Fluorescence-Guided Stereotactic Biopsy: A Proof-of-Concept Study

Introduction: Histopathological diagnoses are often necessary for treating neuro-oncology patients. However, stereotactic biopsy (STB), a common method for obtaining tissue from deep or eloquent brain regions, fails to yield diagnostic tissue in approximately 10% of cases. This can delay initiation of treatment and may result in further invasive procedures for patients. Here, we evaluate if coupling in vivo optical imaging with a STB system can identify diagnostic tissue at the time of biopsy. Methods: A minimally invasive fiber optic imaging system was developed by coupling a 0.65mm diameter fiber optic fluorescence microendoscope to a STB system. Human glioma cells were transduced for stable expression of blue fluorescent protein (U251-BFP) and utilized for in vitro and in vivo experiments. In vitro, blue fluorescence was confirmed, and tumor cell delineation by sodium fluorescein (FNa) was quantified with fluorescence microscopy. Rodent xenografts implanted with U251-BFP cells (n=4) were utilized for in vivo experiments. Five weeks post-implantation, xenografts received 5-10mg/kg intravenous FNa and underwent craniotomies overlying the tumor implantation site and contralateral normal brain. A clinical STB needle containing our 0.65mm imaging fiber was passed through each craniotomy and images were collected. Fluorescence images from regions of interest (ROI) ipsilateral and contralateral to tumor implantation were analyzed. Results: Live-cell fluorescence imaging confirmed blue fluorescence from transduced tumor cells and revealed a strong correlation between tumor cells quantified by blue fluorescence and FNa contrast (R2=0.91, p\u3c0.001). Normalized to background, in vivo FNa fluorescence intensity was significantly greater from tumor regions, verified by blue fluorescence, compared to contralateral brain in all animals (60.65± 17.35 %, p\u3c0.001). Fluorescein fluorescence was not significantly greater from the tumor margin compared to normal brain (p =0.096). Biopsies obtained from regions of strong fluorescein contrast were histologically consistent with tumor. Conclusion: We found in vivo fluorescence imaging with a STB needle containing a submillimeter diameter fluorescence microendoscope provided direct visualization of neoplastic tissue in an animal brain tumor model prior to biopsy. This was confirmed in vivo and by post-hoc histological assessment. In vivo fluorescence guidance may improve the diagnostic yield of stereotactic biopsies

Minimally Invasive In Vivo Real-Time Identification of Human Astrocytoma with Sulforhodamine 101

Abstract and poster under embargo until May 31, 2019

Transformational Steam Infusion Processing for Resilient and Sustainable Food Manufacturing Businesses

Here we show how food and beverage manufacturers report more incisive sustainability and product fulfilment outcomes for their business enterprises when innovative processing technologies are used. The reported steam infusion technology heats food materials within a Vaction Pump device so that steam is directed into the food material within a much reduced volume, reducing the use of steam and processing time. This study reports how such technological interventions will enable supply chain stakeholders to demonstrate responsible consumption by connecting assessments for the reduction of greenhouse gas emissions with consumer-focused outcomes such as product quality. The technology reported in this research not only improves operational agility by improving processing speed, but also improves the responsiveness of factory production to changes in demand. Heating procedures are systemic processes in the food industry that can be used to pasteurize, achieve commercially viable shelf-life, and provide cleaning in place. The reported research defines how these technologies can reduce the carbon footprint of products, improve quality attributes, and lower operating costs across supply chains. They provide an important step in developing distributed manufacturing in the food system because the technologies reported here are modular and can be installed into existing operations. The specific technology can reduce energy consumption by 17.3% compared to basic direct steam heating, with a reduction of 277.8 processing hours and 8.7 tonnes GHG emissions per kettle production line each year. Food and beverage manufacturers are increasingly required to report across the sustainability, nutrition, and product quality outcomes of their business enterprises more incisively so that supply chain stakeholders can demonstrate responsible production and consumption. The steam infusion technologies assessed in this research enable alignment to the UN Sustainable Development Goals, specifically SDG12, Responsible Production and Consumption, using in situ data logging in factory trials for novel heating procedures used to process foods

Synthesis, structure and density functional theory (DFT) study of a rhenium(I) pyridylpyrazol complex as a potential photocatalyst for CO2 reduction

The Re(I) complex, [Re(PyPzH)(CO)3Cl] where PyPzH = 2-(1H-pyrazol-3-yl)pyridine, was successfully synthesised and characterised with an infrared (IR), ultraviolet-visible (UV-Vis), 1H and 13C nuclear magnetic resonance (NMR) spectroscopies and X-ray crystallography. The IR spectrum featured three n(C≡O), n(N-H), n(C=N) and n(C=C) signals at (1860-2020), 3137, 1614 and 1513 cm-1, respectively. The UV-Vis spectrum of the complex exhibited ligand-centred (π®>*) electronic excitations [λmax = 227 nm, ε = 1.942 x 104 M-1cm-1; lmax = 292 nm, ε = 0.853 x 104 M-1cm-1] and a metal-to-ligand charge transfer (MLCT) band [lmax = 331 nm, ε = 0.467 x 104 M-1cm-1]. The 13C and 1H-NMR spectra exhibited the characteristic signals of the three C≡O (189.0 – 199.0 ppm) and NH (14.84 ppm), respectively. The X-ray structure of [Re(PyPzH)(CO)3Cl] showed the crystal adopted a monoclinic system with a C2/c space group [unit cell dimensions: a = 27.7422(14) Å, b = 11.1456(5) Å, c = 9.2461(4) Å with α = γ = 90º and β = 92.552(2)º]. Density functional theory (DFT) and time-dependent (TD) DFT calculations were performed to investigate the optimised structural geometry and electronic properties of the title complex. The results showed that the highest-occupied molecular orbital (HOMO) was predominantly found on the dπ-orbitals of Re(I), Cl and CO. While the lowest-unoccupied molecular orbital (LUMO) was located on the PyPzH moiety. The structural and photophysical properties of the [Re(PyPzH)(CO)3Cl] were established and the reaction enthalpies for the dissociation of Cl atom in the formation of [Re(PyPzH)(CO)3]• were discussed in view of its potential application for photocatalytic CO2 reduction

Modified-Source Gravity and Cosmological Structure Formation

One way to account for the acceleration of the universe is to modify general relativity, rather than introducing dark energy. Typically, such modifications introduce new degrees of freedom. It is interesting to consider models with no new degrees of freedom, but with a modified dependence on the conventional energy-momentum tensor; the Palatini formulation of $f(R)$ theories is one example. Such theories offer an interesting testing ground for investigations of cosmological modified gravity. In this paper we study the evolution of structure in these ``modified-source gravity'' theories. In the linear regime, density perturbations exhibit scale dependent runaway growth at late times and, in particular, a mode of a given wavenumber goes nonlinear at a higher redshift than in the standard $\Lambda$CDM model. We discuss the implications of this behavior and why there are reasons to expect that the growth will be cut off in the nonlinear regime. Assuming that this holds in a full nonlinear analysis, we briefly describe how upcoming measurements may probe the differences between the modified theory and the standard $\Lambda$CDM model.Comment: 22 pages, 6 figures, uses iopart styl

Magnetically Responsive Microbubbles as Delivery Vehicles for Targeted Sonodynamic and Antimetabolite Therapy of Pancreatic Cancer

Magnetically responsive microbubbles (MagMBs), consisting of an oxygen gas core and a phospholipid coating functionalised with Rose Bengal (RB) and/or 5-fluorouracil (5-FU), were assessed as a delivery vehicle for the targeted treatment of pancreatic cancer using combined antimetabolite and sonodynamic therapy (SDT). MagMBs delivering the combined 5-FU/SDT treatment produced a reduction in cell viability of over 50% when tested against a panel of four pancreatic cancer cell lines in vitro. Intravenous administration of the MagMBs to mice bearing orthotopic human xenograft BxPC-3 tumours yielded a 48.3% reduction in tumour volume relative to an untreated control group (p<0.05) when the tumour was exposed to both external magnetic and ultrasound fields during administration of the MagMBs. In contrast, application of an external ultrasound field alone resulted in a 27% reduction in tumour volume. In addition, activated caspase and BAX protein levels were both observed to be significantly elevated in tumours harvested from animals treated with the MagMBs in the presence of magnetic and ultrasonic fields when compared to expression of those proteins in tumours from either the control or ultrasound field only groups (p<0.05). These results suggest MagMBs have considerable potential as a platform to enable the targeted delivery of combined sonodynamic / antimetabolite therapy in pancreatic cancer

Reducing uncertainty with flood frequency analysis: the contribution of palaeoflood and historical flood information

Using a combination of stream gauge, historical, and paleoflood records to extend extreme flood records has proven to be useful in improving flood frequency analysis (FFA). The approach has typically been applied in localities with long historical records and/or suitable river settings for paleoflood reconstruction from slack‐water deposits (SWDs). However, many regions around the world have neither extensive historical information nor bedrock gorges suitable for SWDs preservation and paleoflood reconstruction. This study from subtropical Australia demonstrates that confined, semialluvial channels such as macrochannels provide relatively stable boundaries over the 1000–2000 year time period and the preserved SWDs enabled paleoflood reconstruction and their incorporation into FFA. FFA for three sites in subtropical Australia with the integration of historical and paleoflood data using Bayesian Inference methods showed a significant reduction in uncertainty associated with the estimated discharge of a flood quantile. Uncertainty associated with estimated discharge for the 1% Annual Exceedance Probability (AEP) flood is reduced by more than 50%. In addition, sensitivity analysis of possible within‐channel boundary changes shows that FFA is not significantly affected by any associated changes in channel capacity. Therefore, a greater range of channel types may be used for reliable paleoflood reconstruction by evaluating the stability of inset alluvial units, thereby increasing the quantity of temporal data available for FFA. The reduction in uncertainty, particularly in the prediction of the ≤1% AEP design flood, will improve flood risk planning and management in regions with limited temporal flood data

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Mutations in LAMA1 Cause Cerebellar Dysplasia and Cysts with and without Retinal Dystrophy

Cerebellar dysplasia with cysts (CDC) is an imaging finding typically seen in combination with cobblestone cortex and congenital muscular dystrophy in individuals with dystroglycanopathies. More recently, CDC was reported in seven children without neuromuscular involvement (Poretti-Boltshauser syndrome). Using a combination of homozygosity mapping and whole-exome sequencing, we identified biallelic mutations in LAMA1 as the cause of CDC in seven affected individuals (from five families) independent from those included in the phenotypic description of Poretti-Boltshauser syndrome. Most of these individuals also have high myopia, and some have retinal dystrophy and patchy increased T2-weighted fluid-attenuated inversion recovery (T2/FLAIR) signal in cortical white matter. In one additional family, we identified two siblings who have truncating LAMA1 mutations in combination with retinal dystrophy and mild cerebellar dysplasia without cysts, indicating that cysts are not an obligate feature associated with loss of LAMA1 function. This work expands the phenotypic spectrum associated with the lamininopathy disorders and highlights the tissue-specific roles played by different laminin-encoding genes