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Background The aim of this study was to characterize severe immune-related adverse events (irAEs) seen among hospitalized patients and to examine risk factors for irAE admissions and clinically relevant outcomes, including length of stay, immune checkpoint inhibitor (ICI) discontinuation, readmission, and death. Methods Patients who received ICI therapy (ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or any ICI combination) at Massachusetts General Hospital (MGH) and were hospitalized at MGH following ICI initiation between January 1, 2011, and October 24, 2018, were identified using pharmacy and hospital admission databases. Medical records of all irAE admissions were reviewed, and specialist review with defined criteria was performed. Demographic data, relevant clinical history (malignancy type and most recent ICI regimen), and key admission characteristics, including dates of admission and discharge, immunosuppressive management, ICI discontinuation, readmission, and death, were collected. Results In total, 450 admissions were classified as irAE admissions and represent the study's cohort. Alongside the increasing use of ICIs at our institution, the number of patients admitted to MGH for irAEs has gradually increased every year from 9 in 2011 to 92 in 2018. The hospitalization rate per ICI recipient has declined over that same time period (25.0% in 2011 to 8.5% in 2018). The most common toxicities leading to hospitalization in our cohort were gastrointestinal (30.7%; n = 138), pulmonary (15.8%; n = 71), hepatic (14.2%; n = 64), endocrine (12.2%; n = 55), neurologic (8.4%; n = 38), cardiac (6.7%; n = 30), and dermatologic (4.4%; n = 20). Multivariable logistic regression revealed statistically significant increases in irAE admission risk for CTLA-4 monotherapy recipients (odds ratio [OR], 2.02; p < .001) and CTLA-4 plus PD-1 combination therapy recipients (OR, 1.88; p < .001), relative to PD-1/PD-L1 monotherapy recipients, and patients with multiple toxicity had a 5-fold increase in inpatient mortality. Conclusion This study illustrates that cancer centers must be prepared to manage a wide variety of irAE types and that CTLA-4 and combination ICI regimens are more likely to cause irAE admissions, and earlier. In addition, admissions for patients with multi-organ involvement is common and those patients are at highest risk of inpatient mortality. Implications for Practice The number of patients admitted to Massachusetts General Hospital for immune-related adverse events (irAEs) has gradually increased every year and the most common admissions are for gastrointestinal (30.7%), pulmonary (15/8%), and hepatic (14.2%) events. Readmission rates are high (29% at 30 days, 49% at 180 days) and 64.2% have to permanently discontinue immune checkpoint inhibitor therapy. Importantly, multiple concurrent toxicities were seen in 21.6% (97/450) of irAE admissions and these patients have a fivefold increased risk of inpatient death.

The surge in cases of severe COVID-19 has resulted in clinicians triaging intensive care unit (ICU) admissions in places where demand has exceeded capacity. In order to assist difficult triage decisions, clinicians require clear guidelines on how to prioritise patients. Existing guidelines show significant variability in their development, interpretation, implementation and an urgent need for a robust synthesis of published guidance. To understand how to manage which patients are admitted to ICU, and receive mechanical ventilatory support, during periods of high demand during the COVID-19 pandemic, a systematic review was performed. Databases of indexed literature (Medline, Embase, Web of Science, and Global Health) and grey literature (Google.com and MedRxiv), published from 1 January until 2 April 2020, were searched. Search terms included synonyms of COVID-19, ICU, ventilation, and triage. Only formal written guidelines were included. There were no exclusion criteria based on geographical location or publication language. Quality appraisal of the guidelines was performed using the Appraisal of Guidelines for Research and Evaluation Instrument II (AGREE II) and the Appraisal of Guidelines for Research and Evaluation Instrument Recommendation EXcellence (AGREE REX) appraisal tools, and key themes related to triage were extracted using narrative synthesis. Of 1902 unique records identified, nine relevant guidelines were included. Six guidelines were national or transnational level guidance (UK, Switzerland, Belgium, Australia and New Zealand, Italy, and Sri Lanka), with one state level (Kansas, USA), one international (Extracorporeal Life Support Organization) and one specific to military hospitals (Department of Defense, USA). The guidelines covered several broad themes: use of ethical frameworks, criteria for ICU admission and discharge, adaptation of criteria as demand changes, equality across health conditions and healthcare systems, decision-making processes, communication of decisions, and guideline development processes. We have synthesised the current guidelines and identified the different approaches taken globally to manage the triage of intensive care resources during the COVID-19 pandemic. There is limited consensus on how to allocate the finite resource of ICU beds and ventilators, and a lack of high-quality evidence and guidelines on resource allocation during the pandemic. We have developed a set of factors to consider when developing guidelines for managing intensive care admissions, and outlined implications for clinical leads and local implementation.

The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2(+) malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called ‘Don’t eat me’ signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic ‘Eat me’ signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment.

Acute aerobic exercise has been shown to improve fine motor skills and alter activation of the motor cortex (M1). The intensity of exercise may influence M1 activation, and further impact whole-body motor skill performance. The aims of the current study were to compare a whole-body motor skill via a piano task following moderate-intensity training (MIT) and high-intensity interval training (HIIT), and to determine if M1 activation is linked to any such changes in performance. Nine subjects (seven females and two males), aged 18 ± 1 years completed a control, MIT, and HIIT trial followed by administration of a piano performance task. M1 activation was evaluated by measuring oxyhemoglobin (O2Hb) and hemoglobin difference (Hbdiff) changes during post-exercise piano performance using functional near-infrared spectroscopy (fNIRS). The results indicate that piano performance scores were higher after the MIT trial, but not HIIT trial, compared to the control trial. A negative relationship was detected between heart rate during HIIT and post-HIIT piano scores. M1 activation (as measured by Hbdiff) was significantly increased after the HIIT trial. M1 activation was also positively associated with piano performance when exercise trials (HIIT + MIT) and all trials (HIIT + MIT + Control) were combined. We found that acute moderate-intensity exercise led to an improvement in complex motor skill performance while higher-intensity exercise increased M1 activation. These results demonstrate that moderate-intensity exercise can prime the nervous system for the acquisition of whole-body motor skills, suggesting that similar exercise protocols may be effective in improving the outcomes of other motor tasks performed during regular routines of daily life (e.g., sporting tasks, activities of daily living or rehabilitation). In addition, it appears that improvements in motor task performance may be driven by M1 activation. Our findings provide new mechanistic insight into the complex relationship between exercise intensity, M1 activation, and whole-body motor skill performance.

The introduction of vaccines has inspired hope in the battle against SARS-CoV-2. However, the emergence of viral variants, in the absence of potent antivirals, has left the world struggling with the uncertain nature of this disease. Antibodies currently represent the strongest correlate of immunity against SARS-CoV-2, thus we profiled the earliest humoral signatures in a large cohort of acutely ill (survivors and nonsurvivors) and mild or asymptomatic individuals with COVID-19. Although a SARS-CoV-2–specific immune response evolved rapidly in survivors of COVID-19, nonsurvivors exhibited blunted and delayed humoral immune evolution, particularly with respect to S2-specific antibodies. Given the conservation of S2 across β-coronaviruses, we found that the early development of SARS-CoV-2–specific immunity occurred in tandem with preexisting common β-coronavirus OC43 humoral immunity in survivors, which was also selectively expanded in individuals that develop a paucisymptomatic infection. These data point to the importance of cross-coronavirus immunity as a correlate of protection against COVID-19.

Therapeutic blockade of co-inhibitory immune receptors PD-1 and CTLA-4 has revolutionized oncology, but treatments are limited by immune-related adverse events (IRAEs). IRAE Colitis (irColitis) is the most common, severe IRAE affecting up to 25% of patients on dual PD-1 and CTLA-4 inhibition. Here, we present a systems biology approach to define the cell populations and transcriptional programs driving irColitis. We collected paired colon mucosal biopsy and blood specimens from 13 patients with irColitis, 8 healthy individuals, and 8 controls on immune checkpoint inhibitors (ICIs), and analyzed them with single-cell/nuclei RNA sequencing with paired TCR and BCR sequencing, multispectral fluorescence microscopy, and secreted factor analysis (Luminex). We profiled 299,407 cells from tissue and blood and identified 105 cell subsets that revealed significant tissue remodeling in active disease. Colon mucosal immune populations were dominated by tissue-resident memory (TRM) ITGAE-expressing CD8 T cells representing a phenotypic spectrum defined by gene programs associated with T cell activation, cytotoxicity, cycling, and exhaustion. CD8 TRM and effector CD4 T cells upregulated type 17 immune programs (IL17A, IL26) and Tfh-like programs (CXCL13, PDCD1). We also identified for the first time an increased abundance of two KLRG1 and ITGB2-expressing CD8 T cell populations with circulatory cell markers, including a GZMK TRM-like population and a CX3CR1 population that is predicted to be intravascular. These two populations were more abundant in irColitis patients treated with dual PD-1/CTLA-4 inhibition than those receiving anti-PD-1 monotherapy. They also had significant TCR sharing with PBMCs, suggesting a circulatory origin. In irColitis we observed significant epithelial turnover marked by fewer LGR5-expressing stem cells, more transit amplifying cells, and upregulation of apoptotic and DNA-sensing programs such as the cGAS-STING pathway. Mature epithelial cells with top crypt genes upregulated interferon-stimulated pathways, CD274 (PD-L1), anti-microbial genes, and MHC-class II genes, and downregulated aquaporin and solute-carrier gene families, likely contributing to epithelial cell damage and absorptive dysfunction. Mesenchymal remodeling was defined by increased endothelial cells, both in irColitis patients and specifically in patients on dual PD-1/CTLA-4 blockade. Cell-cell communication analysis identified putative receptor-ligand pairs that recruit CD8 T cells from blood to inflamed endothelium and positive feedback loops such as the CXCR3 chemokine system that retain cells in tissue. This study highlights the cellular and molecular drivers underlying irColitis and provides new insights into the role of CTLA-4 and PD-1 signaling in maintaining CD8 TRM homeostasis, regulating CD8 T recruitment from blood, and promoting epithelial-immune crosstalk critical to gastrointestinal immune tolerance and intestinal barrier function.

Mechanisms underlying severe coronavirus disease 2019 (COVID-19) disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNA-seq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune-cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell-type-specific intracellular death signatures, cellular angiotensin-converting enzyme 2 (ACE2) expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease., Graphical abstract, Filbin et al. use plasma proteomics in 306 coronavirus disease 2019 (COVID-19) patients and 78 symptomatic controls over time to better understand the role of circulating immune cells and tissue cells in inflammation, disease severity, and survival. They propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage.

Background: Previous research has mainly focused on the impacts of epidemics on those people who are directly affected by the epidemic infection, or of healthcare workers caring for them. Less is known about the impact on mental health of their relatives, and potential interventions to support them. Methods: Systematic review and narrative synthesis. Outcomes: 28 studies were identified, sixteen quantitative and twelve qualitative. One involved health workers' relatives, and the rest covered relatives of directly affected individuals. We found considerable burden of mental ill-health in both groups. Among relatives of healthcare workers, 29.4% reported symptoms consistent with probable anxiety disorder and 33.7% with probable depression. Prevalence rates for probable anxiety disorder ranged from 24 to 42% and probable depression 17–51% for the relatives of affected people. One study found a 2% prevalence of PTSD and another found odds of PTSS were significantly higher among relatives of affected individuals compared with the general population. Only two intervention studies were identified and both were descriptive in nature. Interpretation: Available evidence suggests relatives of people affected by infective outbreaks report mental ill-health. Having a relative who died particularly increased risk. Good outcomes for relatives of affected individuals were promoted by practical and social support, public health guidance that recognises the caring role of relatives, and being supported to see the positives as well as negatives in their situation. Good outcomes for relatives of health workers were promoted by perceived effectiveness of protective equipment. High quality evidence on potential interventions to support relatives is lacking. Funding: No external funding sought.

2507 Background: Myocarditis due to immune checkpoint inhibitors (ICIs) is uncommon; however, myocarditis due to ICIs leads to severe morbidity and even death in 20-40% of cases. The molecular underpinnings of ICI-associated myocarditis are poorly understood, and there is an unmet clinical need to identify therapeutic targets and biomarkers that can aid in disease management. Methods: Heart tissue was obtained through endomyocardial biopsy or autopsy of patients receiving ICIs and was profiled with paired single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR) using the 10x Genomics Chromium system. A control dataset was constructed using scRNAseq data of heart tissue from patients receiving ICIs but without myocarditis and a published dataset from healthy patients not receiving ICIs. Peripheral blood mononuclear cells (PBMCs) were collected at the time of myocarditis diagnosis in a larger cohort of patients and analyzed with ICI-treated controls. The CITE-Seq protocol was used to measure paired scRNA-seq, TCR, and surface proteomics in PBMCs, using serial timepoints where available. Results: Heart tissue from 13 patients with myocarditis, including three fatal cases, and seven controls yielded 77,712 single cells. Blood profiling from 27 patients with ICI myocarditis and ICI-treated controls across 54 samples yielded over 230,000 cells. ICI myocarditis tissue demonstrated an increased T cell infiltrate (OR 8.94, FDR = 0.0021). Expression of multiple inflammatory pathways, most notably interferon responses, was up-regulated across multiple immune and non-immune cell types in the setting of myocarditis, providing important pathophysiological insights. T cell clones were also found to be shared between blood and heart, enabling the identification of putative pathogenic T cell subsets. Conclusions: Increased intramyocardial T cells and the activation of interferon response gene networks were seen in the setting of ICI myocarditis. These preliminary findings highlight potential pathological pathways in ICI myocarditis that could serve as biomarkers or therapeutic targets.

BACKGROUND: SARS-CoV-2 plasma viremia has been associated with severe disease and death in COVID-19 in small-scale cohort studies. The mechanisms behind this association remain elusive. METHODS: We evaluated the relationship between SARS-CoV-2 viremia, disease outcome, and inflammatory and proteomic profiles in a cohort of COVID-19 emergency department participants. SARS-CoV-2 viral load was measured using a quantitative reverse transcription PCR–based platform. Proteomic data were generated with Proximity Extension Assay using the Olink platform. RESULTS: This study included 300 participants with nucleic acid test–confirmed COVID-19. Plasma SARS-CoV-2 viremia levels at the time of presentation predicted adverse disease outcomes, with an adjusted OR of 10.6 (95% CI 4.4–25.5, P < 0.001) for severe disease (mechanical ventilation and/or 28-day mortality) and 3.9 (95% CI 1.5–10.1, P = 0.006) for 28-day mortality. Proteomic analyses revealed prominent proteomic pathways associated with SARS-CoV-2 viremia, including upregulation of SARS-CoV-2 entry factors (ACE2, CTSL, FURIN), heightened markers of tissue damage to the lungs, gastrointestinal tract, and endothelium/vasculature, and alterations in coagulation pathways. CONCLUSION: These results highlight the cascade of vascular and tissue damage associated with SARS-CoV-2 plasma viremia that underlies its ability to predict COVID-19 disease outcomes. FUNDING: Mark and Lisa Schwartz; the National Institutes of Health (U19AI082630); the American Lung Association; the Executive Committee on Research at Massachusetts General Hospital; the Chan Zuckerberg Initiative; Arthur, Sandra, and Sarah Irving for the David P. Ryan, MD, Endowed Chair in Cancer Research; an EMBO Long-Term Fellowship (ALTF 486-2018); a Cancer Research Institute/Bristol Myers Squibb Fellowship (CRI2993); the Harvard Catalyst/Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH awards UL1TR001102 and UL1TR002541-01); and by the Harvard University Center for AIDS Research (National Institute of Allergy and Infectious Diseases, 5P30AI060354).

T cell-mediated immunity plays an important role in controlling SARS-CoV-2 infection; yet the repertoire of naturally processed and presented viral epitopes on HLA class I remains uncharacterized. Here, we report the first HLA-I immunopeptidome of SARS-CoV-2 in two cell lines at different times post-infection using mass spectrometry. We found HLA-I peptides derived not only from canonical ORFs, but also from internal out-of-frame ORFs in Spike and Nucleocapsid not captured by current vaccines. Some peptides from out-of-frame ORFs elicited T cell responses in a humanized mouse model and COVID-19 patients that exceeded responses to canonical peptides including some of the strongest epitopes reported to date. Whole proteome analysis of infected cells revealed that early expressed viral proteins contribute more to HLA-I presentation and immunogenicity. These biological insights as well as the discovery of out-of-frame ORF epitopes will facilitate selection of peptides for immune monitoring and vaccine development., Analysis of the HLA-1 peptidome of SARS-CoV-2 infection identifies peptides derived from canonical and out- of-frame ORFs in viral S and N protein that are not captured by current vaccines and yield potent T cell responses in a mouse model as well as patients with COVID-19.

Immunotherapy for cancer holds great promise, but immune dysregulation of checkpoint blockade has resulted in new autoimmune adverse events. Hepatic toxicity occurs in 1%–17% of patients on immune checkpoint inhibitors. Hepatitis is usually a low‐grade toxicity, but grade 3 and 4 hepatotoxicity does occur. This article answers frequently asked questions about immune‐related hepatitis to assist in the recognition and management of this important condition., Many human tumors are recognized by the adaptive immune system, but these spontaneous antitumor responses are typically inadequate to mediate regression. Blockade of immune regulatory “checkpoint” receptors such as cytotoxic T‐lymphocyte‐associated antigen 4 and programmed cell death 1 can unleash antitumor immunity, resulting in tumor responses that can be durable. Alongside the enormous promise of immunotherapy for cancer, the immune dysregulation of checkpoint blockade has led to a plethora of new autoimmune adverse events. Hepatic toxicity occurs in 1%–17% of patients on immune checkpoint inhibitors, with the precise incidence dependent on both the drug used and the underlying malignancy. Hepatitis is most commonly a low‐grade toxicity, but grade 3 and 4 hepatotoxicity does occur. Here we will answer frequently asked questions regarding immune‐related hepatitis to assist in the recognition and management of this important condition. Key Points. Immune related hepatitis is a potentially serious complication of checkpoint blockade.The differential for elevated liver function tests in patients on checkpoint blockade is broad.Diagnostic testing such as viral serologies, liver ultrasound, cross sectional imaging, and liver biopsy may help in the diagnosis of immune related hepatitis in select patients.Patients with underlying cirrhosis are an at risk population for whom current grading criteria may underestimate the severity of liver inflammation.Severe immune related hepatitis is best managed by a multi‐disciplinary team that includes a hepatologist.Most patients with immune related hepatitis respond to corticosteroids, but a substantial fraction require treatment with a secondary immunosuppressive agent.

The exposure of high surface area with NiO mesoporous material and assembling hetero-structures by incorporating TiO2 nanoparticles represent a valuable way for producing high-performance photocatalysts and sensitive electrochemical sensor. Acid base free modified sol–gel route was used to synthesize highly porous and photoactive NiO, NiO/TiO2 and NiO/TiO2/Dextran catalysts. Powder X-ray diffraction analysis, UV–Vis spectroscopy, Energy dispersive X-ray (EDX) spectroscopy, Scanning electron microscopy, Transmission electron microscopy, Atomic force microscopy, Thermo-gravimetric analysis and Brunauer-Emmitt- Teller (BET) adsorption isotherm techniques were used to characterize the materials. The as-synthesized mesoporous NiO/TiO2/Dextran is crystalline, pure and highly porous with the surface area of 225 m2g− 1. The mesoporous NiO/TiO2/Dextran exhibited significant photochemical degradation capability for Malachite Green Oxalate (MG-Oxalate) dye. It was found that MG-Oxalate dye of 20 ppm concentration has been completely degraded and decolorized with the optimum NiO/TiO2/Dextran catalyst dose of 0.8 g/L in 60 min at pH 8.0. The reaction kinetics revealed that the photocatalytic degradation of MG-Oxalate dye follows pseudo-first-order reaction kinetics with the rate constant, k of 0.049 min− 1 and can be recycled up to 10 cycles. An electrochemical sensor was developed based on NiO/TiO2/Dextran modified Glassy carbon electrode (GCE) for sensitive and selective sensing of dye. The differential pulse voltammetry response of NiO/TiO2/Dextran/GCE for MG-Oxalate shows linear dependence in the concentration range of 1–25 ppm with a limit of detection 0.0056 µM and Sensitivity 0.16 µA mM− 1 cm− 2.

BackgroundIn 2017, Massachusetts General Hospital implemented the Severe Immunotherapy Complications (SIC) Service, a multidisciplinary care team for patients hospitalized with immune-related adverse events (irAEs), a unique spectrum of toxicities associated with immune checkpoint inhibitors (ICIs). This study’s objectives were to evaluate the intervention’s (1) effect on patient outcomes and healthcare utilization, and (2) ability to collect biological samples via a central infrastructure, in order to study the mechanisms responsible for irAEs.MethodsA hospital database was used to identify patients who received ICIs for a malignancy and were hospitalized with severe irAEs, before (April 2, 2016–October 3, 2017) and after (October 3, 2017–October 24, 2018) SIC Service initiation. The primary outcome was readmission rate after index hospitalization. Secondary outcomes included length of stay (LOS) for admissions, corticosteroid and non-steroidal second-line immunosuppression use, ICI discontinuation, and inpatient mortality.ResultsIn the pre-SIC period, 127 of 1169 patients treated with ICIs were hospitalized for irAEs; in the post-SIC period, 122 of 1159. After SIC service initiation, reductions were observed in irAE readmission rate (14.8% post-SIC vs 25.9% pre-SIC; OR 0.46; 95% CI 0.22 to 0.95; p=0.036) and readmission LOS (median 6 days post-SIC vs 7 days pre-SIC; 95% CI −16.03 to –0.14; p=0.046). No significant pre-initiation and post-initiation differences were detected in corticosteroid use, second-line immunosuppression, ICI discontinuation, or inpatient mortality rates. The SIC Service collected 789 blood and tissue samples from 234 patients with suspected irAEs.ConclusionsThis is the first study to report that establishing a highly subspecialized care team focused on irAEs is associated with improved patient outcomes and reduced healthcare utilization. Furthermore, the SIC Service successfully integrated blood and tissue collection safety into routine care.

Cold stress is one of the major abiotic factors that influence the productivity and geographical distribution of many agriculturally important crops like Hevea brasiliensis. Cultivation of H. brasiliensis in India is being extended to northeastern regions, where low temperature during winter adversely affects its survival, growth, and productivity. Developing cold-tolerant genotypes is a primary requisite to maximize the productivity under such challenging environmental conditions. However, lack of methods for early evaluation of cold tolerance in the newly developed clones and the extensive time required for assessing their tolerance in the field are major constraints for clonal selection. The present study was initiated with an objective to identify and characterize cold stress responsive miRNAs from H. brasiliensis that show stronger association with cold tolerance. Next generation sequencing using Illumina HiSeq method revealed the expression of 21 and 29 conserved miRNA (from clone RRIM 600) families in cold-stressed and control samples, respectively. Forty-two novel miRNAs were identified from this study. Upon differential expression analysis, eight conserved miRNAs were found commonly expressed in both the samples. When expression analyses were performed subsequently with six selected miRNAs in two Hevea clones (viz. RRII 105 and RRIM 600), miR169 showed a strong association with cold tolerance. miRNAs such as miR482 and miR159 also exhibited association with cold tolerance. This study suggests the possibility of employing these miRNAs as markers for cold tolerance after validation in more number of genotypes with varying levels of cold tolerance.

Self-organized strontium ion crosslinked alginate/carboxymethyl cellulose composite materials with gold nanoparticles (Au-NPs) and graphene oxide (GO) were effectively fabricated using dissipative convective procedures followed by the freeze-drying method. Composite gels were characterized by using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscopy with Energy dispersive X-ray analysis (SEM-EDAX) and transmission electron microscopy (TEM) analysis. Moreover, thermal, mechanical and rheological properties were also performed to identify their strength and stability. The results revealed that Sr/Alg/CMC/Au and Sr/Alg/CMC/GO/Au composites showed remarkably porous structures with ordered capillaries; rheologically gel-like structures with high mechanical strength. Moreover, composites were tested for the reduction of o-nitroaniline and Suzuki-Miyaura cross-coupling reaction. The Sr/Alg/CMC/GO/Au composite competently reduced the o-nitroaniline within 2min (k=4.86×10-2s-1) with recyclability up to 7 consecutive cycles and also displayed 98% isolated yield (TOF value is 4900h-1) for Suzuki-Miyaura cross-coupling reaction with 6cycles recyclability. This approach of using nanoparticles incorporated composite systems as reusable catalysts opens a door of new materials for various catalytic applications.

We synthesized Co3O4 and Co3O4@Au-NPs nano structures via simple and economical strategy for high-performance supercapacitors. Co3O4@Au-NPs modified glassy carbon electrode exhibited excellent electrochemical performance including high specific capacitance of 683 Fg−1(current density of 0.5 Ag−1), better retention capability of 65% at high current density (10 Ag−1) with remarkable cycling stability in 1000 continuous cycles at 0.5 Ag−1 current density (only 6% loss after 1000 cycles) and high energy and power densities (94.86 Whkg−1 and 3.48 kWkg−1). The photocatalytic activity of the synthesized mesoporous structures against Methylene Blue dye was also carried out and compared with the standard P25. The study showed that the presence of gold nanoparticles has increased the photocatalytic activity of synthesized porous Co3O4 to many folds. From the results it is believed that the addition of gold nanoparticles (Au-NPs) has largely increased the supercapacitor and photocatalytic activity of Co3O4.

Novel nanocomposites of Sr2+ ion crosslinked alginate/carboxymethyl cellulose (Alg/CMC) with TiO2 nanoparticles (TiO2-NPs) and graphene oxide (GO) incorporation was synthesized using simple dissipative convective route followed by freeze drying processes. As-synthesized nanocomposites were characterized using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), UV- visible-diffuse reflectance spectroscopy (UV-vis-DRS), surface area study, Raman spectroscopy, scanning electron microscopy with energy dispersive X-ray analysis (SEM-EDAX) and transmission electron microscopy (TEM) analysis, respectively. The results revealed that GO and TiO2-NPs were successfully incorporated into alginate/CMC matrix and visible light response of TiO2 was significantly improved. Photocatalytic performance of nanocomposites was evaluated by degradation of congo red (CR) dye under direct sunlight irradiation. The degradation results disclosed that GO and TiO2-NPs incorporated Sr/alginate/CMC nanocomposites (Sr/Alg/CMC/GO/TiO2) can competently degrade the tested CR dye molecules and showed greater degradation efficiency (98%) than the Sr/Alg/CMC/TiO2 (70%), Sr/Alg/CMC (60%) and bare TiO2 (62%) photocatalyst, respectively. Moreover, recyclability study of Sr/Alg/CMC/GO/TiO2 nanocomposite demonstrated that it was highly stable under reaction condition and retained its degradation efficiency up to seven consecutive cycles of degradation reaction. Our results suggested that Sr/Alg/CMC/GO/TiO2 is an efficient visible light responsive photocatalyst for degradation of dye molecules in the presence of direct sunlight irradiation using present reaction conditions.

An elegant method is used to prepare silver monoliths with Pluronic F-127(F-127) as sacrificial template by modified sol-gel method. Si nanoparticles (SiNPs) and graphene oxide (GO) are added in situ to Ag/F-127 hydrogel for the reduction of ο -nitroaniline ( ο -NA) to 1, 2-benzenediamine. Fourier Transform Infrared Spectroscopy (FT-IR), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Thermogravimetric analysis (TGA), Raman Spectroscopy, Powder X-Ray Diffraction (PXRD) analysis and Brunauer-Emmett-Teller (BET) Nitrogen adsorption techniques were used for characterization of monoliths. An epoch-making catalytic activity of Ag/F-127/GO monoliths is observed in the reduction of ο -NA to 1, 2-benzenediamine in presence of NaBH 4 in aqueous media. The catalyst Ag/F-127/GO took only 2 min which is the minimum time reported so far with significant rate constant claimed itself a leading catalyst for the reduction of ο -NA to 1,2-benzenediamine. Pseudo first order rate constant (k) and Turn over frequency (TOF) values are 0.231 min −1 and 30.053×10 19 molecules min −1 respectively suggest that the catalyst has industrial importance. Recyclability and stability of Ag/F-127/GO catalyst are studied successfully up to 10 cycles. Energy of activation (E a ), and thermodynamic parameters viz. activation enthalpy (ΔH ≠ ), activation Gibbs free energy (ΔG ≠ ), and entropy of activation (ΔS ≠ ) were also ascertained. Catalytic activities of Ag/F-127, Ag/F-127/Dextran, Ag/F-127/Trimethylbenzene (TMB), Ag/F-127/SiNPs, and Ag/F-127/Si/GO monoliths were also studied.

2654 Background: The exponential increase in FDA-approved indications for immune checkpoint inhibitors (ICI) in cancer care has resulted in therapeutic success but also in the occurrence of immune-related adverse effects (irAEs) that can represent a significant clinical challenge. On October 3 2017, the Massachusetts General Hospital (MGH) implemented the Severe Immunotherapy Complications (SIC) Service, a multi-disciplinary care team for patients hospitalized with irAEs. The objectives of this study were to evaluate the impact of SIC Service on 1) healthcare utilization and 2) patients outcomes. Methods: Using pharmacy and hospital admission databases, a list of patients was identified that both received ICI for a malignancy and were hospitalized with severe irAEs in the period prior to initiation of the SIC service and after SIC initiation. The pre-SIC period was defined as an admission between 4/2/2016 through 10/3/2017, and the post-SIC period as an admission from 10/3/2017 through 10/24/2018. The rate of readmission after the index hospitalization was the primary outcome. Secondary outcomes included lengths of stay (LOS) for both initial irAE admissions and readmissions, use of corticosteroids and non-steroidal second-line immunosuppression, ICI discontinuation, and inpatient mortality in the pre- and post-SIC periods. Results: Among 1169 patients treated in the pre-SIC service intervention period; 127 were hospitalized for irAE. Among 1159 patients treated in the post-SIC intervention 122 were hospitalized for irAE. SIC Service implementation was associated with a significant reduction in irAE readmission rates (post-SIC 14.8% vs. pre-SIC 25.9%; odds ratio [OR], 0.46; 95% CI, 0.22-0.95; p=0.036). The length of stay, rates of corticosteroid use, second-line immunosuppression, and ICI discontinuation for irAE, as well as inpatient mortality rates were not significantly different before and after SIC Service implementation. Conclusions: This is the first study to report that establishing a highly subspecialized care team focused on irAEs can be associated with improved clinical outcomes for patients receiving ICI therapy. Such care teams may play an essential part in optimizing irAE care.

Nanocomposite hydrogels of barium ion crosslinked alginate/carboxymethyl cellulose (CMC) with encapulation of TiO 2 -NPs were synthesized sucessfully using dissipative convective method followed by freeze-drying procedure. As-prepared composite hydrogels were charecterized by different techniques such as Fourier Transform Infrared spectroscopy (FT-IR), Powder X-ray diffraction (PXRD), UV- Diffuse reflectance spectroscopy (UV-DRS), BET-Surface area study, Scanning Electron Microscopy with Energy Dispersive X-ray analysis (SEM-EDAX), Transmission Electron Microscopy (TEM) and mechanical strength study. Ba/Alg/CMC/TiO2 composite hydrogels exhibited excellent photocatalytic activity towards CR under direct solar light irradiation with pseudo-first order kinetics. The recycling ability of Ba/Alg/CMC/TiO2 composite hydrogels confirms that photocatalyst is highly photostable.

An innovative method is presented to produce anisotropically ordered capillaries and small pores by dissipative convective process followed by simple freezing in liquid nitrogen of Ba/alginate/dextran hydrogels with and without nanoparticles. Magnetite, gold, silica or titanium dioxide nanoparticles were encapsulated safely into the gels with protecting their stability and microstructures. Mechanical strength and rheological studies of the gels were also investigated. Ba/alginate/dextran/Au composite gel has shown excellent catalytic activity for the reduction of 4-nitrophenol (4-NP) to 4-aminophenol (4-AP) in presence of NaBH 4 with a rate constant of 6.85 × 10 − 3 min − 1 . Ba/Alg/Dex/Au-GCE exhibits non-enzymatic electrocatalytic oxidation of glucose with linear range from 1 mM to 10 mM (r = 0.998) and the detection limit to 63 μM at a signal-to-noise ratio of 3.

Drought, in combination with high temperature and low humidity affects the productivity of Hevea brasiliensis, the natural rubber tree and its expansion to non-traditional regions. The genotypes of H. brasiliensis that perform well in traditional regions often failed in non-traditional regions thus necessitating breeding for stress-tolerant genotypes. This can be accomplished by adopting molecular-assisted selection method. Recent developments in identification of drought-responsive transcripts from H. brasiliensis and the findings on role of small RNAs indicate the possibility of employing them as markers for identification of suitable genotypes. In this study, we attempted to identify drought-responsive miRNAs from H. brasiliensis through next-generation sequencing (Illumina HiSeq) method. The results revealed the expression of 33 conserved and 32 novel drought-responsive miRNAs. Further, validation of differentially expressed miRNAs by quantitative expression analysis indicated the association of two novel miRNAs, viz., HbmiRn_63 and HbmiRn_42 and two conserved miRNAs, viz., miR168 and miR160 miRNAs with drought tolerance. These miRNAs can be employed as markers for drought tolerance after validation in a larger set of genotypes. This study opens up the possibility of employing miRNAs as markers for drought tolerance in Hevea.

Mixed anatase–rutile and pure anatase mesoporous TiO2 photocatalysts have been synthesized for the first time via a modified greener sol–gel approach at low temperature without the involvement of any acid or base. Non-ionic surfactant Brij-35 was used as a sacrificial agent for the synthesis. The effect of additives like dextran and silica nanoparticles on different physical parameters of catalysts was also studied. The chemical, electronic and physical properties of the as-synthesized catalysts were studied by FTIR, TGA, PXRD, DRS, SEM, EDAX, TEM, and BET techniques and the photocatalytic potentiality was also tested by photocatalytic degradation of methyl orange (MO) azo dye. The photocatalytic activity of the synthesized catalysts was found to be in the order TiO2/Brij-35/Si-NPs > TiO2/Brij-35 > TiO2/Brij-35/dextran. The higher photocatalytic activity of TiO2/Brij-35/Si-NPs provided direct evidence of the surface area-dependent photocatalytic activity. As a comparative study, the catalysts were also tested for other environmentally harmful dyes like Rhodamine B and Congo Red and were proven to be highly efficient catalysts for the photodegradation of these dyes.

Tween-80 templated mesoporous CuO (mpCuO) nanostructures were explored via a facile, environmentally friendly and scalable sol–gel route for heterogeneous catalysis and sensor technology. Silica nanoparticles (Si-NPs) were used as structural directing agents (SDAs) for the shape selective morphological changes of porous materials which resulted in the fabrication of nanoflowers of CuO/Si-NPs along with a great change in surface area. The mpCuO nanostructures were well characterized by FTIR, TGA, PXRD, FESEM-EDX, TEM, BET techniques. Interestingly, the as-synthesized mpCuO nanostructures showed excellent catalytic activity against the direct hydrogenation of acetone to isopropanol in the presence of sodium borohydride (NaBH4). In addition, mpCuO nanostructures have proved to be excellent sensor materials for simultaneous detection of some metals and biomolecules.