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Supplementary Data from High-Content Phenotypic Profiling of Drug Response Signatures across Distinct Cancer Cells

Brody disease is a rare myopathy characterized by exercise-induced muscle stiffness caused by mutations in the ATP2A1 gene. In the largest cohort of Brody patients to date, Molenaar et al. clarify the phenotype and diagnostic possibilities to help improve understanding and recognition of this distinct myopathy., Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.

Thermal runaway is a major issue facing widespread adaptation of lithium-ion batteries. To achieve safe, thermally stable energy storage, various approaches have been proposed to regulate exothermic electrochemical reactions at high temperature, yet these have could only be either applied in aqueous systems or impractical in large-format cells. In this communication, we demonstrate that a copolymer, poly(2-chloroethyl vinyl ether-alt-maleic anhydride), or poly(CVE-MA), which exhibits a temperature-activated phase transition in organic solvents at high temperature, can be utilized as a thin film to inhibit lithium-ion migration/intercalation chemistries at the electrode/electrolyte interface. A large voltage drop and capacity decrease were observed at 80 °C due to interfacial hindrances imposed by the phase transition and resultant precipitation of poly(CVE-MA). This development of responsive polymers in organic solvents holds great potential for the future thermal safety of lithium-ion batteries.

Type 1 myotonic dystrophy (DM1) causes sleep disordered breathing and respiratory failure due to a combination of obstructive sleep apnoea, reduced central drive and respiratory muscle weakness. Noninvasive ventilation (NIV) is commonly used for treating respiratory failure in neuromuscular disease; however, there have been few studies assessing the role of NIV in DM1. The aim of this retrospective service evaluation was to investigate the impact of NIV adherence on hypercapnia and symptoms of hypoventilation in patients with DM1. Data on capillary carbon dioxide tension (PCO2), lung function, adherence to NIV and symptoms of hypoventilation were obtained from the records of 40 patients with DM1. Mean capillary PCO2 significantly reduced from 6.81±1.17 kPa during supervised inpatient set-up to 5.93±0.82 kPa after NIV set-up (p, Commencing patients with myotonic dystrophy on noninvasive ventilation appears to reverse respiratory failure despite poor adherence to ventilation https://bit.ly/343XUGK

Purpose of review To examine recent developments relating to cardiac involvement in the adult idiopathic inflammatory myopathies (IIM) and those inherited muscle diseases which may present in adulthood and mimic IIM.Recent findings Cardiac involvement is a common feature of IIM and inherited muscle diseases. Frequency according to disease subtype varies, with serotype having particular influence in IIM, and genotype in the inherited muscle diseases. Innovative techniques for examining cardiac function have been investigated further, including speckle-tracking echocardiography and cardiac magnetic resonance tomography. The present work has highlighted a likely underestimate of the burden of cardiac disease to date. The complex relationship between IIM, atherosclerosis, and traditional cardiovascular risk factors has been further elucidated. Consensus recommendations for managing patients with inherited muscle diseases and prominent cardiac involvement have been recently published. In addition to supportive care, disease modifying treatments are increasingly becoming available for inherited muscle diseases which may also improve cardiac outcomes.Summary Cardiac involvement is associated with significant morbidity and mortality. We suggest having a low threshold for considering the possibility of cardiac involvement in all patients with muscle disease.

Thermally stable electrochemical devices are ideal due to their stabilized performance and longer service life at extreme temperatures. However, ageing in supercapacitors, which is caused by generation of heat induced by high voltage, current, temperature, and aided by temperature induced self-accelerating reactions, plague the performance and lead to shortened service life. Poly(N-isopropylacrylamide) (PNIPAM) has been one of the most studied temperature responsive polymers (TRPs) in the past decades; it has a lower critical solution temperature (LCST) around 32 °C. By integrating PNIPAM into aqueous electrolyte, it was found that once LCST is reached, the specific capacitance of supercapacitors is reduced, which is accredited to drag of ion migration and precipitated polymer chains reside upon electrode surface. The capacitance reduction is even more obvious when the electrolyte solute changed into large size solute potassium ferricyanide. In terms of specific capacitance, comparing to an increase of the control, the PNIPAM integrated systems experienced a decrease under 70 °C. The integration of TRPs into electrochemical systems offers alternative approach to suppress high temperature capacitive reactions and ageing, thus could guarantee longer service life, performance stabilized supercapacitors.

Thermal runaway is posing big threat towards common electrochemical devices, such as lithium ion batteries and supercapacitors. It is caused by heat accumulated within electrochemical device and can cause devices to lose functionality, shorten service-life, or even cause hazardous fires and explosions. One effective approach to tackle thermal runaway is to break the electrochemical reaction Arrhenius thermal loop by introducing reaction inhibiting components into the system. Herein, through facile wet casting method, a temperature responsive polymer, poly(N-isopropylacrylamide) (PNIPAM) was cast into thin film and sandwiched in between polypropylene (PP) to make into a temperature responsive separator. It was found that once the temperature rose to 70 °C, instead of increasing in capacitance like in the control, PNIPAM-included batches decreased in capacitance. This capacitance reduction was mainly contributed by increased charge transfer resistance, which was caused by the sol–gel transition and precipitating PNIPAM chains residing upon PP membrane. A similar capacitance reduction was also observed for the ferricyanide redox system. Further investigation also revealed thicker PNIPAM films exhibited enhanced capacitance reduction and scan rate dependency. Temperature responsive polymer separators may prove to be an effective method to suppress high temperature electrochemical reactions and thus offer promise to reversible, thermally stabilized electrochemical devices.

Idiopathic inflammatory myopathies represent a rare group of diseases characterized by a central role of autoimmune processes and the inflammation of skeletal muscle. There has been significant recent progress in understanding disease pathogenesis, phenotyping subtypes of disease and investigating effective therapeutic options. Patients typically present with progressive, proximal weakness and functional impairment, and elevated muscle enzymes. There can also have extramuscular manifestations, including skin, respiratory, articular, gastrointestinal and cardiovascular involvement, which can precede or occur in the absence of clinically detectable muscle involvement. There are therefore a multitude of potential differential diagnoses to consider. A conscientious initial evaluation supported by pragmatically structured investigations remains critical to accurate diagnosis and appropriate management of these complex conditions.

The power density of redox flow batteries (RFBs) utilized on iron‐containing electrolytes is improved by incorporating iron particle redox mediators into the electrodes. Nonpurified carbon nanotube (CNT) electrodes containing iron nanoparticles, formed during the synthesis of CNTs using the ferrocene−xylene process, are activated to create “hotspots” for faradaic energy storage that reduces losses associated with kinetical, ohmic, and mass transfer resistances. CNT electrodes are activated through cyclic voltammetry to initiate charge transfer interactions between redox electrolytes and iron nanoparticles in the electrode. RFBs with modified electrodes experience a 140% increase in power density and a 57% increase in energy density in coin‐cell configurations. Economic value and ready availability of iron paired with enhanced performance make iron RFBs a viable option for future RFB research. Herein, the highest peak power density yet reported for an iron‐based RFB at 180 mW cm−2 with iron‐modified electrodes under no electrolyte flow is demonstrated.

Rapid resource consumption and shifting public perspective on traditional electricity sources has forced the development of renewable energy sources, such as wind and solar energy. Redox flow batteries have become an important research area due to their independent power density and energy density, which is unique for electrochemical energy conversion and storage devices. These batteries are designed for grid-scale energy storage to be paired with wind and solar energy to create power grids that are not dependent on fossil fuels. The DOE has issued a 2023 target of 150 $/KWh and current all-vanadium chemistries approach these levels solely in vanadium costs. Therefore, other chemistries need to be developed that have long term stability, affordability, high performance, and utilize the high conductivity of water. Electrode doping facilitates charge transfer reactions at the electrode/electrolyte interface by improving the wettability and activity of the electrode to permit higher power and energy systems. These developments and inventive chemistries provide opportunities to employ cheaper chemistries to help meet the future demand for renewable energy. The recent developments in aqueous redox flow batteries utilizing chemistries other than vanadium are discussed in this review.

Metabolic myopathies are a diverse group of rare genetic disorders and their associated muscle symptoms may be subtle. Patients may present with indolent myopathic features, exercise intolerance or recurrent rhabdomyolysis. Diagnostic delays are common and clinicians need a high index of suspicion to recognise and differentiate metabolic myopathies from other conditions that present in a similar fashion. Standard laboratory tests may be normal or non-specific, particularly between symptomatic episodes. Targeted enzyme activity measurement and next-generation genetic sequencing are increasingly used. There are now specific enzyme replacement therapies available, and other metabolic strategies and gene therapies are undergoing clinical trials. Here, we discuss our approach to the adult patient with suspected metabolic myopathy. We outline key features in the history and examination and discuss some mimics of metabolic myopathies. We highlight some disorders of glycogen and fatty acid utilisation that present in adulthood and outline current recommendations on management.

Mitochondrial complex I deficiency is associated with a diverse range of clinical phenotypes and can arise due to either mitochondrial DNA (mtDNA) or nuclear gene defects. We investigated two adult patients who exhibited non-syndromic neurological features and evidence of isolated mitochondrial complex I deficiency in skeletal muscle biopsies. The first presented with indolent myopathy, progressive since age 17, while the second developed deafness around age 20 and other relapsing-remitting neurological symptoms since. A novel, likely de novo, frameshift variant in MT-ND6 (m.14512_14513del) and a novel maternally-inherited transversion mutation in MT-ND1 were identified, respectively. Skewed tissue segregation of mutant heteroplasmy level was observed; the mutant heteroplasmy levels of both variants were greater than 70% in muscle homogenate, however, in blood the MT-ND6 variant was undetectable while the mutant heteroplasmy level of the MT-ND1 variant was low (12%). Assessment of complex I assembly by Blue-Native PAGE demonstrated a decrease in fully assembled complex I in the muscle of both cases. SDS-PAGE and immunoblotting showed decreased levels of mtDNA-encoded ND1 and several nuclear encoded complex I subunits in both cases, consistent with functional pathogenic consequences of the identified variants. Pathogenicity of the m.14512_14513del was further corroborated by single-fiber segregation studies.

Importance Malignant pleural effusion (MPE) is challenging to manage. Talc pleurodesis is a common and effective treatment. There are no reliable data, however, regarding the optimal method for talc delivery, leading to differences in practice and recommendations. Objective To test the hypothesis that administration of talc poudrage during thoracoscopy with local anesthesia is more effective than talc slurry delivered via chest tube in successfully inducing pleurodesis. Design, Setting, and Participants Open-label, randomized clinical trial conducted at 17 UK hospitals. A total of 330 participants were enrolled from August 2012 to April 2018 and followed up until October 2018. Patients were eligible if they were older than 18 years, had a confirmed diagnosis of MPE, and could undergo thoracoscopy with local anesthesia. Patients were excluded if they required a thoracoscopy for diagnostic purposes or had evidence of nonexpandable lung. Interventions Patients randomized to the talc poudrage group (n = 166) received 4 g of talc poudrage during thoracoscopy while under moderate sedation, while patients randomized to the control group (n = 164) underwent bedside chest tube insertion with local anesthesia followed by administration of 4 g of sterile talc slurry. Main Outcomes and Measures The primary outcome was pleurodesis failure up to 90 days after randomization. Secondary outcomes included pleurodesis failure at 30 and 180 days; time to pleurodesis failure; number of nights spent in the hospital over 90 days; patient-reported thoracic pain and dyspnea at 7, 30, 90, and 180 days; health-related quality of life at 30, 90, and 180 days; all-cause mortality; and percentage of opacification on chest radiograph at drain removal and at 30, 90, and 180 days. Results Among 330 patients who were randomized (mean age, 68 years; 181 [55%] women), 320 (97%) were included in the primary outcome analysis. At 90 days, the pleurodesis failure rate was 36 of 161 patients (22%) in the talc poudrage group and 38 of 159 (24%) in the talc slurry group (adjusted odds ratio, 0.91 [95% CI, 0.54-1.55]; P = .74; difference, –1.8% [95% CI, –10.7% to 7.2%]). No statistically significant differences were noted in any of the 24 prespecified secondary outcomes. Conclusions and Relevance Among patients with malignant pleural effusion, thoracoscopic talc poudrage, compared with talc slurry delivered via chest tube, resulted in no significant difference in the rate of pleurodesis failure at 90 days. However, the study may have been underpowered to detect small but potentially important differences. Trial Registration ISRCTN Identifier: ISRCTN47845793

Mitochondrial complex I deficiency is associated with a diverse range of clinical phenotypes and can arise due to either mitochondrial DNA (mtDNA) or nuclear gene defects. We investigated two adult patients who exhibited non-syndromic neurological features and evidence of isolated mitochondrial complex I deficiency in skeletal muscle biopsies. The first presented with indolent myopathy, progressive since age 17, while the second developed deafness around age 20 and other relapsing-remitting neurological symptoms since. A novel, likely de novo, frameshift variant in MT-ND6 (m.14512_14513del) and a novel maternally-inherited transversion mutation in MT-ND1 were identified, respectively. Skewed tissue segregation of mutant heteroplasmy level was observed; the mutant heteroplasmy levels of both variants were greater than 70% in muscle homogenate, however, in blood the MT-ND6 variant was undetectable while the mutant heteroplasmy level of the MT-ND1 variant was low (12%). Assessment of complex I assembly by Blue-Native PAGE demonstrated a decrease in fully assembled complex I in the muscle of both cases. SDS-PAGE and immunoblotting showed decreased levels of mtDNA-encoded ND1 and several nuclear encoded complex I subunits in both cases, consistent with functional pathogenic consequences of the identified variants. Pathogenicity of the m.14512_14513del was further corroborated by single-fiber segregation studies.

Nanoporous carbon materials are widely utilized in high-power supercapacitors due to their structural properties, chemical stability and conductivity, despite their limited energy density and charge storage capacity. Conducting polymers, on the other hand, possess high charge capacities; however, their application in commercial devices is hindered by degradation arising from their poor chemical and physical stability. Composites of carbon nanomaterials and conducting polymers have synergistic properties beneficial to supercapacitors, such as high capacitance and stability, but the limitations in scalable synthesis and polymer aggregation prevent widespread utilization. In this work, robust freestanding carbon nanotube (CNT)/electrically conducting polymer (ECP) electrodes are prepared using a simple dispersion filtration method, which can easily be scaled up. This process eliminates the use of binder, substrate or additional inactive weight. Composite CNT/ECP electrodes showed enhanced capacitance and charge capacity, achieving values up to 448 F/g and 84 mAh/g compared to 27 F/g and 10 mAh/g for pure CNT electrodes in aqueous electrolyte. Resulting symmetric cells exhibited energy and power densities of similar to 5 Wh/kg and similar to 283 W/kg, respectively, in aqueous electrolytes; and 12 Wh/kg and 744 W/kg, respectively, in organic electrolytes when using PEDOT/CNT electrodes. Given the process simplicity, relatively low cost and high throughput, the present composites have great potential for large-scale manufacturing of CP/CNTs supercapacitor electrodes. (C) 2016 Elsevier B.V. All rights reserved.

Enzymatic cell disruption is a promising, highly energy-efficient technology for recovery of cellular compounds from microalgal cells, but it has not been applied at large scale because of its low cost-efficiency. In this work, we present a novel and highly efficient approach to enhance enzymatic disruption of Chlorella protothecoides cell walls to recover the lipid contents and cell wall compositional sugars. When thermoresponsive polymers, such as poly-( N -isopropylacrylimide-co-allylamine), were mixed with microalgal cell suspensions, cell disruption was increased from 22 to 68%, with equivalent increases in lipid recovery. The use of thermoresponsive polymers allows for simple and efficient separation of polymers after product recovery for reuse in subsequent batches. The highest cell disruption and associated lipid yield reached about 68% and 59%, respectively, which was achieved using 10 mol-% amine copolymers with a loading of 0.05 g/g algal biomass dry weight (BDW). During this process, about 50% of dry algal cell wall was converted to reducing sugars. Furthermore, we found that copolymers were able to disrupt algal cells in the absence of enzyme. Polymer loadings of 0.1 g/g BDW led to the highest cell disruption and lipid recovery for 6 h contact time reaching 32% and 30%, respectively. A quantitative and morphological analysis on polymer-enhanced microalgal cell disruption is presented, indicating that the polymer may function by stressing and breaking the cell wall and/or protecting enzyme from denaturation.

ObjectivesWith the tools available currently, confirming the diagnosis of inclusion body myositis (IBM) can be difficult. Many patients are initially misdiagnosed with polymyositis (PM). In this observational study at a UK adult neuromuscular centre, we investigated whether amyloid positron emission tomography could differentiate between IBM and PM.MethodsTen patients with IBM and six with PM underwent clinical review, [18F]florbetapir positron emission tomography and MRI of skeletal musculature. Differences in [18F]florbetapir standardised uptake value ratios in skeletal muscle regions of interest were evaluated. Relationships between [18F]florbetapir standardised uptake value ratios and measures of disease severity (clinical and by MRI of skeletal muscle) were assessed.Results[18F]florbetapir standardised uptake value ratios were significantly higher in those with IBM compared with PM for all assessed regions (total-[18F]florbetapir standardised uptake value ratio 1.45 (1.28 to 2.05) vs 1.01 (0.80 to 1.22), p=0.005). For total-[18F]florbetapir standardised uptake value ratios≥1.28, sensitivity and specificity for IBM was 80% and 100%, respectively.Conclusions[18F]florbetapir amyloid positron emission tomography differentiates IBM from PM. Successful development could facilitate accurate diagnosis, inclusion in clinical trials and help avoid unnecessary exposure to potentially harmful treatments.

Background The recently published 2017 European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups reflect a long-appreciated need for more accurate case definition in ongoing research in these complex and heterogenous diseases.1 However a number of issues remain unresolved. There was a high frequency of missing data in both the derivation and validation samples, only one of the now numerous myositis specific autoantibodies is included, and certain well recognised IIM subtypes are not specifically classified despite their well phenotyped and differing natural histories, clinical features and treatment modalities.2 3 Objectives To perform an external validation of the EULAR/ACR classification criteria in an incident IIM cohort and examine how classification criteria-assigned IIM subtype correlates with expert opinion. Methods Adults with newly diagnosed IIM attending Salford Royal NHS Foundation Trust Neuromuscular services were identified. A retrospective review of all putative cases was performed, and cases fulfilling a consensus expert-opinion diagnosis of definite IIM included. A broad range of clinical, serological and histological data were collected and each case assigned a single IIM subtype by expert opinion. The EULAR/ACR classification criteria were applied and sensitivity, specificity, positive and negative predictive value calculated, presented with 95% confidence intervals (CI). Results A total of 922 cases were screened with 255 expert opinion definite IIM identified. The sensitivity to diagnose an IIM was 99.6% (97.2–100) and 80.9% (76.0–85.8) for the classification criteria cut-points of ‘probable’ and ‘definite’ respectively. The sensitivity for ‘definite’ IIM improved to 90.2% (86.5–93.8) when biopsy data for 24/34 initially missed cases were excluded. In 94/255 cases the IIM subtype differed between expert opinion and classification criteria, most strikingly in the group subtyped ‘polymyositis’ using the EULAR/ACR criteria, where there was discrepancy in the majority (87/161). Conclusions The criteria performed with high sensitivity in identifying IIM in an external cohort of IIM patients. However, substantial disagreement exists in subtype assignment, especially resulting in a larger proportion of cases of ‘polymyositis’ with heterogeneous features, important to consider in the application of these criteria to subsequent research. References [1] Lundberg IE, Tjarnlund A, Bottai M, Werth VP, Pilkington C, Visser M De, et al. EULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis2017;76:1955–64. [2] Betteridge Z, McHugh N. Myositis-specific autoantibodies: An important tool to support diagnosis of myositis. J Intern Med2016;280:8–23. [3] Longo DL, Dalakas MC. Inflammatory muscle diseases. N Engl J Med2015;372:1734–47. Disclosure of Interest None declared

Background Studying the epidemiology of rare conditions such as the idiopathic inflammatory myopathies (IIM) can assist in the identification of risk factors, disease associations and temporal trends. Interrogation of differing geographically and genetically diverse populations can help to construct a more complete picture of underlying disease patterns. A number of UK centres have contributed to national and international IIM research collaborations, but to date there has been no published report detailing the incidence or prevalence of adult IIM in the UK, or to establish the relative proportion of the varying clinical subtypes. Moreover, previous international studies have focussed on specific IIM subtypes, such as inclusion body myositis (IBM) or immune-mediated necrotising myopathy (IMNM), are historic, were undertaken before recent developments in our understanding of the range of IIM subtypes, and utilised widely varying methodologies and case acquisition strategies. The recently published combined European League Against Rheumatism and American College of Rheumatology (EULAR/ACR) classification criteria for adult and juvenile IIM represent potential progress in identifying IIM, as well as various disease subtypes 1 . We present here the first epidemiological study to utilise these new criteria as part of disease verification. Objectives Identify and characterise all incident adult cases of IIM between Jan 1 st 2007 and Dec 31 st 2016 in the City of Salford, UK. Methods Adults first diagnosed with IIM within the study period were identified by: i) a Salford Royal NHS Foundation Trust (SRFT)inpatient episode IIM-specific ICD-10 coding search; ii) all new patient appointments to SRFT neuromuscular outpatient clinics; iii) all Salford residents enrolled within the UKMYONET study. All patients with ‘definite’ IIM by the 2017 EULAR/ACR classification criteria were included, as were ‘probable’ cases if expert opinion agreed. Cases were excluded if Results The case ascertainment procedures identified 1156 cases which, after review and application of exclusion criteria, resulted in 32 incident cases during the study period. 23/32 were female with a mean age of 58.1 years. The mean incidence of adult IIM was 17.6/1,000,000 person years (py), higher for females than for males (25.2 versus 10.0/1,000,000py respectively). A significant incidence increase over time was apparent (13.6 versus 21.4/1,000,000py; p=0.032). Using EULAR/ACR classification criteria, the largest IIM subtype (21/32) was polymyositis, followed by dermatomyositis (8/32), inclusion body myositis (2/32) and amyopathic dermatomyositis (1/32). Expert opinion subtype differed from EULAR/ACR Classification criteria in 19/32 cases. Conclusions The incidence of adult IIM in Salford is 17.6/1,000,000py, higher in females and is increasing over time. Disagreement exists between EULAR/ACR-derived and expert opinion-derived IIM subtype assignments. References [1] Lundberg IE, Tjarnlund A, Bottai M, et al. EULAR/ACR Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies and their Major Subgroups. Ann Rheum Dis. 2017;76:1955–64. Disclosure of Interest None declared

Drug combination testing in the pharmaceutical industry has typically been driven by late-stage opportunistic strategies rather than by early testing to identify drug combinations for clinical investigation that may deliver improved efficacy. A rationale for combinations exists across a number of diseases in which pathway redundancy or resistance to therapeutics are evident. However, early assays are complicated by the absence of both assay formats representative of disease biology and robust infrastructure to screen drug combinations in a medium-throughput capacity. When applying drug combination testing studies, it may be difficult to translate a study design into the required well contents for assay plates because of the number of compounds and concentrations involved. Dispensing these plates increases in difficulty as the number of compounds and concentration points increase and compounds are subsequently rolled onto additional labware. We describe the development of a software tool, in conjunction with the use of acoustic droplet technology, as part of a compound management platform, which allows the design of an assay incorporating combinations of compounds. These enhancements to infrastructure facilitate the design and ordering of assay-ready compound combination plates and the processing of combinations data from high-content organotypic assays.

Lignin is unique among renewable biopolymers in having significant aromatic character, making it potentially attractive for a wide range of uses from coatings to carbon fibers. Recent research has shown that hot acetic acid (AcOH)–water mixtures can be used to recover “ultraclean” lignins of controlled molecular weight from Kraft lignins. A key feature of this discovery is the existence of a region of liquid–liquid equilibrium (LLE), with one phase being rich in the purified lignin and the other rich in solvent. Although visual methods can be used to determine the temperature at which solid lignin melts in the presence of AcOH–water mixtures to form LLE, the phase transition can be seen only at lower AcOH concentrations due to solvent opacity. Thus, an electrochemical impedance spectroscopy (EIS) technique was developed for measuring the phase-transition temperature of a softwood Kraft lignin in AcOH–water mixtures. In electrochemical cells, the resistance to double-layer charging (i.e., polarization resistance Rp) is related to the concentration and mobility of free ions in the electrolyte, both of which are affected by the phases present. When the lignin–AcOH–water mixture was heated through the phase transition, RP was found to be a strong function of temperature, with the maximum in RP corresponding to the transition temperature obtained from visual observation. As the system is heated, acetate ions associate with the solid lignin, forming a liquefied, lignin-rich phase. This association increases the overall impedance of the system, as mobile acetate ions are stripped from the solvent phase and thus are no longer available to adsorb on the polarizing electrode surfaces. The maximum in RP occurs once the new lignin-rich phase has completely formed, and no further association of the lignin polymer with AcOH is possible. Except at sub-ambient temperatures, the phase-transition temperature was a strong function of solvent composition, increasing linearly from 18 °C at 70/30 AcOH/water to 97 °C at 10/90 wt% AcOH/water.

Microalga is a promising feedstock for biofuel, chemical, food, and animal feed; however, harvesting is a critical barrier for its commercial application. This communication demonstrates a new harvesting technology by utilizing the phase separation of thermoresponsive polymers and charged copolymers of N-isopropylacrylamide and allylamine. Chlorella protothecoides cells are separated from solution when the mixture of algae and polymers is heated above the lower critical solution temperature of polymers (~ 32 °C), where the polymer phase separates from the aqueous media and aggregates into a solid–gel phase. It was found that copolymer concentration, allylamine content (mol%) and charge (based on initial solution pH) affect the extent of polymer phase separation and alga separation efficiency. The copolymer containing allylamine with lower than 2.6 mol% displayed nearly complete algal cell separation at polymer concentrations of 25–50 mg/mL and pH 7. The results indicated that thermoresponsive polymers provide a promising technology for alga harvesting using recyclable and reusable materials.

Macromolecular ionomer solutions exhibiting macroscopic properties that change in response to temperature are referred to as thermally responsive polymer electrolytes (RPEs). Such materials provide a means to control electrochemical systems using an external stimulus that affects the polymer phase behavior and electrolyte properties. RPEs were synthesized with N-isopropylacrylamide, which governs the thermal properties, and varying fractions of acrylic acid, which provides ionic properties. These polymers undergo a thermally activated phase separation in aqueous solutions at a given temperature, thereby altering the ionic strength, pH, and conductivity of the electrolyte solution. In this article, we demonstrate how the molecular properties of RPEs, specifically the ionic composition, influence the temperature-dependent electrolyte properties and the extent to which these electrolytes can control the activity of redox electrodes. Materials with high ionic content provide the highest room temperature ion conductivity and redox activity; however, RPEs with low ionic content provide the highest “on–off” ratio in electrochemical activity at elevated temperatures.

Objectives The aim was to identify and characterize all incident adult cases of idiopathic inflammatory myopathies (IIM) between 1 January 2007 and 31 December 2016 in the City of Salford, UK. Methods Adults first diagnosed with IIM within the study period were identified by: a Salford Royal NHS Foundation Trust (SRFT) inpatient episode IIM-specific ICD-10 coding search; all new patient appointments to SRFT neuromuscular outpatient clinics; and all Salford residents enrolled within the UKMYONET study. All patients with definite IIM by the 2017 EULAR/ACR classification criteria were included, as were probable cases if consensus expert opinion agreed. Cases were excluded if

A 43-year-old woman with a history of recently diagnosed metastatic melanoma was commenced on systemic therapy with nivolumab, an anti-programmed cell death-1 monoclonal antibody and one of an increasing group of the so-called ‘immune checkpoint inhibitors’. She experienced a dramatic complete response within 6 months of initiation. However, in addition to developing incident autoimmune hypothyroidism, she also developed progressive fatigue, proximal weakness, myalgia and dysphagia. Initial investigations with blood tests, electrophysiology and a muscle biopsy were non-specific or normal. Subsequent examination revealed ‘woody’ thickening of the subcutaneous tissues of the forearms, thighs and calves consistent with fasciitis. MRI and a full-thickness skin–muscle biopsy were ultimately diagnostic of a likely iatrogenic autoimmune myofasciitis. The clinical manifestations only responded partly to prednisolone 30 mg orally and treatment was escalated to include intravenous immunoglobulin. At 3 months, this has only resulted in a modest incremental improvement.

Metabolic myopathies are caused by defects in the metabolic processes of energy storage and utilization, and can present with exercise intolerance, fatigue, muscle pain, and weakness. Metabolic myopathies are rare and can be difficult to diagnose. However, the clinical presentation can be similar to, and thus mimic, both the idiopathic inflammatory myopathies and other genetic muscle disorders including the muscular dystrophies. Careful enquiry about the nature and timing of muscle pain, as well as identification of other clinical ‘red-flags’, can highlight the possibility of a metabolic myopathy. The possibility of metabolic myopathy or muscular dystrophy mimicking myositis should be considered early in ‘treatment-resistant myositis’ or ‘seronegative myositis’. The diagnosis of metabolic myopathies depends on a multidisciplinary team, an awareness of the increasing availability of enzyme activity testing and the utility of expanding genetic technologies. In some cases, dietary manipulation and enzyme replacement therapies are useful treatments.

The integration of new materials in commercial energy storage systems faces many challenges, such as scalable manufacturing, charge–discharge efficiency, long term cycle stability, and high power and high energy density. Compared with conventional high-surface area carbon nanomaterials, electroactive conducting polymers (ECPs) exhibit an increase in energy density, which is attractive for next generation supercapacitor electrode materials. When designed with micro- and nanoscale dimensions, ECP electrodes display an increase in power density by decreasing the ion diffusion length in bulk electrodes. Here, we describe a template-free method for synthesizing polypyrrole microtubes on various stainless steel meshes with a process inherently scalable to large-area substrates. Microtube growth is governed by the nucleation of hydrogen gas at the mesh joints as a result of proton reduction at the platinum counter electrode. Depending on the size and spacing of the mesh wires and the substrate proximity to the working electrode, polypyrrole microtubes can be created with cylindrical and conical shapes with diameters ranging from 50–400 μm and heights up to 1400 μm. Polymer electrodes exhibiting cylindrical structures electrochemically grown with electrode potentials below 0.8 V exhibit excellent electrochemical performance comparable to thin polymer films. The process scalability is demonstrated using larger area substrates (up to 4 cm2) by carefully controlling the spacing between the working (substrate) and counter electrodes, which also provides an increase in microtube density from 350 cm−2 to 560 cm−2 without any loss in performance.

For the purpose of realizing inherently safe high-power Li-ion batteries, a model Li4Ti5O12/LiFePO4 rechargeable battery is investigated using the thermally responsive polymer, poly(benzyl methacrylate), in an ionic liquid. At high temperature, battery operation is inhibited as a result of increased internal resistance caused by polymer and ionic liquid phase separation. Li-ion concentration is shown to affect the phase transition temperature and the extent to which batteries are deactivated.

Energy storage has emerged as a critical challenge due to the increasing demand to utilize energy from intermittent, renewable resources. Furthermore, growing interest in decreasing our dependence on petroleum necessitates the development of safe and efficient energy storage for transportation. Li-ion batteries have emerged as the premier candidate to meet these demands; however, such systems are limited by thermal hazards (runaway reactions, fires, explosions), which become increasingly dangerous in large-format batteries. We have developed an electrolyte system comprising poly(ethylene oxide), an ionic liquid and lithium salt that exhibits an intrinsic mechanism for inhibiting device operation when the temperature increases beyond a given threshold, which is attributed to polymer–ionic liquid phase separation. In the following article, we describe how the thermally activated phase separation causes a decrease in ion conductivity, thereby affecting the concentration of ions at the electrode, in addition to an increase in charge transfer resistance from the formation of a polymer coating on the porous electrode. Such mixtures provide a transformative approach to regulating electrochemical processes, which is necessary to achieve inherently safe operation of large format Li-ion batteries.

Advances in materials chemistry are necessary for low-cost energy storage to support energy generation from renewable sources and electric transportation. Renewable biopolymers, such as sodium lignosulfate (SLS), have attracted interest for electrodes when mixed with conducting polymers due to their higher charge-capacity and natural abundance. The availability of SLS is limited and will continue to decrease, while alkali lignin (AL), which accounts for 98% of lignin from paper-pulping, exhibits poor solubility in acidic electrolytes used for electropolymerization of conducting polymers. Here, we utilize organic acid solvents to overcome processing limitations in order to synthesize electrodes comprising polypyrrole (PPy) and SLS. Compared to PPy/SLS, electrodes containing PPy/AL exhibit an increase in capacitance from 312 F g−1 to 444 F g−1, and a decrease in relaxation time constant from 1.7 to 1 s. Furthermore, we showed that the electrochemical performance of PPy/AL electrodes could be further increased by incorporating AL with higher phenolic content that is obtained from an elevated-temperature, pH-driven fractionation process.

Considering muscle investigations may be appropriatein patients with connective tissue disease withunusual weakness.

ObjectivesAutoantibodies directed against cytosolic 5′-nucleotidase 1A have been identified in many patients with inclusion body myositis. This retrospective study investigated the association between anticytosolic 5′-nucleotidase 1A antibody status and clinical, serological and histopathological features to explore the utility of this antibody to identify inclusion body myositis subgroups and to predict prognosis.Materials and methodsData from various European inclusion body myositis registries were pooled. Anticytosolic 5′-nucleotidase 1A status was determined by an established ELISA technique. Cases were stratified according to antibody status and comparisons made. Survival and mobility aid requirement analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression.ResultsData from 311 patients were available for analysis; 102 (33%) had anticytosolic 5′-nucleotidase 1A antibodies. Antibody-positive patients had a higher adjusted mortality risk (HR 1.89, 95% CI 1.11 to 3.21, p=0.019), lower frequency of proximal upper limb weakness at disease onset (8% vs 23%, adjusted OR 0.29, 95% CI 0.12 to 0.68, p=0.005) and an increased prevalence of excess of cytochrome oxidase deficient fibres on muscle biopsy analysis (87% vs 72%, adjusted OR 2.80, 95% CI 1.17 to 6.66, p=0.020), compared with antibody-negative patients.InterpretationDifferences were observed in clinical and histopathological features between anticytosolic 5′-nucleotidase 1A antibody positive and negative patients with inclusion body myositis, and antibody-positive patients had a higher adjusted mortality risk. Stratification of inclusion body myositis by anticytosolic 5′-nucleotidase 1A antibody status may be useful, potentially highlighting a distinct inclusion body myositis subtype with a more severe phenotype.

The promise of multiwalled carbon nanotubes (MWNTs) for supercapacitor electrodes remains unfulfilled due to their poor energy density, which is limited by their redox inactivity. Here, we show a simple, alternative path to achieve Faradaic charge storage by harnessing intrinsic heterogeneity (e.g., Fe catalyst) of as-synthesized MWNTs, obviating the challenges of combining disparate materials in hybrid composite electrodes. In acidic solutions, MWNTs are ruptured by voltammetric cycling beyond the electrolysis limit, thereby exposing residual catalyst nanoparticles. The addition of Faradaic charge storage associated with the Fe2+/Fe3+ transition, results in a 4-fold increase in peak capacitance of MWNT electrodes (290 F/g) compared to purified MWNT electrodes (70 F/g), along with a 60% increase in charge capacity.

Research in carbon nanomaterials has seen tremendous growth in recent years; however, technological advances are limited by the lack of continuous and scalable synthesis methods. Here we present a scalable roll-to-roll process for synthesizing vertically-aligned multi-walled carbon nanotubes (VACNTs) on Al foil ribbons which are continuously drawn through a chemical vapor deposition (CVD) reactor operating at ambient pressure and a relatively low growth temperature (600 degrees C). Electrodes comprised of VACNT forests synthesized in this process are directly assembled into supercapacitor cells, which yield high power densities (1270 W/kg) and energy densities (11.5 Wh/kg). These devices exhibit excellent cycle stability with no loss in performance over more than a thousand cycles. (C) 2014 Elsevier Ltd. All rights reserved.

Electrochemical performance of iron redox flow batteries (RFBs) was improved through incorporating iron redox mediators into the electrodes. Unpurified carbon nanotubes electrodes containing ferrocene catalysts, from the carbon nanotubes synthesis, are activated to create “hotspots” for Faradaic charge transfer that reduces losses associated with activation, Ohmic, and mass transfer resistances. This permits higher discharge voltages at elevated discharge currents, which from Ohm’s Law (P = iE) establishes augmented power densities. Carbon nanotube electrodes are activated utilizing cyclic voltammetry, in an acidic environment, to initiate charge transfer interactions between redox electrolytes and iron nanoparticles in the electrode. Modified electrodes exhibited 141% gain in power density and a 56.5% improvement in energy density in coin cell devices. Economic value and ready availability of iron paired with enhanced performance makes iron RFBs a viable option for future RFB research. The highest peak power density reported for all-iron RFBs to the author’s awareness was accomplished at 176 mW cm-2 with iron-modified electrodes under no electrolyte flow.

The advancement of novel materials to ameliorate interfacial charge transfer properties will drastically improve energy storage, heterogeneous catalysis, and various other electrochemical applications. Here we discuss a facile method that can utilize the Faradaic capabilities of residual iron nanoparticle catalysts that are captured within Multi-walled Carbon Nanotubes (MWNT) post-synthesis, thereby correcting the difficulties associated with creating hybrid nanocomposite electrodes. Non-purified MWNTs, experience a chemical oxidation procedure in an acidic environment with KMnO4 to partly “unzip” the MWNTs and reveal the redox-active iron nanoparticles to the electrolyte. A consistent redox peak affiliated with the Fe2+/3+ transition is achieved during the MWNT oxidation procedure yielding a ~350% improvement in capacitance (>300 F g-1) when compared to purified MWNT electrodes (70 F g-1). While these materials solely may be applicable as energy storage electrodes, the integration of redox species within an inert carbon electrode will also provide new opportunities to accelerate heterogeneous charge transfer reactions.

Growing demands for high energy/high power energy storage systems have driven research efforts toward devices such as supercapacitors that bridge the gap between high power capacitors and high energy batteries. Supercapacitors have experienced commercial success with high surface area activated carbon electrodes; however, these systems are limited by the surface area and physical charge storage through the electrical double layer mechanism. Redox materials, such as metal oxides and conductive polymers, have attracted interest because of the increase in energy density obtained through faradaic charge storage processes. One of the main drawbacks of conducting polymers, which are far more abundant and cost-effective relative to oxides, is their relatively low theoretical charge capacity. In this work, we report the use of a high-charge capacity redox molecule, 1,4-benzoquinone, to increase the energy density of polypyrrole electrodes. The electrode synthesis conditions are shown to have a significant influen...

Item does not contain fulltext Quantitative microscopy has proven a versatile and powerful phenotypic screening technique. Recently, image-based profiling has shown promise as a means for broadly characterizing molecules' effects on cells in several drug-discovery applications, including target-agnostic screening and predicting a compound's mechanism of action (MOA). Several profiling methods have been proposed, but little is known about their comparative performance, impeding the wider adoption and further development of image-based profiling. We compared these methods by applying them to a widely applicable assay of cultured cells and measuring the ability of each method to predict the MOA of a compendium of drugs. A very simple method that is based on population means performed as well as methods designed to take advantage of the measurements of individual cells. This is surprising because many treatments induced a heterogeneous phenotypic response across the cell population in each sample. Another simple method, which performs factor analysis on the cellular measurements before averaging them, provided substantial improvement and was able to predict MOA correctly for 94% of the treatments in our ground-truth set. To facilitate the ready application and future development of image-based phenotypic profiling methods, we provide our complete ground-truth and test data sets, as well as open-source implementations of the various methods in a common software framework.

Background The idiopathic inflammatory myopathies (IIM, myositis) are a heterogeneous group of chronic autoimmune disorders causing considerable physical and mental health impact. There is a lack of formalised guidance defining best practice for the management of myositis, contributing to inconsistent care provision and some patients feeling isolated and unsupported. To address these issues, we evaluated the clinical services available to adults with myositis in the UK. We then created patient-centred standards of care using a structured process involving patients, their relatives and caregivers, physicians and allied healthcare professionals. Methods After an initial focus group, the clinical services available to patients with myositis were evaluated using a patient-completed questionnaire. Draft standards of care were created, each addressing deficits in care provision identified by patients. In response to feedback, including a two-stage modified Delphi exercise, these draft standards were iteratively improved until consensus was reached. Accompanying plain language versions of the standards of care and an audit tool were also created. Results We identified issues regarding diagnostic pathways, access to specialist services, advice and support regarding employment, medication-related adverse events and the treatment of extra-muscular manifestations. Fifteen standards of care were drafted. After modification, agreement was reached on eleven final standards of care. Conclusion These patient-centred standards of care for adults with myositis provide a benchmark for the evaluation of local practice. Their implementation will promote consistent good practice across care providers and empower patients when seeking access to local services. Electronic supplementary material The online version of this article (10.1186/s41927-017-0002-7) contains supplementary material, which is available to authorized users.

Many reactions in both chemistry and biology rely on the ability to precisely control and fix the solution concentrations of either protons or hydroxide ions. In this report, we describe the behavior of thermally programmable pH buffer systems based on the copolymerization of varying amounts of acrylic acid (AA) groups into N-isopropylacrylamide polymers. Because the copolymers undergo phase transitions upon heating and cooling, the local environment around the AA groups can be reversibly switched between hydrophobic and hydrophilic states affecting the ionization behavior of the acids. Results show that moderate temperature variations can be used to change the solution pH by two units. However, results also indicate that the nature of the transition and its impact on the pH values are highly dependent on the AA content and the degree of neutralization.

Organic electronics are beginning to attract more interest for biosensor technology as they provide an amenable interface between biology and electronics. Stable biosensor based on electronic detection platform would represent a significant advancement in technology as costs and analysis time would decrease immensely. Organic materials provide a route toward that goal due to their compatibility with electronic applications and biological molecules. In this report, we detail the effects of experimental parameters, such as pH and concentration, toward the selective detection of DNA via surface-bound peptide nucleic acid (PNA) sequences on organic transistor biosensors. The OTFT biosensors are fabricated with thin-films of the organic semiconductor, 5,5′-bis-(7-dodecyl-9H-fluoren-2-yl)-2,2′-bithiophene (DDFTTF), in which they exhibit a stable mobility of 0.2 cm2 V−1 s−1 in buffer solutions (phosphate-buffer saline, pH 7.4 or sodium acetate, pH 7). Device performance were optimized to minimize the deleterious effects of pH on gate–bias stress such that the sensitivity toward DNA detection can be improved. In titration experiments, the surface-bound PNA probes were saturated with 50 nM of complementary target DNA, which required a 10-fold increase in concentration of single-base mismatched target DNA to achieve a similar surface saturation. The binding constant of DNA on the surface-bound PNA probes was determined from the concentration-dependent response (titration measurements) of our organic transistor biosensors.