Medium-Term Clinical Outcomes of the Global Icon Stemless Shoulder System: Results of a 2-Year Follow-Up.

The primary aim of this study was to assess the medium-term outcomes of the Global Icon stemless shoulder replacement in patients who have undergone primary total shoulder arthroplasty (TSA) for glenohumeral joint osteoarthritis. A retrospective review of patients who had undergone a TSA using the Global Icon stemless shoulder system was performed. The Western Ontario Osteoarthritis Shoulder (WOOS) Index and Oxford Shoulder Score (OSS) were evaluated pre-operatively and at 12 to 24 months post-operatively. Radiological outcomes, operation time, and post-operative complications were reported. Primary analysis for the WOOS Index and OSS focused on detecting within-group treatment effects at 24 months using a repeated measures ANOVA. Thirty patients were included in the study. Post-surgery, there was a significant improvement at 24 months on the OSS (ES = 0.932, CI: 41.7 to 47.7, p < 0.001) and the WOOS Index (ES = 0.906, CI: 71.9 to 99.8, p < 0.001). Radiographs revealed that no component loosened, migrated, or subsided. The median operative time was 75.5 (IQR: 12.25, range: 18 to 105) min. No implant-related complications were reported. The Global Icon stemless replacements have excellent clinical outcomes in this cohort at 12- and 24-month follow-up with no implant-related complications.

Common health assets protocol: a mixed-methods, realist evaluation and economic appraisal of how community-led organisations (CLOs) impact on the health and well-being of people living in deprived areas.

INTRODUCTION: This research investigates how community-led organisations' (CLOs') use of assets-based approaches improves health and well-being, and how that might be different in different contexts. Assets-based approaches involve 'doing with' rather than 'doing to' and bring people in communities together to achieve positive change using their own knowledge, skills and experience. Some studies have shown that such approaches can have a positive effect on health and well-being. However, research is limited, and we know little about which approaches lead to which outcomes and how different contexts might affect success. METHODS AND ANALYSIS: Using a realist approach, we will work with 15 CLOs based in disadvantaged communities in England, Scotland and Northern Ireland. A realist synthesis of review papers, and a policy analysis in different contexts, precedes qualitative interviews and workshops with stakeholders, to find out how CLOs' programmes work and identify existing data. We will explore participants' experiences through: a Q methodology study; participatory photography workshops; qualitative interviews and measure outcomes using a longitudinal survey, with 225 CLO participants, to assess impact for people who connect with the CLOs. An economic analysis will estimate costs and benefits to participants, for different contexts and mechanisms. A 'Lived Experience Panel' of people connected with our CLOs as participants or volunteers, will ensure the appropriateness of the research, interpretation and reporting of findings. ETHICS AND DISSEMINATION: This project, research tools and consent processes have been approved by the Glasgow Caledonian University School of Health and Life Sciences Ethics Committee, and affirmed by Ethics Committees at Bournemouth University, Queen's University Belfast and the University of East London. Common Health Assets does not involve any National Health Service sites, staff or patients.Findings will be presented through social media, project website, blogs, policy briefings, journal articles, conferences and visually in short digital stories, and photographic exhibitions.

Telemedicine in Orthopedic Surgery: A Systematic Review of Current Evidence.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has triggered transformative changes in how clinicians interact with patients. There has been a shift toward virtual consultations. The evidence to support this change in practice is unclear. The aim of this study was to systematically review the evidence base for virtual consultations for orthopedics. Materials and Methods: Two independent reviewers performed a literature search based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, utilizing the MEDLINE, EMBASE, and Scopus databases. Only studies reporting outcomes following the use of telemedicine for diagnosis, consultation, rehabilitation, and follow-up were included. Outcomes analyzed were: (1) patient and clinician satisfaction, (2) clinical outcome measures, and (3) cost analysis of traditional versus teleconsultation. Results: A total of 41 studies were included. Fifteen studies compared clinical outcomes of telemedicine against a matched traditional cohort. Of these 15 studies, 2 demonstrated noninferiority, 9 showed no statistically significant difference, and 4 found telemedicine to be superior. Eleven studies recorded patient reported outcomes, which demonstrated high patient satisfaction. Nine studies reported decreased costs when telemedicine was compared to traditional care. The remaining six studies had varied aims and methodologies that didn't fit well with any of these subheadings. Discussion: While the available evidence is limited, the studies assessed here show that telemedicine can deliver high quality health care with good clinical outcomes and high patient satisfaction in a cost-effective manner. Our team thinks what this has highlighted is that communication technology is advancing rapidly and that we as a community of surgeons need to be able to adapt rapidly and adopt innovative technology to continue to improve patient experience and outcomes.

Identifying Cancer Drivers Using DRIVE: A Feature-Based Machine Learning Model for a Pan-Cancer Assessment of Somatic Missense Mutations.

Sporadic cancer develops from the accrual of somatic mutations. Out of all small-scale somatic aberrations in coding regions, 95% are base substitutions, with 90% being missense mutations. While multiple studies focused on the importance of this mutation type, a machine learning method based on the number of protein-protein interactions (PPIs) has not been fully explored. This study aims to develop an improved computational method for driver identification, validation and evaluation (DRIVE), which is compared to other methods for assessing its performance. DRIVE aims at distinguishing between driver and passenger mutations using a feature-based learning approach comprising two levels of biological classification for a pan-cancer assessment of somatic mutations. Gene-level features include the maximum number of protein-protein interactions, the biological process and the type of post-translational modifications (PTMs) while mutation-level features are based on pathogenicity scores. Multiple supervised classification algorithms were trained on Genomics Evidence Neoplasia Information Exchange (GENIE) project data and then tested on an independent dataset from The Cancer Genome Atlas (TCGA) study. Finally, the most powerful classifier using DRIVE was evaluated on a benchmark dataset, which showed a better overall performance compared to other state-of-the-art methodologies, however, considerable care must be taken due to the reduced size of the dataset. DRIVE outlines the outstanding potential that multiple levels of a feature-based learning model will play in the future of oncology-based precision medicine.

RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways.

Current therapeutic options for treating colorectal cancer have little clinical efficacy and acquired resistance during treatment is common, even following patient stratification. Understanding the mechanisms that promote therapy resistance may lead to the development of novel therapeutic options that complement existing treatments and improve patient outcome. Here, we identify RAC1B as an important mediator of colorectal tumourigenesis and a potential target for enhancing the efficacy of EGFR inhibitor treatment. We find that high RAC1B expression in human colorectal cancer is associated with aggressive disease and poor prognosis and deletion of Rac1b in a mouse colorectal cancer model reduces tumourigenesis. We demonstrate that RAC1B interacts with, and is required for efficient activation of the EGFR signalling pathway. Moreover, RAC1B inhibition sensitises cetuximab resistant human tumour organoids to the effects of EGFR inhibition, outlining a potential therapeutic target for improving the clinical efficacy of EGFR inhibitors in colorectal cancer.

Use of confocal Raman microscopy to characterise ethyl cyanoacrylate adhesive depth curing.

In situ spatial temporal measurement of monomer conversion during adhesive bondline curing remains a challenging area. The aim of this work was to demonstrate the effectiveness of using confocal Raman microscopy in a specially configured experimental set-up, as a versatile tool for measuring monomer concentration changes as a function of both time and adhesive bond depth during ethyl cyanoacrylate polymerisation. This also allowed monitoring of the extent of polymerisation at the adhesive substrate interface independently of the bulk bondline polymerisation region. Key kinetic parameters such as inhibition time tlag, rate of reaction Rmax and extent of reaction [αt]max were obtained by fitting the experimental data to sigmoidal growth curves using simple piecewise regression models. A systematic characterisation of a polymerisation reaction was conducted using different sample substrate types (copper alloy (red brass), aluminium, aluminium alloy, stainless steel and borosilicate glass) and at various reaction temperatures. Reaction rates were found to decrease further away from the substrate interface in the bulk volume region. The fastest kinetics occurred in the vicinity of nucleophilic hydroxyl rich surfaces such as at the copper alloy (red brass). In addition to substrate surface chemistry, surface roughness was also a factor, with the highest reaction rates occurring with a grit blasted (roughened) aluminium alloy (2024 T3) surface. An approximately linear dependence of the ln Rmaxvs. 1/T (Arrhenius) plot was recorded within the temperature range of 291-328 K. A better fit was obtained however through the use of two separate linear slopes, possibly indicative of a change of polymerisation reaction mechanism taking place at elevated temperatures with two distinct activation energies. Further work conducted using a larger number of temperatures would be useful to verify this finding. This work confirmed that differences in the rates of interfacial and bulk polymerisation processes could be readily measured in situ using confocal Raman microscopy which is a powerful technique for investigating such surface-confined and bulk polymerisation reactions.

Formation of p-n junctions in nanoparticle cerium oxide electrolytic cells displaying memristive switching behaviour.

A macro-scale metal-semiconductor-metal device comprising CeO2 nanoparticles cast from a suspension of cerium dioxide formed by a novel synthetic method was fabricated. Thin CeO2 films of 40 nm thickness placed between panels of aluminium and/or copper displayed memristive-like resistive switching behaviour upon the application of potential sweeps ranging between -0.6 V and 0.6 V. A mechanism is proposed based on the notion that an electrolytic cell operates under such conditions with the initial formation of p and n-type regions within the central semiconductive thin film. Evidence is presented for the existence of numerous point defects in these nanosized CeO2 films, which are also likely to play a role in the device's operation acting as internal dopants. Steady currents were observed upon the imposition of constant potentials, most notably at higher potential values (both anodic and cathodic). It is suggested that electrons and holes act as charge carriers in these devices rather than ionic species as proposed in some other mechanisms.

Non-vascularised Fibular Autograft for Reconstruction of Paediatric Bone Defects: An Analysis of 10 Cases.

AIM AND OBJECTIVE: Fibular autograft is a known technique for the reconstruction of traumatic and non-traumatic bone defects in both adult and paediatric populations. We aim to describe our outcomes using various stabilisation methods for non-vascularised fibular autograft to reconstruct both benign and malignant tumours in a paediatric population in a National Paediatric Centre over the past 14 years. MATERIALS AND METHODS: This was a retrospective review of 10 paediatric cases with non-traumatic primary bone defects in a National Paediatric Centre. Criteria for inclusion were all non-traumatic primary bone defects requiring reconstruction with a non-vascularised fibular autograft in the diaphyseal or metaphyseal regions of the bone. The primary outcome measures were union and time to union (weeks). Time to union was illustrated using Kaplan-Meier curves. Secondary outcome measures included postoperative fracture, infection (deep and superficial), time to full weight-bearing and all-cause revision surgery. RESULTS: The mean length of follow-up was 63 months for the entire cohort (9-168, SD = 48.6). There was no loss to follow-up. Six lesions were located in the tibia, two in the femur and the remaining two were located in the ulna and third metacarpal. Union was ultimately achieved in 8 of the 10 patients using this donor autograft. The mean time to union was 28 weeks (10-99, SD = 29.8). There were four complications of autograft fracture. The mean time to fracture was 17 weeks (9-32, SD = 10.71). In all four of these cases, the patient achieved union at final follow-up. There were two superficial and two deep infections recorded. Three resolved with the use of antimicrobial therapy and one deep infection ultimately required insertion of an intercalary prosthesis to treat the infected non-union of the fibular graft site. CONCLUSION: The use of non-vascularised fibular autograft for the reconstruction of tumours is an effective surgical technique in a paediatric cohort. We report the largest known series of malignant paediatric tumours treated with this technique to date. CLINICAL SIGNIFICANCE: Non-vascularised fibular autograft is successful in the reconstruction of large bone defects secondary to malignant paediatric bone tumours. HOW TO CITE THIS ARTICLE: Sheridan GA, Cassidy JT, Donnelly A, et al. Non-vascularised Fibular Autograft for Reconstruction of Paediatric Bone Defects: An Analysis of 10 Cases. Strategies Trauma Limb Reconstr 2020;15(2):84-90.

Autoantibodies to mRNA processing pathways (glycine and tryptophan-rich bodies antibodies): prevalence and clinical utility in a South Australian cohort.

Autoantibodies to glycine and tryptophan-rich bodies (GWB) can be detected on routine antinuclear antibodies (ANA) testing and might have important disease associations. The aim of this study was to investigate the prevalence of anti-GWB antibodies identified on routine ANA testing, define their antigenic specificities and describe their clinical association. Anti-GWB antibodies were identified by distinct cytoplasmic staining pattern on all samples referred for ANA testing over a 6-month period. All positive anti-GWB samples were further tested on a multiplex addressable bead immunoassay (ALBIA) with known GWB antigens. Extractable nuclear antigens (ENA) were characterised by line immunoblot assay. Clinical details were collected retrospectively by contacting patients and the requesting clinicians. Eleven patients (7 females, 4 males) out of a total of 2136 positive ANAs requested on 11,265 samples had the classical GWB pattern (0.5%). The median age of patients was 66 years (range 39-92). There was no consistent disease association. Ten were confirmed to have distinct antigenic specificity for known GWB antigens. Ge-1/Hedls and RAP55 were the most common antigenic specificity targets [seen in 7 patients (64%) and in 5 patients (45%), respectively]. Ro52 was positive in 5/9 (56%) patients, SSB in 2/9 (22%) patients and Ro60 in 1/9 (11%) patient. The clinical association of anti-GWB antibodies is uncertain but might point towards autoimmune origin of certain non-specific musculoskeletal symptoms. The antigenic specificity of anti-GWB reactivity could point towards specific clinical associations: anti-RAP55 and Ge-1 in non-specific musculoskeletal conditions versus anti-GW182 in neurological diseases.

Modified Surface Relief Layer Created by Holographic Lithography: Application to Selective Sodium and Potassium Sensing.

Point-of-care diagnostics will rely upon the development of low-cost, noncomplex, and easily integrated systems in order to examine biological samples such as blood and urine obtained from the patient. The development of metal ion sensors is a subject of significant relevance for physiological samples. The level of different blood electrolytes, mainly H⁺, Na⁺, K⁺ and Cl- is considerably used to monitor irregular physiologies. The particular challenge in biosensing, and in fact for any other sensor, is signal differentiation between non-specifically bound material and the specific detecting of the target molecule/ion. The biosensors described in this paper are fabricated by a holographic recording of surface relief structures in a photopolymer material. The surface structures are modified by coating with either dibenzo-18-crown-6 (DC) or tetraethyl 4-tert-butylcalix[4]arene (TBC), which are embedded in a polymer matrix. Interrogation of these structures by light allows indirect measurement of the concentration of the analyte. The influence of polymer matrices with different porosities, plasticised polyvinyl chloride (PVC) and a sol-gel matrix, on the performance of the sensors for detection of K⁺ and Na⁺ is examined. Here we demonstrate a proof of concept that by using a matrix with higher porosity one can increase the sensitivity of the sensor. The results showed that the DC sensing layer provides a selective response to K⁺ over Na⁺ and the TBC modified grating is more responsive to Na⁺ over K⁺. The sensor responds to K⁺ and Na⁺ within the physiological concentration ranges.

"90/90" Plating of proximal humerus fracture-a technical note.

INTRODUCTION: While locking plates have markedly improved fixation of proximal humerus fractures, a cohort of fractures remains difficult to treat. This cohort has been identified as fractures with marked medial comminution and varus deformity. Loss of reduction and fixation failure are the most frequently reported complications for this cohort. We report the use of an orthogonal 1/3 tubular plate to augment the proximal humerus locking plate. METHODS: The subject underwent osteosynthesis for a four-part proximal humerus fracture with medial comminution. Fixation was performed within 24 h of injury. Standard deltopectoral approach exposed the fracture. Sutures were sited to control the tuberosities and cuff. Initial reduction was held with a K-wire and augmented with a three-hole 1/3 tubular plate. Proximal humerus locking plate was sited in standard fashion including locked medial support screws. Reduction was confirmed both clinically and with intra-operative radiography. RESULTS: The technique provided satisfactory results. At 6 months, the fracture had fully united with no loss of reduction. At 1 year, the patient had excellent range of motion. CONCLUSION: The use of a 1/3 tubular plate to augment fixation of proximal humerus fractures with medial comminution may provide a simple, reproducible, and cost-effective method to decrease loss of reduction and subsequent malunion.

Is a government-regulated rehabilitation guideline more effective than general practitioner education or preferred-provider rehabilitation in promoting recovery from acute whiplash-associated disorders? A pragmatic randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of a government-regulated rehabilitation guideline compared with education and activation by general practitioners, and to a preferred-provider insurance-based rehabilitation programme on self-reported global recovery from acute whiplash-associated disorders (WAD) grade I-II. DESIGN: Pragmatic randomised clinical trial with blinded outcome assessment. SETTING: Multidisciplinary rehabilitation clinics and general practitioners in Ontario, Canada. PARTICIPANTS: 340 participants with acute WAD grade I and II. Potential participants were sampled from a large automobile insurer when reporting a traffic injury. INTERVENTIONS: Participants were randomised to receive one of three protocols: government-regulated rehabilitation guideline, education and activation by general practitioners or a preferred-provider insurance-based rehabilitation. PRIMARY AND SECONDARY OUTCOME MEASURES: Our primary outcome was time to self-reported global recovery. Secondary outcomes included time on insurance benefits, neck pain intensity, whiplash-related disability, health-related quality of life and depressive symptomatology at 6 weeks and 3, 6, 9 and 12 months postinjury. RESULTS: The median time to self-reported global recovery was 59 days (95% CI 55 to 68) for the government-regulated guideline group, 105 days (95% CI 61 to 126) for the preferred-provider group and 108 days (95% CI 93 to 206) for the general practitioner group; the difference was not statistically significant (Χ2=3.96; 2 df: p=0.138). We found no clinically important differences between groups in secondary outcomes. Post hoc analysis suggests that the general practitioner (hazard rate ratio (HRR)=0.51, 95% CI 0.34 to 0.77) and preferred-provider groups (HRR=0.67, 95% CI 0.46 to 0.96) had slower recovery than the government-regulated guideline group during the first 80 days postinjury. No major adverse events were reported. CONCLUSIONS: Time-to-recovery did not significantly differ across intervention groups. We found no differences between groups with regard to neck-specific outcomes, depression and health-related quality of life. TRIAL REGISTRATION NUMBER: NCT00546806.

A Custom Radiopaque Thermoresponsive Chemotherapy-Loaded Hydrogel for Intratumoural Injection: An In Vitro and Ex Vivo Assessment of Imaging Characteristics and Material Properties.

PURPOSE: Thermoresponsive hydrogels are gels which have different properties at varying temperatures. The objective of this study was to assess the material characteristics, imaging properties and chemotherapeutic drug release profile of a novel radiopaque thermoresponsive hydrogel in vitro, which is liquid at room temperature but solidifies at body temperature, to determine potential suitability for intratumoural delivery. MATERIALS AND METHODS: An iodinated radiopaque thermoresponsive hydrogel was formulated using iodixanol at a range of concentrations and assessed for sol-gel transition, radiopacity and imaging using CT and US. A lead formulation containing iodixanol at a concentration of 9.22% weight by weight (w/w, g of iodixanol per g of hydrogel) was evaluated in vitro for injectability, disintegration and dual drug release of cisplatin and paclitaxel from the hydrogel formulation. RESULTS: Radiopacity of the hydrogel increased in a concentration-dependent manner, but the highest concentration of iodixanol evaluated in this study (13.83% w/w) adversely affected the sol-gel transition of the hydrogel; therefore, 9.22% w/w iodixanol hydrogel was identified as the lead formulation. This formulation was readily visible on both CT and US. The formulation was hand injectable through a range of clinically relevant devices, had a sustained disintegration profile for up to 28 days and was able to deliver a sustained release of chemotherapeutic drug for up to 10 days. CONCLUSIONS: Favourable in vitro and ex vivo imaging and material characteristics of this thermoresponsive gel are demonstrated, suggesting potential interventional oncology applications for image-guided intratumoural delivery of sustained-release chemotherapy.

Proteolytically released Lasso/teneurin-2 induces axonal attraction by interacting with latrophilin-1 on axonal growth cones.

A presynaptic adhesion G-protein-coupled receptor, latrophilin-1, and a postsynaptic transmembrane protein, Lasso/teneurin-2, are implicated in trans-synaptic interaction that contributes to synapse formation. Surprisingly, during neuronal development, a substantial proportion of Lasso is released into the intercellular space by regulated proteolysis, potentially precluding its function in synaptogenesis. We found that released Lasso binds to cell-surface latrophilin-1 on axonal growth cones. Using microfluidic devices to create stable gradients of soluble Lasso, we show that it induces axonal attraction, without increasing neurite outgrowth. Using latrophilin-1 knockout in mice, we demonstrate that latrophilin-1 is required for this effect. After binding latrophilin-1, Lasso causes downstream signaling, which leads to an increase in cytosolic calcium and enhanced exocytosis, processes that are known to mediate growth cone steering. These findings reveal a novel mechanism of axonal pathfinding, whereby latrophilin-1 and Lasso mediate both short-range interaction that supports synaptogenesis, and long-range signaling that induces axonal attraction.

The Role of Prognostic Scoring Systems in Assessing Surgical Candidacy for Patients With Vertebral Metastasis: A Narrative Review.

STUDY DESIGN: Narrative review. OBJECTIVES: To review the relevant literature regarding scoring systems for vertebral metastases and quantify their role in contemporary orthopedic practice. METHODS: A literature search of PubMed, Google Scholar, and Embase was performed on February 7, 2017. Eight scoring systems were selected for detailed review-7 of which were scores focused solely on patient prognosis (Tokuhashi, Tomita, Bauer, Oswestry Spinal Risk Index, Van der Linden, Rades, and Katagiri). The eighth system reviewed was the Spinal Instability Neoplastic Score, which examines for impending spinal instability in patients with vertebral metastases and represents a novel approach compared with hitherto scoring systems. RESULTS: The Bauer and Oswestry Spinal Risk Index have the most accurate prognostic predictive ability, with the newer Oswestry Spinal Risk Index being favored by the contemporary literature as it demands less investigation and is therefore more readily accessible. There was a growing trend in studies designed to customize scoring systems for individual cancer pathological subtypes. The Spinal Instability Neoplastic Score shows good reliability for predicting instability among surgeons and oncologists. CONCLUSIONS: The increased understanding of cancer pathology and subsequent development of customized treatments has led to prolonged survival. For patients with vertebral metastases, this affects surgical candidacy not only on the basis of prognosis but also provides prolonged opportunity for the development of spinal instability. Scoring systems have a useful guidance role in these deciding for/against surgical intervention, but in order to remain contemporary ongoing review, development, and revalidation is mandatory.

Self-processing photopolymer materials for versatile design and fabrication of holographic sensors and interactive holograms.

The aim of this paper is to discuss the benefits as well as the limitations of utilizing photopolymer materials in the design of holograms that are responsive to changes in their environment, such as changes in the concentration of a specific substance, temperature, and pressure. Three different case studies are presented, including both surface and volume phase holograms, in order to demonstrate the flexibility in the approach of utilizing holographic photopolymers for the design of sensors and interactive optical devices. First, a functionalized surface relief hologram is demonstrated to operate as an optical sensor for the detection of metal ions in water. The sensitivity and selectivity of the sensor are investigated. The second example demonstrates a volume transmission hologram recorded in a temperature-sensitive photopolymer and the memory effects of its exposure to elevated temperature. Finally, a pressure-sensitive reflection hologram that changes color under application of pressure is characterized, and its potential application in document authentication is described.

A novel quantitative electrochemical method to monitor DNA double-strand breaks caused by a DNA cleavage agent at a DNA sensor.

To date, DNA cleavage, caused by cleavage agents, has been monitored mainly by gel and capillary electrophoresis. However, these techniques are time-consuming, non-quantitative and require gel stains. In this work, a novel, simple and, importantly, a quantitative method for monitoring the DNA nuclease activity of potential anti-cancer drugs, at a DNA electrochemical sensor, is presented. The DNA sensors were prepared using thiol-modified oligonucleotides that self-assembled to create a DNA monolayer at gold electrode surfaces. The quantification of DNA double-strand breaks is based on calculating the DNA surface coverage, before and after exposure to a DNA cleavage agent. The nuclease properties of a model DNA cleavage agent, copper bis-phenanthroline ([CuII(phen)2]2+), that can cleave DNA in a Fenton-type reaction, were quantified electrochemically. The DNA surface coverage decreased on average by 21% after subjecting the DNA sensor to a nuclease assay containing [CuII(phen)2]2+, a reductant and an oxidant. This percentage indicates that 6 base pairs were cleaved in the nuclease assay from the immobilised 30 base pair strands. The DNA cleavage can be also induced electrochemically in the absence of a chemical reductant. [CuII(phen)2]2+ intercalates between DNA base pairs and, on application of a suitable potential, can be reduced to [CuI(phen)2]+, with dissolved oxygen acting as the required oxidant. This reduction process is facilitated through DNA strands via long-range electron transfer, resulting in DNA cleavage of 23%. The control measurements for both chemically and electrochemically induced cleavage revealed that DNA strand breaks did not occur under experimental conditions in the absence of [CuII(phen)2]2+.

An unusual pattern of peritubular capillary injury involving apoptosis in a renal transplant patient.

Microvascular injury is an important factor in renal allograft survival. Repeated episodes of endothelial injury from chronic antibody-mediated rejection typically manifest at the ultrastructural level as circumferential multilayering of remodeled glomerular basement membrane material and peritubular capillary basal lamina. In contrast to this typical pattern of microvascular injury, a renal transplantation case is presented in which focally dilated and multilayered segments of peritubular capillary basal lamina bearing lipid droplets were interspersed with ultrastructurally normal unilayered segments of basal lamina devoid of lipid droplets. Glomerular basement membranes were not affected by this process. The peak incidence of lipid droplets within the peritubular capillary walls coincided with a peak in apoptotic activity within the allograft. Lesser amounts of the same lipidic material were identified in the mesangial matrix and an arteriolar wall. Mesangial electron-dense deposits were detected at two weeks posttransplantation and their appearance coincided with elevated immunological activity in the glomeruli, as determined by immunofluorescence microscopy. The unusual ultrastructure and immunological activity observed in this case may reflect a process of impaired apoptotic clearance within the allograft. The six biopsies from a single patient are discussed in the setting of a highly sensitized renal transplant recipient who received prophylactic terminal complement blockade by eculizumab. The findings may be relevant to the study of apoptosis, efferocytosis, microvascular injury, eculizumab, rejection, lupus, and drug-related disease.

Profiling lung adenocarcinoma by liquid biopsy: can one size fit all?

BACKGROUND: Cancer is first and foremost a disease of the genome. Specific genetic signatures within a tumour are prognostic of disease outcome, reflect subclonal architecture and intratumour heterogeneity, inform treatment choices and predict the emergence of resistance to targeted therapies. Minimally invasive liquid biopsies can give temporal resolution to a tumour's genetic profile and allow the monitoring of treatment response through levels of circulating tumour DNA (ctDNA). However, the detection of ctDNA in repeated liquid biopsies is currently limited by economic and time constraints associated with targeted sequencing. METHODS: Here we bioinformatically profile the mutational and copy number spectrum of The Cancer Genome Network's lung adenocarcinoma dataset to uncover recurrently mutated genomic loci. RESULTS: We build a panel of 400 hotspot mutations and show that the coverage extends to more than 80% of the dataset at a median depth of 8 mutations per patient. Additionally, we uncover several novel single-nucleotide variants present in more than 5% of patients, often in genes not commonly associated with lung adenocarcinoma. CONCLUSION: With further optimisation, this hotspot panel could allow molecular diagnostics laboratories to build curated primer banks for 'off-the-shelf' monitoring of ctDNA by droplet-based digital PCR or similar techniques, in a time- and cost-effective manner.