Metal free synthesis of thermally stable blue fluorescent m-terphenyls by ring transformation of 2H-pyran-2-ones: chemical synthesis, spectroscopy and computational studies.

A simple yet convenient nucleophile-induced synthetic route for the construction of thermally stable fluorescent active functionalized stilbenes has been delineated. The nucleophile-induced base encouraged synthetic protocol was performed under mild conditions without harming the environment and products were achieved in good yields. The synthesized stilbenes showed amazing emission properties and good thermal stability. Synthesized products displayed interesting positive solvatochromism in different solvents based on variation in polarity. Further, we present a comprehensive analysis of the eight molecules, leveraging a combination of Density Functional Tight Binding (DFTB), Density Functional Theory (DFT) calculations, and Molecular Dynamics (MD) simulations. This integrated approach allowed for an in-depth exploration of the electronic structures, reactivity profiles, and dynamic behaviors of these complex molecular systems. Our findings reveal significant insights into the physicochemical properties of the synthesized molecules, contributing to a deeper understanding of their potential applications in various fields.

Testing three primate species' attentional biases toward preferred and unpreferred foods: Seeing red or high valued food?

Animals navigate complex environments that present both hazards and essential resources. The prioritization of perceptual information that is relevant to their next actions, such as accessing or avoiding different resources, poses a potential challenge to animals, one that can impact survival. While animals' attentional biases toward negatively valanced and threatening stimuli have been explored, parallel biases toward differently valued resources remain understudied. Here, we assessed whether three primate species (chimpanzees [Pan troglodytes], gorillas [Gorilla gorilla gorilla], and Japanese macaques [Macaca fuscata]) prioritized their attention to positively valued resources-preferred foods compared to unpreferred foods. We employed a computerized dot probe attentional bias task in which we presented participants with paired images of their preferred and unpreferred foods in randomized locations (left or right). Latencies to touch the "probe" that replaced either image revealed that all three species responded faster to the probe when it replaced the preferred option (χ²(1) = 284.50, SE² = .03, p < .001). The uniformity of the primates' responses hints that a propensity to prioritize highly preferred items is rooted in these primates' evolutionary past, one that may serve as a mechanism to rapidly detect and locate resources such as highly valued foods. Future research will help disentangle the role that color plays in these biases. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy.

Chimeric antigen receptor T cells (CAR-Ts) have remarkable efficacy in liquid tumors, but limited responses in solid tumors. We conducted a Phase I trial (NCT02107963) of GD2 CAR-Ts (GD2-CAR.OX40.28.z.iC9), demonstrating feasibility and safety of administration in children and young adults with osteosarcoma and neuroblastoma. Since CAR-T efficacy requires adequate CAR-T expansion, patients were grouped into good or poor expanders across dose levels. Patient samples were evaluated by multi-dimensional proteomic, transcriptomic, and epigenetic analyses. T cell assessments identified naive T cells in pre-treatment apheresis associated with good expansion, and exhausted T cells in CAR-T products with poor expansion. Myeloid cell assessment identified CXCR3+ monocytes in pre-treatment apheresis associated with good expansion. Longitudinal analysis of post-treatment samples identified increased CXCR3- classical monocytes in all groups as CAR-T numbers waned. Together, our data uncover mediators of CAR-T biology and correlates of expansion that could be utilized to advance immunotherapies for solid tumor patients.

Use of FLOSIC for understanding anion-solvent interactions.

An Achille's heel of lower-rung density-functional approximations is that the highest-occupied-molecular-orbital energy levels of anions, known to be stable or metastable in nature, are often found to be positive in the worst case or above the lowest-unoccupied-molecular-orbital levels on neighboring complexes that are not expected to accept charge. A trianionic example, [Cr(C2O4)3]3-, is of interest for constraining models linking Cr isotope ratios in rock samples to oxygen levels in Earth's atmosphere over geological timescales. Here we describe how crowd sourcing can be used to carry out self-consistent Fermi-Löwdin-Orbital-Self-Interaction corrected calculations (FLOSIC) on this trianion in solution. The calculations give a physically correct description of the electronic structure of the trianion and water. In contrast, uncorrected local density approximation (LDA) calculations result in approximately half of the anion charge being transferred to the water bath due to the effects of self-interaction error. Use of group-theory and the intrinsic sparsity of the theory enables calculations roughly 125 times faster than our initial implementation in the large N limit reached here. By integrating charge density densities and Coulomb potentials over regions of space and analyzing core-level shifts of the Cr and O atoms as a function of position and functional, we unambiguously show that FLOSIC, relative to LDA, reverses incorrect solute-solvent charge transfer in the trianion-water complex. In comparison to other functionals investigated herein, including Hartree-Fock and the local density approximation, the FLOSIC Cr 1s eigenvalues provide the best agreement with experimental core ionization energies.

Microinclusions: Treating women as respected work partners increases a sense of fit in technology companies.

When people enter new work settings, we theorized that they are vulnerable to questioning whether they will be received in ways that allow them to contribute to shared goals. If so, treatment that clarifies the stance that others take toward the self, which we call microinclusions, that convey a receptivity and supportiveness to one's contributions may bolster a sense of fit. Further, in examining this question in technology contexts, we theorized that such microinclusions may be particularly impactful for women for whom underrepresentation and negative stereotypes make opportunities to contribute especially fraught. Four primary experiments (N = 1,861, Nwomen in STEM = 1,430) tested this theorizing. In Experiment 1, both men and women at a large technology company anticipated greater fit in a work group described with microinclusions, yet this effect was greatest for women. Experiments 2-4 replicated this effect among women science, technology, engineering, and mathematics (STEM) professionals and college students considering a career in technology and showed that women's anticipated fit arose over and beyond socially warm treatment (Experiment 2); arose more when the microinclusion came from a man (vs. another woman; Experiment 3); and arose even when observing another woman receive a microinclusion (Experiment 4). Microinclusions also increased women's commitment to the company (Experiments 2 and 4) and reduced their anticipated experience of stereotype threat (Experiment 3). This research highlights the ambiguity women face in technology settings about whether they will be received in ways that allow them to contribute to shared work goals and the importance of treatment from coworkers that affirms this opportunity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Calculation of Self, Corrected, and Transport Diffusivities of Isopropyl Alcohol in UiO-66.

The UiO-6x family of metal-organic frameworks has been extensively studied for applications in chemical warfare agent (CWA) capture and destruction. An understanding of intrinsic transport phenomena, such as diffusion, is key to understanding experimental results and designing effective materials for CWA capture. However, the relatively large size of CWAs and their simulants makes diffusion in the small-pored pristine UiO-66 very slow and hence impractical to study directly with direct molecular simulations because of the time scales required. We used isopropanol (IPA) as a surrogate for CWAs to investigate the fundamental diffusion mechanisms of a polar molecule within pristine UiO-66. IPA can form hydrogen bonds with the µ3-OH groups bound to the metal oxide clusters in UiO-66, similar to some CWAs, and can be studied by direct molecular dynamics simulations. We report self, corrected, and transport diffusivities of IPA in pristine UiO-66 as a function of loading. Our calculations highlight the importance of the accurate modeling of the hydrogen bonding interactions on diffusivities, with about an order of magnitude decrease in diffusion coefficients when the hydrogen bonding between IPA and the µ3-OH groups is included. We found that a fraction of the IPA molecules have very low mobility during the course of a simulation, while a small fraction are highly mobile, exhibiting mean square displacements far greater than the ensemble average.

Evaluation of the Effect of Distant Cold Stimulation on Pain During Palatal Injection: A Randomized Split-Mouth Study.

Objective Delivery of a robust local anesthetic injection aids in the successful management of all patients' fears, anxieties, and discomfort during dental treatments. The most expected or frightening stimuli in the dental operatory are local anesthetic injections. The objective of this trial was to study the analgesic efficacy of distant cold stimulation in relieving injection pain from the greater palatine nerve block. Before receiving local anesthetic injections, employing cryotherapy by using an ice bath changes the pain perceptions and also increases the pain threshold. Purpose The aim of this study is to evaluate the effect of distant cold stimulation on palatal injection pain using an ice-cold bath. Method This was a randomized, controlled trial conducted at an oral and maxillofacial surgery department. A split-mouth technique was employed for the study, in which patients requiring bilateral greater palatine nerve block for any dental procedures were included. The bilateral greater palatine nerve block was given one at a time, separated by an interval of three days. The inclusion criteria for this study were no history of drug allergy and an extraction site free of any active infection. There were 28 participants in this experimental study. Two groups were randomly created from this research sample: group A (palatal injection with distant cold stimulation) and group B (palatal injection without distant cold stimulation). In group A, the patient was asked to put his or her hand of the same side as the palatal injection in an ice-cold bath till the time patient could tolerate it; immediately after the patient removed his hand, the greater palatine nerve block was given, and the patient was assessed for the injection pain. In group B, the patient was directly given the greater palatine nerve block without any distant cold stimulation. The time interval between the two extractions/dental procedures was three days. Outcomes of interest were pain severity with and without distant cold stimulation which were assessed using a Visual Analogue Scale (VAS) pain scale, and a comparison was made between the two groups. Results As per our study, in terms of pain, there was a statistically significant difference between the two interventions at all time points. Patients in group A had a lower score on the VAS pain scale as compared to group B. The standard deviation (STD) for group A was 0.81, and the standard deviation for group B was 0.92. P value was derived to be P < 0.001, which is suggestive of a significant difference between the pain scores of both groups. Conclusion Hence, we conclude that the use of distant cryotherapy as an adjunct is an effective way to reduce pain perception and increase pain threshold. This technique is comparatively simple, painless, and easy for the surgeon and for apprehensive patients, and it offers a fair cost solution for the suffering often associated with dental procedures requiring local anesthetic injections.

How Do Self-Interaction Errors Associated with Stretched Bonds Affect Barrier Height Predictions?

Density functional theory (DFT) suffers from self-interaction errors (SIEs) that generally result in the underestimation of chemical reaction barrier heights. This is commonly attributed to the tendency of density functional approximations to overstabilize delocalized densities that typically occur in the stretched bonds of transition state structures. The Perdew-Zunger self-interaction correction (PZSIC) and locally scaled self-interaction correction (LSIC) improve the prediction of barrier heights of chemical reactions, with LSIC giving better accuracy than PZSIC on average. These methods employ an orbital-by-orbital correction scheme to remove the one-electron SIE. In the context of barrier heights, this allows an analysis of how the self-interaction correction (SIC) for each orbital contributes to the calculated barriers using Fermi-Löwdin orbitals (FLOs). We hypothesize that the SIC contribution to the reaction barrier comes mainly from a limited number of orbitals that are directly involved in bond-breaking and bond-making in the reaction transition state. We call these participant orbitals (POs), in contrast to spectator orbitals (SOs) which are not directly involved in changes to the bonding. Our hypothesis is that ΔETotalSIC ≈ ΔEPOSIC, where ΔETotalSIC is the difference in the SIC corrections for the reactants or products and the transition state. We test this hypothesis for the reaction barriers of the BH76 benchmark set of reactions. We find that the stretched-bond orbitals indeed make the largest individual SIC contributions to the barriers. These contributions increase the barrier heights relative to LSDA, which underpredicts the barrier. However, the full stretched-bond hypothesis does not hold in all cases for either PZSIC or LSIC. There are many cases where the total SIC contribution from the SOs is significant and cannot be ignored. The size of the SIC contribution to the barrier height is a key indicator. A large SIC correction is correlated to a large LSDA error in the barrier, showing that PZSIC properly gives larger corrections when corrections are needed most. A comparison of the performance of PZSIC and LSIC shows that the two methods have similar accuracy for reactions with large LSDA errors, but LSIC is clearly better for reactions with small errors. We trace this to an improved description of reaction energies in LSIC.

A 25-Year Retrospective Review of Mortality in Chimpanzees (Pan troglodytes) in Accredited U.S. Zoos from a Management and Welfare Perspective.

Understanding causes of death allows adjustment of health management strategies for animals in managed care. From 224 documented chimpanzee deaths occurring from 1995 to 2019 in 42 accredited U.S. zoos, post-mortem records and necropsy reports were analyzed for the primary cause of death, which were available for 214 individuals. In total, 37 cases of stillbirth and neonatal deaths were assessed (16.5%); however, the focus was otherwise placed on the remaining 177 cases in which the death occurred in individuals aged greater than 1 month. There were no sex-related differences in etiology; however, age variation in the cause of death was statistically significant (p < 0.001). Elderly (35 years and older) chimpanzees tended to die of intrinsic, often degenerative, etiologies, whereas infants, juveniles, and adolescents (less than 15 years) were more likely to be involved in fatal trauma. Overall, there were 27 deaths (15.3% of all post-neonatal deaths) related to trauma and 13 of these were directly or indirectly related to conspecific aggression. Understanding causes of mortality and the interrelation with management can benefit managed populations of chimpanzees.

Single-Cell Immune Mapping of Melanoma Sentinel Lymph Nodes Reveals an Actionable Immunotolerant Microenvironment.

PURPOSE: Improving our understanding of the immunologic response to cancer cells within the sentinel lymph nodes (SLN) of primary tumors is expected to identify new approaches to stimulate clinically meaningful cancer immunity. EXPERIMENTAL DESIGN: We used mass cytometry by time-of-flight (CyTOF), flow cytometry, and T-cell receptor immunosequencing to conduct simultaneous single-cell analyses of immune cells in the SLNs of patients with melanoma. RESULTS: We found increased effector-memory αß T cells, TCR clonality, and γδ T cells selectively in the melanoma-bearing SLNs relative to non-melanoma-bearing SLNs, consistent with possible activation of an antitumor immune response. However, we also observed a markedly immunotolerant environment in the melanoma-bearing SLNs indicated by reduced and impaired NK cells and increased levels of CD8+CD57+PD-1+ cells, which are known to display low melanoma killing capabilities. Other changes observed in melanoma-bearing SLNs when compared with non-melanoma-bearing SLNs include (i) reduced CD8+CD69+ T cell/T regulatory cell ratio, (ii) high PD-1 expression on CD4+ and CD8+ T cells, and (iii) high CTLA-4 expression on γδ T cells. CONCLUSIONS: Our data suggest that these immunologic changes compromise antimelanoma immunity and contribute to a high relapse rate. We propose the development of clinical trials to test the neo-adjuvant administration of anti-PD-1 antibodies prior to SLN resection in patients with stage III melanoma. See related commentary by Lund, p. 1996.

A review on recent advancements in recovery of valuable and toxic metals from e-waste using bioleaching approach.

This review is intent on the environmental pollution generated from printed circuit boards and the methods employed to retrieve valuable and hazardous metals present in the e-wastes. Printed circuit boards are the key components in the electronic devices and considered as huge e-pollutants in polluting our surroundings and the environment as a whole. Composing of toxic heavy metals, it causes serious health effects to the plants, animals and humans in the environment. A number of chemical, biological and physical approaches were carried out to recover the precious metals and to remove the hazardous metals from the environment. Chemical leaching is one of the conventional PCBs recycling methods which was carried out by using different organic solvents and chemicals. Need of high cost for execution, generation of secondary wastes in the conventional methods, forces to discover the advanced recycling methods such as hydrometallurgical, bio-metallurgical and bioleaching processes to retrieve the valuable metals generate through e-wastes. Among them, bioleaching process gain extra priority due to its higher efficiency of metal recovery from printed circuit boards. There are different classes of microorganisms have been utilized for precious metal recovery from the PCBs through bioleaching process such as chemolithoautotrophy, heterotrophy and different fungal species including Aspergillus sp. and Penicillium sp. The current status and scope for further studies in printed circuit boards recycling are discussed in this review.

Identifying UiO-67 Metal-Organic Framework Defects and Binding Sites through Ammonia Adsorption.

Ammonia is a widely used toxic industrial chemical that can cause severe respiratory ailments. Therefore, understanding and developing materials for its efficient capture and controlled release is necessary. One such class of materials is 3D porous metal-organic frameworks (MOFs) with exceptional surface areas and robust structures, ideal for gas storage/transport applications. Herein, interactions between ammonia and UiO-67-X (X: H, NH2 , CH3 ) zirconium MOFs were studied under cryogenic, ultrahigh vacuum (UHV) conditions using temperature-programmed desorption mass spectrometry (TPD-MS) and in-situ temperature-programmed infrared (TP-IR) spectroscopy. Ammonia was observed to interact with µ3 -OH groups present on the secondary building unit of UiO-67-X MOFs via hydrogen bonding. TP-IR studies revealed that under cryogenic UHV conditions, UiO-67-X MOFs are stable towards ammonia sorption. Interestingly, an increase in the intensity of the C-H stretching mode of the MOF linkers was detected upon ammonia exposure, attributed to NH-π interactions with linkers. These same binding interactions were observed in grand canonical Monte Carlo simulations. Based on TPD-MS, binding strength of ammonia to three MOFs was determined to be approximately 60 kJ mol-1 , suggesting physisorption of ammonia to UiO-67-X. In addition, missing linker defect sites, consisting of H2 O coordinated to Zr4+ sites, were detected through the formation of nNH3 ⋅H2 O clusters, characterized through in-situ IR spectroscopy. Structures consistent with these assignments were identified through density functional theory calculations. Tracking these bands through adsorption on thermally activated MOFs gave insight into the dehydroxylation process of UiO-67 MOFs. This highlights an advantage of using NH3 for the structural analysis of MOFs and developing an understanding of interactions between ammonia and UiO-67-X zirconium MOFs, while also providing directions for the development of stable materials for efficient toxic gas sorption.

Posterior Reversible Encephalopathy Syndrome: Nitroglycerine a Friend or a Foe?

Posterior reversible encephalopathy syndrome (PRES) refers to a clinico-radiological entity with characteristic features on neuroimaging and rapid onset of nonspecific symptoms including headache, seizure, altered consciousness and visual disturbance. It is a neurotoxic state in response to the acute changes in blood pressure leading to vasogenic oedema. It is often but not always associated with hypertension. However, control blood pressure is one of the mainstays of management in such cases. Nitroglycerine (NTG) is a potent vasodilator and is one of the drugs for treatment of hypertensive emergencies. It is found to worsen the cerebral oedema in PRES which is considered due to failure of cerebral blood pressure autoregulation. Here, we report two such cases where patients with PRES deteriorated with NTG infusion. However, the neurological condition of the patients improved drastically the next day. NTG could have further enhanced vasodilation, thus aggravating developing PRES, after autoregulation was lost because of high blood pressure.

Normative appeals motivate people to contribute to collective action problems more when they invite people to work together toward a common goal.

A common method to promote behavior change, particularly in contexts related to collective action, is to reference a social norm and ask people to comply with it. We argue that such appeals will be more effective when they couch the norm as an invitation to work with others toward a common goal. In six experiments, we found that working-together normative appeals, which invited people to "join in" and "do it together," increased interest in (Experiments 1, 4, and 5) and actual charitable giving (Experiment 2), reduced paper-towel use in public restrooms (Experiment 3), and increased interest in reducing personal carbon emissions (Experiment 6). By contrast, normative-information appeals, which included the same normative information but no reference to working together, did not affect interest or behavior. Mediation analyses suggest that working-together normative appeals were more effective because they fostered a feeling in participants that they were working together with others, which increased motivation, while inducing less social pressure, which undermined effectiveness. Results show how the very collective nature of collective action problems can be leveraged to promote personal behavior change and help solve societal problems. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Novel Circulating and Tissue Monocytes as Well as Macrophages in Pancreatitis and Recovery.

BACKGROUND AND AIMS: Acute pancreatitis (AP) is an inflammatory disease with mild to severe course that is associated with local and systemic complications and significant mortality. Uncovering inflammatory pathways that lead to progression and recovery will inform ways to monitor and/or develop effective therapies. METHODS: We performed single-cell mass Cytometry by Time Of Flight (CyTOF) analysis to identify pancreatic and systemic inflammatory signals during mild AP (referred to as AP), severe AP (SAP), and recovery using 2 independent experimental models and blood from patients with AP and recurrent AP. Flow cytometric validation of monocytes subsets identified using CyTOF analysis was performed independently. RESULTS: Ly6C+ inflammatory monocytes were the most altered cells in the pancreas during experimental AP, recovery, and SAP. Deep profiling uncovered heterogeneity among pancreatic and blood monocytes and identified 7 novel subsets during AP and recovery, and 6 monocyte subsets during SAP. Notably, a dynamic shift in pancreatic CD206+ macrophage population was observed during AP and recovery. Deeper profiling of the CD206+ macrophage identified 7 novel subsets during AP, recovery, and SAP. Differential expression analysis of these novel monocyte and CD206+ macrophage subsets revealed significantly altered surface (CD44, CD54, CD115, CD140a, CD196, podoplanin) and functional markers (interferon-γ, interleukin 4, interleukin 22, latency associated peptide-transforming growth factor-ß, tumor necrosis factor-α, T-bet, RoRγt) that were associated with recovery and SAP. Moreover, a targeted functional analysis further revealed distinct expression of pro- and anti-inflammatory cytokines by pancreatic CD206+ macrophage subsets as the disease either progressed or resolved. Similarly, we identified heterogeneity among circulating classical inflammatory monocytes (CD14+CD16-) and novel subsets in patients with AP and recurrent AP. CONCLUSIONS: We identified several novel monocyte/macrophage subsets with unique phenotype and functional characteristics that are associated with AP, recovery, and SAP. Our findings highlight differential innate immune responses during AP progression and recovery that can be leveraged for future disease monitoring and targeting.

Mass Cytometry Analysis of T-Helper Cells.

CD4+ T cells or helper T cells play various roles in the immune response to pathogens, tumors, as well as in asthma, allergy, and autoimmunity. Consequently, there is great interest in the comprehensive investigation of different T helper cell subsets. Here, we use mass cytometry (CyTOF), which is similar to flow cytometry but uses metal ion-tagged antibodies, which are detected using time-of-flight mass spectrometry. CyTOF allows the simultaneous detection of over 40 different antibodies, allowing us to collect high-dimensional single-cell proteomic data on T helper subsets. We use an extensive staining panel with a large number of lineage markers, cytokines, and other functional markers to identify and characterize CD4+ T cell subsets. In this method, human peripheral blood mononuclear cells are stimulated ex vivo with PMA and ionomycin, which activates T cells. The activated CD4+ T cells can then be identified as Th1, Th2, or Th17 cells based on their production of IFNγ, IL-4, and IL-17, respectively. Tregs are identified as CD4+CD25+CD127lo. Once Th1, Th2, Th17, and Tregs have been identified, they can be characterized in more detail using the large number of phenotypic and functional markers included in the CyTOF staining panel. Finally, automated and unbiased high-dimensional data analysis tools can be employed to comprehensively characterize T helper cells and discover novel features.

In Situ Nuclear Magnetic Resonance Investigation of Molecular Adsorption and Kinetics in Metal-Organic Framework UiO-66.

Thermodynamic and kinetic properties of molecular adsorption and transport in metal-organic frameworks (MOFs) are crucially important for many applications, including gas adsorption, filtration, and remediation of harmful chemicals. Using the in situ 1H nuclear magnetic resonance (NMR) isotherm technique, we measured macroscopic thermodynamic and kinetic properties such as isotherms and rates of mass transfer while simultaneously obtaining microscopic information revealed by adsorbed molecules via NMR. Upon investigating isopropyl alcohol adsorption in MOF UiO-66 by in situ NMR, we obtained separate isotherms for molecules adsorbed at distinct environments exhibiting distinct NMR characteristics. A mechanistic view of the adsorption process is obtained by correlating such resolved isotherms with the cage structure effect on the nucleus-independent chemical shift, molecular dynamics such as the crowding effect at high loading levels, and the loading level dependence of the mass transfer rate as measured by NMR and elucidated by classical Monte Carlo simulations.

Mass Cytometry Defines Virus-Specific CD4+ T Cells in Influenza Vaccination.

The antiviral response to influenza virus is complex and multifaceted, involving many immune cell subsets. There is an urgent need to understand the role of CD4+ T cells, which orchestrate an effective antiviral response, to improve vaccine design strategies. In this study, we analyzed PBMCs from human participants immunized with influenza vaccine, using high-dimensional single-cell proteomic immune profiling by mass cytometry. Data were analyzed using a novel clustering algorithm, denoised ragged pruning, to define possible influenza virus-specific clusters of CD4+ T cells. Denoised ragged pruning identified six clusters of cells. Among these, one cluster (Cluster 3) was found to increase in abundance following stimulation with influenza virus peptide ex vivo. A separate cluster (Cluster 4) was found to expand in abundance between days 0 and 7 postvaccination, indicating that it is vaccine responsive. We examined the expression profiles of all six clusters to characterize their lineage, functionality, and possible role in the response to influenza vaccine. Clusters 3 and 4 consisted of effector memory cells, with high CD154 expression. Cluster 3 expressed cytokines like IL-2, IFN-γ, and TNF-α, whereas Cluster 4 expressed IL-17. Interestingly, some participants had low abundance of Clusters 3 and 4, whereas others had higher abundance of one of these clusters compared with the other. Taken together, we present an approach for identifying novel influenza virus-reactive CD4+ T cell subsets, a method that could help advance understanding of the immune response to influenza, predict responsiveness to vaccines, and aid in better vaccine design.

Clinical Validation of Integrated Point-of-Care Devices for the Management of Non-Communicable Diseases.

Non-communicable diseases are the leading cause of death and disability across India, including in the poorest states. Effective disease management, particularly for cardiovascular diseases, requires the tracking of several biochemical and physiological parameters over an extended period of time. Currently, patients must go to diagnostic laboratories and doctors' clinics or invest in individual point-of-care devices for measuring the required parameters. The cost and inconvenience of current options lead to inconsistent monitoring, which contribute to suboptimal outcomes. Furthermore, managing multiple individual point-of-devices is challenging and helps track some parameters to the exclusion of others. To address these issues, HealthCubed, a primary care technology company, has designed integrated devices that measure blood glucose, hemoglobin, cholesterol, uric acid, blood pressure, capillary oxygen saturation and pulse rate. Here we report data from clinical studies undertaken in healthy subjects establishing the validity of an integrated device for monitoring multiple parameters.

A Prospective, Phase 1 Trial of Nivolumab, Ipilimumab, and Radiotherapy in Patients with Advanced Melanoma.

PURPOSE: Preclinical data suggest that radiotherapy (RT) is beneficial in combination with immune checkpoint blockade. Clinical trials have explored RT with single-agent immune checkpoint blockade, but no trials have reported RT with the combination of nivolumab and ipilimumab. PATIENTS AND METHODS: We conducted a phase 1 study of patients with stage IV melanoma receiving nivolumab and ipilimumab with two different dose-fractionation schemes of RT. Patients had at least one melanoma metastasis that would benefit from palliative RT and one metastasis that would not be irradiated. Nivolumab 1 mg/kg + ipilimumab 3 mg/kg and extracranial RT with a dose of 30 Gy in 10 fractions was administered in Cohort A, and then 27 Gy in 3 fractions was administered in Cohort B. The primary outcome was safety. RESULTS: Twenty patients were treated (10 in each cohort). The rates of treatment-related grade 3-4 adverse events in Cohort A and B were 40% and 30%, respectively. There were no grade ≥3 adverse events attributed to RT. Patients responded to treatment outside of the irradiated volume (Cohort A 5/10; Cohort B 1/9). No evaluable patients had progression of irradiated metastases. Immunologic changes were seen in the peripheral blood with increases in T-cell receptor diversity in some responding patients. CONCLUSIONS: RT with nivolumab and ipilimumab was safe compared with historical data of nivolumab and ipilimumab alone. Immunologic effects were observed in the peripheral blood. Randomized studies are ongoing to assess whether RT increases the efficacy of nivolumab and ipilimumab.