Crizanlizumab for retinal vasculopathy with cerebral leukoencephalopathy in a phase II clinical study.

BackgroundRetinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare, autosomal dominant, universally fatal disease without effective treatment options. This study explores the safety and preliminary efficacy of crizanlizumab, a humanized monoclonal antibody against P-selectin approved for the prevention of sickle cell crises, in slowing retinal nonperfusion and preserving vision in patients with RVCL-S.METHODSEleven patients with RVCL-S with confirmed exonuclease 3 prime repair exonuclease 1 (TREX1) mutations received monthly crizanlizumab infusions over 2 years. The study measured the nonperfusion index within 3 retinal zones and the total retina with fluorescein angiography, visual acuity, intraocular pressure (IOP), and optical coherence tomography central subfield thickness (CST) at baseline, 1 year, and 2 years. A mixed repeated-measures analysis was performed to assess the progression rates and changes from baseline.RESULTSEleven participants received crizanlizumab infusions. All of the participants tolerated crizanlizumab well, with 8 of 11 (72.7%) reporting mild adverse effects such as nausea, fatigue, and gastrointestinal symptoms. The change in total retinal nonperfusion was 7.22% [4.47, 9.97] in year 1 and -0.69% [-4.06, 2.68] in year 2 (P < 0.001). In the mid periphery, the change in nonperfusion was 10.6% [5.1, 16.1] in year 1 and -0.68% [-3.98, 5.35] in year 2 (P < 0.01), demonstrating a reduction in progression of nonperfusion in the second year of treatment. Visual acuity, IOP, and CST remained stable.CONCLUSIONCrizanlizumab has an acceptable safety profile. These results show promising potential for examining crizanlizumab in larger studies of RVCL-S and similar small-vessel diseases and for using the retina as a biomarker for systemic disease.Trial registrationClinicalTrials.gov NCT04611880.FUNDINGThe Clayco Foundation; DeNardo Education and Research Foundation Grant; Jeffrey T. Fort Innovation Fund; Siteman Retina Research Fund; unrestricted grant from Research to Prevent Blindness Inc.; National Heart,Lung, and Blood Institute (NHLBI), NIH (R01HL129241); National Institute of Neurological Disorders and Stroke (NINDS), NIH (RF1NS116565).

Interventions for Proliferative Vitreoretinopathy.

Clinical Question: What is the efficacy of pharmacologic interventions in preventing proliferative vitreoretinopathy? Bottom Line: There is limited high-quality evidence to support currently available pharmacological options for prevention of proliferative vitreoretinopathy.

Multimodal Structural and Functional Characterization of Retinal Vasculopathy with Cerebral Leukoencephalopathy.

OBJECTIVE: To describe and quantify the structural and functional consequences of retinal vasculopathy with cerebral leukoencephalopathy (RVCL) on the neurosensory retina. DESIGN: Cross sectional descriptive study from December 2021 to December 2022. PARTICIPANTS: Retinal vasculopathy with cerebral leukoencephalopathy patients (n = 9, 18 eyes) recruited from the RVCL Research Center at Washington University in St. Louis. METHODS: Retinal vasculopathy with cerebral leukoencephalopathy patients underwent comprehensive ophthalmological evaluation including OCT, OCT angiography (OCTA), ultrawidefield fundus imaging, retinal autofluorescence, dark adaptation, electroretinography (ERG), Goldmann kinetic perimetry, and fluorescein angiography (FA). MAIN OUTCOME MEASURES: Comprehensive characterization from various modalities including best-corrected visual acuity, central subfield thickness (µm) from OCT, foveal avascular zone (mm2) from OCTA, dark adaptation rod intercept (seconds), cone response in ERG, and presence or absence of vascular abnormalities, leakage, neovascularization, and nonperfusion on FA. RESULTS: A total of 18 eyes from 9 individuals were included in this study. The best-corrected visual acuity ranged from 20/15 to 20/70. The mean central subfield thickness from OCT was 275.8 µm (range, 217-488 µm). The mean foveal avascular zone (FAZ) from OCTA was 0.65 (range, 0.18-1.76) mm2. On dark adaptometry, the mean time was 5.02 (range, 2.9-6.5) minutes, and 1 individual had impaired dark adaptation. Electroretinography demonstrated mild cone response impairment in 4 eyes. On FA, there was evidence of macular and peripheral capillary nonperfusion in 16 of 18 eyes and notable areas of vascular leakage and retinal edema in 5 of the 18 eyes. CONCLUSIONS: This study illustrates the phenotypic spectrum of disease and may be clinically valuable for aiding diagnosis, monitoring disease progression, and further elucidating the pathophysiology of RVCL to aid in the development of therapies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Smart Sensor-Based Monitoring Technology for Machinery Fault Detection.

Rotary machines commonly use rolling element bearings to support rotation of the shafts. Most machine performance imperfections are related to bearing defects. Thus, reliable bearing condition monitoring systems are critically needed in industries to provide early warning of bearing fault so as to prevent machine performance degradation and reduce maintenance costs. The objective of this paper is to develop a smart monitoring system for real-time bearing fault detection and diagnostics. Firstly, a smart sensor-based data acquisition (DAQ) system is developed for wireless vibration signal collection. Secondly, a modified variational mode decomposition (MVMD) technique is proposed for nonstationary signal analysis and bearing fault detection. The proposed MVMD technique has several processing steps: (1) the signal is decomposed into a series of intrinsic mode functions (IMFs); (2) a correlation kurtosis method is suggested to choose the most representative IMFs and construct the analytical signal; (3) envelope spectrum analysis is performed to identify the representative features and to predict bearing fault. The effectiveness of the developed smart sensor DAQ system and the proposed MVMD technique is examined by systematic experimental tests.

A New Monitoring Technology for Bearing Fault Detection in High-Speed Trains.

In this work, a new monitoring system is developed for bearing fault detection in high-speed trains. Firstly, a data acquisition system is developed to collect vibration and other related signals wirelessly. Secondly, a new multiple correlation analysis (MCA) technique is proposed for bearing fault detection. The MCA technique consists of the three processing steps: (1) the collected vibration signal is decomposed by variational modal decomposition (VMD) to formulate the representative intrinsic mode functions (IMFs); (2) the MCA is used to process and identify the characteristic features for signal analysis; (3) bearing fault is diagnosed by examining bearing characteristic frequency information on the envelope power spectrum. The effectiveness of the proposed MCA fault detection technique is verified by experimental tests corresponding to different bearing conditions.

A New Recursive Trigonometric Technique for FPGA-Design Implementation.

This paper presents a new recursive trigonometric (RT) technique for Field-Programmable Gate Array (FPGA) design implementation. The traditional implementation of trigonometric functions on FPGAs requires a significant amount of data storage space to store numerous reference values in the lookup tables. Although the coordinate rotation digital computer (CORDIC) can reduce the required FPGA storage space, their implementation process can be very complex and time-consuming. The proposed RT technique aims to provide a new approach for generating trigonometric functions to improve communication accuracy and reduce response time in the FPGA. This new RT technique is based on the trigonometric transformation; the output is calculated directly from the input values, so its accuracy depends only on the accuracy of the inputs. The RT technique can prevent complex iterative calculations and reduce the computational errors caused by the scale factor K in the CORDIC. Its effectiveness in generating highly accurate cosine waveform is verified by simulation tests undertaken on an FPGA.

Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis.

Adenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than the chronic myeloid leukemia blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21) or inv(16) translocations. In t(8;21) AML, RUNX1-driven transcription of ADAR2 was repressed by the RUNX1-ETO additional exon 9a fusion protein in a dominant-negative manner. Further functional studies confirmed that ADAR2 could suppress leukemogenesis specifically in t(8;21) and inv16 AML cells dependent on its RNA editing capability. Expression of 2 exemplary ADAR2-regulated RNA editing targets coatomer subunit α and component of oligomeric Golgi complex 3 inhibits the clonogenic growth of human t(8;21) AML cells. Our findings support a hitherto, unappreciated mechanism leading to ADAR2 dysregulation in CBF AML and highlight the functional relevance of loss of ADAR2-mediated RNA editing to CBF AML.

Pan-cancer pervasive upregulation of 3' UTR splicing drives tumourigenesis.

Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) that are important post-transcriptional regulators. In cancer, shortening at 3' UTR ends via alternative polyadenylation can activate oncogenes. However, internal 3' UTR splicing remains poorly understood as splicing studies have traditionally focused on protein-coding alterations. Here we systematically map the pan-cancer landscape of 3' UTR splicing and present this in SpUR ( http://www.cbrc.kaust.edu.sa/spur/home/ ). 3' UTR splicing is widespread, upregulated in cancers, correlated with poor prognosis and more prevalent in oncogenes. We show that antisense oligonucleotide-mediated inhibition of 3' UTR splicing efficiently reduces oncogene expression and impedes tumour progression. Notably, CTNNB1 3' UTR splicing is the most consistently dysregulated event across cancers. We validate its upregulation in hepatocellular carcinoma and colon adenocarcinoma, and show that the spliced 3' UTR variant is the predominant contributor to its oncogenic functions. Overall, our study highlights the importance of 3' UTR splicing in cancer and may launch new avenues for RNA-based anti-cancer therapeutics.

Silver-substituted hydroxyapatite inhibits Pseudomonas aeruginosa outer membrane protein F: A potential antibacterial mechanism.

Bone fractures are one of the most common injuries, and they have a big effect on population health worldwide. Traumatic bone injuries can be partially treated with implanting bone-graft substitutes, for example, hydroxyapatite (HA), a bioceramic that is similar materially to natural bones with good bioactivity and osteoconductivity. It could, however, be vulnerable to infections because of the way an HA-based bone graft is put in, which could be a weakness in the host's defense. This study incorporated silver (Ag) into hydroxyapatite (Ag-HA) and silicon-containing hydroxyapatite (AgSi-HA) discs to combat this implant-triggered infection. Further, we investigated the antibacterial activities and potential underlying mechanism against a gram-negative bacterium, Pseudomonas aeruginosa. We noticed that the rich calcium (Ca2+) content in HA discs could trigger the change in P. aeruginosa physiology that leads to the enhanced bacterial growth on non­silver incorporated HA discs. But the released Ag+ from Ag-HA and AgSi-HA discs caused significant damage to bacterial cells at a low concentration of 0.3 ppm. We also observed dramatic morphological changes of Ag-HA and AgSi-HA surface-attached bacteria cells. Finally, we identified a potential action mechanism - the surface-bound Ag+ from Ag-HA and AgSi-HA potently inhibited the outer membrane protein F (OprF) expression of P. aeruginosa. Collectively, our results indicate that incorporating silver ions into HA could contribute viably to excellent antibacterial activities against P. aeruginosa to prevent HA-based bone graft infection.

3D-printed nails for aesthetic silicone prostheses.

BACKGROUND AND AIM: The nail is a crucially important part that needs to be closely reproduced in aesthetic silicone prostheses. The traditional method of producing prosthetic nails is a laborious process often fraught with errors and rejects. In this article, additive manufacturing or 3D printing intervention was sought to make this process less time-consuming and more exacting. STUDY DESIGN AND TECHNIQUE: With a focus on finger prosthesis, the process involves reverse engineering a patient's hand using a 3D scanner to obtain a digital blue print for referencing. 3D models of the nail shapes were created using CAD software. Colors sampling is obtained using image processing software from 2D digital images. Using specifically the inkjet technology from Stratasys, batches of nails of different sizes and colors were printed, which were then used for manual adhesion to silicone finger prostheses. RESULTS AND CONCLUSIONS: This article has demonstrated that 3D printing is able to produce nails of comparable quality with those produced by traditional methods in size, shape, curvature, and thickness. More consistent thickness, better size, and shape-matching using 3D files also minimize rejects and grinding time when finishing a prosthesis, leading to significant time savings. However, 3D-printed nails fall short in color match, surface texture, and life-likeness. Traditionally produced nails that are made using a more translucent grade of acrylic than that used in the 3D-printed nails are better able to reproduce the life-like coloration of the translucent human nail. The limitations encountered with 3D printing as applied to prosthetic nails production relate to camera settings, digital image color capture and display, differences in color system used in the printer and monitor, ambient lighting, and suitability of acrylic grade used with the proprietary 3D printing system for material translucency or opacity.

p53-NEIL1 co-abnormalities induce genomic instability and promote synthetic lethality with Chk1 inhibition in multiple myeloma having concomitant 17p13(del) and 1q21(gain).

Recurrent cytogenetic abnormalities are the main hallmark of multiple myeloma (MM) and patients having 2 or more high-risk prognostic events are associated with extremely poor outcome. 17p13(del) and 1q21(gain) are critical and independent high-risk cytogenetic markers, however, the biological significance underlying the poor outcome in MM patients having co-occurrence of both these chromosomal aberrations has never been interrogated. Herein, we identified that patients harbouring concomitant 17p13(del) with 1q21(gain) demonstrated the worst prognosis as compared to patients with single- (either 17p13(del) or 1q21(gain)) and with no chromosomal events (WT for both chromosomal loci); and they are highly enriched for genomic instability (GI) signature. We discovered that the GI feature in the patients with concomitant 17p13(del)-1q21(gain) was recapitulating the biological properties of myeloma cells with co-existing p53-deficiency and NEIL1 mRNA-hyper-editing (associated with chromosome 17p and 1q, respectively) that have inherent DNA damage response (DDR) and persistent activation of Chk1 pathway. Importantly, this became a vulnerable point for therapeutic targeting whereby the cells with this co-abnormalities demonstrated hyper-sensitivity to siRNA- and pharmacological-mediated-Chk1 inhibition, as observed at both the in vitro and in vivo levels. Mechanistically, this was attributable to the synthetic lethal relationship between p53-NEIL1-Chk1 abnormalities. The Chk1 inhibitor (AZD7762) tested showed good synergism with standard-of-care myeloma drugs, velcade and melphalan, thus further reinforcing the translational potential of this therapeutic approach. In summary, combination of NEIL1-p53 abnormalities with an ensuing Chk1 activation could serve as an Achilles heel and predispose MM cells with co-existing 1q21(gain) and 17p13(del) to therapeutic vulnerability for Chk1 inhibition.

Development of a Smart Clinical Bluetooth Thermometer Based on an Improved Low-Power Resistive Transducer Circuit.

Smart sensors have been used in many engineering monitoring and control applications. This work focuses on the development of a new type of clinical Bluetooth thermometer, based on an improved low-power resistive transducer circuit. Most existing resistive transducers use relatively complicated circuits with higher cost and power consumption. To tackle these problems, especially in real applications, an improved low-power resistive transducer circuit is proposed in this work and is used to develop smart Bluetooth thermometers. The parameters of the resistive transducer circuit are selected by quantitative analysis and optimization to improve the performance of the low-power resistive transducer circuit. The effectiveness of the proposed design technology was verified by tests. The temperature measurement error of the new smart Bluetooth thermometer is less than 0.1 °C, which can not only meet the clinical use requirements but also has lower cost and power consumption.

Linear-based gain-determining method for adaptive backstepping controller.

This paper presents a linear-based gain-determining method for nonlinear adaptive backstepping controllers. Usually, the gains for nonlinear controllers are tuned by the trial and error method. This method becomes more difficult as the number of gains increases. A user-friendly method is proposed in this work to deal with the problem. Firstly, a linear auxiliary system is formed by separating the linear parts from the nonlinear system. Then, linear state-space techniques are used to determine the gains for state-feedback by the linear auxiliary system. After that, by converting the state-feedback gains to backstepping gains, the gains of the nonlinear backstepping controller can be determined. The proficiency of the gain-determining method is proved by simulations with two linear techniques.

An evolving neuro-fuzzy classifier for fault diagnosis of gear systems.

Gear systems (or gearboxes) are widely used in rotating machinery. Reliable gear fault diagnostic techniques and systems are critically needed to provide early warning of a possible defect so as to prevent machinery operation degradation and to reduce costs related to predictive maintenance. In this work, a new evolving neuro-fuzzy (eNF) classifier is proposed for real-time gear system fault diagnostics. In evolving process, the constraints related to gear health states are used to guide the partition of the output space, to prevent possible misleading clusters. A new training algorithm based on the normalized Adadelta function is suggested to improve eNF training convergence and accuracy. The effectiveness of the proposed eNF classifier is tested by simulation and experiment tests.

Silver, silicon co-substituted hydroxyapatite modulates bacteria-cell competition for enhanced osteogenic function.

Combating bacteria while promoting tissue regeneration is an aim of highest priority for employing biomaterials in orthopedics that often embroiled with pre-operative contamination. Through simulating a surgical site infection environment and an infected implant site, we showcase the ability of a functionally modified hydroxyapatite, Ag,Si-HA that permits preferential adhesion of human bone marrow derived mesenchymal stem cells (BMSCs) over co-cultured bacterial pathogen,Pseudomonas aeruginosa, by displaying immediate suppression and killing of the bacteria present with minimum cytotoxicity for 28 d. And, at the same time, Ag,Si-HA stimulates BMSCs towards osteogenic differentiation despite being within the contaminated milieu. These findings provide well-defined requirements for incorporating antibacterial properties to biomaterials in managing pre-operative contamination. In addition, it highlights the dual positive attributes of Ag,Si-HA as an effective antibacterial biomaterial and at the same time, promotes bone tissue regeneration.

Carboxylic acid-functionalized polycarbonates as bone cement additives for enhanced and sustained release of antibiotics.

Despite the good clinical outcomes of total joint replacements, prosthetic joint infections still remain a significant cause of implant failure. Primary prophylaxis is key to stemming this burgeoning problem and its associated complications. In this study, a series of bone cement formulations with enhanced antibacterial performance have been developed through the addition of carboxylic acid-functionalized polycarbonate block copolymers to commercially available bone cement. Block copolymer design features were specifically tailored to modulate the acidity for adsorption of antibiotic and phase separation of the copolymers within the polymerizing/hardening of the cement during application. The best performing polymers demonstrated sustained antimicrobial release for more than 259 days and 147 days against S. aureus and P. aeruginosa, respectively, compared to 70 days of activity seen with commercially available gentamicin-containing cement control; whilst in vitro gentamicin release was increased by 8-fold. Total porosity was also increased 3-fold from 4.3% to 12.5%, whilst maintaining the mechanical integrity, working characteristics and osteoblastic biocompatibility of bone cement. Taken together, carboxylic acid-functionalized polycarbonates represent a promising class of bone cement additives that can be used to enhance the antibacterial performance of the bone cement whilst maintaining mechanical strength and cellular biocompatibility.

Short-duration chemoprophylaxis might reduce incidence of deep vein thrombosis in Asian patients undergoing total knee arthroplasty.

BACKGROUND: Venous thromboembolism (VTE) is a serious complication that may occur after total knee arthroplasty (TKA), leading to the recommendation of routine chemoprophylaxis by international guidelines. This study aims to determine if short-duration chemoprophylaxis after TKA reduces the incidence of VTE in an Asian population. METHODS: A retrospective study of 316 patients who underwent unilateral primary TKA between 1 January 2011 and 31 December 2013 was conducted. All patients received mechanical prophylaxis. One hundred seventeen patients (37%) received additional chemoprophylaxis, whereas 199 patients (63%) did not. A Doppler ultrasound (DUS) of both lower limbs was conducted for all patients within 6 days after surgery (median = 3 days) to assess for both proximal and distal DVT. Chemoprophylaxis in the form of enoxaparin (low molecular weight heparin; LMWH), aspirin, or heparin was administered until patients had a normal DUS, for a median duration of 4 days. Patients were followed up clinically for a minimum of 6 months to monitor for delayed or recurrent VTE and at least 2 years for patient-reported outcome measures. RESULTS: Overall, 24 patients (7.59%) developed deep vein thrombosis (DVT): three proximal and 21 distal DVTs. Twenty-three of the 24 patients were asymptomatic. Twenty of 199 patients (10.05%) with only mechanical prophylaxis developed DVT, whereas four of 117 patients (3.42%) with additional chemoprophylaxis developed DVT. Multivariate analysis showed that chemoprophylaxis use was associated with reduced incidence of DVT (odds ratio = 0.19, p value = 0.011). Other factors associated with increased DVT incidence include female gender (odds ratio = 5.45, p value = 0.034), positive history of cancer (odds ratio = 5.14, p value = 0.044), and increased length of stay in hospital (odds ratio = 1.19, p value < 0.001). CONCLUSIONS: Our study has shown that despite the low incidence of DVT in Asian patients undergoing TKA, short-duration chemoprophylaxis might be effective in reducing the incidence of DVT. However, most DVTs observed in our study were distal and may be of limited clinical significance. Further studies are needed to investigate the impact of chemoprophylaxis use on the incidence of PE and overall mortality rates among Asian patients.

Power-Saving Design of Radio Frequency Identification Sensor Networks in Bus Seatbelt Monitoring Systems.

Seatbelt state monitoring is important in intercity buses for passenger safety. This paper discusses the issues and challenges in power-saving design of radio frequency identification (RFID) sensor networks in bus seatbelt monitoring. A new design approach is proposed in this work for low-power layout and parameter setting in RFID sensor nodes in hardware and software design. A one-to-many pairing registration method is suggested between the concentrator and the seat nodes. Unlike using extra computer software to write seat identification (ID) into an integrated circuit (IC) card, the node ID in this project can be stored into the concentrator directly, which can reduce intermediate operations and reduce development costs. The effectiveness of the proposed low-power design approach is verified by some experimental tests.

Targeted Neuronal Injury for the Non-Invasive Disconnection of Brain Circuitry.

Surgical intervention can be quite effective for treating certain types of medically intractable neurological diseases. This approach is particularly useful for disorders in which identifiable neuronal circuitry plays a key role, such as epilepsy and movement disorders. Currently available surgical modalities, while effective, generally involve an invasive surgical procedure, which can result in surgical injury to non-target tissues. Consequently, it would be of value to expand the range of surgical approaches to include a technique that is both non-invasive and neurotoxic. Here, a method is presented for producing focal, neuronal lesions in the brain in a non-invasive manner. This approach utilizes low-intensity focused ultrasound together with intravenous microbubbles to transiently and focally open the Blood Brain Barrier (BBB). The period of transient BBB opening is then exploited to focally deliver a systemically administered neurotoxin to a targeted brain area. The neurotoxin quinolinic acid (QA) is normally BBB-impermeable, and is well-tolerated when administered intraperitoneally or intravenously. However, when QA gains direct access to brain tissue, it is toxic to the neurons. This method has been used in rats and mice to target specific brain regions. Immediately after MRgFUS, successful opening of the BBB is confirmed using contrast enhanced T1-weighted imaging. After the procedure, T2 imaging shows injury restricted to the targeted area of the brain and the loss of neurons in the targeted area can be confirmed post-mortem utilizing histological techniques. Notably, animals injected with saline rather than QA do demonstrate opening of the BBB, but dot not exhibit injury or neuronal loss. This method, termed Precise Intracerebral Non-invasive Guided surgery (PING) could provide a non-invasive approach for treating neurological disorders associated with disturbances in neural circuitry.