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.

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.

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.

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.

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.

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.

Toward an Electrical Analog of the Cardiovascular System in Hemorrhage.

Current quantitative descriptions of the cardiovascular system in hemorrhagic shock focus on pressure based metrics. This approach is often incomplete; overlooking the important role of tissue perfusion. Electrical analogs to the cardiovascular system may offer a more complete description of hemorrhage. Application of fundamental concepts in electrical circuit theory (i.e.; Kirchhoff's Voltage Law and Ohm's Law) to analogs of the cardiovascular system offers a more refined description of this complex process. This manuscript hopes to serve as a starting point for a more mathematically robust, and clinically relevant description of hemorrhagic shock.

Impact of prehospital airway interventions on outcome in cardiac arrest following drowning: A study from the CARES Surveillance Group.

INTRODUCTION: Drowning results in more than 360,000 deaths annually, making it the 3rd leading cause of unintentional injury death worldwide. Prior studies have examined airway interventions affecting patient outcomes in cardiac arrest, but less is known about drowning patients in arrest. This study evaluated the outcomes of drowning patients in the Cardiac Arrest Registry to Enhance Survival (CARES) who received advanced airway management. METHODS: A retrospective analysis of the CARES database identified cases of drowning etiology between 2013 and 2018. Patients were stratified by airway intervention performed by EMS personnel. Demographics, sustained return of spontaneous circulation [ROSC], survival to hospital admission, survival to hospital discharge, and neurological outcomes were compared between airway groups using chi-squared tests and logistic regression. RESULTS: Among 2388 drowning patients, 70.4% were male, 41.8% white, and 13.1% survived to hospital discharge. Patients that received supraglottic airways [SGA] had statistically significantly lower odds of survival to hospital admission compared to endotracheal tube [ETT] use (adjusted odds ratio [aOR] = 0.56, 95% confidence interval [CI] 0.42-0.76) as well as lower odds of survival to discharge compared to bag valve mask [BVM] use (aOR = 0.40, 95% CI 0.19-0.86) when accounting for relative ROSC timing. CONCLUSION: In this national cohort of drowning patients in cardiac arrest, SGA use was associated with significantly lower odds of survival to hospital admission and discharge. However, survival to discharge with favorable neurological outcome did not differ significantly between airway management techniques. Further studies will need to examine if airway intervention order or time to intervention affects outcomes.

Airway Management in Prolonged Field Care.

This Role 1, prolonged field care (PFC) clinical practice guideline (CPG) is intended to be used after Tactical Combat Casualty Care (TCCC) Guidelines, when evacuation to higher level of care is not immediately possible. A provider must first and foremost be an expert in TCCC, the Department of Defense standard of care for first responders. The intent of this PFC CPG is to provide evidence and experience-based solutions to those who manage airways in an austere environment. An emphasis is placed on utilizing the tools and adjuncts most familiar to a Role 1 provider. The PFC capability of airway is addressed to reflect the reality of managing an airway in a Role 1 resource-constrained environment. A separate Joint Trauma System CPG will address mechanical ventilation. This PFC CPG also introduces an acronym to assist providers and their teams in preparing for advanced procedures, to include airway management.

Immunotherapeutic options for inflammation in trauma.

BACKGROUND: Surgical management of trauma in the last 20 years has evolved in parallel with the military's experience in the current conflicts. Therapies such as widespread tourniquet use, empiric administration of fresh frozen plasma, and airborne intensive care units had been viewed skeptically but are now common practice. There is an opportunity to expand the envelope of care even further through similarly innovative approaches and varied avenues of research. RESULTS: As the molecular biology of trauma is elucidated, research methodologies must also be developed to capitalize on innovative approaches to resuscitation. Blood component therapy and control of bleeding remain as the fundamental concepts in trauma care. The inflammo-immune response to injury, however, plays an increasingly recognized role in recovery of organ function. Perhaps the inflammatory cascade of trauma can be manipulated to extend the treatment envelope of at risk trauma patients.In trauma, the additional challenge of delivering effective treatment, often required very early after injury, necessitates the development of treatments to be implemented on the front lines of trauma care that are cost-effective, portable, and environmentally stable. Future conflicts may not offer ready access to high-level surgical care; therefore, resuscitative therapies will be needed for wounded service members because they are evacuated to the surgeon. Manipulation of the inflammatory response to trauma may offer a solution. As our understanding of the immune response continues to develop, the potential for improved outcomes for the wounded expands. CONCLUSION: A review of basic concepts in immunology is necessary to appreciate any potential impact of immunotherapeutic approaches to trauma and inflammation. An overview of current options will focus on outcome benefits of available therapies and suggest possible areas for future investigation. Quantitative approaches will leverage basic science to identify high-yield strategies to improve care of the injured combatant. LEVEL OF EVIDENCE: Review, level III.

Influenza Suppresses Neutrophil Recruitment to the Lung and Exacerbates Secondary Invasive Pulmonary Aspergillosis.

Aspergillus fumigatus is an environmental fungus that can cause invasive pulmonary aspergillosis when spores are inhaled into the respiratory tract and invade airway or lung tissue. Influenza is a common respiratory virus that can cause severe respiratory disease, and postinfluenza invasive pulmonary aspergillosis, which is becoming a well-recognized clinical problem, typically occurs in critically ill patients. Mice challenged with influenza A PR/8/34 H1N1 and subsequently challenged with A. fumigatus had increased fungal burden, viral burden, inflammation, and mortality compared with single infected mice. Neutrophil recruitment in the lung of superinfected mice was decreased; however, mice were not neutropenic, and there was no difference in absolute blood neutrophils between groups. Additionally, CXCL1 and CXCL2 were decreased in lungs of superinfected mice compared with controls. IFN levels were increased in mice that received influenza, and deletion of STAT1 resulted in decreased fungal burden, increased airway and lung neutrophils, and increased CXCL1 compared with wild-type mice, whereas deletion of STAT2 did not change fungal burden or airway neutrophilia compared with wild-type mice. These data demonstrate a mechanism by which influenza A-induced STAT1 signaling inhibits neutrophil recruitment and increases susceptibility to postinfluenza invasive pulmonary aspergillosis.

Outcome of Conventional Bystander Cardiopulmonary Resuscitation in Cardiac Arrest Following Drowning.

INTRODUCTION: The concept of compressions only cardiopulmonary resuscitation (CO-CPR) evolved from a perception that lay rescuers may be less likely to perform mouth-to-mouth ventilations during an emergency. This study hopes to describe the efficacy of bystander compressions and ventilations cardiopulmonary resuscitation (CV-CPR) in cardiac arrest following drowning. HYPOTHESIS/PROBLEM: The aim of this investigation is to test the hypothesis that bystander cardiopulmonary resuscitation (CPR) utilizing compressions and ventilations results in improved survival for cases of cardiac arrest following drowning compared to CPR involving compressions only. METHODS: The Cardiac Arrest Registry for Enhanced Survival (CARES) was queried for patients who suffered cardiac arrest following drowning from January 1, 2013 through December 31, 2017, and in whom data were available on type of bystander CPR delivered (ie, CV-CPR CO-CPR). The primary outcome of interest was neurologically favorable survival, as defined by cerebral performance category (CPC). RESULTS: Neurologically favorable survival was statistically significantly associated with CV-CPR in pediatric patients aged five to 15 years (aOR = 2.68; 95% CI, 1.10-6.77; P = .03), as well as all age group survival to hospital discharge (aOR = 1.54; 95% CI, 1.01-2.36; P = .046). There was a trend with CV-CPR toward neurologically favorable survival in all age groups (aOR = 1.35; 95% CI, 0.86-2.10; P = .19) and all age group survival to hospital admission (aOR = 1.29; 95% CI, 0.91-1.84; P = .157). CONCLUSION: In cases of cardiac arrest following drowning, bystander CV-CPR was statistically significantly associated with neurologically favorable survival in children aged five to 15 years and survival to hospital discharge.

IL-22-binding protein exacerbates influenza, bacterial super-infection.

Secondary bacterial pneumonia is a significant complication of severe influenza infection and Staphylococcus aureus and Streptococcus pneumoniae are the primary pathogens of interest. IL-22 promotes S. aureus and S. pneumoniae host defense in the lung through epithelial integrity and induction of antimicrobial peptides and is inhibited by the soluble decoy receptor IL-22-binding protein (IL-22BP). Little is known about the effect of the IL-22/IL-22BP regulatory pathway on lung infection, and it has not been studied in the setting of super-infection. We exposed wild-type and IL-22BP-/- mice to influenza A/PR/8/34 for 6 days prior to infection with S. aureus (USA300) S. pneumoniae. Super-infected IL-22BP-/- mice had decreased bacterial burden and improved survival compared to controls. IL-22BP-/- mice exhibited decreased inflammation, increased lipocalin 2 expression, and deletion of IL-22BP was associated with preserved epithelial barrier function with evidence of improved tight junction stability. Human bronchial epithelial cells treated with IL-22Fc showed evidence of improved tight junctions compared to untreated cells. This study revealed that IL-22BP-/- mice are protected during influenza, bacterial super-infection, suggesting that IL-22BP has a pro-inflammatory role and impairs epithelial barrier function likely through interaction with IL-22.

Survival during influenza-associated bacterial superinfection improves following viral- and bacterial-specific monoclonal antibody treatment.

Postinfluenza bacterial superinfections cause increased morbidity and mortality compared with singular infection with influenza during both pandemics and seasonal epidemics. Vaccines and current treatments provide limited benefit, a rationale to conduct studies utilizing alternative therapies. FY1 and an optimized version, MEDI8852, anti-influenza HA mAbs, have been shown to neutralize influenza virus during singular influenza infection. MEDI4893*, an anti-Staphylococcus aureus α-toxin mAb, has been shown to improve survival when administered prophylactically prior to S. aureus pneumonia. Our objective was to determine if mAbs can improve survival during postinfluenza bacterial pneumonia. We administered FY1 in a murine model of postinfluenza methicillin-resistant S. aureus (MRSA) pneumonia and observed improved survival rates when given early during the course of influenza infection. Our findings indicate decreased lung injury and increased uptake and binding of bacteria by macrophages in the mice that received FY1 earlier in the course of influenza infection, corresponding to decreased bacterial burden. We also observed improved survival when mice were treated with a combination of FY1 and MEDI4893* late during the course of postinfluenza MRSA pneumonia. In conclusion, both FY1 and MEDI4893* prolong survival when used in a murine model of postinfluenza MRSA pneumonia, suggesting pathogen-specific mAbs as a possible therapeutic in the context of bacterial superinfection.

Functional Mapping of Transcription Factor Grf10 That Regulates Adenine-Responsive and Filamentation Genes in Candida albicans.

Grf10, a homeodomain-containing transcription factor, regulates adenylate and one-carbon metabolism and morphogenesis in the human fungal pathogen Candida albicans Here, we identified functional domains and key residues involved in transcription factor activity using one-hybrid and mutational analyses. We localized activation domains to the C-terminal half of the Grf10 protein by one-hybrid analysis and identified motifs using bioinformatic analyses; one of the characterized activation domains (AD1) responded to temperature. The LexA-Grf10 fusion protein activated the lexAop-HIS1 reporter in an adenine-dependent fashion, and this activation was independent of Bas1, showing that the adenine limitation signal is transmitted directly to Grf10. Overexpression of LexA-Grf10 led to filamentation, and this required a functioning homeodomain, consistent with Grf10 controlling the expression of key filamentation genes; filamentation induced by LexA-Grf10 overexpression was independent of adenine levels and Bas1. Alanine substitutions were made within the conserved interaction regions (IR) of LexA-Grf10 and Grf10 to investigate roles in transcription. In LexA-Grf10, the D302A mutation activated transcription constitutively, and the E305A mutation was regulated by adenine. When these mutations were introduced into the native gene locus, the D302A mutation was unable to complement the ADE phenotype and did not promote filamentation under hypha-inducing conditions; the E305A mutant behaved as the native gene with respect to the ADE phenotype and was partially defective in inducing hyphae. These results demonstrate allele-specific responses with respect to the different phenotypes, consistent with perturbations in the ability of Grf10 to interact with multiple partner proteins.IMPORTANCE Metabolic adaptation and morphogenesis are essential for Candida albicans, a major human fungal pathogen, to survive and infect diverse body sites in the mammalian host. C. albicans utilizes transcription factors to tightly control the transcription of metabolic genes and morphogenesis genes. Grf10, a critical homeodomain transcription factor, controls purine and one-carbon metabolism in response to adenine limitation, and Grf10 is necessary for the yeast-to-hypha morphological switching, a known virulence factor. Here, we carried out one-hybrid and mutational analyses to identify functional domains of Grf10. Our results show that Grf10 separately regulates metabolic and morphogenesis genes, and it contains a conserved protein domain for protein partner interaction, allowing Grf10 to control the transcription of multiple distinct pathways. Our findings contribute significantly to understanding the role and mechanism of transcription factors that control multiple pathogenic traits in C. albicans.

Anesthesia for Trauma Patients.

An improved understanding of the pathophysiology of combat trauma has evolved over the past decade and has helped guide the anesthetic care of the trauma patient requiring surgical intervention. Trauma anesthesia begins before patient arrival with warming of the operating room, preparation of anesthetic medications and routine anesthetic machine checks. Induction of anesthesia must account for potential hemodynamic instability and intubation must consider airway trauma. Maintenance of anesthesia is accomplished with anesthetic gas, intravenous infusions or a combination of both. Resuscitation must precede or be ongoing with the maintenance of anesthesia. Blood product transfusion, antibiotic administration, and use of pharmacologic adjuncts (e.g., tranexamic acid, calcium) all occur simultaneously. Ventilatory strategies to mitigate lung injury can be initiated in the operating room, and resuscitation must be effectively transitioned to the intensive care setting after the case. Good communication is vital to efficient patient movement along the continuum of care. The resuscitation that is undertaken before, during and after operative management must incorporate important changes in care of the trauma patient. This Clinical Practice Guideline hopes to provide a template for care of this patient population. It outlines a method of anesthesia that incorporates the induction and maintenance of anesthesia into an ongoing resuscitation during surgery for a trauma patient in extremis.