Trends in diabetic retinopathy screening attendance and associations with vision impairment attributable to diabetes in a large nationwide cohort.

AIMS: To investigate diabetic retinopathy screening attendance and trends in certified vision impairment caused by diabetic eye disease. METHODS: This was a retrospective study of attendance in three urban UK diabetic eye screening programmes in England. A survival analysis was performed to investigate time from diagnosis to first screen by age and sex. Logistic regression analysis of factors influencing screening attendance during a 15-month reporting period was conducted, as well as analysis of new vision impairment certifications (Certificate of Vision Impairment) in England and Wales from 2009 to 2019. RESULTS: Of those newly registered in the Routine Digital Screening pathway (n = 97 048), 80% attended screening within the first 12 months and 88% by 36 months. Time from registration to first eye screening was longer for people aged 18-34 years, and 20% were unscreened after 3 years. Delay in first screen was associated with increased risk of referable retinopathy. Although 95% of participants (n = 291 296) attended during the 15-month reporting period, uptake varied considerably. Younger age, social deprivation, ethnicity and duration of diabetes were independent predictors of non-attendance and referable retinopathy. Although the last 10 years has seen an overall reduction in vision impairment certification attributable to diabetic eye disease, the incidence of vision impairment in those aged <35 years was unchanged. CONCLUSIONS: Whilst the majority of participants are screened in a timely manner, there is considerable variation in uptake. Young adults, have sub-optimal attendance, and levels of vision impairment in this population have not changed over the last 10 years. There is an urgent need to explore barriers to/enablers of attendance in this group to inform policy initiatives and tailored interventions to address this issue.

Machine learning at the interface of structural health monitoring and non-destructive evaluation.

While both non-destructive evaluation (NDE) and structural health monitoring (SHM) share the objective of damage detection and identification in structures, they are distinct in many respects. This paper will discuss the differences and commonalities and consider ultrasonic/guided-wave inspection as a technology at the interface of the two methodologies. It will discuss how data-based/machine learning analysis provides a powerful approach to ultrasonic NDE/SHM in terms of the available algorithms, and more generally, how different techniques can accommodate the very substantial quantities of data that are provided by modern monitoring campaigns. Several machine learning methods will be illustrated using case studies of composite structure monitoring and will consider the challenges of high-dimensional feature data available from sensing technologies like autonomous robotic ultrasonic inspection. This article is part of the theme issue 'Advanced electromagnetic non-destructive evaluation and smart monitoring'.

Best practices for the management of local-regional recurrent chordoma: a position paper by the Chordoma Global Consensus Group.

Chordomas are rare, malignant bone tumors of the skull-base and axial skeleton. Until recently, there was no consensus among experts regarding appropriate clinical management of chordoma, resulting in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation, the global chordoma patient advocacy group, convened a multi-disciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published, covering the management of primary and metastatic chordomas. Additional evidence and further discussion were needed to develop recommendations about the management of local-regional failures. Thus, ESMO and CF convened a second consensus group meeting in November 2015 to address the treatment of locally relapsed chordoma. This meeting involved over 60 specialists from Europe, the United States and Japan with expertise in treatment of patients with chordoma. The consensus achieved during that meeting is the subject of the present publication and complements the recommendations of the first position paper.

Chemotherapeutic response to cisplatin-like drugs in human breast cancer cells probed by vibrational microspectroscopy.

Studies of drug-cell interactions in cancer model systems are essential in the preclinical stage of rational drug design, which relies on a thorough understanding of the mechanisms underlying cytotoxic activity and biological effects, at a molecular level. This study aimed at applying complementary vibrational spectroscopy methods to evaluate the cellular impact of two Pt(ii) and Pd(ii) dinuclear chelates with spermine (Pt2Spm and Pd2Spm), using cisplatin (cis-Pt(NH3)2Cl2) as a reference compound. Their effects on cellular metabolism were monitored in a human triple-negative metastatic breast cancer cell line (MDA-MB-231) by Raman and synchrotron-radiation infrared microspectroscopies, for different drug concentrations (2-8 µM) at 48 h exposure. Multivariate data analysis was applied (unsupervised PCA), unveiling drug- and concentration-dependent effects: apart from discrimination between control and drug-treated cells, a clear separation was obtained for the different agents studied - mononuclear vs. polynuclear, and Pt(ii) vs. Pd(ii). Spectral biomarkers of drug action were identified, as well as the cellular response to the chemotherapeutic insult. The main effect of the tested compounds was found to be on DNA, lipids and proteins, the Pd(ii) agent having a more significant impact on proteins while its Pt(ii) homologue affected the cellular lipid content at lower concentrations, which suggests the occurrence of distinct and unconventional pathways of cytotoxicity for these dinuclear polyamine complexes. Raman and FTIR microspectroscopies were confirmed as powerful non-invasive techniques to obtain unique spectral signatures of the biochemical impact and physiological reaction of cells to anticancer agents.

Automated analysis of single cells using Laser Tweezers Raman Spectroscopy.

In recent years, significant progress has been made into the label-free detection and discrimination of individual cancer cells using Laser Tweezers Raman Spectroscopy (LTRS). However, the majority of examples reported have involved manual trapping of cells, which is time consuming and may lead to different cell lines being analysed in discrete batches. A simple, low-cost microfluidic flow chamber is introduced which allows single cells to be optically trapped and analysed in an automated fashion, greatly reducing the level of operator input required. Two implementations of the flow chamber are discussed here; a basic single-channel device in which the fluid velocity is controlled manually, and a dual-channel device which permits the automated capture and analysis of multiple cell lines with no operator input. Results are presented for the discrimination of live epithelial prostate cells and lymphocytes, together with a consideration of the consequences of traditional 'batch analysis' typically used for LTRS of live cells.

Characterising cytotoxic agent action as a function of the cell cycle using Fourier transform infrared microspectroscopy.

Fourier Transform Infrared (FTIR) micro-spectroscopy measurements were acquired to study infrared signatures of chemotherapeutic response as a function of the cell cycle. Renal carcinoma Caki-2 cells were exposed to IC50 doses of 5-fluorouracil and Paclitaxel for a period of 24 hours. The inherent cell cycle infrared signatures from untreated and drug-treated cells were successfully retrieved by the construction of a robust SVM able to discriminate the cell cycle phases of this cell line with an average accuracy of 83.7%. The overriding infrared signature observed relates to an apoptotic biochemical response that does not appear to be correlated with the events affected by the drugs' mode of action or the cell cycle. Since apoptosis is a well conserved mechanism among living species, these results suggest that both the stages of proliferation as well as the absence/presence of apoptosis need to be taken into account in order to elucidate the fine biochemical details revealing the immediate cellular response to the drug in order to assign reliable spectral patterns of drug action.

Enhanced FTIR bench-top imaging of single biological cells.

A new optical system has recently been developed that enables infrared images to be obtained with a pixel resolution of 1 micron on a bench-top instrument using a thermal source. We present here imaging data from two contrasting cellular systems that represent different challenges. Renal carcinoma cells cytospun onto CaF2 have a largely rounded morphology and thus suffer from strong resonant Mie scattering. Skin fibroblast cells, cultured onto CaF2 on the other hand are very spread out so scatter less strongly but are so thin they deliver extremely weak signals. Using suitable pre-processing methods, including PCA noise reduction and RMieS correction, we demonstrate that useful high resolution images can be obtained from either sample.

Exploring the spectroscopic differences of Caki-2 cells progressing through the cell cycle while proliferating in vitro.

FTIR micro-spectral images of Caki-2 cells cytospun onto calcium fluoride (CaF2) slides were used to build a computational model in order to discriminate between the biochemical events of the continuous cell cycle during proliferation. Multivariate analysis and machine learning techniques such as PCA, PLSR and SVMs were used to highlight the chemical differences among the cell cycle phases and also to point out the need for removing the distortion of the spectra due to the morphology of the cells. Results showed cell cycle dependant scattering profiles that enabled the training of a SVM in order to recognise, with a relative high accuracy, each cell cycle phase purely with the scattering curve removed from the FTIR data after being subject to the RMieS-EMSC algorithm.

Ecchordosis Physaliphora: Does It Even Exist?

The term ecchordosis physaliphora (EP) has been used historically to describe a benign notochordal remnant with no growth potential, most commonly occuring in the central clivus. Unfortunately, the radiologic appearance of EP overlaps considerably with the appearance of low-grade chordomas, which do have the potential for growth. In this article, we review new pathologic terminology that better describes this family of diseases, and we propose new radiologic terms that better address the uncertainty of the radiologic diagnosis. The surgical importance of accurate terminology and the implications for patient care are discussed.

Investigating cellular responses to novel chemotherapeutics in renal cell carcinoma using SR-FTIR spectroscopy.

SR-FTIR spectroscopy was evaluated as a technique to discriminate spectral signals of cellular response at the single cell level, when cancer cells are exposed to chemotherapeutics. 5-Fluorouracil, an established drug of known mode of action, was tested against a renal carcinoma cell line (Caki-2), along with two experimental analogues of gold-based compounds. The use of unsupervised principal component analysis (PCA) failed to clearly define any distinction between control and drug treated cell spectra. Supervised principal component linear discriminant analysis (PC-LDA) did have some potential to reveal signatures of cell response and repair but again failed to distinctly discriminate groups of spectra with different drug treatments. Alternatively, clear PCA discrimination was observed in spectra from average cell populations via single point benchtop spectroscopy, probing several cells simultaneously with an increased aperture. The Caki-2 cell line initially appeared to be sensitive to the novel compounds, inducing a cellular response prior to subsequential cell recovery which was assessed by both PCA and cell viability assays.

Highlighting a need to distinguish cell cycle signatures from cellular responses to chemotherapeutics in SR-FTIR spectroscopy.

Previous research has seen difficulties in establishing clear discrimination by principal component analysis (PCA) between drug-treated cells analysed by single point SR-FTIR spectroscopy, relative to multisampling cell monolayers by conventional FTIR. It is suggested that the issue arises due to signal mixing between cellular-response signatures and cell cycle phase contributions in individual cells. Consequently, chemometric distinction of cell spectra treated with multiple drugs is difficult even with supervised methods. In an effort to separate cell cycle chemistry from cellular response chemistry in the spectra, renal carcinoma cells were stained with propidium iodide and fluorescent-activated cell sorted (FACS) after exposure to a number of chemotherapeutic compounds; 5-fluorouracil (5FU) and a set of novel gold-based experimental compounds. The cell spectra were analysed separately by PCA in G(1), S or G(2)/M phase. The mode of action of established drug 5FU, known to disrupt S phase, was confirmed by FACS analysis. The chemical signature of 5FU-treated cells discriminated against both the control and gold-compound (KF0101)-treated cell spectra, suggesting a different mode of action due to a difference in cellular response.

Exploring factors influencing physiotherapists' perceptions of measuring reactive balance following a theory-based multi-component intervention: a qualitative descriptive study.

Purpose: Reactive balance is a critical consideration for mobility and fall avoidance, but is under-assessed among physiotherapists. The objective of this study was to explore factors influencing physiotherapist perceptions about measuring reactive balance upon completion of a 12-month theory-based, multi-component intervention to increase use of a measure of reactive balance.Methods: A qualitative descriptive approach was used. Semi-structured interviews were conducted with 28 physiotherapists treating adults with balance impairment in three urban Canadian rehabilitation hospitals that participated in the intervention. Interviews explored perceptions of reactive balance measurement and perceived changes in clinical behavior. Thematic analysis involved multiple rounds of coding, review and discussion, theme generation, and interpretation of findings through individual analysis and team meetings.Findings: Participants expressed contrasting views about integrating reactive balance measurement in their practice, despite consistent acknowledgement of the importance of reactive balance for function. Three themes were identified highlighting factors that mediated perceptions about measuring reactive balance: patient characteristics; trust between physiotherapist and patient; and the role of physiotherapist fear.Conclusions: The findings highlight that decision making for measuring reactive balance in rehabilitation settings is complex. There is a need for additional work to facilitate long-term implementation of clinical reactive balance measurement, such as refining patient criteria for administration, ensuring sufficient time to establish a trusting relationship, and developing and testing strategies to address physiotherapist fear.IMPLICATIONS FOR REHABILITATIONReactive balance is important for falls prevention and mobility, but is under-assessed among physiotherapists.This study identified three factors that influenced uptake of reactive balance measurement among physiotherapists in rehabilitation settings: patient characteristics; trust between physiotherapist and patient; and the role of physiotherapist fear.Knowledge of the identified factors may assist with design and use of reactive and other balance measurements.Strategies aimed at developing trusting relationships between physiotherapist and patient along with addressing physiotherapist fear could facilitate the uptake of clinical reactive balance measurement.

Nerve-specific extracellular matrix hydrogel promotes functional regeneration following nerve gap injury.

Nerve transection requires surgical intervention to restore function. The standard of care involves coaptation when a tension-free repair is achievable, or interposition of a graft or conduit when a gap remains. Despite advances, nerve gap injury is associated with unsatisfactory recovery. This study investigates the use of a decellularized, porcine nerve-derived hydrogel filler (peripheral nerve matrix, PNM) for conduits in an 8 mm rat sciatic nerve gap model. The decellularized tissue maintained multiple nerve-specific matrix components and nerve growth factors. This decellularized tissue was used to formulate hydrogels, which were deployed into conduits for nerve gap repair. Nerve recovery was assessed up to 24 weeks post injury by gait analysis, electrophysiology, and axon counting. Deployment of PNM within conduits was shown to improve electrophysiologic response and axon counts compared with those of empty conduit controls. These results indicate that PNM has potential benefits when used as a filler for conduits in nerve gap injuries.

Influence of omega-6 PUFA arachidonic acid and bone marrow adipocytes on metastatic spread from prostate cancer.

BACKGROUND: Prostate cancer (CaP) preferentially metastasises to the bone, and we have previously shown that the poly-unsaturated fatty acid (PUFA) arachidonic acid (AA) is a potent stimulator of CaP invasion. Here we present that AA promotes CaP invasion by inducing bone marrow adipocyte formation. METHODS: Boyden invasion-chamber assays assessed the ability of dietary oils, their PUFA components, and specific PUFA-loaded adipocytes to induce PC-3 invasion. Lipid transfer and metabolism was followed using deuterated AA and Fourier Transform Infrared spectroscopy (FTIR). RESULTS: Poly-unsaturated fatty acid constituents, but not their corresponding dietary oils, induced PC-3 invasion. PUFAs induce bone marrow adipocyte (BM-Ad) differentiation with AA inducing higher levels of BM-Ad differentiation, as compared with other PUFAs (3998+/-514.4 vs 932+/-265.8; P=0.00002), which stimulated greater PC-3 invasion than free AA (22 408.5+/-607.4 vs 16 236+/-313.9; P=0.01111) or adipocytes generated in the presence of other PUFAs. In bone marrow co-culture PC-3 and BM-Ad interactions result in direct uptake and metabolism of AA by PC-3 cells, destruction of the adipocyte and subsequent formation of a bone metastasis. CONCLUSION: The data supports the hypothesis that AA not only promotes CaP invasion, it also prepares the 'soil', making it more supportive for implantation and propagation of the migrating metastatic cell.

An investigation of the RWPE prostate derived family of cell lines using FTIR spectroscopy.

Interest in developing robust, quicker and easier diagnostic tests for cancer has lead to an increased use of Fourier transform infrared (FTIR) spectroscopy to meet that need. In this study we present the use of different experimental modes of infrared spectroscopy to investigate the RWPE human prostate epithelial cell line family which are derived from the same source but differ in their mode of transformation and their mode of invasive phenotype. Importantly, analysis of the infrared spectra obtained using different experimental modes of infrared spectroscopy produces similar results. The RWPE family of cell lines can be separated into groups based upon the method of cell transformation rather than the resulting invasiveness/aggressiveness of the cell line. The study also demonstrates the possibility of using a genetic algorithm as a possible standardised pre-processing step and raises the important question of the usefulness of cell lines to create a biochemical model of prostate cancer progression.

Animal model for endoscopic neurosurgical training: technical note.

OBJECTIVE: The learning curve for endonasal endoscopic and neuroendoscopic port surgery is long and often associated with an increase in complication rates as surgeons gain experience. We present an animal model for laboratory training aiming to encourage the young generation of neurosurgeons to pursue proficiency in endoscopic neurosurgical techniques. METHODS: 20 Wistar rats were used as models. The animals were introduced into a physical trainer with multiple ports to carry out fully endoscopic microsurgical procedures. The vertical and horizontal dimensions of the paired ports (simulated nostrils) were: 35×20 mm, 35×15 mm, 25×15 mm, and 25×10 mm. 2 additional single 11.5 mm endoscopic ports were added. Surgical depth varied as desired between 8 and 15 cm. The cervical and abdominal regions were the focus of the endoscopic microsurgical exercises. RESULTS: The different endoscopic neurosurgical techniques were effectively trained at the millimetric dimension. Levels of progressive surgical difficulty depending upon the endoneurosurgical skills set needed for a particular surgical exercise were distinguished. LEVEL 1 is soft-tissue microdissection (exposure of cervical muscular plane and retroperitoneal space); LEVEL 2 is soft-tissue-vascular and vascular-capsule microdissection (aorto-cava exposure, carotid sheath opening, external jugular vein isolation); LEVEL 3 is artery-nerve microdissection (carotid-vagal separation); LEVEL 4 is artery-vein microdissection (aorto-cava separation); LEVEL 5 is vascular repair and microsuturing (aortic rupture), which verified the lack of current proper instrumentation. CONCLUSION: The animal training model presented here has the potential to shorten the length of the learning curve in endonasal endoscopic and neuroendoscopic port surgery and reduce the incidence of training-related surgical complications.

A cAMP-regulated chloride channel in lymphocytes that is affected in cystic fibrosis.

A defect in regulation of a chloride channel appears to be the molecular basis for cystic fibrosis (CF), a common lethal genetic disease. It is shown here that a chloride channel with kinetic and regulatory properties similar to those described for secretory epithelial cells is present in both T and B lymphocyte cell lines. The regulation of the channels by adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase in transformed B cells from CF patients is defective. Thus, lymphocytes may be an accessible source of CF tissue for study of this defect, for cloning of the chloride channel complex, and for diagnosis of the disease.

Phenolic plant compounds functioning as reproductive inhibitors in Microtus montanus.

Naturally occurring cinnamic acids and their related vinylphenols were found to inhibit reproductive function in Microtus montanus. When fed on these compounds, the rodents exhibited decreased uterine weight, inhibition of follicular development, and a cessation of breeding activity. It is suggested that these animals utilize plant compounds as a cue to terminate their reproductive effort in natural populations.

Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3.

The transcription factor NF-AT responds to Ca2+-calcineurin signals by translocating to the nucleus, where it participates in the activation of early immune response genes. Calcineurin dephosphorylates conserved serine residues in the amino terminus of NF-AT, resulting in nuclear import. Purification of the NF-AT kinase revealed that it is composed of a priming kinase activity and glycogen synthase kinase-3 (GSK-3). GSK-3 phosphorylates conserved serines necessary for nuclear export, promotes nuclear exit, and thereby opposes Ca2+-calcineurin signaling. Because GSK-3 responds to signals initiated by Wnt and other ligands, NF-AT family members could be effectors of these pathways.