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Neovascular age-related macular degeneration (nAMD) is a major cause of visual impairment and blindness. Anti-vascular endothelial growth factor (VEGF) agents, such as ranibizumab, bevacizumab, aflibercept, brolucizumab and faricimab have revolutionized the clinical management of nAMD. However, there remains an unmet clinical need for new and improved therapies for nAMD, since many patients do not respond optimally, may lose response over time or exhibit sub-optimal durability, impacting on real world effectiveness. Evidence is emerging that targeting VEGF-A alone, as most agents have done until recently, may be insufficient and agents that target multiple pathways (e.g., aflibercept, faricimab and others in development) may be more efficacious. This article reviews issues and limitations that have arisen from the use of existing anti-VEGF agents, and argues that the future may lie in multi-targeted therapies including alternative agents and modalities that target both the VEGF ligand/receptor system as well as other pathways.

Inherited retinal diseases (IRDs) are a heterogenous group of orphan eye diseases that typically result from monogenic mutations and are considered attractive targets for gene-based therapeutics. Following the approval of an IRD gene replacement therapy for Leber’s congenital amaurosis due to RPE65 mutations, there has been an intensive international research effort to identify the optimal gene therapy approaches for a range of IRDs and many are now undergoing clinical trials. In this review we explore therapeutic challenges posed by IRDs and review current and future approaches that may be applicable to different subsets of IRD mutations. Emphasis is placed on five distinct approaches to gene-based therapy that have potential to treat the full spectrum of IRDs: 1) gene replacement using adeno-associated virus (AAV) and nonviral delivery vectors, 2) genome editing via the CRISPR/Cas9 system, 3) RNA editing by endogenous and exogenous ADAR, 4) mRNA targeting with antisense oligonucleotides for gene knockdown and splicing modification, and 5) optogenetic approaches that aim to replace the function of native retinal photoreceptors by engineering other retinal cell types to become capable of phototransduction.

Most home energy management systems (HEMS) of fuel cell-based CHPs in existing literature are designed to dispatch fuel cell energy using forecasted electric and/or thermal load as direct input. This leads to dispatching errors associated with inaccurate forecasting. To address that issue, HEMSs of fuel cell-based CHP that features electric and thermal load scheduling have been proposed. However, these HEMSs were modelled assuming that fuel cell electric efficiency is constant. This results in poorer accuracy because, in practice, fuel cell electric efficiency varies with fuel cell electric output in a nonlinear manner. Rather than assuming that fuel cell electric efficiency is constant, nonlinear functions are used in this paper to represent fuel cell electric efficiency thus presenting a more accurate modelling for the HEMS of fuel cell-based CHP that features electric and thermal load scheduling. Simulation results show that the proposed HEMS is formulated correctly and performs energy management optimally.

Summary Extracellular vesicles (EVs) harbor a rich glycome—diverse sugar modifications—that mediates and reflects disease progression. Despite its clinical potential, the analysis of EV glycans remains challenging due to limitations of current glycomics technologies. Here, we develop a dedicated analytical platform to directly profile EV glycans in native biofluids. Termed integrated magnetic analysis of glycans in extracellular vesicles (iMAGE), the platform utilizes rationally designed polycore magnetic nanoparticles to transduce EV-bound glycans, but not that of free-floating glycoproteins, into magnetic signals; the resultant signals are readily quantified through a built-in magnetoresistance sensor. The iMAGE assay is thus fast (

The controlled assembly of nanomaterials into desired architectures presents many opportunities; however, current preparations lack spatial precision and versatility in developing complex nano-architectures. Inspired by the amphiphilic nature of surfactants, we develop a facile approach to guide nanomaterial integration – spatial organization and distribution – in metal-organic frameworks (MOFs). Named surfactant tunable spatial architecture (STAR), the technology leverages the varied interactions of surfactants with nanoparticles and MOF constituents, respectively, to direct nanoparticle arrangement while molding the growing framework. By surfactant matching, the approach achieves not only tunable and precise integration of diverse nanomaterials in different MOF structures, but also fast and aqueous synthesis, in solution and on solid substrates. Employing the approach, we develop a dual-probe STAR that comprises peripheral working probes and central reference probes to achieve differential responsiveness to biomarkers. When applied for the direct profiling of clinical ascites, STAR reveals glycosylation signatures of extracellular vesicles and differentiates cancer patient prognosis., Current methods for controlled assembly of nanomaterials into desired architectures often lack the precision and versatility to develop complex architectures. Here the authors report STAR, surfactant tunable spatial architecture, to guide nanomaterial integration in metal-organic frameworks.

Competitions and ever-changing customer requirements are the driven forces behind manufacturers to reevaluate their planning and scheduling methods and manufacturing systems. Customers’ satisfaction in most cases can be measured by the ability of the manufacturing firms to provide goods with reasonably good prices, acceptable quality standard and deliver at the right time. Scheduling plays an important role in all of the important issues that are considered to measure customers’ satisfaction. In recent years, there has been an increased interest in production planning problems in the multi product chemical and pharmaceutical industry. Multi product chemical plants use either a continuous production system or a batch production system. Batch process plants involve small amounts of a large variety of finished products, therefore are suitable for the production of small-volume, high-value added products. In such industry, products are often grouped into incompatible product families, where an intensive setup is incurred, whenever production changes from one product family to another. A classical example of the multi product chemical plants is the manufacturing of resins. Typically, in the resin production environment , the planning and scheduling task starts by considering a set of orders where each order specifies the product and the amount to be manufactured as well as the promised due date. The most important task of the planner is the so-called batching of orders. Batching of orders is the process of transforming customers’ product orders into sets of batches to be planned and subsequently assigned due date. This process is commonly practiced in the industry such as this, since a batch is frequently shared by several orders with the earliest one determining the batch due date. Moreover, while the planner is carrying out this task, his/her objective is to minimize as much as possible the setups between products that are generated from incompatible families. Therefore, in such manufacturing environment, setup activities cannot be disregarded and the production range is usually composed of a number of incompatible product families, in a way that no setup is required between production of two products belonging to the same family; long and expensive setup operations are required otherwise. Scheduling is known as a decision-making process of allocating limited resources over time in order to perform a collection of tasks for the purpose of optimizing certain objectives functions (Baker 1974). Tasks can have difference in their priority levels, ready time, and O pe n A cc es s D at ab as e w w w .ite ch on lin e. co m

OBJECTIVES To investigate the effects of pre-hospital stroke screening and notification on reperfusion therapy for patients with acute ischaemic stroke. METHODS Pre-hospital stroke screening criteria were established based on a modified version of the Face Arm Speech Time (FAST) test. Screening was performed during ambulance transport by emergency medical service (EMS) personnel who completed a 2-hour training session on stroke screening. Temporal trends affecting acute ischaemic stroke investigation and intervention were compared before and after implementation of the pre-hospital screening. RESULTS From July 2018 to October 2019, 298 patients with suspected stroke were screened by EMS personnel during ambulance transport prior to hospital arrival. Of these 298 patients, 213 fulfilled the screening criteria, 166 were diagnosed with acute stroke, and 32 received reperfusion therapy. The onset-to-door time was shortened by more than 1.5 hours (100.6 min vs 197.6 min, P

The utility of mechanical metamaterials for biomedical applications has seldom been explored. Here we show that a metamaterial that is mechanically responsive to antibody-mediated biorecognition can serve as an optical interferometric mask to molecularly profile extracellular vesicles in ascites fluid from patients with cancer. The metamaterial consists of a hydrogel responsive to temperature and redox activity functionalized with antibodies to surface biomarkers on extracellular vesicles, and is patterned into micrometric squares on a gold-coated glass substrate. Through plasmonic heating, the metamaterial is maintained in a transition state between a relaxed form and a buckled state. Binding of extracellular vesicles from the patient samples to the antibodies on the hydrogel causes it to undergo crosslinking, induced by free radicals generated via the activity of horseradish peroxidase conjugated to the antibodies. Hydrogel crosslinking causes the metamaterial to undergo fast chiral re-organization, inducing amplified changes in its mechanical deformation and diffraction patterns, which are detectable by a smartphone camera. The mechanical metamaterial may find broad utility in the sensitive optical immunodetection of biomolecules.

Biologically templated plasmonics enables simultaneous biophysical and biomolecular analysis of exosome biomarkers., Exosomes are nanoscale vesicles distinguished by characteristic biophysical and biomolecular features; current analytical approaches, however, remain univariate. Here, we develop a dedicated platform for multiparametric exosome analysis—through simultaneous biophysical and biomolecular evaluation of the same vesicles—directly in clinical biofluids. Termed templated plasmonics for exosomes, the technology leverages in situ growth of gold nanoshells on vesicles to achieve multiselectivity. For biophysical selectivity, the nanoshell formation is templated by and tuned to distinguish exosome dimensions. For biomolecular selectivity, the nanoshell plasmonics locally quenches fluorescent probes only if they are target-bound on the same vesicle. The technology thus achieves multiplexed analysis of diverse exosomal biomarkers (e.g., proteins and microRNAs) but remains unresponsive to nonvesicle biomarkers. When implemented on a microfluidic, smartphone-based sensor, the platform is rapid, sensitive, and wash-free. It not only distinguished biomarker organizational states in native clinical samples but also showed that the exosomal subpopulation could more accurately differentiate patient prognosis.

INTRODUCTION The human brain is a highly neuroplastic ‘complex’ network: it self-organises without a hard blueprint, adapts to evolving circumstances, and can withstand insults. However, similar to other naturally occurring networks, brain networks can only endure a finite amount of damage before cognitive processes are affected. In this study, we first sought to establish the brain networks governing domain-general cognition (DGC) in healthy individuals across the lifespan. We then sought to map, track, and potentially rehabilitate networks governing DGC through connectomics and non-invasive brain stimulation (NIBS) when damaged by low-grade gliomas (LGG) and surgical oncology. METHODS Using MRI and cognitive data from n=629 individuals (aged 18–88, Female= 51%), we assessed the structural, functional, and topological relevance of the spatially-distributed multiple-demand (MD) system for DGC. Next, in n=17 patients undergoing glioma surgery, we longitudinally acquired connectomic and cognitive data at multiple time points: pre-surgery and post-surgery Day 1, Month 3, Month 12. In an independent cohort of n=34 patients, we sought to establish the safety profile for “interventional neurorehabilitation”: connectome-driven NIBS in the acute post-operative period to accelerate cognitive recovery. RESULTS In healthy individuals, the MD system across multiple scales of biological organisation was positively associated with higher-order cognition (Catell’s fluid intelligence). In our patients, pre-operative LGG infiltration into the structural MD system was negatively associated with the number of long-term cognitive deficits, suggesting a functional reorganisation. Mixed-effects modelling demonstrated the resilience of the functional MD system to infiltration and resection, while the early post-operative period was critical for effective neurorehabilitation. Graph analyses revealed increased perioperative modularity can distinguish patients with long-term cognitive improvements at one-year follow-up. Finally, NIBS within two weeks post-craniotomy had a 90% (n=31/34) recruitment rate into the trial. There were no seizures or serious complications due to NIBS in this patient population. Transient headaches and tingling were reported in a minority of patients. CONCLUSION For the first time, we elucidate long-term cognitive and network trajectories following LGG surgery while establishing a positive safety-profile for NIBS in the acute post-operative period. We argue that “mesoscale” brain mapping serves as a robust biomarker for intervention-related plasticity for future clinical trials. While we performed these experiments in the context of neurosurgery, connectomics and NIBS could be adopted across diverse neuro-oncological care pathways (i.e. chemotherapy/radiation).

Novel approaches to pre-transplant conditioning are needed to improve treatment of advanced T-cell malignancies. We investigated the synergism of fludarabine (Flu), clofarabine (Clo), busulfan (Bu), and romidepsin (Rom) in T-cell lines and patient-derived cell samples. [Flu+Clo+Bu+Rom] had combination indexes of 0.4-0.5 at ∼50% cytotoxicity in PEER and SUPT1 cells, suggesting synergism. Drug exposure resulted in histone modifications, DNA-damage response (DDR), increased reactive oxygen species (ROS), decreased glutathione (GSH) and mitochondrial membrane (MM) potential, and apoptosis. Similar activation of DDR and apoptosis was observed in patient samples. The PI3K-AKT-mTOR, NFκB, Raf-MEK-ERK, JAK-STAT and Wnt/β-catenin pro-survival pathways were inhibited by the 4-drug combination. The SAPK/JNK stress pathway was activated. A novel finding was the down-regulation of the drug transporter MRP1. We propose the following mechanisms of synergism: Flu, Clo and Rom induce histone modifications and chromatin remodeling, exposing DNA to Bu alkylation; the increased production of ROS, due to drug-mediated stress response and decreased GSH, damages the MM causing leakage of pro-apoptotic factors; down-regulation of MRP1 increases intracellular Bu concentration and exacerbates the DDR; and inhibition of multiple survival pathways. Our results provide the basis for a clinical trial to evaluate [Flu+Clo+Bu+Rom] as part of conditioning regimen for refractory T-cell malignancy patients undergoing stem cell transplantation.

Background Response to disease-modifying antirheumatic drugs (DMARDs) is heterogenous. Clinical information and baseline characteristics do not allow reliable prediction of which trajectory patients will follow after DMARD initiation. Objectives We analysed the change in disease activity over the first two years of treatment in rheumatoid arthritis (RA) to identify different treatment response patterns among RA patients initiating DMARDs. We wanted to establish a predictive model for identifying patients with different treatment response patterns. Methods We selected patients from our prospective RA disease registry who have been treated for three months or fewer at study entry. We analysed the change of the disease activity, as defined by the DAS28–ESR, over the subsequent two years. A predictive model with parameters from three time points is proposed to stratify patients according to the outcomes. Results We analysed the data from 179 patients over 1044 study visits. We discerned three groups of patients according to disease activity trajectories:1the first group (53%) has high DAS at study entry and approach remission after 18 months;2the second group (22%) has high DAS at entry that remained elevated throughout the study period; and,3the third group of patients (25%) started with moderately high DAS and reached remission after 3 months of treatment. Patients at risk of being in the third group can be identified using data from three time points, at initiation of DMARDs, at 3 months and at 6 months. Conclusions RA patients showed three distinct disease activity trajectories with treatment. Our model can categorise patients into these groups. References [1] Aga Ab, et al. Time trends in disease activity, response and remission rates in rheumatoid arthritis during the past decade: results from the NOR-DMARD study 2000–2010. Ann Rheum Dis2015;381–8. [2] Courvoisier DS, et al. Rheumatoid arthritis patients after initiation of a new biologic agent: trajectories of disease activity in a large multinational cohort study. EBioMedicine 2016;302–306. [3] Siemons L, Ten Klooster PM, Vonkeman HE, Glas CAW, Van de Laar MAF. J. Distinct trajectories of disease activity over the first year in early rheumatoid arthritis patients following a treat to-target strategy. Arthritis Care Res2014;66:625–630. [4] Aga Ab, et al. Time trends in disease activity, response and remission rates in rheumatoid arthritis during the past decade: results from the NOR-DMARD study 2000–2010. Ann Rheum Dis 2015,381–8 [5] Courvoisier DS, et al. Rheumatoid arthritis patients after initiation of a new biologic agent: trajectories of disease activity in a large multinational cohort study. EBioMedicine 2016,302–306 [6] Siemons, L., Ten Klooster, P. M., Vonkeman, H. E., Glas, C. A. W. & Van de Laar, M. a F. J. Distinct trajectories of disease activity over the first year in early rheumatoid arthritis patients following a treat to-target strategy. Arthritis Care Res.66, 625–630(2014) Disclosure of Interest None declared

AIMS Rejection of renal allografts following transplantation continues to be a major impediment to long-term graft survival. Although acute vascular rejection (AVR) is associated with a high risk of graft loss, it remains unclear whether AVR with accompanied cellular or acute humoral rejection (AHR) have dissimilar outcomes. The aim of this registry study was to examine the association between subtypes of AVR and graft loss. METHODS Using Australia and New Zealand Dialysis and Transplant registry, primary kidney transplant recipients between 2005 and 2012 whose first rejection episode was AVR were included and categorized into AVR-none (AVR without other rejections), AVR-CG (AVR with cellular and/or glomerular rejections), and AVR-AHR (AVR with AHR). Association between AVR groups and graft loss was examined using logistic and Cox regression models. RESULTS Of the 274 recipients, 61 (22.3%) experienced AVR-none, 79 (28.8%) AVR-AHR and 134 (48.9%) AVR-CG. Compared with AVR-none and AVR-CG, AVR-AHR was associated with the highest incidence of overall graft loss at 3 months (12%, 10% and 27%, respectively, χ(2) = 11.88, P = 0.003). AVR-AHR was associated with almost a threefold greater risk of death-censored graft loss compared with AVR-none (adjusted hazard ratio 2.84, 95% confidence interval 1.22-2.62, P

Monoclonal antibodies (moAb) represent a novel way of delivering therapy through specific target antigens expressed on lymphoma cells and minimizes the collateral damage that is common with conventional chemotherapy. The paradigm of this approach is the targeting of CD20 by rituximab. Since its FDA approval in 1997, rituximab has become the standard of care in almost every line of therapy in most B-cell lymphomas. This review will briefly highlight some of the key rituximab trials while looking more closely at the evidence that is bringing other antibodies, including next generation anti-CD20 moAbs, and anti-CD30 moAbs, among others to the forefront of lymphoma therapy.