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Purpose:The Philadelphia chromosome–negative myeloproliferative neoplasms (MPN) polycythemia vera, essential thrombocythemia, and primary myelofibrosis are characterized by JAK/STAT pathway activation. JAK inhibitors are approved for MPN treatment, but persistence has been observed, due to JAK/STAT reactivation.Experimental Design:Using MPN patient samples, JAK2-mutated cell lines, and MPN mouse models, we examined both the efficacy and mechanism by which crizotinib, the ALK/MET/RON/ROS1 inhibitor approved for the treatment of non–small cell lung cancer, alters MPN cell proliferation and JAK/STAT activation.Results:We found that crizotinib suppresses proliferation and activation of JAK/STAT signaling, and decreases the disease burden in the JAK2V617F mouse model of MPN. Furthermore, we found that crizotinib could overcome JAK inhibitor persistence to ruxolitinib. Interestingly, phosphorylation of the crizotinib target RON kinase was enhanced in ruxolitinib-persistent cells. We show that phospho-JAK2 and phospho-RON can physically interact to sustain JAK/STAT signaling, and that the combination of crizotinib and ruxolitinib disrupts this interaction. Furthermore, RON knockdown suppresses proliferation and activation of JAK/STAT signaling in JAK2-mutated cells, and RON deletion in a JAK2V617F mouse MPN model decreases the disease burden. We also observed RON hyperactivation in MPN patient cells, suggesting that RON may be an important target of crizotinib in MPN.Conclusions:In summary, we demonstrate that crizotinib has preclinical efficacy in MPN patient cells, JAK2-mutated cell lines, and a JAK2-mutated mouse model, and that the combination of crizotinib with JAK inhibitors suppresses JAK inhibitor persistence. Our work suggests that crizotinib should be investigated for the treatment of patients with MPN.

Poorly designed and implemented medication labels have been identified as a source of medication errors within anesthesia delivery. Previous studies noted that simplified text and icons are useful in warning labels used for prescription drugs, especially for people with low literacy levels. In addition, Tallman lettering can reduce errors due to the custom capitalization of text. However, icons, color, and Tallman lettering have not been explored for improving the readability of anesthesia medication labels. This study utilizes a user- centered approach to design and evaluate icons and other graphical features to be included on secondary medication labels placed on infusion bags within anesthesia point-of-care. The study utilizes an iterative design process to examine the potential efficacy of these design characteristics by evaluating them with the anesthesia providers/clinicians through an online survey. Findings suggest that introducing graphical components like icons and color may be useful and accepted by clinicians to improve medication recognition.

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Purpose:The Philadelphia chromosome–negative myeloproliferative neoplasms (MPN) polycythemia vera, essential thrombocythemia, and primary myelofibrosis are characterized by JAK/STAT pathway activation. JAK inhibitors are approved for MPN treatment, but persistence has been observed, due to JAK/STAT reactivation.Experimental Design:Using MPN patient samples, JAK2-mutated cell lines, and MPN mouse models, we examined both the efficacy and mechanism by which crizotinib, the ALK/MET/RON/ROS1 inhibitor approved for the treatment of non–small cell lung cancer, alters MPN cell proliferation and JAK/STAT activation.Results:We found that crizotinib suppresses proliferation and activation of JAK/STAT signaling, and decreases the disease burden in the JAK2V617F mouse model of MPN. Furthermore, we found that crizotinib could overcome JAK inhibitor persistence to ruxolitinib. Interestingly, phosphorylation of the crizotinib target RON kinase was enhanced in ruxolitinib-persistent cells. We show that phospho-JAK2 and phospho-RON can physically interact to sustain JAK/STAT signaling, and that the combination of crizotinib and ruxolitinib disrupts this interaction. Furthermore, RON knockdown suppresses proliferation and activation of JAK/STAT signaling in JAK2-mutated cells, and RON deletion in a JAK2V617F mouse MPN model decreases the disease burden. We also observed RON hyperactivation in MPN patient cells, suggesting that RON may be an important target of crizotinib in MPN.Conclusions:In summary, we demonstrate that crizotinib has preclinical efficacy in MPN patient cells, JAK2-mutated cell lines, and a JAK2-mutated mouse model, and that the combination of crizotinib with JAK inhibitors suppresses JAK inhibitor persistence. Our work suggests that crizotinib should be investigated for the treatment of patients with MPN.

Supplementary Figures and figure legends

In India, approximately 70% of the total population is dependent on agriculture for their livelihood. Hence, it is essential to pay attention to agriculture to increase crop quality and quantity, thus increasing the overall cultivation yield. The traditional methods used require a lot of farmer’s effort and hard work, which results in delayed crop cultivation. Moreover, it’s challenging to predict the environmental conditions and detect the particular area where there are weeds, insects, etc., which requires immediate treatments, thus affecting overall crop production. So, there is a need to make it automated, and this can be done by adopting advanced techniques of precision agriculture (PA) or intelligent agriculture. Precision agriculture is one of the fields in which wireless sensor networks (WSNs) are widely adopted, which consists of a large number of sensors placed in the field to monitor and measure the various environmental parameters, such as humidity, temperature, soil moisture, soil PH value, precipitation, water level, etc., for enhancing the productivity, profitability, quantity, and quality of crops. The machine learning techniques can be applied to precision agriculture to increase crop growth, manage the process of crop cultivation, and create a perfect environment for the crops to increase productivity with less human effort. This paper provides an insight into various machine learning techniques used for precision agriculture using wireless sensor networks.

Ruxolitinib (JAK inhibitor) is effective in myelofibrosis, but suboptimal responses occur potentially from PI3K/AKT activation. In INCB50465-201 (NCT02718300), add-on parsaclisib (PI3Kδ inhibitor) showed preliminary efficacy in myelofibrosis patients. JAK inhibitors are associated with thrombocytopenia and patients with low platelet count (PC) are generally difficult to treat.Evaluate efficacy and safety of add-on parsaclisib in a subgroup analysis of study INCB50465-201 by baseline PC.Open-label, phase 2.Clinical study.Primary/secondary myelofibrosis patients with a suboptimal response (palpable spleen10 cm below left subcostal margin [LSM]; or palpable spleen 5-10 cm below LSM and active symptoms) after ≥6 months of receiving ruxolitinib (5-25 mg BID; stable dose ≥8 weeks).Patients on stable ruxolitinib dose randomized to either add-on parsaclisib 10 or 20 mg QD for 8 weeks then same dose QW or parsaclisib 5 or 20 mg QD for 8 weeks then 5 mg QD.Spleen volume (SV), Myelofibrosis-Symptoms Assessment Form Total Symptom Score (MFSAF-TSS v3.0), and safety based on baseline PC (low PC, 50-100×10At data cutoff (08/27/2020), 67 patients (low PC, n=21; higher PC, n=46) were enrolled. For low versus higher PC, the median prior duration of ruxolitinib treatment was 34.7 versus 14.9 months and baseline median (range) MFSAF-TSS was 21.4 (0.6-47) versus 10.0 (0-43), respectively. For low versus higher PC patients: 9/18 (50%) versus 15/38 (39.4%) had spleen volume reduction (SVR) ≥10% at week 12, 6/17 (35.2%) versus 13/35 (37.1%) at week 24; 0 versus 1 had SVR ≥35% at week 12, 2 versus 1 at week 24; median change in MFSAF-TSS was -20.5% versus -22.2% at week 12, -26.1% versus -23.1% at week 24, respectively. Nonhematologic treatment-emergent adverse events were mostly grade 1 or 2; most common (≥25%) were dyspnea (7/21, 33%), falls (7/21, 33%), and peripheral edema (6/21, 29%) for low PC; diarrhea (13/46, 28%) for higher PC. Thrombocytopenia led to parsaclisib interruption in 9/21 low-PC versus 3/46 higher-PC patients and ruxolitinib interruption in 1/21 low-PC patients.Add-on parsaclisib showed promising efficacy and combination therapy was generally well-tolerated in myelofibrosis patients with low or higher baseline PC.

Misreading labels, syringes, and ampoules is reported to make up a 54.4% of medication administration errors. The addition of icons to medication labels in an operating room setting could add additional visual cues to the label, allowing for improved discrimination, visibility, and easily processed information that might reduce medication administration errors. A multi-disciplinary team proposed a method of enhancing visual cues and visibility of medication labels applied to vasoactive medication infusions by adding icons to the labels. Participants were 1.12 times more likely to correctly identify medications from farther away (p < 0.001, AOR = 1.12, 95% CI: 1.02, 1.22) with icons. When icons were present, participants were 2.16 times more likely to be more confident in their identifications (p < 0.001, AOR = 2.16, 95%CI: 1.80, 2.57). Carefully designed icons may offer an additional method for identifying medications, and thus reducing medication administration errors.

The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people and crippled economies worldwide. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for this pandemic has triggered avid research on its pathobiology to better understand the pathophysiology of COVID-19. In the absence of approved antiviral therapeutic strategies or vaccine platforms capable of effectively targeting this global threat, the hunt for effective therapeutics has led to many candidates being actively evaluated for their efficacy in controlling or preventing COVID-19. In this review, we gathered current evidence on the innate nucleic acid-sensing pathways expected to be elicited by SARS-CoV-2 and the immune evasion mechanisms they have developed to promote viral replication and infection. Within the nucleic acid-sensing pathways, SARS-CoV-2 infection and evasion mechanisms trigger the activation of NOD-signaling and NLRP3 pathways leading to the production of inflammatory cytokines, IL-1β and IL-6, while muting or blocking cGAS-STING and interferon type I and III pathways, resulting in decreased production of antiviral interferons and delayed innate response. Therefore, blocking the inflammatory arm and boosting the interferon production arm of nucleic acid-sensing pathways could facilitate early control of viral replication and dissemination, prevent disease progression, and cytokine storm development. We also discuss the rationale behind therapeutic modalities targeting these sensing pathways and their implications in the treatment of COVID-19.

p53 together with its downstream product p21 plays an important role in tumorigenesis development. MDM2 and MDM4 are two p53 regulators. We studied the expression of p53, p21, MDM2, and MDM4 in a total of 120 cases of myeloid neoplasms including MDS, AML or MDS/MPN, and control, using single and double immunohistochemical stains. We found TP53 mutations had a worse outcome in patients with AML/MDS, and p53 expression detected by immunohistochemistry had a similar prognostic value. p21 expression was strongly related to TP53 mutation status, with loss of expression in almost all TP53 mutated cases. MDM2 and MDM4 were highly expressed in hematopoietic cells in both benign and neoplastic cells. MDM2/p53 double positive cells exceeded MDM4/p53 double positive cells in neoplastic cases. Finally, we observed that p21 protein expression was up regulated upon the use of ALRN-6924 (Aileron) while no significant changes were seen in p53, MDM2 and MDM4 expression.

BackgroundHigh throughput non-destructive phenotyping is emerging as a significant approach for phenotyping germplasm and breeding populations for the identification of superior donors, elite lines, and QTLs. Detection and counting of spikes, the grain bearing organs of wheat, is critical for phenomics of a large set of germplasm and breeding lines in controlled and field conditions. It is also required for precision agriculture where the application of nitrogen, water, and other inputs at this critical stage is necessary. Further, counting of spikes is an important measure to determine yield. Digital image analysis and machine learning techniques play an essential role in non-destructive plant phenotyping analysis.ResultsIn this study, an approach based on computer vision, particularly object detection, to recognize and count the number of spikes of the wheat plant from the digital images is proposed. For spike identification, a novel deep-learning network, SpikeSegNet, has been developed by combining two proposed feature networks: Local Patch extraction Network (LPNet) and Global Mask refinement Network (GMRNet). In LPNet, the contextual and spatial features are learned at the local patch level. The output of LPNet is a segmented mask image, which is further refined at the global level using GMRNet. Visual (RGB) images of 200 wheat plants were captured using LemnaTec imaging system installed at Nanaji Deshmukh Plant Phenomics Centre, ICAR-IARI, New Delhi. The precision, accuracy, and robustness (F1score) of the proposed approach for spike segmentation are found to be 99.93%, 99.91%, and 99.91%, respectively. For counting the number of spikes, “analyse particles”—function of imageJ was applied on the output image of the proposed SpikeSegNet model. For spike counting, the average precision, accuracy, and robustness are 99%, 95%, and 97%, respectively. SpikeSegNet approach is tested for robustness with illuminated image dataset, and no significant difference is observed in the segmentation performance.ConclusionIn this study, a new approach called as SpikeSegNet has been proposed based on combined digital image analysis and deep learning techniques. A dedicated deep learning approach has been developed to identify and count spikes in the wheat plants. The performance of the approach demonstrates that SpikeSegNet is an effective and robust approach for spike detection and counting. As detection and counting of wheat spikes are closely related to the crop yield, and the proposed approach is also non-destructive, it is a significant step forward in the area of non-destructive and high-throughput phenotyping of wheat.

Anti-COVID-19 immunity dynamics were assessed in patients with cancer in a prospective clinical trial. Waning of immunity was detected 4-6 months post-vaccination with significant increases in anti-spike IgG titers after booster dosing, and 56% of seronegative patients seroconverted post-booster vaccination. Prior anti-CD20/BTK inhibitor therapy was associated with reduced vaccine efficacy.

A system based on service-oriented architecture is distributed in nature. Services can be obtained from various sources and assembled through loose coupling. This provides flexibility and scalability in development. On the other hand, involvement of multiple components in a systems causes new sources of faults. Faults may come due to individual services and their interactions during service composition. For reliable systems, one has to consider these newer faults and possibility of system functionality in presence of those faults. Hence, for avoiding failure of critical services in faults presence, fault tolerance needs to be incorporated in the system. In this paper, architecture analysis and design language (AADL) has been used to model different types of errors in a SOA based systems. The AADL is supplemented with error model annex (EMV) that helps to demonstrate error propagation, failure behavior of the design errors. These facilities of EMV are exploited for obtaining error propagations among components in SOA based systems. The proposed fault tolerance modeling may provide useful information for fault tolerance and software testing.

Background Patients with myeloproliferative neoplasms (MPNs), such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are at an increased risk of recurrent thromboembolic events (TEs) and hemorrhagic complications. Anticoagulation with vitamin K antagonists (VKAs) had been the standard of care until the recent US Food and Drug Administration approval of direct oral anticoagulants (DOACs) for treatment of cancer‐associated thrombosis. However, since patients with MPNs were underrepresented in large studies, the use of DOACs in patients with MPN‐associated thrombosis remains understudied. Objectives The primary objective of this study was to establish the incidence of recurrent TEs and hemorrhagic complications in patients with MPN‐associated thrombosis treated with DOACs versus VKAs as first‐line therapy. Methods Data from 30 patients ≥18 years old with established diagnoses of PV or ET who were treated with either DOACs or VKAs as the first‐line anticoagulant for arterial and/or venous thrombosis were reviewed to determine the incidence of recurrent TEs as well as hemorrhagic complications. Results Nineteen patients were treated with DOACs, and 11 were treated with VKAs. Of those on DOACs, 1 had a recurrent thrombosis, and 4 had bleeding events. Of the 11 patients treated with VKAs, 1 had a recurrent thrombotic event, and 1 had a bleeding event. Conclusion Our data did not demonstrate a significant difference in recurrent TEs or bleeding events in patients with MPN‐associated thrombosis anticoagulated with either DOACs or VKAs.

Objective: The objectives of this study are to graphically depict specific clinical challenges encountered in a mirrored pediatric intensive care unit patient room and to represent potential solutions to address these challenges using a systems approach. Background: The intensive care unit (ICU) patient room is a highly complex patient care environment where the design of the room must support patient care delivery safely and efficiently. There is a lack of research examining how ICU design elements interact with other system components to impact patient care. Methods: An observational case study method utilizing a systems approach was used to observe and graphically depict clinical challenges with mirrored room configurations and to identify potential solutions. Video recordings of the three clinical scenarios were analyzed in detail in conjunction with three rounds of interviews with a clinical expert. Results: Equipment or task characteristics that require orienting to a specific side of a patient create challenges in a mirrored room. In order to deliver care safely and efficiently in the mirrored room, adaptations would be required including changing boom, equipment and team member locations, purchasing new equipment, staff training, and inventory management. Some procedures such as extracorporeal membrane oxygenation would be difficult to conduct safely in the mirrored room, even with significant adaptations. Conclusion: Solutions to the challenges presented in mirrored room configurations are multifaceted and require simultaneous and ongoing changes to multiple systems elements, while others can be addressed relatively easily, for example, purchasing new equipment.

Interleukin (IL)-19, a designated IL-20 subfamily cytokine, has been implicated in inflammatory disorders including rheumatoid arthritis, psoriasis and, lately, asthma. Here, through the analysis of transcriptomic datasets of lung tissue of large asthma cohorts, we report that IL-19 expression is upregulated in asthma and correlates with disease severity. The gene expression of IL-19 was significantly higher in lung tissue from patients with severe and mild/moderate asthma compared to healthy controls. IL-19 protein level, however, was significantly higher in the blood and saliva of patients with severe asthma compared to mild/moderate subgroups as measured by ELISA assay. IL-19 protein level was not affected by corticosteroid treatment in plasma. Our data provide insights into the potential use of IL-19 as a saliva marker for asthma severity and a potential therapeutic target., Plasma and saliva IL-19 are significantly upregulated in asthma and correlate with disease severity. Plasma IL-19 is not affected by steroid treatment. This suggests that IL-19 can be used as a biomarker of asthma severity. https://bit.ly/2QfYwpc