Ultra-low oxygen, liquid sample cell for in situ synchrotron-based small-wide angle scattering (SAXS-WAXS).

Here, we report the design and successful implementation of an ultra-low oxygen sample cell for use on the SAXS-WAXS (small-wide angle x-ray scattering) beamline I22 at DIAMOND. The rigorous exclusion of oxygen is found to require double jacketing with purge gas throughout the entire system, pipework, pumps, and the sample cell itself. This particularly includes a "double-window" arrangement at the sample location to accommodate the very tight geometrical restrictions of the sample position. The in situ cell design also requires the additional complexity of heating the sample/solution and real-time electrochemical measurements. We demonstrate the successful implementation of this arrangement with real-time in situ characterization of an iron foil corrosion evolving under the "sweet-scale environment," very anoxic conditions common, in particular, commercial situations. The formation of iron carbonate, siderite, rather than iron oxide, indicates that our system is oxygen free down very low levels (<35 ppb at 80 °C).

The Joys of Older Motherhood: A questionnaire-based survey of mothers who delivered over the age of 50 years.

OBJECTIVE: It is recognised that advanced maternal age is associated with adverse pregnancy outcomes. It is less known what the psychological impact of having a pregnancy in later maternal age is. This study aimed to establish whether women having children over 50 experience challenges with regards to their mental well-being during the pregnancy and thereafter. STUDY DESIGN: 17 women delivered aged ≥ 50 at our maternity unit in a central London hospital between 2014 and 2020. Of these, one had died of metastatic ampullary carcinoma two years following delivery, one declined taking part, and two we were unable to get hold of, leaving 13 women in the study. Two validated questionnaires were used to survey the women: (i) Warwick-Edinburgh Mental Well-being Scale (WEMWBS), (ii) Parenting Daily Hassles Scale (PDHS). We analysed the questionnaire data using their individual scoring systems. RESULTS: The WEMWBS showed a median score of 60 out of a possible 70 (range: 45-70), indicating a high level of mental well-being among these women. The PDHS results indicated that reported hassles were overall low in both frequency and intensity for the mothers. CONCLUSION: Women giving birth over 50 have often experienced long, emotional and financially-burdensome journeys in order to fall pregnant, usually involving assisted reproductive techniques (ART), with multiple antenatal and delivery complications thereafter. As a result, they are extremely happy and grateful to have the child, and are often in better socioeconomic positions that can help with the stress that comes with child-caring.

Stabilized entanglement of massive mechanical oscillators.

Quantum entanglement is a phenomenon whereby systems cannot be described independently of each other, even though they may be separated by an arbitrarily large distance 1 . Entanglement has a solid theoretical and experimental foundation and is the key resource behind many emerging quantum technologies, including quantum computation, cryptography and metrology. Entanglement has been demonstrated for microscopic-scale systems, such as those involving photons2-5, ions 6 and electron spins 7 , and more recently in microwave and electromechanical devices8-10. For macroscopic-scale objects8-14, however, it is very vulnerable to environmental disturbances, and the creation and verification of entanglement of the centre-of-mass motion of macroscopic-scale objects remains an outstanding goal. Here we report such an experimental demonstration, with the moving bodies being two massive micromechanical oscillators, each composed of about 10 12 atoms, coupled to a microwave-frequency electromagnetic cavity that is used to create and stabilize the entanglement of their centre-of-mass motion15-17. We infer the existence of entanglement in the steady state by combining measurements of correlated mechanical fluctuations with an analysis of the microwaves emitted from the cavity. Our work qualitatively extends the range of entangled physical systems and has implications for quantum information processing, precision measurements and tests of the limits of quantum mechanics.

Quantum Backaction Evading Measurement of Collective Mechanical Modes.

The standard quantum limit constrains the precision of an oscillator position measurement. It arises from a balance between the imprecision and the quantum backaction of the measurement. However, a measurement of only a single quadrature of the oscillator can evade the backaction and be made with arbitrary precision. Here we demonstrate quantum backaction evading measurements of a collective quadrature of two mechanical oscillators, both coupled to a common microwave cavity. The work allows for quantum state tomography of two mechanical oscillators, and provides a foundation for macroscopic mechanical entanglement and force sensing beyond conventional quantum limits.

The Epidemiology of Staphylococcus aureus and Panton-Valentine Leucocidin (pvl) in Central Australia, 2006-2010.

BACKGROUND: The Central Australian Indigenous population has a high incidence of Staphylococcus aureus bacteremia (SAB) but little is known about the local molecular epidemiology. METHODS: Prospective observational study of bacteremic and nasal colonizing S.aureus isolates between June 2006 to June 2010. All isolates underwent single nucleotide polymorphism (SNP) genotyping and testing for the presence of the Panton-Valentine Leucocidin (pvl) gene. RESULTS: Invasive isolates (n = 97) were predominantly ST93 (26.6 %) and pvl positive (54.3 %), which was associated with skin and soft tissue infections (OR 4.35, 95 % CI 1.16, 16.31). Non-multiresistant MRSA accounted for 31.9 % of bacteremic samples and showed a trend to being healthcare associated (OR 2.16, 95 % CI 0.86, 5.40). Non-invasive isolates (n = 54) were rarely ST93 (1.9 %) or pvl positive (7.4 %). CONCLUSIONS: In Central Australia, ST93 was the dominant S.aureus clone, and was frequently pvl positive and associated with an aggressive clinical phenotype. Whether non-nasal carriage is more important with invasive clones or whether colonization occurs only transiently remains to be elucidated.

Convection-enhanced delivery of MANF--volume of distribution analysis in porcine putamen and substantia nigra.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a 20kDa human protein which has both neuroprotective and neurorestorative activity on dopaminergic neurons and therefore may have application for the treatment of Parkinson's Disease. The aims of this study were to determine the translational potential of convection-enhanced delivery (CED) of MANF for the treatment of PD by studying its distribution in porcine putamen and substantia nigra and to correlate histological distribution with co-infused gadolinium-DTPA using real-time magnetic resonance imaging. We describe the distribution of MANF in porcine putamen and substantia nigra using an implantable CED catheter system using co-infused gadolinium-DTPA to allow real-time MRI tracking of infusate distribution. The distribution of gadolinium-DTPA on MRI correlated well with immunohistochemical analysis of MANF distribution. Volumetric analysis of MANF IHC staining indicated a volume of infusion (Vi) to volume of distribution (Vd) ratio of 3 in putamen and 2 in substantia nigra. This study confirms the translational potential of CED of MANF as a novel treatment strategy in PD and also supports the co-infusion of gadolinium as a proxy measure of MANF distribution in future clinical studies. Further study is required to determine the optimum infusion regime, flow rate and frequency of infusions in human trials.

Photon-assisted tunnelling with nonclassical light.

Among the most exciting recent advances in the field of superconducting quantum circuits is the ability to coherently couple microwave photons in low-loss cavities to quantum electronic conductors. These hybrid quantum systems hold great promise for quantum information-processing applications; even more strikingly, they enable exploration of new physical regimes. Here we study theoretically the new physics emerging when a quantum electronic conductor is exposed to nonclassical microwaves (for example, squeezed states, Fock states). We study this interplay in the experimentally relevant situation where a superconducting microwave cavity is coupled to a conductor in the tunnelling regime. We find that the conductor acts as a nontrivial probe of the microwave state: the emission and absorption of photons by the conductor is characterized by a nonpositive definite quasi-probability distribution, which is related to the Glauber-Sudarshan P-function of quantum optics. These negative quasi-probabilities have a direct influence on the conductance of the conductor.

Convection-enhanced delivery of AAV2 in white matter--a novel method for gene delivery to cerebral cortex.

BACKGROUND: Convection-enhanced delivery (CED) is currently under investigation for delivering therapeutic agents to subcortical targets in the brain. Direct delivery of therapies to the cerebral cortex, however, remains a significant challenge. NEW METHOD: We describe a novel method of targeting adeno-associated viral vector (AAV) mediated gene therapies to specific cerebral cortical regions by performing high volume, high flow rate infusions into underlying white matter in a large animal (porcine) model. RESULTS: Infusion volumes of up to 700 µl at flow rates as high as 10 µl/min were successfully performed in white matter without adverse neurological sequelae. Co-infusion of AAV2/5-GFP with 0.2% Gadolinium in artificial CSF confirmed transgene expression in the deep layers of cerebral cortex overlying the infused areas of white matter. COMPARISON WITH EXISTING METHODS: AAV-mediated gene therapies have been previously targeted to the cerebral cortex by performing intrathalamic CED and exploiting axonal transport. The novel method described in this study facilitates delivery of gene therapies to specific regions of the cerebral cortex without targeting deep brain structures. CONCLUSIONS: AAV-mediated gene therapies can be targeted to specific cortical regions by performing CED into underlying white matter. This technique could be applied to the treatment of neurological disorders characterised by cerebral cortical degeneration.

In vitro and in vivo testing of a novel recessed-step catheter for reflux-free convection-enhanced drug delivery to the brain.

INTRODUCTION: The optimisation of convection-enhanced drug delivery (CED) to the brain is fundamentally reliant on minimising drug reflux. The aim of this study was to evaluate the performance of a novel reflux-resistant CED catheter incorporating a recessed-step and to compare its performance to previously described stepped catheters. METHODS: The in vitro performance of the recessed-step catheter was compared to a conventional "one-step" catheter with a single transition in outer diameter (OD) at the catheter tip, and a "two-step" design comprising two distal transitions in OD. The volumes of distribution and reflux were compared by performing infusions of Trypan blue into agarose gels. The in vivo performance of the recessed-step catheter was then analysed in a large animal model by performing infusions of 0.2% Gadolinium-DTPA in Large White/Landrace pigs. RESULTS: The recessed-step catheter demonstrated significantly higher volumes of distribution than the one-step and two-step catheters (p=0.0001, one-way ANOVA). No reflux was detected until more than 100 ul had been delivered via the recessed-step catheter, whilst reflux was detected after infusion of only 25 ul via the 2 non-recessed catheters. The recessed-step design also showed superior reflux resistance to a conventational one-step catheter in vivo. Reflux-free infusions were achieved in the thalamus, putamen and white matter at a maximum infusion rate of 5 ul/min using the recessed-step design. CONCLUSION: The novel recessed-step catheter described in this study shows significant potential for the achievement of predictable high volume, high flow rate infusions whilst minimising the risk of reflux.

Robot-guided convection-enhanced delivery of carboplatin for advanced brainstem glioma.

BACKGROUND: Patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis with median survival reported as 9 months. The failure of systemic chemotherapy to improve prognosis may be due to inadequate penetration of the blood-brain barrier (BBB). Convection-enhanced delivery (CED) has the potential to improve outcomes by facilitating bypass of the BBB. We describe the first use of carboplatin for the treatment of advanced DIPG using a robot-guided catheter implantation technique. METHODS: A 5-year-old boy presented with a pontine mass lesion. The tumor continued to progress despite radiotherapy. Using an in-house modification to neuroinspire stereotactic planning software (Renishaw Plc., Gloucestershire, UK), the tumor volume was calculated as 43.6 ml. A transfrontal trajectory for catheter implantation was planned facilitating the in-house manufacture of a recessed-step catheter. The catheter was implanted using a neuromate robot (Renishaw Plc., Gloucestershire, UK). The initial infusion of carboplatin (0.09 mg/ml) was commenced with real-time T2-weighted MRI, facilitating estimation of the volume of infusate distribution. Infusions were repeated on a total of 5 days. RESULTS: The catheter implantation and infusions were well tolerated. A total volume of 49.8 ml was delivered over 5 days. T2-weighted MRI on completion of the final infusion demonstrated signal change through a total volume of 35.1 ml, representing 95 % of the targeted tumor volume. Follow-up at 4 weeks revealed clinical signs of improvement and increased T2 signal change throughout the volume of distribution. However, there was tumor progression in the regions outside the volume of distribution. CONCLUSIONS: This case demonstrates the feasibility of accurately and safely delivering small-diameter catheters to the brainstem using a robot-guided implantation procedure, and real-time MRI tracking of infusate distribution.

Intermittent convection-enhanced delivery to the brain through a novel transcutaneous bone-anchored port.

Convection-enhanced delivery (CED) describes a novel method of drug delivery to the brain through intraparenchymal microcatheters. One of the barriers to effective translation of CED to clinical trials is the requirement for intermittent delivery over prolonged periods. This is particularly relevant for delivery of neurotrophins for the treatment of Parkinson's disease where chronic infusion of glial cell-line derived neurotrophic factor (GDNF) with subcutaneously implanted pumps has been associated with poor distribution and local toxicity due to point source accumulation. We have previously described the development of an implantable catheter for CED which facilitates repeated drug administrations at intervals of up to one month. The aim of this study was to determine the feasibility of implanting a transcutaneous bone-anchored port (TBAP) which facilitates chronic intermittent drug delivery to the brain. We describe the design and development of a titanium port which was implanted in Large White and NIH miniature pigs for periods of up to three months. By intermittently accessing the port with a needle administration set it was possible to repeatedly perform CED infusions at one month intervals. This study confirms the safety and feasibility of performing intermittent CED through a transcutaneous bone-anchored port. The use of a transcutaneous port has the potential to facilitate clinical translation of CED of therapeutics requiring intermittent delivery to achieve optimum efficacy whilst negating the need for subcutaneously implanted pumps.

Quantum interface between an electrical circuit and a single atom.

We show how to bridge the divide between atomic systems and electronic devices by engineering a coupling between the motion of a single ion and the quantized electric field of a resonant circuit. Our method can be used to couple the internal state of an ion to the quantized circuit with the same speed as the internal-state coupling between two ions. All the well-known quantum information protocols linking ion internal and motional states can be converted to protocols between circuit photons and ion internal states. Our results enable quantum interfaces between solid state qubits, atomic qubits, and light, and lay the groundwork for a direct quantum connection between electrical and atomic metrology standards.

The development of an implantable catheter system for chronic or intermittent convection-enhanced delivery.

Convection-enhanced delivery (CED) is a promising technique for the administration of therapeutic agents such as cytotoxics, neurotrophins and enzymes to the brain. In this study we describe the development of an implantable catheter system that is compatible with long-term intermittent CED. Catheters made from fused silica, PEEK or carbothane, and of various internal and external diameters were implanted in the striatum of rats and assessed for patency at 21 or 28 days. A high-rate of catheter blockage was observed with all fused silica and PEEK catheters. Carbothane catheters with an outer diameter of 0.6mm and an inner diameter of 0.35 mm had significantly lower rates of blockage (P≤0.01). Carbothane catheters were then implanted into 4 Large White/Landrace pigs and 4 NIH miniature pigs and infusions undertaken at monthly intervals to evaluate catheter patency and infusate distribution. Catheter patency was demonstrated for a maximum period of 163 days in one animal. Widespread and reproducible intraputamenal CED could be achieved with intermittent drug delivery at flow-rates as high as 5 µl/min. Problems were encountered using the pig model due to catheter distortion from rapid animal growth. In conclusion, it is possible to achieve intermittent high-flow CED with a chronic implanted carbothane catheter with a low rate of catheter blockage.

A robust MRI-compatible system to facilitate highly accurate stereotactic administration of therapeutic agents to targets within the brain of a large animal model.

Achieving accurate intracranial electrode or catheter placement is critical in clinical practice in order to maximise the efficacy of deep brain stimulation and drug delivery respectively as well as to minimise side-effects. We have developed a highly accurate and robust method for MRI-guided, stereotactic delivery of catheters and electrodes to deep target structures in the brain of pigs. This study outlines the development of this equipment and animal model. Specifically this system enables reliable head immobilisation, acquisition of high-resolution MR images, precise co-registration of MRI and stereotactic spaces and overall rigidity to facilitate accurate burr hole-generation and catheter implantation. To demonstrate the utility of this system, in this study a total of twelve catheters were implanted into the putamen of six Large White Landrace pigs. All implants were accurately placed into the putamen. Target accuracy had a mean Euclidean distance of 0.623 mm (standard deviation of 0.33 mm). This method has allowed us to accurately insert fine cannulae, suitable for the administration of therapeutic agents by convection-enhanced delivery (CED), into the brain of pigs. This study provides summary evidence of a robust system for catheter implantation into the brain of a large animal model. We are currently using this stereotactic system, implantation procedure and animal model to develop catheter-based drug delivery systems that will be translated into human clinical trials, as well as to model the distribution of therapeutic agents administered by CED over large volumes of brain.

Effects of subchronic phencyclidine on behaviour of female rats on the elevated plus maze and open field.

Female hooded-Lister rats received either subchronic phencyclidine (PCP) (2 mg/kg, n = 20) or vehicle (1 ml/kg, n = 20) intraperitoneally twice daily for 7 days, followed by a 7-day washout period. Rats were challenged with acute PCP or vehicle and tested for locomotor activity to ensure hyperactivity was observed in the subchronic PCP-treated rats. Rats were then tested on the elevated plus maze and in an open field for 10 min. Subchronic PCP did not significantly affect behaviour on the elevated plus maze or in the open field. In conclusion, subchronic PCP does not induce anxiety-like behaviour.

Evaluation of the pro-cognitive effects of the AMPA receptor positive modulator, 5-(1-piperidinylcarbonyl)-2,1,3-benzoxadiazole (CX691), in the rat.

RATIONALE: Positive allosteric modulators of the glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor do not stimulate AMPA receptors directly but delay deactivation of the receptor and/or slow its desensitisation. This results in increased synaptic responses and enhanced long-term potentiation. Thus, it has been suggested that such compounds may have utility for the treatment of cognitive impairment. OBJECTIVES: The objective of the study was to investigate the effect of an AMPA positive modulator, CX691, (1) in three rodent models of learning and memory, (2) on neurochemistry in the dorsal hippocampus and medial prefrontal cortex following acute administration, and (3) on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) expression in the rat hippocampus following acute and sub-chronic administration. RESULTS: CX691 attenuated a scopolamine-induced impairment of cued fear conditioning following acute administration (0.1 mg/kg p.o.) and a temporally induced deficit in novel object recognition following both acute (0.1 and 1.0 mg/kg p.o.) and sub-chronic (bi-daily for 7 days) administration (0.01, 0.03, 0.1 mg/kg p.o.). It also improved attentional set-shifting following sub-chronic administration (0.3 mg/kg p.o.). Acute CX691 (0.1, 0.3 and 1.0 mg/kg, p.o.) increased extracellular levels of acetylcholine in the dorsal hippocampus and medial prefrontal cortex and dopamine in the medial prefrontal cortex. Sub-chronic administration of CX691 (0.1 mg/kg, p.o.) elevated BDNF mRNA expression in both the whole and CA(1) sub-region of the hippocampus (P < 0.05). CONCLUSIONS: Collectively, these data support the pro-cognitive activity reported for AMPA receptor positive modulators and suggest that these compounds may be of benefit in treating disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia.

The mGlu2 but not the mGlu3 receptor mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity.

RATIONALE: Group II metabotropic glutamate receptors (mGluRs) comprise the mGluR2 and mGluR3 subtypes, the activation and modulation of which has been suggested to be beneficial for treating schizophrenia. Genetic association studies suggest limited association between mGluR2 and schizophrenia but some association between mGluR3 and schizophrenia. Conversely, pre-clinical studies suggest that mGluR2 may be responsible for mediating the antipsychotic activity of mGluR2/3 agonists, although to date, the role of mGluR3 has not been specifically assessed. OBJECTIVES: The aim of this study is to use recently generated mGluR3 and mGluR2 knockout mice to investigate which of the group II mGluRs mediates the actions of the mGluR2/3 agonist, LY379268, in two mouse models predictive of antipsychotic activity. MATERIALS AND METHODS: LY379268 (0.3-10 mg/kg SC), phencyclidine (PCP; 1-5 mg/kg IP), and amphetamine 1-10 mg/kg IP) were assessed on locomotor activity and behaviour in C57Bl/6J and transgenic mice. LY379268 was then assessed on PCP (5 mg/kg IP)- and amphetamine (2.5 mg/kg IP)-induced hyperactivity and behaviour in C57Bl/6J and transgenic mice. RESULTS: PCP (5 mg/kg)-evoked hyperactivity and behavioural alterations, i.e. circling, falling, stereotypy and ataxia, as well as amphetamine (2.5 mg/kg)-evoked hyperactivity, were dose-dependently attenuated by LY379268 (0.3-3 mg/kg) in C57Bl/6J mice. One milligram per kilogram of LY379268 reversed PCP-evoked hyperactivity and behavioural alterations in wild-type (WT) and mGluR3 knockout mice but not in mice lacking mGluR2. Similarly, 3 mg/kg LY379268 reversed amphetamine-evoked hyperactivity in WT and mGluR3 knockout mice but not in mice lacking mGluR2. CONCLUSION: The mGlu2 but not the mGlu3 receptor subtype mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity.

Association of progression-free survival with patient-reported outcomes and survival: results from a randomised phase 3 trial of panitumumab.

In a randomised phase 3 trial, panitumumab significantly improved progression-free survival (PFS) in patients with refractory metastatic colorectal cancer (mCRC). This analysis characterises the association of PFS with CRC symptoms, health-related quality of life (HRQoL), and overall survival (OS). CRC symptoms (NCCN/FACT CRC symptom index, FCSI) and HRQoL (EQ-5D) were assessed for 207 panitumumab patients and 184 best supportive care (BSC) patients who had at least one post-baseline patient-reported outcome (PRO) assessment. Patients alive at week 8 were included in the PRO and OS analyses and categorised by their week 8 progression status as follows: no progressive disease (no PD; best response of at least stable disease) vs progressive disease (PD). Standard imputation methods were used to assign missing values. Significantly more patients were progression free at weeks 8-24 with panitumumab vs BSC. After excluding responders, a significant difference in PFS remained favouring panitumumab (HR=0.63, 95% CI=0.52-0.77; P<0.0001). At week 8, lack of disease progression was associated with significantly and clinically meaningful lower CRC symptomatology for both treatment groups and higher HRQoL for panitumumab patients only. Overall survival favoured no PD patients vs PD patients alive at week 8. Lack of disease progression was associated with better symptom control, HRQoL, and OS.

Investigating the effect of bilateral amygdala lesions on fear conditioning and social interaction in the male Mongolian gerbil.

Identification of the selective neurokinin NK(1) receptor antagonist, 2-(R)-(1-(R)-3,5-Bis(trifluromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5yl)methylmor-phine (MK-869), as a novel therapeutic approach for anxiety/depression has led to increased use of the Mongolian gerbil in behavioural studies since the gerbil NK(1) receptor pharmacology is similar to human, but not rat or mouse. Within this species, foot tapping and immobility elicited by aversive conditioning, as well as social interaction have been shown to be sensitive to clinically used anxiolytic and antidepressant agents and also NK(1) receptor antagonists. The high levels of NK(1) receptor binding in the amygdala as well as preclinical studies demonstrating increased release of substance P and corresponding internalisation of NK(1) receptors in the basolateral amygdala in response to stressful stimuli suggest that the BLA may represent a potential site of action for NK(1) receptor antagonists in anxiety and/or depression. Therefore, in the current study, we assessed the effect of bilateral BLA lesions in male Mongolian gerbils on footshock-induced foot tapping and immobility, social interaction, and NK(1)-agonist-induced foot tapping. Lesioned gerbils exhibited reduced immobility time during fear conditioning, a non-significant reduction in immobility time when re-exposed to the conditioned stimulus (CS) 24 h later, and increased social interaction in the gerbil social interaction task. In contrast, BLA lesions had no effect on NK(1)-agonist-induced foot tapping. These data provide further support that the gerbil BLA is a potential site for NK(1) receptor antagonists to attenuate anxiety-related behaviours.