIONS: This review shows moderate-quality evidence of no difference between the percutaneous approach compared with cut-down femoral artery access group for short-term mortality, aneurysm exclusion, major complications, wound infection and long-term (six month) complications, and high-quality evidence for no difference in bleeding complications and haematoma. There was a difference in operating time, with moderate-quality evidence showing that the percutaneous approach was faster than the cut-down femoral artery access technique. We downgraded the quality of the evidence to moderate as a result of the limited number of studies, low event numbers and imprecision. As the number of included studies were limited, further research into this technique would be beneficial. The search identified one ongoing study, which may provide an improved evidence base in the future.

Hubs and spokes of the lateral hypothalamus: cell types, circuits and behaviour.

The hypothalamus is among the most phylogenetically conserved regions in the vertebrate brain, reflecting its critical role in maintaining physiological and behavioural homeostasis. By integrating signals arising from both the brain and periphery, it governs a litany of behaviourally important functions essential for survival. In particular, the lateral hypothalamic area (LHA) is central to the orchestration of sleep-wake states, feeding, energy balance and motivated behaviour. Underlying these diverse functions is a heterogeneous assembly of cell populations typically defined by neurochemical markers, such as the well-described neuropeptides hypocretin/orexin and melanin-concentrating hormone. However, anatomical and functional evidence suggests a rich diversity of other cell populations with complex neurochemical profiles that include neuropeptides, receptors and components of fast neurotransmission. Collectively, the LHA acts as a hub for the integration of diverse central and peripheral signals and, through complex local and long-range output circuits, coordinates adaptive behavioural responses to the environment. Despite tremendous progress in our understanding of the LHA, defining the identity of functionally discrete LHA cell types, and their roles in driving complex behaviour, remain significant challenges in the field. In this review, we discuss advances in our understanding of the neurochemical and cellular heterogeneity of LHA neurons and the recent application of powerful new techniques, such as opto- and chemogenetics, in defining the role of LHA circuits in feeding, reward, arousal and stress. From pioneering work to recent developments, we review how the interrogation of LHA cells and circuits is contributing to a mechanistic understanding of how the LHA coordinates complex behaviour.

Octreotide Functionalized Nano-Contrast Agent for Targeted Magnetic Resonance Imaging.

Reversible addition-fragmentation chain transfer (RAFT) polymerization has been employed to synthesize branched block copolymer nanoparticles possessing 1,4,7,10-tetraazacyclododecane-N,N,'N,″N,‴-tetraacetic acid (DO3A) macrocycles within their cores and octreotide (somatostatin mimic) cyclic peptides at their periphery. These polymeric nanoparticles have been chelated with Gd3+ and applied as magnetic resonance imaging (MRI) nanocontrast agents. This nanoparticle system has an r1 relaxivity of 8.3 mM-1 s-1, which is 3 times the r1 of commercial gadolinium-based contrast agents (GBCAs). The in vitro targeted binding efficiency of these nanoparticles shows 5 times greater affinity to somatostatin receptor type 2 (SSTR2) with Ki = 77 pM (compared to somatostatin with Ki = 0.385 nM). We have also evaluated the tumor targeting molecular imaging ability of these branched copolymer nanoparticle in vivo using nude/NCr mice bearing AR42J rat pancreatic tumor (SSTR2 positive) and A549 human lung carcinoma tumor (SSTR2 negative) xenografts.

Differential effects of antidepressants escitalopram versus lithium on Gs alpha membrane relocalization.

BACKGROUND: Plasma membrane localization can play a significant role in the ultimate function of certain proteins. Specific membrane domains like lipid rafts have been shown to be inhibitory domains to a number of signaling proteins, including Gsα, and chronic antidepressant treatment facilitates Gs signaling by removing Gsα form lipid rafts. The intent of this study is to compare the effects of the selective serotnin reuptake inhibitor, escitalopram, with that of the mood stabilizing drug, lithium. RESULTS: There are a number of mechanisms of action proposed for lithium as a mood stabilizing agent, but the interactions between G proteins (particularly Gs) and mood stabilizing drugs are not well explored. Of particular interest was the possibility that there was some effect of mood stabilizers on the association between Gsα and cholesterol-rich membrane microdomains (lipid rafts), similar to that seen with long-term antidepressant treatment. This was examined by biochemical and imaging (fluorescence recovery after photobleaching: FRAP) approaches. Results indicate that escitalopram was effective at liberating Gsα from lipid rafts while lithium was not. CONCLUSIONS: There are a number of drug treatments for mood disorders and yet there is no unifying hypothesis for a cellular or molecular basis of action. It is evident that there may in fact not be a single mechanism, but rather a number of different mechanisms that converge at a common point. The results of this study indicate that the mood stabilizing agent, lithium, and the selective serotonin reuptake inhibitor, escitalopram, act on their cellular targets through mutually exclusive pathways. These results also validate the hypothesis that translocation of Gsα from lipid rafts could serve as a biosignature for antidepressant action.

Patterns of oxygen consumption during simultaneously occurring elevated metabolic states in the viviparous snake Thamnophis marcianus.

Snakes exhibit large factorial increments in oxygen consumption during digestion and physical activity, and long-lasting sub-maximal increments during reproduction. Under natural conditions, all three physiological states may occur simultaneously, but the integrated response is not well understood. Adult male and female checkered gartersnakes (Thamnophis marcianus) were used to examine increments in oxygen consumption (i.e. V̇(O2)) and carbon dioxide production (i.e. V̇(CO2)) associated with activity (Act), digestion (Dig) and post-prandial activity (Act+Dig). For females, we carried out these trials in the non-reproductive state, and also during the vitellogenic (V) and embryogenic (E) phases of a reproductive cycle. Endurance time (i.e. time to exhaustion, TTE) was recorded for all groups during Act and Act+Dig trials. Our results indicate that male and non-reproductive female T. marcianus exhibit significant increments in V̇(O2) during digestion (∼5-fold) and activity (∼9-fold), and that Act+Dig results in a similar increment in V̇(O2) (∼9- to 10-fold). During reproduction, resting V̇(O2) increased by 1.6- to 1.7-fold, and peak increments during digestion were elevated by 30-50% above non-reproductive values, but values associated with Act and Act+Dig were not significantly different from non-reproductive values. During Act+Dig, endurance time remained similar for all of the groups in the present study. Overall, our results indicate that prioritization is the primary pattern of interaction in oxygen delivery exhibited by this species. We propose that the metabolic processes associated with digestion, and perhaps reproduction, are temporarily compromised during activity.

Totally percutaneous versus standard femoral artery access for elective bifurcated abdominal endovascular aneurysm repair.

BACKGROUND: Abdominal aortic aneurysms (AAAs) are a vascular condition with significant risk attached, particularly if they rupture. It is, therefore, critical to identify and repair these as an elective procedure before they rupture and require emergency surgery. Repair has traditionally been an open surgical technique that required a large incision across the abdomen. More recently endovascular aneurysm repairs (EVARs) have become a common alternative. In this procedure, the common femoral artery is exposed via a cut-down approach and a graft is introduced to the aneurysm in this way. This review examines a totally percutaneous approach to EVAR. This technique gives a minimally invasive approach to femoral artery access that may reduce groin wound complication rates and improve recovery time. The technique may, however, be less applicable in patients with, for example, groin scarring or arterial calcification. OBJECTIVES: This review aims to compare the clinical outcomes of percutaneous access with standard femoral artery access in elective bifurcated abdominal endovascular aneurysm repair (EVAR). SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched their Specialised Register (last searched July 2013), CENTRAL (2013, Issue 6) and clinical trials databases. Reference lists of retrieved articles were checked. SELECTION CRITERIA: Only randomised controlled trials were considered. The primary intervention was a totally percutaneous endovascular repair. All device types were considered. This was compared against standard femoral artery endovascular repair. Only studies investigating elective repairs were considered. Studies reporting emergency surgery for a ruptured abdominal aortic aneurysm (rAAA) and those reporting aorto-uni-iliac repairs were excluded. DATA COLLECTION AND ANALYSIS: All data were collected independently by two review authors. Owing to the small number of trials identified, no formal assessment of heterogeneity or sensitivity analysis was conducted. MAIN RESULTS: Only one trial met the inclusion criteria, involving a total of 30 participants, 15 undergoing the percutaneous technique and 15 treated by the standard femoral cut-down approach. There were no significant differences between the two groups at baseline.No mortality or failure of aneurysm exclusion was observed in either group. Three wound infections occurred in the standard femoral cut-down group, whereas none were observed in the percutaneous group. This was not statistically significant. Only one major complication was observed in the study, a conversion to the cut-down technique in the percutaneous access group. No long-term outcomes were reported. One episode of a bleeding complication was reported in the percutaneous group. Significant differences were detected in surgery time (percutaneous 86.7 ± 27 minutes versus conventional 107.8 ± 38.5 minutes; P < 0.05).The included study had a small sample size and failed to report adequately the method of randomisation, allocation concealment and the pre-selected outcomes. AUTHORS' CONCLUSIONS: Only one small study was identified, which did not provide adequate evidence to determine the efficacy and safety of the percutaneous approach compared with endovascular aneurysm repairs. This review has identified a clear need for further research into this potentially beneficial technique. One ongoing study was identified in the search, which may provide an improved evidence base in the future.

Prevention of accidental awareness under general anaesthesia: A regional service evaluation.

The United Kingdom's Fifth National Audit Project investigated the incidence and causes of accidental awareness during general anaesthesia. Subsequently, guidelines produced by the Association of Anaesthetists of Great Britain and Ireland provide key recommendations to minimise awareness. These include using processed electroencephalogram for patients receiving total intravenous anaesthesia while paralysed and using audible low end-tidal anaesthetic concentration alarms. The Southcoast Perioperative Audit and Research Collaboration undertook a five-day regional service evaluation, assessing the measures in place to minimise awareness and conducting a practitioner survey. Eight hospitals participated with 382 theatre attendances were analysed. Processed electroencephalograph monitoring for patients receiving total intravenous anaesthesia with neuromuscular blockade has been widely adopted into regional practice, from 23% of cases in the Fifth National Audit Project, to 85% in this snapshot. During volatile anaesthesia, age-adjusted low end-tidal anaesthetic concentration alarms were used in 34% cases. The range was 0-97% at different hospitals, suggesting heterogeneity in practice. Seventy-six per cent of anaesthetists rarely alter the default anaesthetic machine alarm settings. Therefore, instigating default low end-tidal anaesthetic concentration alarms could improve compliance with guidelines and reduce the risk of awareness for patients.

Predicting DNA toehold-mediated strand displacement rate constants using a DNA-BERT transformer deep learning model.

Dynamic DNA nanotechnology is driving exciting developments in molecular computing, cargo delivery, sensing and detection. Combining this innovative area of research with the progress made in machine learning will aid in the design of sophisticated DNA machinery. Herein, we present a novel framework based on a transformer architecture and a deep learning model which can predict the rate constant of toehold-mediated strand displacement, the underlying process in dynamic DNA nanotechnology. Initially, a dataset of 4450 DNA sequences and corresponding rate constants were generated in-silico using KinDA. Subsequently, a 1D convolution neural network was trained using specific local features and DNA-BERT sequence embedding to produce predicted rate constants. As a result, the newly trained deep learning model predicted toehold-mediated strand displacement rate constants with a root mean square error of 0.76, during testing. These findings demonstrate that DNA-BERT can improve prediction accuracy, negating the need for extensive computational simulations or experimentation. Finally, the impact of various local features during model training is discussed, and a detailed comparison between the One-hot encoder and DNA-BERT sequences representation methods is presented.

Automated Growth Rate Measurement of the Facet Surfaces of Single Crystals of the ß-Form of l-Glutamic Acid Using Machine Learning Image Processing.

Precision measurement of the growth rate of individual single crystal facets (hkl) represents an important component in the design of industrial crystallization processes. Current approaches for crystal growth measurement using optical microscopy are labor intensive and prone to error. An automated process using state-of-the-art computer vision and machine learning to segment and measure the crystal images is presented. The accuracies and efficiencies of the new crystal sizing approach are evaluated against existing manual and semi-automatic methods, demonstrating equivalent accuracy but over a much shorter time, thereby enabling a more complete kinematic analysis of the overall crystallization process. This is applied to measure in situ the crystal growth rates and through this determining the associated kinetic mechanisms for the crystallization of ß-form l-glutamic acid from the solution phase. Growth on the {101} capping faces is consistent with a Birth and Spread mechanism, in agreement with the literature, while the growth rate of the {021} prismatic faces, previously not available in the literature, is consistent with a Burton-Cabrera-Frank screw dislocation mechanism. At a typical supersaturation of σ = 0.78, the growth rate of the {101} capping faces (3.2 × 10-8 m s-1) is found to be 17 times that of the {021} prismatic faces (1.9 × 10-9 m s-1). Both capping and prismatic faces are found to have dead zones in their growth kinetic profiles, with the capping faces (σc = 0.23) being about half that of the prismatic faces (σc = 0.46). The importance of this overall approach as an integral component of the digital design of industrial crystallization processes is highlighted.

Sex differences in neural projections of fear memory processing in mice and humans.

It remains unexplored in the field of fear memory whether functional neuronal connectivity between two brain areas is necessary for one sex but not the other. Here, we show that chemogenetic silencing of centromedial (CeM)-Tac2 fibers in the lateral posterior BNST (BNSTpl) decreased fear memory consolidation in male mice but not females. Optogenetic excitation of CeM-Tac2 fibers in the BNSTpl exhibited enhanced inhibitory postsynaptic currents in males compared to females. In vivo calcium imaging analysis revealed a sex-dimorphic fear memory engram in the BNSTpl. Furthermore, in humans, the single-nucleotide polymorphism (SNP) in the Tac2 receptor (rs2765) (TAC3R) decreased CeM-BNST connectivity in a fear task, impaired fear memory consolidation, and increased the expression of the TAC3R mRNA in AA-carrier men but not in women. These sex differences in critical neuronal circuits underlying fear memory formation may be relevant to human neuropsychiatric disorders with fear memory alterations such as posttraumatic stress disorder.

The development of potential new fluorine-18 labelled radiotracers for imaging the GABA(A) receptor.

Positron emission tomography (PET) using the tracer [(11)C]Flumazenil has shown changes in the distribution and expression of the GABA(A) receptor in a range of neurological conditions and injury states. We aim to develop a fluorine-18 labelled PET agent with comparable properties to [(11)C]Flumazenil. In this study we make a direct comparison between the currently known fluorine-18 labelled GABA(A) radiotracers and novel imidazobenzodiazepine ligands. A focussed library of novel compound was designed and synthesised where the fluorine containing moiety and the position of attachment is varied. The in vitro affinity of twenty-two compounds for the GABA(A) receptor was measured. Compounds containing a fluoroalkyl amide or a longer chain ester group were eliminated due to low potency. The fluorine-18 radiochemistry of one compound from each structural type was assessed to confirm that an automated radiosynthesis in good yield was feasible. Eleven of the novel compounds assessed appeared suitable for in vivo assessment as PET tracers.

Microfluidics: a groundbreaking technology for PET tracer production?

Application of microfluidics to Positron Emission Tomography (PET) tracer synthesis has attracted increasing interest within the last decade. The technical advantages of microfluidics, in particular the high surface to volume ratio and resulting fast thermal heating and cooling rates of reagents can lead to reduced reaction times, increased synthesis yields and reduced by-products. In addition automated reaction optimization, reduced consumption of expensive reagents and a path towards a reduced system footprint have been successfully demonstrated. The processing of radioactivity levels required for routine production, use of microfluidic-produced PET tracer doses in preclinical and clinical imaging as well as feasibility studies on autoradiolytic decomposition have all given promising results. However, the number of microfluidic synthesizers utilized for commercial routine production of PET tracers is very limited. This study reviews the state of the art in microfluidic PET tracer synthesis, highlighting critical design aspects, strengths, weaknesses and presenting several characteristics of the diverse PET market space which are thought to have a significant impact on research, development and engineering of microfluidic devices in this field. Furthermore, the topics of batch- and single-dose production, cyclotron to quality control integration as well as centralized versus de-centralized market distribution models are addressed.

Complications and consequences: short-term harm has long-term impact.

In this editorial, we discuss a large observational study demonstrating increased healthcare usage and higher mortality over 2 yr in patients who experienced specific postoperative complications. These findings are in keeping with the existing literature and draw into focus the need for ongoing work to understand and communicate these long-term consequences to patients.

Data for crystallisation of a homologous series of single and mixed n-alkanes (C16 - C23) from representative hydrocarbon fuel solvents.

The data presented in this article relates to the crystallisation of 8 single n-alkanes, C16H34 - C23H48 in representative diesel solvents dodecane and toluene, as well as a mixture of these 8-alkanes with a composition representative of real diesel fuel in the same solvents. For the single alkane systems, the data was collected over a range of 5 concentrations ranging from 0.09 - 0.311xi, depending upon the system, and 4 concentrations for the 8-alkane mixture, 0.1 - 0.5xi. Raw average crystallisation and dissolution points as a function of cooling rate (q) from a polythermal methodology are presented. Along with the equilibrium crystallisation and dissolution temperatures, van't Hoff fitting parameters, relative critical undercooling (uc) values as a function of q as well as the calculated values of KG and αdet.