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Background Although coaching programs have become a prominent piece of graduate medical education, they have yet to become an integral part of undergraduate medical education. A handful of medical schools have utilized longitudinal coaching experiences as a method for professional identity formation, developing emotional intelligence and leadership. Objective We developed A Whole New Doctor (AWND), a medical student leadership development and coaching program at Georgetown University, with the aim of fostering resilience, leadership, and emotional intelligence at the nascent stage of physician training. To our knowledge, ours is the only program that is largely student-managed and uses certified executive coaches in the medical student population. Methods Cohort 1 of AWND started in October 2016. For each cohort, we hold a kickoff workshop that is highly interactive, fast-paced and covers coaching, complex thinking, reflective writing, and a coaching panel for Q&A. Following the workshop, students work with coaches individually to address self-identified weaknesses, tensions, and areas of conflict. We believe the program’s student-driven nature provides a new structural approach to professional development and leadership programs, offering students a simultaneously reflective and growth-oriented opportunity to develop essential non-technical skills for physician leaders. Results Of the 132 students in the program, 107 have worked with one of our coaches (81%). Student testimonials have been uniformly positive with students remarking on an increased sense of presence, improvements in communication, and more specific direction in their careers. Conclusion Our pilot coaching program has received positive feedback from students early in their medical training. It will be important to further scale the program to reach an increasing number of students and quantitatively evaluate participants for the long-term effects of our interventions.

ABSTRACT: Objective: Microcephalic primordial dwarfism (MPD) is a group of clinically and genetically heterogeneous disorders which result in severe prenatal and postnatal growth failure. X-ray repair cross-complementing protein 4 (XRCC4) is a causative gene for an autosomal recessive form of MPD. The objective of this report is to describe novel XRCC4 mutations in a female infant with MPD, dilated cardiomyopathy, and subclinical hypothyroidism. Methods: Genetic testing was performed using a comprehensive next generation sequencing panel for MPD, followed by targeted XRCC4 gene sequencing. Results: We report the case of a 970-gram, 35-cm, female infant (weight z score -5.05, length z score -4.71) born at 36 weeks and 3 days gestation. Physical examination revealed triangular facies, micrognathism, clinodactyly, and second and third toe syndactyly. Initial echocardiogram at birth was normal. Follow-up echocardiogram at 60 days of life revealed dilated cardiomyopathy with moderate left ventricular systolic dysfunction (ejection fraction was 40 to 45%), and anticongestive therapy was initiated. Thyroid testing revealed subclinical hypothyroidism with elevated thyroid-stimulating hormone of 13.0 μIU/mL (reference range is 0.3 to 5.0 μIU/mL) and normal free thyroxine by dialysis of 1.6 ng/dL (reference range is 0.8 to 2.0 ng/dL). Levothyroxine was initiated. Postnatal growth remained poor (weight z score at 3 months -4.93, length z score at 3 months -6.48), including progressive microcephaly (head circumference z score at 3 months -10.94). Genetic testing revealed novel compound heterozygous XRCC4 variants in trans: c.628A>T and c.638+3A>G. The child ultimately had cardiopulmonary arrest and died at 6 months of life. Conclusion: Molecular diagnosis in MPD is key to defining the natural history, management, and prognosis for patients with these rare disorders.

Background:. Finances impact every aspect of our daily lives. Despite this, they are rarely discussed in medical school or surgical training. Consequently, more than half the medical students we interview report no formal teaching about personal finance. The purpose of this article was to present 5 topics every graduating medical student, resident, and young surgeon should understand to start the path to financial independence. Methods:. We synthesized recommendations and data from several books on financial literacy, blogs on the topic, and the personal experiences of the 4 authors. Results:. The following 5 topics were identified as critical for young surgeons: learn about and manage your own finances, consider the financial implications of your career choices, make a plan to pay off your student loans, make a budget and stick to it, and think carefully before buying property. Central to these 5 lessons is the idea that starting to invest and save early is essential to taking advantage of interest and capital gains. We also demonstrate pay and cost differences in 5 regions of the country and outline the 2 main pathways one can take to repaying their student loans. Conclusions:. Financial literacy is an important aspect of being an effective surgeon. With minimal effort, you can take these 5 steps now toward financial freedom. Doing so will improve your sense of control over your financial life and decrease anxiety about the unknown.

We compared emergency department and ambulatory care syndromic surveillance systems during the pandemic (H1N1) 2009 outbreak in New York City. Emergency departments likely experienced increases in influenza-like-illness significantly earlier than ambulatory care facilities because more patients sought care at emergency departments, differences in case definitions existed, or a combination thereof. [ABSTRACT FROM AUTHOR]

The Hub Population Health System enables the creation and distribution of queries for aggregate count information, clinical decision support alerts at the point-of-care for patients who meet specified conditions, and secure messages sent directly to provider electronic health record (EHR) inboxes. Using a metronidazole medication recall, the New York City Department of Health was able to determine the number of affected patients and message providers, and distribute an alert to participating practices. As of September 2011, the system is live in 400 practices and within a year will have over 532 practices with 2500 providers, representing over 2.5 million New Yorkers. The Hub can help public health experts to evaluate population health and quality improvement activities throughout the ambulatory care network. Multiple EHR vendors are building these features in partnership with the department's regional extension center in anticipation of new meaningful use requirements. [ABSTRACT FROM AUTHOR]

A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis , which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.

Cross-presentation of dead cell-associated antigens by conventional dendritic cells type 1 (cDC1s) is critical for CD8 + T cells response against many tumors and viral infections. It is facilitated by DNGR-1 (CLEC9A), an SYK-coupled cDC1 receptor that detects dead cell debris. Here, we report that DNGR-1 engagement leads to rapid activation of CBL and CBL-B E3 ligases to cause K63-linked ubiquitination of SYK and terminate signaling. Genetic deletion of CBL E3 ligases or charge-conserved mutation of target lysines within SYK abolishes SYK ubiquitination and results in enhanced DNGR-1-dependent antigen cross-presentation. We also find that cDC1 deficient in CBL E3 ligases are more efficient at cross-priming CD8 + T cells to dead cell-associated antigens and promoting host resistance to tumors. Our findings reveal a role for CBL-dependent ubiquitination in limiting cross-presentation of dead cell-associated antigens and highlight an axis of negative regulation of cDC1 activity that could be exploited to increase anti-tumor immunity., Competing Interests: Declaration of interests C.R.S. is a founder of Adendra Therapeutics and owns stock options and/or is a paid consultant for Adendra Therapeutics, Bicara Therapeutics, Montis Biosciences, and Bicycle Therapeutics, all unrelated to this work. C.R.S. also has an additional appointment as Visiting Professor in the Faculty of Medicine at Imperial College London and holds honorary professorships at University College London and King’s College London. H.B. received a research grant from Nimbus Therapeutics for unrelated work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Artificial sweeteners are used as calorie-free sugar substitutes in many food products and their consumption has increased substantially over the past years 1 . Although generally regarded as safe, some concerns have been raised about the long-term safety of the consumption of certain sweeteners 2-5 . In this study, we show that the intake of high doses of sucralose in mice results in immunomodulatory effects by limiting T cell proliferation and T cell differentiation. Mechanistically, sucralose affects the membrane order of T cells, accompanied by a reduced efficiency of T cell receptor signalling and intracellular calcium mobilization. Mice given sucralose show decreased CD8 + T cell antigen-specific responses in subcutaneous cancer models and bacterial infection models, and reduced T cell function in models of T cell-mediated autoimmunity. Overall, these findings suggest that a high intake of sucralose can dampen T cell-mediated responses, an effect that could be used in therapy to mitigate T cell-dependent autoimmune disorders., (© 2023. The Author(s).)

Protection from infection with respiratory viruses such as influenza A virus (IAV) requires T cell–mediated immune responses initiated by conventional dendritic cells (cDCs) that reside in the respiratory tract. Here, we show that effective induction of T cell responses against IAV in mice requires reinforcement of the resident lung cDC network by cDC progenitors. We found that CCR2-binding chemokines produced during IAV infection recruit pre-cDCs from blood and direct them to foci of infection, increasing the number of progeny cDCs next to sites of viral replication. Ablation of CCR2 in the cDC lineage prevented this increase and resulted in a deficit in IAV-specific T cell responses and diminished resistance to reinfection. These data suggest that the homeostatic network of cDCs in tissues is insufficient for immunity and reveal a chemokine-driven mechanism of expansion of lung cDC numbers that amplifies T cell responses against respiratory viruses.

Cross-presentation of antigens from dead tumor cells by type 1 conventional dendritic cells (cDC1s) is thought to underlie priming of anti-cancer CD8 + T cells. cDC1 express high levels of DNGR-1 (a.k.a. CLEC9A), a receptor that binds to F-actin exposed by dead cell debris and promotes cross-presentation of associated antigens. Here, we show that secreted gelsolin (sGSN), an extracellular protein, decreases DNGR-1 binding to F-actin and cross-presentation of dead cell-associated antigens by cDC1s. Mice deficient in sGsn display increased DNGR-1-dependent resistance to transplantable tumors, especially ones expressing neoantigens associated with the actin cytoskeleton, and exhibit greater responsiveness to cancer immunotherapy. In human cancers, lower levels of intratumoral sGSN transcripts, as well as presence of mutations in proteins associated with the actin cytoskeleton, are associated with signatures of anti-cancer immunity and increased patient survival. Our results reveal a natural barrier to cross-presentation of cancer antigens that dampens anti-tumor CD8 + T cell responses., Competing Interests: Declaration of interests E.G., O.S., K.H.J.L., N.S., O.G., S.Z., S.S., P.C., and C.R.S. are named as inventors on a patent application on the use of sGSN for immunotherapies. C.R.S. owns stock options and/or is a paid consultant for Bicara Therapeutics, Montis Biosciences, Oncurious NV, Bicycle Therapeutics, and Sosei Heptares. C.R.S. holds a professorship at Imperial College London and honorary professorships at University College London and King’s College London. None of these activities are related to this work., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

In mammals, early resistance to viruses relies on interferons, which protect differentiated cells but not stem cells from viral replication. Many other organisms rely instead on RNA interference (RNAi) mediated by a specialized Dicer protein that cleaves viral double-stranded RNA. Whether RNAi also contributes to mammalian antiviral immunity remains controversial. We identified an isoform of Dicer, named antiviral Dicer (aviD), that protects tissue stem cells from RNA viruses-including Zika virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-by dicing viral double-stranded RNA to orchestrate antiviral RNAi. Our work sheds light on the molecular regulation of antiviral RNAi in mammalian innate immunity, in which different cell-intrinsic antiviral pathways can be tailored to the differentiation status of cells., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show that in activated CD8 + T cells, exposure to febrile temperature (39 °C) augmented metabolic activity and T cell effector functions, despite having a limited effect on proliferation or activation marker expression. Transcriptional profiling revealed an up-regulation of mitochondrial pathways, which was consistent with increased mass and metabolism observed in T cells exposed to 39 °C. Through in vitro and in vivo models, we determined that mitochondrial translation is integral to the enhanced metabolic activity and function of CD8 + T cells exposed to febrile temperature. Transiently exposing donor lymphocytes to 39 °C prior to infusion in a myeloid leukemia mouse model conferred enhanced therapeutic efficacy, raising the possibility that exposure of T cells to febrile temperatures could have clinical potential., Competing Interests: Competing interest statement: E.L.P. is a Scientific Advisory Board member of ImmunoMet Therapeutics, and E.J.P. and E.L.P. are founders of Rheos Medicines., (Copyright © 2021 the Author(s). Published by PNAS.)

The ongoing pandemic of SARS-CoV-2 calls for rapid and cost-effective methods to accurately identify infected individuals. The vast majority of patient samples is assessed for viral RNA presence by RT-qPCR. Our biomedical research institute, in collaboration between partner hospitals and an accredited clinical diagnostic laboratory, established a diagnostic testing pipeline that has reported on more than 252,000 RT-qPCR results since its commencement at the beginning of April 2020. However, due to ongoing demand and competition for critical resources, alternative testing strategies were sought. In this work, we present a clinically-validated procedure for high-throughput SARS-CoV-2 detection by RT-LAMP that is robust, reliable, repeatable, specific, and inexpensive., Competing Interests: Competing interests: D. Miller and K. Gulati are employees of New England Biolabs, which provided the WarmStart Colorimetric LAMP 2X Master Mix used in this work. C. Swanton receives or has received grant support from Pfizer, AstraZeneca, Bristol-Myers Squibb (BMS), Roche-Ventana, Boehringer-Ingelheim, and Ono Pharmaceutical and has consulted for or received an honorarium from Pfizer, Novartis, GlaxoSmithKline, Merck Sharp & Dohme, BMS, Celgene, AstraZeneca, Illumina, Genentech, Roche-Venatana, GRAIL, Medicxi, and the Sarah Cannon Research Institute. C. Swanton also is a shareholder of Apogen Biotechnologies, Epic Bioscience, and GRAIL and has stock options in and is a cofounder of Achilles Therapeutics., (Copyright: © 2021 Buck MD et al.)

Type 1 conventional dendritic (cDC1) cells are necessary for cross-presentation of many viral and tumor antigens to CD8 + T cells. cDC1 cells can be identified in mice and humans by high expression of DNGR-1 (also known as CLEC9A), a receptor that binds dead-cell debris and facilitates XP of corpse-associated antigens. Here, we show that DNGR-1 is a dedicated XP receptor that signals upon ligand engagement to promote phagosomal rupture. This allows escape of phagosomal contents into the cytosol, where they access the endogenous major histocompatibility complex class I antigen processing pathway. The activity of DNGR-1 maps to its signaling domain, which activates SYK and NADPH oxidase to cause phagosomal damage even when spliced into a heterologous receptor and expressed in heterologous cells. Our data reveal the existence of innate immune receptors that couple ligand binding to endocytic vesicle damage to permit MHC class I antigen presentation of exogenous antigens and to regulate adaptive immunity.

The contribution of self-peptide-MHC signaling in CD4 + T cells to metabolic programming has not been definitively established. In this study, we employed LLO118 and LLO56, two TCRtg CD4 + T cells that recognize the same Listeria epitope. We previously have shown that LLO56 T cells are highly self-reactive and respond poorly in a primary infection, whereas LLO118 cells, which are less self-reactive, respond well during primary infection. We performed metabolic profiling and found that naive LLO118 had a dramatically higher basal respiration rate, a higher maximal respiration rate, and a higher glycolytic rate relative to LLO56. The LLO118 cells also exhibited a greater uptake of 2-NBD-glucose, in vitro and in vivo. We extended the correlation of low self-reactivity (CD5 lo ) with high basal metabolism using two other CD4 + TCRtg cells with known differences in self-reactivity, AND and Marilyn. We hypothesized that the decreased metabolism resulting from a strong interaction with self was mediated through TCR signaling. We then used an inducible knock-in mouse expressing the Scn5a voltage-gated sodium channel. This channel, when expressed in peripheral T cells, enhanced basal TCR-mediated signaling, resulting in decreased respiration and glycolysis, supporting our hypothesis. Genes and metabolites analysis of LLO118 and LLO56 T cells revealed significant differences in their metabolic pathways, including the glycerol phosphate shuttle. Inhibition of this pathway reverts the metabolic state of the LLO118 cells to be more LLO56 like. Overall, these studies highlight the critical relationship between peripheral TCR-self-pMHC interaction, metabolism, and the immune response to infection., (Copyright © 2020 The Authors.)

The importance of cancer-cell-autonomous functions of the tumour suppressor p53 (encoded by TP53 ) has been established in many studies, but it is now clear that the p53 status of the cancer cell also has a profound impact on the immune response. Loss or mutation of p53 in cancers can affect the recruitment and activity of myeloid and T cells, allowing immune evasion and promoting cancer progression. p53 can also function in immune cells, resulting in various outcomes that can impede or support tumour development. Understanding the role of p53 in tumour and immune cells will help in the development of therapeutic approaches that can harness the differential p53 status of cancers compared with most normal tissue., Competing Interests: Competing interestsK.H.V. is on the Board of Directors and shareholder of Bristol Myers Squibb, a shareholder of GRAIL, Inc. and on the Science Advisory Board of PMV Pharma, RAZE Therapeutics, Volestra Therapeutics and Ludwig Cancer. She is a co-founder and consultant of Faeth Therapeutics, funded by Khosla Ventures. She has been in receipt of research funding from Astex Pharmaceuticals and AstraZeneca and contributed to CRUK Cancer Research Technology filing of Patent Application WO/2017/144877., (© 2020. Published by The Company of Biologists Ltd.)

How cells adapt metabolism to meet demands is an active area of interest across biology. Among a broad range of functions, the polyamine spermidine is needed to hypusinate the translation factor eukaryotic initiation factor 5A (eIF5A). We show here that hypusinated eIF5A (eIF5A H ) promotes the efficient expression of a subset of mitochondrial proteins involved in the TCA cycle and oxidative phosphorylation (OXPHOS). Several of these proteins have mitochondrial targeting sequences (MTSs) that in part confer an increased dependency on eIF5AH. In macrophages, metabolic switching between OXPHOS and glycolysis supports divergent functional fates stimulated by activation signals. In these cells, hypusination of eIF5A appears to be dynamically regulated after activation. Using in vivo and in vitro models, we show that acute inhibition of this pathway blunts OXPHOS-dependent alternative activation, while leaving aerobic glycolysis-dependent classical activation intact. These results might have implications for therapeutically controlling macrophage activation by targeting the polyamine-eIF5A-hypusine axis., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here, we show that acetate rescues effector function in glucose-restricted CD8 + T cells. Mechanistically, acetate promotes histone acetylation and chromatin accessibility and enhances IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increases IFN-γ production by exhausted T cells, whereas reducing ACSS expression in T cells impairs IFN-γ production by tumor-infiltrating lymphocytes and tumor clearance. Thus, hyporesponsive T cells can be epigenetically remodeled and reactivated by acetate, suggesting that pathways regulating the use of substrates alternative to glucose could be therapeutically targeted to promote T cell function during cancer., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here, we show that PGE2 caused mitochondrial membrane potential (Δψ m ) to dissipate in interleukin-4-activated (M(IL-4)) macrophages. Effects on Δψ m were a consequence of PGE2-initiated transcriptional regulation of genes, particularly Got1, in the malate-aspartate shuttle (MAS). Reduced Δψ m caused alterations in the expression of 126 voltage-regulated genes (VRGs), including those encoding resistin-like molecule α (RELMα), a key marker of M(IL-4) cells, and genes that regulate the cell cycle. The transcription factor ETS variant 1 (ETV1) played a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψ m -sensitive transcription factor and Δψ m as a mediator of mitochondrial-directed nuclear gene expression., (Copyright © 2018 Elsevier Inc. All rights reserved.)

T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation-cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Choices have consequences. Immune cells survey and migrate throughout the body and sometimes take residence in niche environments with distinct communities of cells, extracellular matrix, and nutrients that may differ from those in which they matured. Imbedded in immune cell physiology are metabolic pathways and metabolites that not only provide energy and substrates for growth and survival, but also instruct effector functions, differentiation, and gene expression. This review of immunometabolism will reference the most recent literature to cover the choices that environments impose on the metabolism and function of immune cells and highlight their consequences during homeostasis and disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Activated effector T (TE) cells augment anabolic pathways of metabolism, such as aerobic glycolysis, while memory T (TM) cells engage catabolic pathways, like fatty acid oxidation (FAO). However, signals that drive these differences remain unclear. Mitochondria are metabolic organelles that actively transform their ultrastructure. Therefore, we questioned whether mitochondrial dynamics controls T cell metabolism. We show that TE cells have punctate mitochondria, while TM cells maintain fused networks. The fusion protein Opa1 is required for TM, but not TE cells after infection, and enforcing fusion in TE cells imposes TM cell characteristics and enhances antitumor function. Our data suggest that, by altering cristae morphology, fusion in TM cells configures electron transport chain (ETC) complex associations favoring oxidative phosphorylation (OXPHOS) and FAO, while fission in TE cells leads to cristae expansion, reducing ETC efficiency and promoting aerobic glycolysis. Thus, mitochondrial remodeling is a signaling mechanism that instructs T cell metabolic programming., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Greater understanding of the complex host responses induced by type 1 interferon (IFN) cytokines could allow new therapeutic approaches for diseases in which these cytokines are implicated. We found that in response to the Toll-like receptor-9 agonist CpGA, plasmacytoid dendritic cells (pDC) produced type 1 IFNs, which, through an autocrine type 1 IFN receptor-dependent pathway, induced changes in cellular metabolism characterized by increased fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). Direct inhibition of FAO and of pathways that support this process, such as fatty acid synthesis, prevented full pDC activation. Type 1 IFNs also induced increased FAO and OXPHOS in non-hematopoietic cells and were found to be responsible for increased FAO and OXPHOS in virus-infected cells. Increased FAO and OXPHOS in response to type 1 IFNs was regulated by PPARα. Our findings reveal FAO, OXPHOS and PPARα as potential targets to therapeutically modulate downstream effects of type 1 IFNs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Group 2 innate lymphoid cells (ILC2s) regulate tissue inflammation and repair after activation by cell-extrinsic factors such as host-derived cytokines. However, the cell-intrinsic metabolic pathways that control ILC2 function are undefined. Here we demonstrate that expression of the enzyme arginase-1 (Arg1) during acute or chronic lung inflammation is a conserved trait of mouse and human ILC2s. Deletion of mouse ILC-intrinsic Arg1 abrogated type 2 lung inflammation by restraining ILC2 proliferation and dampening cytokine production. Mechanistically, inhibition of Arg1 enzymatic activity disrupted multiple components of ILC2 metabolic programming by altering arginine catabolism, impairing polyamine biosynthesis and reducing aerobic glycolysis. These data identify Arg1 as a key regulator of ILC2 bioenergetics that controls proliferative capacity and proinflammatory functions promoting type 2 inflammation.

The antiviral activity of UV-4 was previously demonstrated against dengue virus serotype 2 (DENV2) in multiple mouse models. Herein, step-wise minimal effective dose and therapeutic window of efficacy studies of UV-4B (UV-4 hydrochloride salt) were conducted in an antibody-dependent enhancement (ADE) mouse model of severe DENV2 infection in AG129 mice lacking types I and II interferon receptors. Significant survival benefit was demonstrated with 10-20 mg/kg of UV-4B administered thrice daily (TID) for seven days with initiation of treatment up to 48 h after infection. UV-4B also reduced infectious virus production in in vitro antiviral activity assays against all four DENV serotypes, including clinical isolates. A set of purified enzyme, in vitro, and in vivo studies demonstrated that inhibition of endoplasmic reticulum (ER) α-glucosidases and not the glycosphingolipid pathway appears to be responsible for the antiviral activity of UV-4B against DENV. Along with a comprehensive safety package, these and previously published data provided support for an Investigational New Drug (IND) filing and Phases 1 and 2 clinical trials for UV-4B with an indication of acute dengue disease., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Host genes that regulate systemic inflammation upon chronic viral infection are incompletely understood. Murine gammaherpesvirus 68 (MHV68) infection is characterized by latency in macrophages, and reactivation is inhibited by interferon-γ (IFN-γ). Using a lysozyme-M-cre (LysMcre) expression system, we show that deletion of autophagy-related (Atg) genes Fip200, beclin 1, Atg14, Atg16l1, Atg7, Atg3, and Atg5, in the myeloid compartment, inhibited MHV68 reactivation in macrophages. Atg5 deficiency did not alter reactivation from B cells, and effects on reactivation from macrophages were not explained by alterations in productive viral replication or the establishment of latency. Rather, chronic MHV68 infection triggered increased systemic inflammation, increased T cell production of IFN-γ, and an IFN-γ-induced transcriptional signature in macrophages from Atg gene-deficient mice. The Atg5-related reactivation defect was partially reversed by neutralization of IFN-γ. Thus Atg genes in myeloid cells dampen virus-induced systemic inflammation, creating an environment that fosters efficient MHV68 reactivation from latency., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-γ production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic "regressor" tumor is sufficient to override the protective ability of T cells to control tumor growth. We also show that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, restore glucose in tumor microenvironment, permitting T cell glycolysis and IFN-γ production. Furthermore, we found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes, reflecting a role for PD-L1 in tumor glucose utilization. Our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Lymphocytes must adapt to a wide array of environmental stressors as part of their normal development, during which they undergo a dramatic metabolic remodeling process. Research in this area has yielded surprising findings on the roles of diverse metabolic pathways and metabolites, which have been found to regulate lymphocyte signaling and influence differentiation, function and fate. In this review, we integrate the latest findings in the field to provide an up-to-date resource on lymphocyte metabolism., (© 2015 Buck et al.)

Unlabelled: The host-targeted antiviral drug UV-4B reduces viral replication and promotes survival in a mouse model of experimental dengue virus (DENV) infection. UV-4B is an iminosugar that inhibits the α-glucosidase family of enzymes and subsequently the folding of glycosylated proteins, both viral and host. Here, we utilized next-generation sequencing to investigate evolution of a flavivirus under selective pressure by a host-targeted antiviral in vivo. In viral populations recovered from UV-4B-treated mice, there was a significant increase in the number of single-nucleotide polymorphisms (SNPs) and the ratio of nonsynonymous to synonymous SNPs compared to findings in viral populations from vehicle-treated mice. The strongest evidence of positive selection was in the glycosylated membrane protein, thereby providing in vivo validation of the mechanism of action of an iminosugar. In addition, mutations in glycosylated proteins were present only in drug-treated mice after a single passage. However, the bulk of the other mutations were present in both populations, indicating nonspecific selective pressure. Together with the continued control of viremia by UV-4B, these findings are consistent with the previously predicted high genetic barrier to escape mutations in host-targeted antivirals., Importance: Although hundreds of millions of people are infected with DENV every year, there is currently no approved vaccine or antiviral therapy. UV-4B has demonstrated antiviral activity against DENV and is expected to enter clinical trials soon. Therefore, it is important to understand the mechanisms of DENV resistance to UV-4B. Host-targeted antivirals are thought to have a higher genetic barrier to escape mutants than directly acting antivirals, yet there are very few published studies of viral evolution under host-targeted antivirals. No study to date has described flavivirus evolution in vivo under selective pressure by a host-based antiviral drug. We present the first in vivo study of the sequential progression of viral evolution under selective pressure by a host-targeted antiviral compound. This study bolsters support for the clinical development of UV-4B as an antiviral drug against DENV, and it provides a framework to compare how treatment with other host-targeted antiflaviviral drugs in humans and different animal models influence viral genetic diversity., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: Hypertension is a leading risk factor for cardiovascular disease. Although control rates have improved over time, racial/ethnic disparities in hypertension control persist. Self-blood pressure monitoring, by itself, has been shown to be an effective tool in predominantly white populations, but less studied in minority, urban communities. These types of minimally intensive approaches are important to test in all populations, especially those experiencing related health disparities, for broad implementation with limited resources., Methods and Results: The New York City Health Department in partnership with community clinic networks implemented a randomized clinical trial (n=900, 450 per arm) to investigate the effectiveness of self-blood pressure monitoring in medically underserved and largely black and Hispanic participants. Intervention participants received a home blood pressure monitor and training on use, whereas control participants received usual care. After 9 months, systolic blood pressure decreased (intervention, 14.7 mm Hg; control, 14.1 mm Hg; P=0.70). Similar results were observed when incorporating longitudinal data and calculating a mean slope over time. Control was achieved in 38.9% of intervention and 39.1% of control participants at the end of follow-up; the time-to-event experience of achieving blood pressure control in the intervention versus control groups were not different from each other (logrank P value =0.91)., Conclusions: Self-blood pressure monitoring was not shown to improve control over usual care in this largely minority, urban population. The patient population in this study, which included a high proportion of Hispanics and uninsured persons, is understudied. Results indicate these groups may have additional meaningful barriers to achieving blood pressure control beyond access to the monitor itself., Clinical Trial Registration: http://clinicaltrials.gov. Unique Identifier: NCT01123577., (© 2015 American Heart Association, Inc.)

Mammals are coinfected by multiple pathogens that interact through unknown mechanisms. We found that helminth infection, characterized by the induction of the cytokine interleukin-4 (IL-4) and the activation of the transcription factor Stat6, reactivated murine γ-herpesvirus infection in vivo. IL-4 promoted viral replication and blocked the antiviral effects of interferon-γ (IFNγ) by inducing Stat6 binding to the promoter for an important viral transcriptional transactivator. IL-4 also reactivated human Kaposi's sarcoma-associated herpesvirus from latency in cultured cells. Exogenous IL-4 plus blockade of IFNγ reactivated latent murine γ-herpesvirus infection in vivo, suggesting a "two-signal" model for viral reactivation. Thus, chronic herpesvirus infection, a component of the mammalian virome, is regulated by the counterpoised actions of multiple cytokines on viral promoters that have evolved to sense host immune status., (Copyright © 2014, American Association for the Advancement of Science.)

Generation of CD8(+) memory T cells requires metabolic reprogramming that is characterized by enhanced mitochondrial fatty-acid oxidation (FAO). However, where the fatty acids (FA) that fuel this process come from remains unclear. While CD8(+) memory T cells engage FAO to a greater extent, we found that they acquired substantially fewer long-chain FA from their external environment than CD8(+) effector T (Teff) cells. Rather than using extracellular FA directly, memory T cells used extracellular glucose to support FAO and oxidative phosphorylation (OXPHOS), suggesting that lipids must be synthesized to generate the substrates needed for FAO. We have demonstrated that memory T cells rely on cell intrinsic expression of the lysosomal hydrolase LAL (lysosomal acid lipase) to mobilize FA for FAO and memory T cell development. Our observations link LAL to metabolic reprogramming in lymphocytes and show that cell intrinsic lipolysis is deterministic for memory T cell fate., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Understanding population-level health trends is essential to effectively monitor and improve public health. The Office of the National Coordinator for Health Information Technology (ONC) Query Health initiative is a collaboration to develop a national architecture for distributed, population-level health queries across diverse clinical systems with disparate data models. Here we review Query Health activities, including a standards-based methodology, an open-source reference implementation, and three pilot projects., Materials and Methods: Query Health defined a standards-based approach for distributed population health queries, using an ontology based on the Quality Data Model and Consolidated Clinical Document Architecture, Health Quality Measures Format (HQMF) as the query language, the Query Envelope as the secure transport layer, and the Quality Reporting Document Architecture as the result language., Results: We implemented this approach using Informatics for Integrating Biology and the Bedside (i2b2) and hQuery for data analytics and PopMedNet for access control, secure query distribution, and response. We deployed the reference implementation at three pilot sites: two public health departments (New York City and Massachusetts) and one pilot designed to support Food and Drug Administration post-market safety surveillance activities. The pilots were successful, although improved cross-platform data normalization is needed., Discussions: This initiative resulted in a standards-based methodology for population health queries, a reference implementation, and revision of the HQMF standard. It also informed future directions regarding interoperability and data access for ONC's Data Access Framework initiative., Conclusions: Query Health was a test of the learning health system that supplied a functional methodology and reference implementation for distributed population health queries that has been validated at three sites., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

A characteristic of memory T (TM) cells is their ability to mount faster and stronger responses to reinfection than naïve T (TN) cells do in response to an initial infection. However, the mechanisms that allow this rapid recall are not completely understood. We found that CD8 TM cells have more mitochondrial mass than CD8 TN cells and, that upon activation, the resulting secondary effector T (TE) cells proliferate more quickly, produce more cytokines, and maintain greater ATP levels than primary effector T cells. We also found that after activation, TM cells increase oxidative phosphorylation and aerobic glycolysis and sustain this increase to a greater extent than TN cells, suggesting that greater mitochondrial mass in TM cells not only promotes oxidative capacity, but also glycolytic capacity. We show that mitochondrial ATP is essential for the rapid induction of glycolysis in response to activation and the initiation of proliferation of both TN and TM cells. We also found that fatty acid oxidation is needed for TM cells to rapidly respond upon restimulation. Finally, we show that dissociation of the glycolysis enzyme hexokinase from mitochondria impairs proliferation and blocks the rapid induction of glycolysis upon T-cell receptor stimulation in TM cells. Our results demonstrate that greater mitochondrial mass endows TM cells with a bioenergetic advantage that underlies their ability to rapidly recall in response to reinfection.

The aim of the present study was to evaluate the ability of the iminosugar drug UV-4 to provide in vivo protection from lethal dengue virus (DENV) challenge. This study utilized a well-described model of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS)-like lethal disease in AG129 mice lacking the type I and II interferon receptors. Herein, we present UV-4 as a potent iminosugar for controlling DENV infection and disease in this mouse model. Specifically, administration of UV-4 reduced mortality, as well as viremia and viral RNA in key tissues, and cytokine storm. In addition, UV-4 treatment can be delayed, and it does not alter the anti-DENV antibody response. These results have set the foundation for development of UV-4 as a DENV-specific antiviral in phase I human clinical trials., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Dengue virus is the most prevalent mosquito-borne virus worldwide. In this study, we used pyrosequencing to analyze the whole viral genome of two mouse-adapted strains, D2S10 and D2S20, that induce a dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS)-like lethal disease in mice lacking the type I and/or type II interferon receptors. Previous experiments with D2S10 indicated that N124D and K128E mutations in the envelope protein were responsible for the severe disease induced in mice compared to its parental strain PL046. Here we demonstrate that D2S20 is more virulent than D2S10 and captured the presence of five key amino acid mutations--T70I, N83D, and K122I in envelope (E), and A62T in nonstructural protein 2A (NS2A) and G605V in nonstructural protein 5 (NS5)--that may account for this. These findings set the foundation for further dissection of the viral determinants responsible for dengue disease manifestations in mouse models.

Laboratory testing by clinicians is essential to outbreak investigations. Electronic health records may increase testing through clinical decision support that alerts providers about existing outbreaks and facilitates laboratory ordering. The impact on laboratory testing was evaluated for foodborne disease outbreaks between 2006 and 2009. After controlling for standard public health messaging and season, decision support resulted in a significant increase in laboratory testing and may be useful in enhancing public health messaging and provider action.

The dengue viruses (DENVs) exist as numerous genetic strains that are grouped into four antigenically distinct serotypes. DENV strains from each serotype can cause severe disease and threaten public health in tropical and subtropical regions worldwide. No licensed antiviral agent to treat DENV infections is currently available, and there is an acute need for the development of novel therapeutics. We found that a synthetic small interfering RNA (siRNA) (DC-3) targeting the highly conserved 5' cyclization sequence (5'CS) region of the DENV genome reduced, by more than 100-fold, the titers of representative strains from each DENV serotype in vitro. To determine if DC-3 siRNA could inhibit DENV in vivo, an "in vivo-ready" version of DC-3 was synthesized and tested against DENV-2 by using a mouse model of antibody-dependent enhancement of infection (ADE)-induced disease. Compared with the rapid weight loss and 5-day average survival time of the control groups, mice receiving the DC-3 siRNA had an average survival time of 15 days and showed little weight loss for approximately 12 days. DC-3-treated mice also contained significantly less virus than control groups in several tissues at various time points postinfection. These results suggest that exogenously introduced siRNA combined with the endogenous RNA interference processing machinery has the capacity to prevent severe dengue disease. Overall, the data indicate that DC-3 siRNA represents a useful research reagent and has potential as a novel approach to therapeutic intervention against the genetically diverse dengue viruses.

Dengue virus (DENV) is a mosquito-borne flavivirus, and symptoms of infection range from asymptomatic to the severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). High viral loads correlate with disease severity, and both type I & II interferons (IFNs) are crucial for controlling viral replication. We have previously reported that signal transducer and activator of transcription (STAT) 1-deficient mice are resistant to DENV-induced disease, but little is known about this STAT1-independent mechanism of protection. To determine the molecular basis of the STAT1-independent pathway, mice lacking STAT1, STAT2, or both STAT1 and STAT2 were infected with a virulent mouse-adapted strain of DENV2. In the first 72 hours of infection, the single-deficient mice lacking STAT1 or STAT2 possessed 50-100 fold higher levels of viral RNA than wild type mice in the serum, spleen, and other visceral tissues, but remained resistant to DENV-induced death. In contrast, the double-deficient mice exhibited the early death phenotype previously observed in type I and II IFN receptor knockout mice (AG129), indicating that STAT2 is the mediator of the STAT1-independent host defense mechanism. Further studies demonstrated that this STAT2-dependent STAT1-independent mechanism requires the type I IFN receptor, and contributes to the autocrine amplification of type I IFN expression. Examination of gene expression in the spleen and bone marrow-derived macrophages following DENV infection revealed STAT2-dependent pathways can induce the transcription of a subset of interferon stimulated genes even in the absence of STAT1. Collectively, these results help elucidate the nature of the poorly understood STAT1-independent host defense mechanism against viruses by identifying a functional type I IFN/STAT2 signaling pathway following DENV infection in vivo.

Alerting providers to public health situations requires timeliness and context-relevance, both lacking in current systems. Incorporating decision support tools into electronic health records may provide a way to deploy public health alerts to clinicians at the point of care. A timely process for responding to Health Alert Network messages sent by the New York City Department of Health and Mental Hygiene was developed by a network of community health centers. Alerts with order sets and recommended actions were created to notify primary care providers of local disease outbreaks. The process, effect, and lessons learned from alerts for Legionella, toxogenic E coli, and measles outbreaks are described. Electronic alerts have the potential to improve management of diseases during an outbreak, including appropriate laboratory testing, management guidance, and diagnostic assistance as well as to enhance bi-directional data exchange between clinical and public health organizations.

Background: Some older adults receive potentially inappropriate medications (PIMs), increasing their risk for adverse events. A literature search did not find any US multicenter studies that measured the prevalence of PIMs in outpatient practices based on data from electronic health records (EHRs), using both the Beers and Zhan criteria., Objectives: The aims of the present study were to compare the prevalence of PIMs using standard drug terminologies at 2 disparate institutions using EHRs and to identify characteristics of elderly patients who have a PIM on their active-medication lists., Methods: This cross-sectional study of outpatients' active-medication lists from April 1, 2006, was conducted using data from 2 outpatient primary care settings: Intermountain Healthcare, Salt Lake City, Utah (center 1), and the Cleveland Clinic, Cleveland, Ohio (center 2). Data were included from patients who were aged > or =65 years at the time of the last office visit and had > or =2 documented clinic visits within the previous 2 years. The primary end point was prevalence of PIMs, measured according to the 2002 Beers criteria or the 2001 Zhan criteria., Results: Data from 61,251 patients were included (36,663 women, 24,588 men; center 1: 37,247 patients; center 2: 24,004). A total of 8693 (23.3%) and 5528 (23.0%) patients at centers 1 and 2, respectively, were documented as receiving a PIM as per the Beers criteria; this difference was not statistically significant. Per the Zhan criteria (P < 0.001), these values were 6036 (16.2%) and 4160 (17.3%). Eight of the most common PIMs were the same at both institutions, with propoxyphene and fluoxetine (once daily) being the most prescribed. Female sex, polypharmacy (> or =6 medications), and multiple primary care visits were significantly associated with PIM prescribing., Conclusions: In this analysis of data from elderly patients at 2 outpatient centers, a small set of 8 medications accounted for the majority of PIMs at both centers, irrespective of geographic and demographic variations. Female sex, polypharmacy, and number of primary care visits were significantly associated with PIM prescribing. In this analysis of data from elderly patients at 2 outpatient centers, a small set of 8 medications accounted for the majority of PIMs at both centers, irrespective of geographic and demographic variations.

Introduction: A retrospective drug-drug interaction (DDI) monitoring report was generated from computerized physician order entry (CPOE) medication lists using an existing DDI CPOE alerting knowledgebase., Methods: All active medications ordered for elderly outpatients during the two years prior to February 27th, 2007 were retrieved. Every medication pair was processed using SQL through the DDI knowledgebase to generate a report containing all potential DDIs for each patient., Results: One out of four elderly patients (26.6%) has an existing DDI on their active medication list. There are substantially more DDIs at lower levels of severity (Moderate and Severe), but 70 patients had Level 1, "absolutely harmful" contraindications., Conclusion: The majority of DDIs are of Moderate severity. These results have spurred clinical leadership to form a review committee to assess the clinical relevancy of current DDI knowledgebase content.