PTPN2 deficiency: Amping up JAK/STAT.

Identification of monogenic causes of immune dysregulation provides insight into human immune response and signaling pathways associated with autoimmunity. Here, Jeanpierre et al. (https://doi.org/10.1084/jem.20232337) identify new germline variants in the gene encoding PTPN2 associated with loss of regulatory function, enhanced JAK/STAT signaling, and early-onset autoimmunity.

Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility.

Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies. However, we observe strikingly low intratumoral T cell receptor clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable.

Artificial intelligence and machine learning: Definition of terms and current concepts in critical care research.

With increasing computing power, artificial intelligence (AI) and machine learning (ML) have prospered, which facilitate the analysis of large datasets, especially those found in critical care. It is important to define these terminologies, to inform a standardized approach to critical care research. This manuscript hopes to clarify these terms with examples from medical literature. Three major components that are required for a successful ML implementation: (i) reliable dataset, (ii) ML algorithm, and (iii) unbiased model evaluation, are discussed. A reliable dataset can be structured or unstructured with limited noise, outliers, and missing values. ML, a subset of AI, is typically focused on supervised or unsupervised learning tasks in which the output is based on inputs and derived from iterative pattern recognition algorithms, while AI is the overall ability of a machine to "think" or mimic human behavior; and to analyze data free from human influence. Even with successful implementation, advanced AI and ML algorithms have faced challenges in adoption into practice, mainly due to their lack of interpretability, which hinders trust, buy-in, and engagement from clinicians. Consequently, traditional algorithms, such as linear and logistic regression, that may have reduced predictive power but are highly interpretable, continue to be widely used.

A Theoretical Analysis of Density Peaks Clustering and the Component-Wise Peak-Finding Algorithm.

Density peaks clustering detects modes as points with high density and large distance to points of higher density. Each non-mode point is assigned to the same cluster as its nearest neighbor of higher density. Density peaks clustering has proved capable in applications, yet little work has been done to understand its theoretical properties or the characteristics of the clusterings it produces. Here, we prove that it consistently estimates the modes of the underlying density and correctly clusters the data with high probability. However, noise in the density estimates can lead to erroneous modes and incoherent cluster assignments. A novel clustering algorithm, Component-wise Peak-Finding (CPF), is proposed to remedy these issues. The improvements are twofold: 1) the assignment methodology is improved by applying the density peaks methodology within level sets of the estimated density; 2) the algorithm is not affected by spurious maxima of the density and hence is competent at automatically deciding the correct number of clusters. We present novel theoretical results, proving the consistency of CPF, as well as extensive experimental results demonstrating its exceptional performance. Finally, a semi-supervised version of CPF is presented, integrating clustering constraints to achieve excellent performance for an important problem in computer vision.

Epstein-Barr virus-associated lymphomas decoded.

Epstein-Barr virus (EBV)-associated lymphomas cover a range of histological B- and T-cell non-Hodgkin and Hodgkin lymphoma subtypes. The role of EBV on B-cell malignant pathogenesis and its impact on the tumour microenvironment are intriguing but incompletely understood. Both the International Consensus Classification (ICC) and 5th Edition of the World Health Organization (WHO-HAEM5) proposals give prominence to the distinct clinical, prognostic, genetic and tumour microenvironmental features of EBV in lymphoproliferative disorders. There have been major advances in our biological understanding, in how to harness features of EBV and its host immune response for targeted therapy, and in using EBV as a method to monitor disease response. In this article, we showcase the latest developments and how they may be integrated to stimulate new and innovative approaches for further lines of investigation and therapy.

Prehospital Critical Care Blood Product Administration: Quantifying Clinical Benefit.

BACKGROUND: Prehospital blood transfusion has been widely practiced in the military and is drawing renewed scrutiny after many years of civilian use. OBJECTIVE: The objective of this article is to quantify the benefit derived from prehospital transfusion of blood products. METHODS: Deidentified data were extracted retrospectively from the flight records of a critical care transportation program between April 2018 and January 2020. Patients who were transported before a prehospital blood transfusion protocol were compared with patients after initiation of the blood transfusion protocol. Demographic data, vital signs, laboratory analytics, and other outcome measures were analyzed. RESULTS: Nine scene transport patients who met the transfusion criteria before a blood transfusion protocol were compared with 11 patients transported after initiation of the protocol. Identical outcome measures were analyzed. Patients who received prehospital blood transfusions had a statistically significantly longer hospital length of stay (16.5 vs 3.7 days, P = .03) and were more often taken directly to the operating room (80% vs 28%, P = .04). No statistically significant difference was identified when comparing mean arterial pressure, heart rate, respiratory rate, hemoglobin, hematocrit, or survival to hospital discharge. CONCLUSIONS: Trauma patients who received prehospital blood transfusion had a longer hospital length of stay and were more often taken directly to the operating room, but without improvement in survival.

A systematic review of interventions for resuscitation following drowning.

Objectives: The International Liaison Committee on Resuscitation, in collaboration with drowning researchers from around the world, aimed to review the evidence addressing seven key resuscitation interventions: 1) immediate versus delayed resuscitation; (2) compression first versus ventilation first strategy; (3) compression-only CPR versus standard CPR (compressions and ventilations); (4) ventilation with and without equipment; (5) oxygen administration prior to hospital arrival; (6) automated external defibrillation first versus cardiopulmonary resuscitation first strategy; (7) public access defibrillation programmes. Methods: The review included studies relating to adults and children who had sustained a cardiac arrest following drowning with control groups and reported patient outcomes. Searches were run from database inception through to April 2023. The following databases were searched Ovid MEDLINE, Pre-Medline, Embase, Cochrane Central Register of Controlled Trials. Risk of bias was assessed using the ROBINS-I tool and the certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. The findings are reported as a narrative synthesis. Results: Three studies were included for two of the seven interventions (2,451 patients). No randomised controlled trials were identified. A retrospective observational study reported in-water resuscitation with rescue breaths improved patient outcomes compared to delayed resuscitation on land (n = 46 patients, very low certainty of evidence). The two observational studies (n = 2,405 patients), comparing compression-only with standard resuscitation, reported no difference for most outcomes. A statistically higher rate of survival to hospital discharge was reported for the standard resuscitation group in one of these studies (29.7% versus 18.1%, adjusted odds ratio 1.54 (95% confidence interval 1.01-2.36) (very low certainty of evidence). Conclusion: The key finding of this systematic review is the paucity of evidence, with control groups, to inform treatment guidelines for resuscitation in drowning.

Diffuse large B-cell lymphoma and red cell autoimmunity: clinical role and pathogenesis.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of B-cell non-Hodgkin lymphoma (B-NHL) with significant morbidity and mortality despite advancements in treatment. Lymphoma and autoimmune disease both result from breakdowns in normal cell regulatory pathways, and epidemiological studies have confirmed both that B-NHL is more likely to develop in the setting of autoimmune diseases and vice versa. Red cell immunity, as evidenced by direct antiglobulin test (DAT) positivity, has been linked to DLBCL and more recently the pathogenic causes of this association have begun to be better understood using molecular techniques. This project aimed to explore the relationship between red cell autoimmunity and DLBCL. DAT positivity was more common in DLBCL as compared to healthy controls (20.4% vs 3.7%, p=0.0005). Univariate analysis found a non-significant trend towards poorer overall survival in the DAT positive (DAT+) compared to the DAT negative (DAT-) groups (p=0.087). High throughput sequencing was used to compare mutations in DLBCL from DAT+ and DAT- patients. The most frequently mutated genes in 15 patient samples were KMT2D (n=13), MYOM2 (n=9), EP300 (n=8), SPEN (n=7), and ADAMTSL3 (n=7), which were mutated in both DAT+ and DAT- groups. BIRC3 (n=3), FOXO1 (n=3) and CARD11 (n=2) were found to be mutated only in samples from the DAT+ group. These gene mutations may be involved in disease development and progression, and potentially represent targets for future therapy. The immunoglobulin genotype IGHV4-34 is seen more frequently in DLBCL clones than in normal B cells and has intrinsic autoreactivity to self-antigens on red cells, which is largely mediated by two motifs within the first framework region (FR1); Q6W7 and A24V25Y.26 These motifs form a hydrophobic patch which determines red cell antigen binding and are frequently mutated away from self-reactivity in normal B cells. If this does not occur this may provide constant B cell receptor signalling which encourages lymphoma development, a theory known as antigen driven lymphomagenesis. As with previous studies, IGHV4-34 was over-represented (15.6%) in our DLBCL cohort. Furthermore, of 6 IGHV4-34-expressing DLBCL samples five had unmutated hydrophobic patch mutations providing further evidence for antigen-driven lymphomagenesis. Mutation analysis of these five samples demonstrated high frequency of mutations in several genes, including CREBBP and NCOR2. Further research could explore if mutations in CREBBP and NCOR2 work in conjunction with the preserved QW and AVY motifs to promote lymphomagenesis in IGHV4-34-expressing B cells, and if so, could guide future targeted therapy.

B2 or Not B2: A Systematic Literature Review on Migraine Headaches and Riboflavin Deficiency / B2 ou não B2: uma revisão sistemática da literatura sobre enxaquecas e deficiência de riboflavina

Objective: To assess the prevalence of riboflavin deficiency in patients with migraines or headaches.Methods: Systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: Two articles met the inclusion and exclusion criteria, and neither of these discussed riboflavin deficiency prevalence in those patients who suffer from migraines. Conclusion: The prevalence of riboflavin deficiency in migraineurs and in headache patients is unknown.

Objetivo: Avaliar a prevalência de deficiência de riboflavina em pacientes com enxaquecas ou dores de cabeça. Métodos :Revisão sistemática da literatura seguindo as diretrizes Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Resultados: Dois artigos preencheram os critérios de inclusão e exclusão, e nenhum deles discutiu a prevalência de deficiência de riboflavina em pacientes que sofrem de enxaqueca. Conclusão: A prevalência da deficiência de riboflavina em pacientes com enxaqueca e com dor de cabeça é desconhecida.

The PO4-tential for Less Toxic CAR T-cell Therapies.

Chimeric antigen receptor (CAR) T-cell therapy has yielded remarkable and durable responses for some patients with relapsed and refractory blood cancers. However, life-threatening toxicities such as immune effector cell-associated neurotoxicity syndrome (ICANS) remain a challenge for broad delivery of such therapies. In this issue, Tang and colleagues demonstrate an association between hypophosphatemia and CAR T cell-induced ICANS. Prospective studies are required to establish if phosphate monitoring is an early predictor for ICANS occurrence and if maintenance of phosphate levels has a role as a preventative strategy. See related article by Tang et al., p. 1433 (4).

Reductions in acute medication use and healthcare resource utilization in patients with chronic migraine: a secondary analysis of a phase 3, randomized, double-blind, placebo-controlled study of galcanezumab with open-label extension (REGAIN).

AIMS: To analyze secondary objectives of the REGAIN study related to acute headache medication use and healthcare resource utilization (HCRU) in patients with chronic migraine treated with galcanezumab, a monoclonal antibody to calcitonin gene-related peptide. METHODS: Adults with chronic migraine (N = 1,113) were randomized (2:1:1) and treated with double-blind monthly injections of placebo, galcanezumab-120 mg, or galcanenzumab-240 mg for 3 months, followed by a 9-month open-label extension with 120 or 240 mg/month galcanezumab. Headache and medication information was collected by daily eDiary. HCRU was reported for the 6 months before randomization, monthly thereafter, and converted to rate per 100-patient-years. RESULTS: At baseline, 63-64% of patients met criteria for acute headache medication overuse. At Month 3, incidence of headache medication overuse in the galcanezumab groups (33% and 33%) was significantly lower than in the placebo group (46%, both p < .001) and was 16% and 23% in the previous-galcanezumab groups at Month 12. From a baseline of 14.5 to 15.5, reduction in mean number of monthly migraine headache days with acute headache medication use was also significantly greater in the galcanezumab groups at Month 3 (-4.2 and -4.9) than in placebo (-2.6, both p < .001), with reductions of -6.8 and -7.6 in the previous-galcanezumab groups at Month 12. Migraine-specific HCRU rates decreased for all groups, with no significant between-group differences at Month 3. At Month 12, in the two previous-galcanezumab groups, emergency room visits decreased by 58% and 75%, hospital admissions by 100%, and healthcare professional visits by 54% and 67%. LIMITATIONS: Only 3 months of double-blind, placebo-controlled data, a longer HCRU recall period for baseline than postbaseline, and patients receiving care in the clinical trial itself, may limit generalizability. CONCLUSIONS: Treatment with galcanezumab resulted in significant reductions in headache medication overuse and migraine headache days requiring acute medication use, with notable reductions in migraine-specific HCRU.

Annual indirect cost savings in patients with episodic or chronic migraine: post-hoc analyses from multiple galcanezumab clinical trials.

AIM: This post-hoc analysis estimated annual indirect cost savings with galcanezumab (GMB) treatment in patients with episodic migraine (EM) or chronic migraine (CM). METHODS: Data from 4 randomized, Phase 3, double-blind (DB), placebo (PBO)-controlled studies of GMB were analyzed: EVOLVE-1 and EVOLVE-2 (EM, 6-months DB), REGAIN (CM, 3-months DB), and CONQUER (previous failure of 2-4 migraine preventive medication categories, 3-months DB). Indirect costs were calculated at baseline and Month 3 using the first 2 items in Migraine Disability Assessment (MIDAS): (A + B)/60*country specific annual wage (A = days of missed work/school; B = days of reduced productivity at work/school; assuming 60 working days in 3 months). All costs were annualized and expressed in international dollars (Int$) in 2018. ANCOVA models estimated the indirect cost savings as a change from baseline. Secondary analyses determined cost savings by employment and responder status. RESULTS: Patients (>80% females) from EVOLVE-1 and -2 (n = 1,201; mean age 41.9 years), REGAIN (n = 759; mean age 41.3 years), and CONQUER (n = 453; mean age ∼46.0 years) were analyzed. GMB showed significant indirect cost savings for EM (Int$6256, p < .0001) and CM (Int$7129, p = .0002), with substantial savings for patients with previous failure of 2-4 migraine preventive medication categories (EM: Int$5664, p = .0030; CM: Int$5181, p = .1300). Compared with PBO, GMB showed significantly greater indirect cost savings for EM (p = .0156) and patients with previous failure of 2-4 migraine preventive medication categories (p = .0340). Employed patients with CM (p = .0018) and with previous failure of 2-4 migraine preventive medication categories (p < .0001) had significant cost savings after GMB treatment. GMB showed significant indirect cost savings in patients with a reduction in migraine headache days. CONCLUSION: GMB treatment resulted in annual indirect cost savings in patients with EM, CM, and with previous failure of 2-4 migraine preventive medication categories, with similar observations in the sensitivity analyses.

Subtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma.

B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma. We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumors from each subtype, including frequent genetic deregulation of the ubiquitin proteasome system. In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.

Diagnosis, management and follow up of peripheral T-cell lymphomas: a consensus practice statement from the Australasian Lymphoma Alliance.

Peripheral T-cell lymphomas (PTCL) represent a heterogeneous disease group accounting for 10% of non-Hodgkin lymphomas. PTCL patients have typically poorer outcomes compared with aggressive B-cell lymphomas. However, such outcomes are heavily dependent on subtype. Although anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine and prednisone remain the standard first-line treatment for most aggressive PTCL, there are important variations including incorporation of novel agents, use of radiotherapy and judicious consideration of stem cell transplantation. Relapsed or refractory disease represents a significant area of unmet need where chemotherapy intensification has limited efficacy and novel agents such as brentuximab vedotin and pralatrexate provide additional opportunities for attainment of remission and potential stem cell transplant. In the future, pre-therapy prognostic biomarkers including genomic characterisation, may aid in risk stratification and help guide initial patient management to improve survival. There is an urgent need to understand better the pathogenesis of PTCL to facilitate novel drug combinatorial approaches to improve survival. This position statement represents an evidence-based synthesis of the literature for application in Australian and New Zealand practice.

Joint Trauma System Clinical Practice Guideline (JTS CPG): Prehospital Blood Transfusion. 30 October 2020.

This Clinical Practice Guideline (CPG) provides a brief summary of the scientific literature for prehospital blood use, with an emphasis on the en route care environment. Updates include the importance of calcium administration to counteract the deleterious effects of hypocalcemia, minimal to no use of crystalloid, and stresses the importance of involved and educated en route care medical directors alongside at a competent prehospital and en route care providers (see Table 1). With the paradigm shift to use FDA-approved cold stored low titer group O whole blood (CS-LTOWB) along with the operational need for continued use of walking blood banks (WBB) and point of injury (POI) transfusion, there must be focused, deliberate training incorporating the different whole blood options. Appropriate supervision of autologous blood transfusion training is important for execution of this task in support of deployed combat operations as well as other operations in which traumatic injuries will occur. Command emphasis on the importance of this effort as well as appropriate logistical support are essential elements of a prehospital blood program as part of a prehospital/en route combat casualty care system.

Management and Outcomes of Diffuse Large B-cell Lymphoma Post-transplant Lymphoproliferative Disorder in the Era of PET and Rituximab: A Multicenter Study From the Australasian Lymphoma Alliance.

There are limited data on post-transplant lymphoproliferative disorder (PTLD) in the era of positron emission tomography (PET) and rituximab (R). Furthermore, there is limited data on the risk of graft rejection with modern practices in reduction in immunosuppression (RIS). We studied 91 patients with monomorphic diffuse large B-cell lymphoma PTLD at 11 Australian centers: median age 52 years, diagnosed between 2004 and 2017, median follow-up 4.7 years (range, 0.5-14.5 y). RIS occurred in 88% of patients. For patients initially treated with R-monotherapy, 45% achieved complete remission, rising to 71% with the addition of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) for those not in complete remission. For patients initially treated with R-CHOP, the complete remission rate was 76%. There was no difference in overall survival (OS) between R-monotherapy and R-chemotherapy patients. There was no difference in OS for patients with systemic lymphoma (n = 68) versus central nervous system (CNS) involvement (n = 23) (3-y OS 72% versus 73%; P = 0.78). Treatment-related mortality was 7%. End of treatment PET was prognostic for patients with systemic lymphoma with longer OS in the PET negative group (3-y OS 91% versus 57%; P = 0.01). Graft rejection occurred in 9% (n = 4 biopsy-proven; n = 4 suspected) during the entire follow-up period with no cases of graft loss. RIS and R-based treatments are safe and effective with a low likelihood of graft rejection and high cure rate for patients achieving complete remission with CNS or systemic PTLD.

Defining Combat-Relevant Endpoints for Early Trauma Resuscitation Research in a Resource-Constrained Civilian Setting.

INTRODUCTION: Studies assessing early trauma resuscitation have used long-term endpoints, such as 28- or 30-day mortality or Glasgow Outcomes Scores at 6-months. These endpoints are convenient but may not accurately reflect the effect of early resuscitation. We sought expert opinion and consensus on endpoints and definitions of variables needed to conduct a Department of Defense- (DoD) funded study to epidemiologically assess combat-relevant mortality and morbidity due to timeliness of resuscitation among critically injured civilians internationally. METHODS: We conducted an online modified Delphi process with an international panel of civilian and US military experts. In several iterative rounds, experts reviewed background information, appraised relevant scientific evidence, provided comments, and rendered a vote on each variable. A-priori, we set consensus at ≥80% concordant votes. RESULTS: Twenty panelists participated with a 100% response rate. Eight items were presented, with the following outputs for the epidemiologic study: Assess mortality within 7-days of injury; assess multi-organ failure using SOFA scores measured early (at day 3) and late (at day 7); assess traumatic brain injury mortality early (≤7-days) and late (28-days); hybrid (anatomic and physiologic) injury severity scoring is optimal; capture comorbidities per the US National Trauma Data Standard list with specific additions; assign resuscitative interventions to one of five standardized phases of trauma care; and, use a novel trauma death categorization system. CONCLUSIONS: A modified Delphi process yielded expert-ratified definitions and endpoints of variables necessary to conduct a combat-relevant epidemiologic study assessing outcomes due to early trauma resuscitation. Outputs may also benefit other groups conducting trauma resuscitation research.

A cost-effectiveness analysis of front-line treatment strategies in early-stage follicular lymphoma.

Recent data suggest the use of radiotherapy alone (RT) in Early-Stage Follicular Lymphoma is declining. Cost-effectiveness analysis of treatments has not been performed. We constructed a partitioning model (15-year horizon) to compare RT, combined-modality therapy (CMT) and immunochemotherapy with rituximab maintenance (ICT + RM) from a PET-staged cohort from the Australian Lymphoma Alliance. Lifetime direct health care costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. AUD $75,000 was defined as the willingness-to-pay threshold (WTP). The direct healthcare costs were: RT $12,791, CMT $29,391 and ICT + RM $42,644. Compared with RT, CMT demonstrated minimal improvement in QALYs (+0.01) and an ICER well above the WTP threshold ($1,535,488). Compared with RT, ICT + RM demonstrated an improvement in QALYs (+0.41) with an ICER of $73,319. Modeling a 25% cost reduction with a rituximab biosimilar led to further ICER reductions with ICT + RM ($52,476). ICT + RM is cost-effective in early-stage FL from the Australian taxpayer perspective.

Reliance on Cox10 and oxidative metabolism for antigen-specific NK cell expansion.

Natural killer (NK) cell effector functions are dependent on metabolic regulation of cellular function; however, less is known about in vivo metabolic pathways required for NK cell antiviral function. Mice with an inducible NK-specific deletion of Cox10, which encodes a component of electron transport chain complex IV, were generated to investigate the role of oxidative phosphorylation in NK cells during murine cytomegalovirus (MCMV) infection. Ncr1-Cox10Δ/Δ mice had normal numbers of NK cells but impaired expansion of antigen-specific Ly49H+ NK cells and impaired NK cell memory formation. Proliferation in vitro and homeostatic expansion were intact, indicating a specific metabolic requirement for antigen-driven proliferation. Cox10-deficient NK cells upregulated glycolysis, associated with increased AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) activation, although this was insufficient to protect the host. These data demonstrate that oxidative metabolism is required for NK cell antiviral responses in vivo.