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A variety of methods are available to investigate the bonding in inorganic compounds. In contrast to wavefunction-based analyses, topological analysis of the electron density affords the advantage of analyzing a physical observable: the electron density. Classical topological analyses of bonding interactions within the atoms in molecules framework typically involve location of a bond path between two atoms and evaluation of a range of real-space functions at the (3, -1) critical point in the electron density that exists on that bond path. We show here that counter-intuitive trends are obtained from the analysis of the electron density (ρ), the Laplacian (∇2ρ), and ellipticity (e) at the O-E (3, -1) critical points in the coupled-cluster singles doubles electron densities of a series of compounds featuring a range of oxygen-pnictogen bond types: EO+, HEO, H2EOH, H3EOH+, and H3EO (where E = N, P, As, Sb, or Bi). If, instead, these real-space functions are evaluated along the length of the bond path, the discrepancies in the trends are resolved. We show that robust results are also obtained using electron densities from less computationally demanding density functional theory calculations. The increased computational efficiency allowed us to also investigate organic derivatives of these oxygen-pnictogen-bonded compounds and observe that the trends hold in these instances as well. We anticipate that these results will be of use to inorganic chemists engaged in the synthesis and evaluation of novel bonding interactions, particularly those involving heavy main-group elements.

Pest species control operations are most effective if every individual in a population is targeted. Yet, individual personality drives variation in animal responses to devices such as traps and baits. Failing to account for differences in behavior during control operations may drive a selective removal, resulting in residual animals with biased expressions of personality. If these biased traits are passed onto offspring, control operations would become increasingly problematic. To test if biased trait expressions in founding populations are passed onto offspring, we quantified personality traits in wild-caught house mice (Mus musculus) and created founder populations selected for biased (High, Low) or Intermediate expressions of Activity. We released the behaviorally biased populations into outdoor yards to breed to the F1 generation, and ten weeks later, removed the mice and quantified the personality traits of the offspring. Despite the strong personality bias in founder populations, we observed no transgenerational transfer of personality and detected no personality bias in the F1 generation. Our results provide reassuring evidence that a single intensive control operation which selects for survivors with a personality bias is unlikely to lead to a recovering population inherently more difficult to eradicate, at least for house mice.

For over a decade, the Frustrated Lewis Pair (FLP) concept has helped to extend the frontiers of main-group chemistry. The present-day maturity of the field, coupled with recent research developments highlighting the continuity between FLP chemistry and classical Lewis acid–base chemistry, suggests that FLP chemistry should be introduced into the mainstream undergraduate chemistry curriculum. Herein is described the experience of a pilot project to incorporate FLP chemistry into the undergraduate main-group inorganic chemistry course at the University of California, Santa Cruz. The presentation of the material, which stresses the thermodynamic-based continuity that links classical Lewis acid–base chemistry and FLP chemistry, also suggested that coverage of the FLP material might provide a means of solidifying fundamental concepts from chemical thermodynamics from earlier courses. Preliminary quantitative and qualitative data have been acquired that support this hypothesis.

Detecting small mammal species for wildlife research and management typically depends on animals deciding to engage with a device, for instance, by entering a trap. While some animals engage and are detected, others do not, and we often lack a mechanistic understanding of what drives these decisions. As trappability can be influenced by traits of personality, personality has high potential to similarly influence detection success for non-capture devices (chew-track cards, tracking tunnels, etc.). We present a conceptual model of the detection process where animal behaviours which are detected by different devices are grouped into tiers based on the degree of intimacy with a device (e.g., approach, interact, enter). Each tier is associated with an increase in the perceived danger of engaging with a device, and an increase in the potential for personality bias. To test this model, we first surveyed 36 populations of free-living black rats (Rattus rattus), a global pest species, to uniquely mark individuals (n = 128) and quantify personality traits. We then filmed rat behaviour at novel tracking tunnels with different risk-reward treatments. As predicted, detection biases were driven by personality, the bias increased with each tier and differed between the risk treatments. Our findings suggest that personality biases are not limited to live-capture traps but are widespread across devices which detect specific animal behaviours. In showing that biases can be predictable, we also show biases can be managed. We recommend that studies involving small mammal sampling report on steps taken to manage a personality-driven bias.

Introduction Accumulating evidence for the co-occurrence autism spectrum disorder (ASD) and schizotypal personality disorder (SPD) at both the diagnostic and symptom levels raises important questions about the nature of their association and the effect of their co-occurrence on the individual's phenotype and functional outcome. Research comparing adults with ASD and SPD, as well as the impact of their co-occurrence on outcomes is extremely limited. We investigated executive functioning in terms of response inhibition and sustained attention, candidate endophenotypes of both conditions, in adults with ASD, SPD, comorbid ASD and SPD, and neurotypical adults using both categorical and dimensional approaches. Methods A total of 88 adults (Mean Age = 37.54; SD = 10.17): ASD (n = 26; M/F = 20/6); SPD (n = 20; M/F = 14/6); comorbid ASD and SPD (n=9; M/F=6/3) and neurotypicals (n=33; M/F=23/10) completed the Sustained Attention to Response Task (SART) in both its fixed and random forms. Positive and autistic symptom severity was assessed with the positive subscale of the Positive and Negative Syndrome Scale (PANSSpos) and the PANSS Autism Severity Score (PAUSS), respectively. Results Controlling for full scale IQ, working memory and medication dosage, group analyses revealed that the comorbid group committed fewer omission errors than the ASD group on the fixed SART, and fewer omission errors than the ASD and SPD groups on the random SART. The individual difference analyses of the entire sample revealed that the PANSSpos and PAUSS interactively reduced omission errors in both the fixed and random SARTs, as well as increased d' scores, indicative of improved overall performance. We observed no significant results for commission errors or reaction time. Conclusions Concurrent elevated levels of autistic and positive psychotic symptoms seem to be associated with improved sustained attention abilities (reduced omission errors) but not inhibition (commission errors). Our findings highlight the importance of investigating the concurrent effect of ASD and SPD at both the symptom and diagnostic levels, and raise important questions for future research regarding the clinical and behavioral phenotypes of adults with dual diagnosis and, more generally, about the nature of the relationship between ASD and SPD.

Molecular symmetry plays an important role in many areas of chemistry, and students are generally taught to identify intramolecular symmetries at the undergraduate level. Intermolecular symmetry, the symmetry among groups of molecules, is of great importance in topics such as X-ray crystallography, but it receives substantially less attention. Even when familiar with such symmetries as translations, screw rotations, and glide reflections, students rarely obtain the same level of proficiency in identifying these symmetries via inspection as they do with the proper and improper rotations involved in point group symmetry. We describe a tool designed to scaffold the student’s ability to mentally manipulate molecules and identify the presence and nature of intermolecular symmetry. The tool consists of an algorithm that the student follows to generate centroids between atoms in putatively symmetry-related molecules. The easily recognized patterns formed by the centroids provide key information about the presence and nature of any intermolecular symmetry relating the molecules. The theoretical basis for the patterns formed by the centroids is provided along with worked examples, an example problem set, and a prescription for generating new exercises.

Summary Healthcare workers involved in aerosol‐generating procedures, such as tracheal intubation, may be at elevated risk of acquiring COVID‐19. However, the magnitude of this risk is unknown. We conducted a prospective international multicentre cohort study recruiting healthcare workers participating in tracheal intubation of patients with suspected or confirmed COVID‐19. Information on tracheal intubation episodes, personal protective equipment use, and subsequent provider health status was collected via self‐reporting. The primary endpoint was the incidence of laboratory‐confirmed COVID‐19 diagnosis or new symptoms requiring self‐isolation or hospitalisation after a tracheal intubation episode. Cox regression analysis examined associations between the primary endpoint and healthcare worker characteristics, procedure‐related factors, and personal protective equipment use. Between 23 March and 2 June 2020, 1718 healthcare workers from 503 hospitals in 17 countries reported 5148 tracheal intubation episodes. The overall incidence of the primary endpoint was 10.7% over a median (IQR [range]) follow‐up of 32 (18–48 [0–116]) days. The cumulative incidence within 7, 14 and 21 days of the first tracheal intubation episode was 3.6%, 6.1%, and 8.5%, respectively. The risk of the primary endpoint varied by country and was higher in females, but was not associated with other factors. Around 1 in 10 healthcare workers involved in tracheal intubation of patients with suspected or confirmed COVID‐19 subsequently reported a COVID‐19 outcome. This has human resource implications for institutional capacity to deliver essential healthcare services, and wider societal implications for COVID‐19 transmission.

Dubiety exists over whether clinical symptoms of schizophrenia can be distinguished from affective psychosis, the assumption being that absence of a “point of rarity” indicates lack of nosological distinction, based on prior group-level analyses. Advanced machine learning techniques, using unsupervised (hierarchical clustering) and supervised (regularized logistic regression algorithm and nested-cross-validation) were applied to a dataset of 202 patients with functional psychosis (schizophrenia n = 120, affective psychosis, n = 82). Patients were initially assessed with the Present State Examination (PSE), and followed up 2.5 years later, when DSM III diagnoses were applied (independent of initial PSE). Based on PSE syndromes, unsupervised learning discriminated depressive (approximately unbiased probability, AUP = 0.92) and mania/psychosis (AUP = 0.94) clusters. The mania/psychosis cluster further split into two groups - a mania (AUP = 0.84) and a psychosis cluster (AUP = 0.88). Supervised machine learning classified schizophrenia or affective psychosis with 83.66% (95% CI = 77.83% to 88.48%) accuracy. Area under the ROC curve (AUROC) was 89.14%. True positive rate for schizophrenia was 88.24% (95%CI = 81.05–93.42%) and affective psychosis 77.11% (95%CI = 66.58–85.62). Classification accuracy and AUROC remained high when PSE syndromes corresponding to affective symptoms (those that corresponded to the depressive and mania clusters) were removed. PSE syndromes, based on clinical symptoms, therefore discriminated between schizophrenia and affective psychosis, suggesting validity to these diagnostic constructs.

Proazaphosphatranes, also known as Verkade’s superbases, are among the strongest nonionic bases available. Their extreme basicity derives in part from their ability to form a P–N transannulation up...

Objective Subunit-specific positive allosteric modulators (PAMs) of gamma-aminobutyric acid-A (GABA-A) receptors are commonly used to uncover the role of GABA-A receptor isoforms in brain function. Recently, we have designed novel PAMs selective for β2/3-subunit containing GABA-A receptors (β2/3-selective PAMs) that are nonbenzodiazepine site-mediated and do not show an α-subunit isoform selectivity, yet exhibit anxiolytic efficacy with reduced potential for sedation, cognitive impairment, and tolerance. In this study, we used three novel β2/3-selective PAMs (2-261, 2-262, and 10029) with differential β2/3-subunit potency to identify the role of β2/3-selective receptor isoforms in limbic epileptogenesis. Methods Experimental epileptogenesis was induced in mice by daily hippocampus stimulations until each mouse showed generalized (stage 5) seizures. Patch-clamp electrophysiology was used to record GABA-gated currents. Brain levels of β2/3-selective PAMs were determined for mechanistic correlations. Results Treatment with the β2/3-selective PAMs 2-261 (30 mg/kg), 2-262 (10 mg/kg), and 10029 (30 mg/kg), 30 min prior to stimulations, significantly suppressed the rate of development of kindled seizure activity without affecting the afterdischarge (AD) signal, indicating their disease-modifying activity. The β2/3-selective agents suppressed chemical epileptogenesis in the pentylenetetrazol model. Test doses of these agents were devoid of acute antiseizure activity in the kindling model. Conclusion These findings demonstrate that β2/3-selective PAMs can moderately retard experimental epileptogenesis, indicating the protective role of β2/3-subunit GABA-A receptor isoforms in the development of epilepsy.

B(C6 F5 )3 and P(MeNCH2 CH2 )3 N form a classical Lewis adduct, (C6 F5 )3 BP(MeNCH2 CH2 )3 N. Although (C6 F5 )3 BP(MeNCH2 CH2 )3 N does not exhibit spectroscopic evidence of dissociation into its constituent acid and base, products of frustrated Lewis pair (FLP) addition reactions are seen with PhNCO, PhCH2 N3 , PhNSO, and CO2 . Computational studies show that thermal access to the dissociated acid and base permits FLP reactivity to proceed. These results demonstrate that FLP reactivity extends across the entire continuum of equilibria governing Lewis acid-base adducts.

The electrophilic phosphonium cation (EPC) salt [(3,5-(CF3)2C6H3)3PF][B(C6F5)4] (2) is prepared via oxidation of the precursor phosphine with XeF2 and subsequent abstraction of fluoride with [Et3Si(tol)][B(C6F5)4]. The Lewis acidity of 2 is evaluated by experimental and computational methods and by preliminary catalysis testing. Exchange reactions of 2 and [(C6F5)3PF][B(C6F5)4] with their respective difluorophosphoranes are studied by 2D 19F–19F NOESY/EXSY and selective 1D 19F NMR exchange spectroscopy (SEXSY) experiments affording comparative rates of fluoride exchange. Collectively, although these data show that 2 is less Lewis acidic than [(C6F5)3PF][B(C6F5)4], the improved access to the P center of 2 provides a kinetic acceleration for fluoride exchange and catalysis where the transition states are more sterically demanding.

Diphenyldiazomethane reacts with HB(C6 F5 )2 and B(C6 F5 )3 , resulting in 1,1-hydroboration and adduct formation, respectively. The hydroboration proceeds via a concerted reaction involving initial formation of the Lewis adduct Ph2 CN2 BH(C6 F5 )2 . The highly sensitive adduct Ph2 CN2 (B(C6 F5 )3 ) liberates N2 and generates Ph2 CB(C6 F5 )3 . DFT computations reveal that formation of Ph2 CN2 B(C6 F5 )3 from carbene, N2 , and borane is thermodynamically favourable, suggesting steric frustration could preclude carbene-borane adduct formation and affect FLP-N2 capture.

Autism spectrum disorder (ASD) is associated with two core symptoms (social communication deficits and stereotyped repetitive behaviors) in addition to a number of comorbidities. There are no FDA-approved drugs for the core symptoms and the changes that underlie these behaviors are not fully understood. One hypothesis is an imbalance of the excitation (E)/inhibition (I) ratio with excessive E and diminished I occurring in specific neuronal circuits. Data suggests that both gamma-aminobutyric acidA (GABAA) and α7 nicotinic acetylcholine receptors (nAChRs) significantly impact E/I. BTBR T+tf/J (BTBR) mice are a model that display an autism-like phenotype with impaired social interaction and stereotyped behavior. A β2/3-subunit containing GABAA receptor (GABAAR) subtype selective positive allosteric modulator (PAM), 2-261, and an α7 nAChR subtype selective PAM, AVL-3288, were tested in social approach and repetitive self-grooming paradigms. 2-261 was active in the social approach but not the self-grooming paradigm, whereas AVL-3288 was active in both. Neither compound impaired locomotor activity. Modulating α7 nAChRs alone may be sufficient to correct these behavioral and cognitive deficits. GABAergic and nicotinic compounds are already in various stages of clinical testing for treatment of the core symptoms and comorbidities associated with ASD. Our findings and those of others suggest that compounds that have selective activities at GABAAR subtypes and the α7 nAChR may address not only the core symptoms, but many of the associated comorbidities as well and warrant further investigation in other models of ASD.

Background Accumulating evidence for the co-occurrence Autism spectrum disorder (ASD) and schizotypal personality disorder (SPD) at both the diagnostic and symptom/trait levels raises important questions about the nature of their association and the effect of their co-occurrence on the individual’s phenotype and functional outcome. It has been recommend that informing etiological and phenotypic overlaps between ASD and schizophrenia spectrum disorders (SSD) would require the utilization of a dual-diagnosis cohort compared with two control groups, each singly diagnosed with ASD or SSD, and that the development of a multidimensional model for understanding the relationship between these two spectra would require cohorts to be described not solely by diagnosis, but also by using dimensional measures that cut across diagnostic boundaries. Research comparing adults with ASD and SPD, as well as the impact of their co-occurrence on outcomes is extremely limited. To fill in this gap, we investigated executive functioning in terms of response inhibition and sustained attention, candidate endophenotypes of both conditions, in adults with ASD, SPD, comorbid ASD and SPD, and neurotypical adults using both categorical and dimensional approaches. Methods A total of 88 adults (Mean Age ± SD = 37.54 ± 10.17): ASD (n = 26; m/f = 20/6); SPD (n = 20; m/f = 14/6); comorbid ASD and SPD (n=9; m/f =6/3) and neurotypicals (n=33; m/f =23/10) completed the Sustained Attention to Response Task (SART) in both its fixed and random forms. Individuals with ASD had a DSM-IV diagnosis of either autism or Asperger Syndrome and met ASD cut-offs on the Autism Diagnostic Observational Schedule-Generic (ADOS-G). All individuals with SPD met DSM-IV criteria for SPD using the Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II). Individuals in the comorbid group met criteria for both ASD (determined by DSM-IV and the ADOS) and SPD (determined by the SCID-II). In addition, in both the clinical and healthy participants, positive and autistic symptom severity were assessed with the positive subscale of the Positive and Negative Syndrome Scale (PANSSpos) and the PANSS Autism Severity Score (PAUSS), respectively. Results Controlling for full scale IQ, working memory and medication dosage, group analyses revealed that the comorbid group committed fewer omission errors than the ASD group on the fixed SART, and fewer omission errors than the ASD and SPD groups on the random SART. The individual difference analyses revealed that the PANSSpos and PAUSS interactively reduced omission errors in both the fixed and random SARTs, as well as increased d’ scores, indicative of improved overall performance. Discussion Concurrent elevated levels of autistic and positive psychotic symptoms seem to be associated with improved sustained attention abilities. We propose that sustaining and switching attention may represent two poles of irregularities across the autism and schizotypal spectra, which appear to converge in a compensatory manner in the comorbid group. Our findings highlight the importance of investigating the concurrent effect of ASD and SPD at both the symptom and diagnostic levels, and the potential benefit of this research approach to understanding the underlying mechanisms of seemingly overlapping phenotypes.

Invasive alien species (IAS) are known to be a major threat to biodiversity and ecosystem function and there is increasing evidence of their impacts on human health and economies globally. We undertook horizon scanning using expert-elicitation to predict arrivals of IAS that could have adverse human health or economic impacts on the island of Cyprus. Three hundred and twenty five IAS comprising 89 plants, 37 freshwater animals, 61 terrestrial invertebrates, 93 terrestrial vertebrates, and 45 marine species, were assessed during a two-day workshop involving 39 participants to derive two ranked lists: (1) IAS with potential human health impacts (20 species ranked within two bands: 1–10 species or 11–20 species); and, (2) IAS with potential economic impacts (50 species ranked in three bands of 1–10, 11–20, and 21–50). Five species of mosquitoes (Aedes aegypti, Aedes albopictus, Aedes flavopictus, Aedes japonicus, and Culex quinquefasciatus) were considered a potential threat to both human health and economies. It was evident that the IAS identified through this process could potentially arrive through many pathways (25 and 23 pathways were noted for the top 20 IAS on the human health and economic impact lists respectively). The Convention on Biological Diversity Level II (subcategory) pathways Contaminant on plants, pet/aquarium/terrarium species (including live food for such species), hitchhikers in or on aeroplanes, hitchhikers in or on ship/boats, and vehicles were the main pathways that arose across both lists. We discuss the potential of horizon scanning lists to inform biosecurity policies and communication around IAS, highlighting the importance of increasing understanding amongst all stakeholders, including the public, to reduce the risks associated with predicted IAS arrivals. © Copyright © 2020 Peyton, Martinou, Adriaens, Chartosia, Karachle, Rabitsch, Tricarico, Arianoutsou, Bacher, Bazos, Brundu, Bruno-McClung, Charalambidou, Demetriou, Galanidi, Galil, Guillem, Hadjiafxentis, Hadjioannou, Hadjistylli, Hall-Spencer, Jimenez, Johnstone, Kleitou, Kletou, Koukkoularidou, Leontiou, Maczey, Michailidis, Mountford, Papatheodoulou, Pescott, Phanis, Preda, Rorke, Shaw, Solarz, Taylor, Trajanovski, Tziortzis, Tzirkalli, Uludag, Vimercati, Zdraveski, Zenetos and Roy.

The use of a bis(diphenyl)phosphine functionalized β‐diketiminato ligand, [HC{(CH3)C}2{(ortho‐[P(C6H5)2]2C6H4)N}2]− (PNac), as a support for germanium(II) and tin(II) chloride and phosphaketene compounds, is described. The conformational flexibility and hemilability of this unique ligand provide a versatile coordination environment that can accommodate the electronic needs of the ligated elements. For example, chloride abstraction from [(PNac)ECl] (E=Ge, Sn) affords the cationic germyliumylidene and stannyliumylidene species [(PNac)E]+ in which the pendant phosphine arms associate more strongly with the Lewis acidic main group element centers, providing further electronic stabilization. In a similar fashion, chemical decarbonylation of the germanium phosphaketene [(PNac)Ge(PCO)] with tris(pentafluorophenyl)borane affords a “push–pull” stabilized phosphinidene in which one of the phosphine groups of the ligand backbone associates with the low valent phosphinidene center., The synthesis and reactivity of a family of germanium(II) and tin(II) complexes supported by a bis(diphenyl)phosphine functionalized β‐diketiminato ligand is reported, including an intramolecularly stabilized “push–pull” phosphinidene.

Background and aims There is an ever-increasing number of blocks available within the armamentarium of regional anaesthetists. It is a common for such specialists to be called upon to teach with a particular regional technique. We have aimed to collate some of the free-access, high quality training provisions into an Alexa ‘Regional Skill’ to aid teaching. Methods Alexa is speech-to-text software allowing voice interaction with devices. Amazon have released a rich developer environment alongside Alexa allowing developers to create their own ‘skills’ – programmes that respond to a user’s voice command and return customised pictures and videos. The user can invoke the device by saying ‘Alexa, open Regional Wizard’. This opens a launch screen, allowing users to ask questions relating to regional anaesthesia, such as how to perform a particular block, or the anatomy of a particular body area. This skill was coded through an Amazon Web Service (AWS) developer account in JavaScript Object Notation and Node.js runtime environment which handles the request all within the AWS developer environment. Results We have developed an Alexa-enabled regional teaching device for use with an Amazon Echo Show device, which could be used by clinicians to help teach regional blocks. The skill has a number of supported requests including video footage, examples including serratus plane, adductor canal and supraclavicular blocks. Schematic anatomical diagrams are also supported. Conclusions We have developed what we believe to be the world’s first medical Alexa regional training device, which could be utilised within a theatre environment to aid the delivery of regional anaesthesia techniques.

Seizures induced by organophosphorus nerve agent exposure become refractory to treatment with benzodiazepines because these drugs engage synaptic γ-aminobutyric acid-A receptors (GABAARs) that rapidly internalize during status epilepticus (SE). Extrasynaptic GABAARs, such as those containing α4β3δ subunits, are a putative pharmacological target to comprehensively manage nerve agent-induced seizures since they do not internalize during SE and are continuously available for activation. Neurosteroids related to allopregnanolone have been tested as a possible replacement for benzodiazepines because they target both synaptic and extrasynaptic GABAARs receptors. A longer effective treatment window, extended treatment efficacy, and enhanced neuroprotection represent significant advantages of neurosteroids over benzodiazepines. However, neurosteroid use is limited by poor physicochemical properties arising from the intrinsic requirement of the pregnane steroid core structure for efficacy rendering drug formulation problematic. We tested a non-steroidal enaminone GABAAR modulator that interacts with both synaptic and extrasynaptic GABAARs on a binding site distinct from neurosteroids or benzodiazepines for efficacy to control electrographic SE induced by diisopropyl fluorophosphate or soman intoxication in rats. Animals were treated with standard antidotes, and experimental therapeutic treatment was given following 1 h (diisopropyl fluorophosphate model) or 20 min (soman model) after SE onset. We found that the enaminone 2-261 had an extended duration of seizure termination (>10 h) in the diisopropyl fluorophosphate intoxication model in the presence or absence of midazolam (MDZ). 2-261 also moderately potentiated MDZ in the soman-induced seizure model but had limited efficacy as a stand-alone anticonvulsant treatment due to slow onset of action. 2-261 significantly reduced neuronal death in brain areas associated with either diisopropyl fluorophosphate- or soman-induced SE. 2-261 represents an alternate chemical template from neurosteroids for enhancing extrasynaptic α4β3δ GABAAR activity to reverse SE from organophosphorous intoxication.

A microfluidic strategy has been used for the time- and labour-efficient evaluation of the relative efficiency and thermodynamic parameters of CO2 binding by three Lewis acid/base combinations, where efficiency is based on the amount of CO2 taken up per binding unit in solution. Neither tBu3P nor B(C6F5)3 were independently effective at CO2 capture, and the combination of the imidazolin-2-ylidenamino-substituted phosphine (NIiPr)3P and B(C6F5)3 was equally ineffective. Nonetheless, an archetypal frustrated Lewis pair (FLP) comprised of tBu3P and B(C6F5)3 was shown to bind CO2 more efficiently than either the FLP derived from tetramethylpiperidine (TMP) and B(C6F5)3 or the highly basic phosphine (NIiPr)3P. Moreover, the proposed microfluidic platform was used to elucidate the thermodynamic parameters for these reactions.

The synthesis of the electrophilic phosphonium cation (EPC) salt [C10H6(CF3)PF(C6F5)2][B(C6F5)4] 4 was achieved via oxidation of phosphine [C10H6(CF3)P(C6F5)2] 2 with XeF2 to form phosphorane [C10H6(CF3)PF2(C6F5)2] 3 and subsequent fluoride ion abstraction. Structural and spectroscopic characterization of 4 provides evidence of an interaction between the CF3 functionality and the phosphonium centre. AIM and NBO analyses also support donation from a lone pair on a fluorine atom of the CF3 group to the P–F σ* orbital of the fluorophosphonium unit, consistent with previously proposed mechanisms for main group C–F bond activations.

Two strategies were used to prepare dicationic phosphonium cations. The first method consists of the reaction of 1-chlorocyclopropenium salts with phosphines to obtain cyclopropenium-substituted phosphonium salts 10a–f[BF4]. Anion exchange was performed to access the corresponding [B(C6F5)4]− analogues 10a–f[B(C6F5)4], which showed much higher solubility in organic solvents. In addition, we developed a synthesis of dicationic phosphonium salts containing 2-, 3-, or 4-methylpyridinium substituents 11a–c[TfO], which were converted as well to their [B(C6F5)4]− analogues 11a–c[B(C6F5)4]. Finally, the phenoxy-substituted phosphonium salt 12[B(C6F5)4] was also prepared. All salts demonstrated remarkable stability in air as compared with their fluorinated analogues. The Lewis acidity of these salts was evaluated by means of theoretical calculations and finally, they were shown to be effective in initiating the Mukaiyama-aldol reaction.

Cationic phosphines of the form [(L)PPh2]+ are prepared by reaction of Ph2PCl with carbenes (L) including a chiral bis(oxazoline)-based carbene, a cyclic(alkyl)(amino) carbene (cAAC), and a 1,2,3-triazolium-derived carbene, affording the products, [(IBox-iPr2)PPh2][OSO2CF3] 1, [(cAAC)PPh2][OSO2CF3] 2 and [((TripCH2N2(NMe)C2Ph)PPh2)2(AgCl)2][Cl]23. Using PhPCl2, the related dication [CH2(NC3H2NDipp)2PPh]2+4 was also prepared. Crystallographically-determined metric parameters and computational data indicate that these species are best described as cationic phosphines rather than phosphenium cations. The oxidation of these cations with XeF2 afforded [(IBox-iPr2)PF2Ph2][OSO2CF3] 5, [(cAAC)PF2Ph2][OSO2CF3] 6 and [(TripCH2N2(NMe)C2Ph)PF2Ph2][Cl] 7; 4 was not oxidized. These observations are understood by a computational assessment of the average local ionisation potentials at valence shell charge concentrations identified via topological analysis of the electron density.

Background There is an established link between childhood adversity (CA) and schizophrenia. Hippocampus and amygdala abnormalities pre-date onset in those at high familial risk (fHR) of schizophrenia, but it is not clear whether these alterations are associated with CA in those at elevated risk of schizophrenia. Methods We examined hippocampal and amygdala volumes in those at fHR who had been referred to a social worker or the Children's Panel compared to those who had not. Results The right hippocampus and left amygdala were significantly smaller in those that had been referred to social work and Children's Panel. Conclusions Our findings suggest that CA can influence structural changes in the brain in a cohort at fHR of schizophrenia. These findings provide further evidence that while genetic factors contribute to the structural changes found in schizophrenia, environmental factors such as CA can have a lasting impact on specific brain regions.

Bupivacaine is a commonly used local anaesthetic for spinal anaesthesia for caesarean section, but may produce prolonged motor block, delaying discharge from the post-anaesthesia care unit. Ropivacaine may have a shorter time to recovery of motor function compared with bupivacaine. We performed a meta-analysis to assess the time difference in duration of motor block with intrathecal ropivacaine compared with bupivacaine for caesarean section.We searched MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases for randomised controlled trials comparing ropivacaine with bupivacaine in parturients undergoing elective caesarean section under spinal anaesthesia. The primary outcome was the duration of motor block. Secondary outcomes included the time to onset of sensory block, need for conversion to general anaesthesia and the incidence of hypotension.Thirteen trials comprising 743 spinal anaesthetics were included. Intrathecal ropivacaine resulted in a reduced duration of motor block, regressing 35.7min earlier compared with intrathecal bupivacaine (P0.00001). There was no difference in the time to onset of sensory block (P=0.25) or the incidence of hypotension (P=0.10). Limited data suggested no difference in the rate of conversion to general anaesthesia, but an earlier request for postoperative analgesia with ropivacaine.Compared with bupivacaine, intrathecal ropivacaine is associated with more rapid recovery of motor block despite similar sensory properties and no increased rate of conversion to general anaesthesia. This may be useful in centres in which recovery of motor block is a criterion for discharge from the post-anaesthesia care unit. However, small numbers of trials and significant heterogeneity limit the interpretation of our results.

BackgroundNegative symptoms are perhaps the most disabling feature of schizophrenia. Their pathogenesis remains poorly understood and it has been difficult to assess their development over time with imaging techniques.AimsTo examine, using tensor-based structural imaging techniques, whether there are regions of progressive grey matter volume change associated with the development of negative symptoms.MethodA total of 43 adolescents at risk of psychosis were examined using magnetic resonance imaging and whole brain tensor-based morphometry at two time points, 6 years apart.ResultsWhen comparing the individuals with significant negative symptoms with the remaining participants, we identified five regions of significant grey matter tissue loss over the 6-year period. These regions included the left temporal lobe, the left cerebellum, the left posterior cingulate and the left inferior parietal sulcus.ConclusionsNegative symptoms are associated with longitudinal grey matter tissue loss. The regions identified include areas associated with psychotic symptoms more generally but also include regions uniquely associated with negative symptoms.

BackgroundPsychotic symptoms and psychotic disorders occur at increased rates in adults with intellectual disability, including borderline intellectual functioning, compared with the general population. Little is known about the development of such symptoms in this population.AimsTo examine whether clinical factors predictive of psychotic disorder in a familial study of schizophrenia also apply to those with intellectual disability.MethodAdolescents with special educational needs (SEN) were assessed with the Structured Interview for Schizotypy (SIS) and Childhood Behavioural Checklist (CBCL). These scores were used to prospectively divide participants based on their anticipated risk for psychotic disorder. A subsample were reassessed three times over 6 years, using the Positive and Negative Syndrome Scale (PANSS).ResultsThe SEN group were more symptomatic than controls throughout (Cohen's d range for PANSS subscale scores: 0.54–1.4, all P < 0.007). Over 6 years of follow-up, those above the SIS and CBCL cut-off values at baseline were more likely than those below to display morbid positive psychotic symptoms (odds ratio, 3.5; 95% CI 1.3–9.0) and develop psychotic disorder (odds ratio, 11.4; 95% CI 2.6–50.1). Baseline SIS and CBCL cut-off values predicted psychotic disorder with sensitivity of 0.67, specificity of 0.85, positive predictive value of 0.26 and negative predictive value of 0.97.ConclusionsAdolescents with SEN have increased psychotic and non-psychotic symptoms. The personality and behavioural features associated with later psychotic disorder in this group are similar to those in people with familial loading. Relatively simple screening measures may help identify those in this vulnerable group who do and do not require monitoring for psychotic symptoms.Declaration of interestNone.

Chronic neuropathic pain may be caused, in part, by loss of inhibition in spinal pain processing pathways due to attenuation of local GABAergic tone. Nociception and nocifensive behaviors are reduced after enhancement of tonically activated extrasynaptic GABA(A)R mediated currents by agonist ligands for δ subunit-containing GABA(A)Rs. However, typical ligands that target δ subunit-containing GABA(A)Rs are limited due to sedative effects at higher doses. We used the spinal nerve ligation (SNL) and gp120 models of experimental neuropathic pain to evaluate compound 2–261, a non-benzodiazepine (BZ) site positive allosteric modulator (PAM) of α(4)β(3)δ GABA(A)Rs optimized to be non-sedative by selective activation of β(2/3) subunit-containing GABA(A)Rs over receptor subtypes incorporating β(1) subunits. Similar levels of 2–261 were detected in the brain and plasma following intraperitoneal administration. While systemic 2–261 did not alter sensory thresholds in sham-operated animals, it significantly reversed SNL-induced thermal and tactile hypersensitivity in a GABA(A)R dependent fashion. Intrathecal 2–261 produced conditioned place preference (CPP) and elevated dopamine levels in the nucleus accumbens of nerve-injured, but not sham-operated rats. Additionally, systemic pretreatment with 2–261 blocked CPP from spinal clonidine in SNL rats. Moreover, 2–261 reversed thermal hyperalgesia and partially reversed tactile allodynia in the gp120 model of HIV-related neuropathic pain. The effects of 2–261 likely required interaction with the α(4)β(3)δ GABA(A)R since 2–301, a close structural analog of 2–261 with limited extrasynaptic receptor efficacy, was not active. Thus, 2–261 may produce pain relief with diminished side-effects through selective modulation of β(2/3) subunit-containing extrasynaptic GABA(A)Rs.

Cognitive impairments are a common consequence of traumatic brain injury (TBI). The hippocampus is a subcortical structure that plays a key role in the formation of declarative memories and is highly vulnerable to TBI. The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in the hippocampus and reduced expression and function of this receptor are linked with cognitive impairments in Alzheimer's disease and schizophrenia. Positive allosteric modulation of α7 nAChRs with AVL-3288 enhances receptor currents and improves cognitive functioning in naïve animals and healthy human subjects. Therefore, we hypothesized that targeting the α7 nAChR with the positive allosteric modulator AVL-3288 would enhance cognitive functioning in the chronic recovery period of TBI. To test this hypothesis, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery. At 3 months after recovery, animals were treated with vehicle or AVL-3288 at 30 min prior to cue and contextual fear conditioning and the water maze task. Treatment of TBI animals with AVL-3288 rescued learning and memory deficits in water maze retention and working memory. AVL-3288 treatment also improved cue and contextual fear memory when tested at 24 hr and 1 month after training, when TBI animals were treated acutely just during fear conditioning at 3 months post-TBI. Hippocampal atrophy but not cortical atrophy was reduced with AVL-3288 treatment in the chronic recovery phase of TBI. AVL-3288 application to acute hippocampal slices from animals at 3 months after TBI rescued basal synaptic transmission deficits and long-term potentiation (LTP) in area CA1. Our results demonstrate that AVL-3288 improves hippocampal synaptic plasticity, and learning and memory performance after TBI in the chronic recovery period. Enhancing cholinergic transmission through positive allosteric modulation of the α7 nAChR may be a novel therapeutic to improve cognition after TBI.

Antipsychotic drugs revolutionised psychiatric practice and provided a range of tools for exploring brain function in health and disease. Their development and introduction were largely empirical but based on long and honourable scientific credentials and remarkable powers of clinical observation. The class shares a common core action of attenuating central dopamine transmission, which underlies the major limitation to their use – high liability to disrupt extrapyramidal function – and also the most durable hypothesis of the basis of psychotic disorders, especially schizophrenia. However, the Dopamine Hypothesis, which has driven drug development for almost half a century, has become a straight-jacket, stifling innovation, resulting in a class of compounds that are largely derivative. Recent efforts only cemented this tendency as no clinical evidence supports the notion that newer compounds, modelled on clozapine, share that drug’s unique neurological tolerability and can be considered ‘atypical’. Patients and doctors alike must await a more profound understanding of central dopamine homeostasis and novel methods of maintaining it before they can again experience the intoxicating promise antipsychotics once held.

There is a large amount of information which theatre clinicians need to be able to access on a daily basis, be it logistical (such as the location/phone number of a particular ward or person), knowledge-based (such as the Trust guideline for specific antibiotic surgical prophylaxis) or technical (such as how to perform a specific procedure). It can be difficult to access this information, particularly for members new to the Trust. There has been a rapid increase in the number of voice-activated devices available, including Alexa enabled devices such as the Echo Dot and Echo View. We have coded a Skill to help clinicians, particularly new starters new to the Trust, to help with some of these aspects mentioned. Alexa Skills can be developed using a variety of computer languages (JavaScript, on this occasion) within the Amazon Web Service development environment using an integrated node.js platform, ensuring that the data contained is safe and secure within Amazon’s cloud computing service. We will demonstrate the Skill, which has been coded to include ward locations, bleep numbers and antibiotic prophylaxis guidelines as a proof of concept as to the usefulness that this technology could add to our working environment. There is also the option to have a visual display on the Echo View device, which, again we will demonstrate. The aim is to develop a fully functional Alexa Skill for those based in the theatre environment in the first instance. We believe this technology represents an opportunity to improve our access to guidelines, clinical information, improve our efficiency and improve delivery of care to our patients.

The global electrophilicity index (GEI) has been further explored as a general and base-free metric for Lewis acidity. A number of computational methods, including post-Hartree–Fock, density functional theory, and time-dependent density functional theory, have been explored. In this fashion, we sought the method most applicable to a range of different Lewis acids with differing structural and electronic features, including boron trihalides, silicon tetrahalides, fluoroaryl boranes, and group 15 pentahalides. The most accurate and computationally efficient approach was found to use the energies of the orbitals from a geometry optimization at the B3LYP/def2-TZVP level of theory. In addition, the GEI is shown to act as an effective acidity metric that is complementary to the fluoride ion affinity. The GEI also proved to be a better gauge of Lewis acidity for softer bases, as confirmed by comparison to the iodide ion affinity of the group 15 pentahalides.

Objective: Children with congenital heart disease (CHD) are often growth restricted (low weight- and/or height-for-age) which may increase risk of poor post operative resilience. Bioelectrical impedance spectroscopy (BIS) has been used to determine body composition in different clinical settings and has been shown to mark differences in nutritional state and clinical outcome. In disease conditions were fluid is not normally distributed it is proposed that raw impedance values and BIS derived phase-angle may serve as prognostic indicators of clinical outcome. We sought to describe the relationship betweennutritional status, phase-angle and post-operative outcomes in children with congenital heart disease.Design: Single centre prospective cohort study.Setting: Paediatric Intensive Care Unit (PICU), Southampton Children's Hospital.Patients: 122 children with CHD following cardiac surgery (March 2015eApril 2016). Outcome variables included growth, mechanical-ventilation, PICU length of stay (PICU-LOS) and phase-angle at 50 Hz.Measurements and main results: BIS measurements were taken before and on the day of surgery (day 0), day 2 post-operatively and on discharge from hospital. Pre-operative moderate malnutrition defined as height-for-age-z-score (HAZ) 2 was observed in 28.5% of infants and 20.6% of children. Regression analysis was used to investigate the relationship between phase-angle, HAZ and clinical outcomes. Moderate-malnutrition (HAZ 2) was associated with an increased PICU-LOS (odds ratios (OR) with95% confidence interval: 1.8; 1.1e2.7, p ¼ 0.008) whilst a low phase-angle (2.7 on day 2 was associated with longer PICU-LOS (OR 7.8; 2.7e22.45, p < 0.001)); When the model was adjusted for age, known risk factors and length of surgery, HAZ 2 and phase-angle 2.7 on day 2 were associated with longer PICU-LOS (p ¼ 0.001 and p ¼ 0.04 respectively) and together explained 81.7% of the variability in PICU-LOS.Conclusions: Moderate malnutrition (HAZ 2) in infants and children undergoing cardiac surgery is associated with longer PICU-LOS. Post-operative measures of BIS phase angle may further improve our ability to identifying hose children with an increased risk of prolonged PICU-LOS compared to using preoperativeanthropometry alone.

The electrophilic phosphonium cation (EPC) salt [(3,5-(CF3)2C6H3)3PF][B(C6F5)4] (2) is prepared via oxidation of the precursor phosphine with XeF2 and subsequent abstraction of fluoride with [Et3Si(tol)][B(C6F5)4]. The Lewis acidity of 2 is evaluated by experimental and computational methods and by preliminary catalysis testing. Exchange reactions of 2 and [(C6F5)3PF][B(C6F5)4] with their respective difluorophosphoranes are studied by 2D 19F-19F NOESY/EXSY and selective 1D 19F NMR exchange spectroscopy (SEXSY) experiments affording comparative rates of fluoride exchange. Collectively, although these data show that 2 is less Lewis acidic than [(C6F5)3PF][B(C6F5)4], the improved access to the P center of 2 provides a kinetic acceleration for fluoride exchange and catalysis where the transition states are more sterically demanding.

Colorectal cancer (CRC) is one of the top three most common cancers and among the top four causes of cancer-related deaths worldwide (Torre et al., 2015). CRC patients are well characterised on the transcriptome and proteome level, but proteomics data on representative cell lines as model systems for pre-clinical drug sensitivity studies lag behind. Here, label-free quantitative mass spectrometry was used to characterise the kinomes and full proteomes of 65 CRC cell lines, collectively termed the CRC65 cell line panel. This data was integrated with proteomics data on patient samples, as well as public transcriptome and drug sensitivity datasets, which were reanalysed from raw data in order to unify and streamline the data processing. Protein/mRNA ratios were constant across these datasets, enabling linear prediction of protein abundance from mRNA abundance after appropriate adjustment, which was used for mRNA-guided missing value imputation. An exploration of secondary imputation methods prompted the development of a complementary method for minimum-guided missing value imputation. Combining the proteomics datasets on cell lines and patients led to the discovery of integrated proteomic subtypes of CRC and enabled the identification of representative cell lines for each of them. Modelling publicly available dose-response data generated by four large-scale drug sensitivity studies as a function of kinome/full proteome profiles fuelled the prediction of drug sensitivity for cell lines and patients, allowed the identification of drugs differentially effective between the different integrated proteomic subtypes and revealed MERTK as a predictive biomarker for resistance towards MEK1/2 inhibitors. This predictive role of MERTK was subsequently confirmed using in vitro experiments, while immunohistochemistry of TMAs from 1,074 tumours generated as part of the QUASAR2 clinical trial unveiled that MERTK is also a prognostic biomarker in CRC. This dataset will be made available to the scientific community to facilitate the design of prospective clinical studies.

The global electrophilicity index, GEI, is used as a general, quantitative and base-independent metric of Lewis acidity. This parameter has been benchmarked against the established fluoride ion affinity, FIA, for a range of 22 neutral and cationic Lewis acids from across the p-block, including boranes, trityl derivatives, phosphonium cations and sulfoxonium cations. As a demonstration of utility, the GEI is used to catalogue a library of fluoroaryl boranes as it provides a rapid tool for the comparison of a series of Lewis acids featuring peripheral substituent variation.

We examined the influence that rare variants and low-frequency polymorphisms in the cancer candidate gene CCND1 have on the development of multiple intestinal adenomas and the early onset of colorectal cancer. Individuals with

Primary ciliary dyskinesia (PCD) is a rare, heterogeneous genetic disorder where impaired mucociliary clearance is caused by dysfunctional motile cilia leading to bronchiectasis. There is limited evidence characterising the nutritional status of children with PCD, although lower body mass index (BMI) z-score has been associated with worse lung function (FEVAll children (n = 43) with PCD, aged16 years, from a single tertiary centre were prospectively enrolled. Information on clinical phenotype and nutritional status including bioelectrical impedance spectroscopy (BIS) phase-angle was collected.There was a weak positive association between height-for-age z-score (HAZ) and FEVWe have characterised the nutritional phenotype of a cohort of children with PCD. Monitoring vitamin D levels is important in PCD patients. There is a weak association between lung function and nutritional status, and measures of BIS phase-angle. The use of BIS phase-angle may allow for early identification of at risk children and may therefore be of benefit for nutritional assessments in the clinical setting. These findings will help inform a future nutritional intervention strategy in children with PCD.