Immune activation state modulates infant engram expression across development.

Infantile amnesia is possibly the most ubiquitous form of memory loss in mammals. We investigated how memories are stored in the brain throughout development by integrating engram labeling technology with mouse models of infantile amnesia. Here, we found a phenomenon in which male offspring in maternal immune activation models of autism spectrum disorder do not experience infantile amnesia. Maternal immune activation altered engram ensemble size and dendritic spine plasticity. We rescued the same apparently forgotten infantile memories in neurotypical mice by optogenetically reactivating dentate gyrus engram cells labeled during complex experiences in infancy. Furthermore, we permanently reinstated lost infantile memories by artificially updating the memory engram, demonstrating that infantile amnesia is a reversible process. Our findings suggest not only that infantile amnesia is due to a reversible retrieval deficit in engram expression but also that immune activation during development modulates innate, and reversible, forgetting switches that determine whether infantile amnesia will occur.

Interleukin-17 as a key player in neuroimmunometabolism.

In mammals, interleukin (IL)-17 cytokines are produced by innate and adaptive lymphocytes. However, the IL-17 family has widespread expression throughout evolution, dating as far back as cnidaria, molluscs and worms, which predate lymphocytes. The evolutionary conservation of IL-17 suggests that it is involved in innate defence strategies, but also that this cytokine family has a fundamental role beyond typical host defence. Throughout evolution, IL-17 seems to have a major function in homeostatic maintenance at barrier sites. Most recently, a pivotal role has been identified for IL-17 in regulating cellular metabolism, neuroimmunology and tissue physiology, particularly in adipose tissue. Here we review the emerging role of IL-17 signalling in regulating metabolic processes, which may shine a light on the evolutionary role of IL-17 beyond typical immune responses. We propose that IL-17 helps to coordinate the cross-talk among the nervous, endocrine and immune systems for whole-body energy homeostasis as a key player in neuroimmunometabolism.

Association of Methylene Blue Dosing With Hemodynamic Response for the Treatment of Vasoplegia.

OBJECTIVES: To compare the hemodynamic response of methylene blue dosing regimens (bolus v bolus plus infusion) for the treatment of vasoplegia. DESIGN: A retrospective cohort analysis. SETTING: A single-center academic medical center. PARTICIPANTS: Patients who underwent cardiac surgery at Cleveland Clinic and received methylene blue between 2016 and 2019. Patients were excluded from the analysis if methylene blue was initiated >48 hours after surgery, if the cardiac index was <2.0 L/min/m2, or if they returned to the operating room for postoperative hemorrhage. INTERVENTIONS: Methylene blue bolus-only regimens versus bolus plus continuous infusion methylene blue regimens. MEASUREMENTS AND MAIN RESULTS: The primary outcome was vasopressor requirement over 48 hours (1, 3, 6, 12, 24, and 48 hours) after methylene blue initiation. Other hemodynamic outcomes evaluated included the rate of methylene blue response, mean arterial pressure (MAP), and systemic vascular resistance (SVR) values over time. In total, 44 patients were included in the analysis, 33 of whom only received a methylene blue bolus. Vasopressor requirements at baseline were 95 (95% CI: 70-122) µg/min norepinephrine equivalent (NE) in the bolus-only group and 100 (86-130) µg/min in the infusion group. Vasopressor requirements decreased at each time point in both groups and were similar throughout (hour 1 mean [95% CI] NE, bolus 79 [67-91] µg/min v bolus plus infusion 84 [63-104] µg/min; p = 0.71). MAP, SVR, and rates of methylene blue response were similar between groups at all time points. Clinical outcomes also were similar between groups. CONCLUSIONS: The addition of a methylene blue continuous infusion did not significantly improve hemodynamic response. Bolus-only dosing of methylene blue may be sufficient for the treatment of vasoplegia after cardiac surgery.

Alignment of Fellowship Training with Practice Patterns for Molecular Pathologists: A Report of the Association for Molecular Pathology Training and Education Committee.

In the two decades since Accreditation Council for Graduate Medical Education-accredited Molecular Genetic Pathology fellowships began, the field of clinical molecular pathology has evolved considerably. The American Board of Pathology gathered data from board-certified molecular genetic pathologists assessing the alignment of skills and knowledge gained during fellowship with current needs on the job. The Association of Molecular Pathology conducted a parallel survey of program directors, and included questions on how various topics were taught during fellowship, as well as ranking their importance. Both surveys showed that most training aligned well with the practice needs of former trainees. Genomic profiling of tumors by next-generation sequencing, bioinformatics, laboratory management, and regulatory issues were topics thought to require increased emphasis in training. Topics related to clinical genetics and microbiology were deemed less important by those in practice, perhaps reflecting the increasing subspecialization of molecular pathologists. Program directors still viewed these topics as important to provide foundational knowledge. Parentage, identity, and human leukocyte antigen testing were less important to both survey audiences. These data may be helpful in guiding future adjustments to the Molecular Genetic Pathology curriculum and Accreditation Council for Graduate Medical Education program requirements.

Suppressive effects of the obese tumor microenvironment on CD8 T cell infiltration and effector function.

Obesity is one of the leading preventable causes of cancer; however, little is known about the effects of obesity on anti-tumor immunity. Here, we investigated the effects of obesity on CD8 T cells in mouse models and patients with endometrial cancer. Our findings revealed that CD8 T cell infiltration is suppressed in obesity, which was associated with a decrease in chemokine production. Tumor-resident CD8 T cells were also functionally suppressed in obese mice, which was associated with a suppression of amino acid metabolism. Similarly, we found that a high BMI negatively correlated with CD8 infiltration in human endometrial cancer and that weight loss was associated with a complete pathological response in six of nine patients. Moreover, immunotherapy using anti-PD-1 led to tumor rejection in lean and obese mice and partially restored CD8 metabolism and anti-tumor immunity. These findings highlight the suppressive effects of obesity on CD8 T cell anti-tumor immunity, which can partially be reversed by weight loss and/or immunotherapy.

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part II: Cardiac, surgical, perioperative, operative, and post-operative challenges and management statements.

Patients with connective tissue disease (CTD) present unique surgical, perioperative, operative, and postoperative challenges related to the often underlying severe pulmonary hypertension and right ventricular dysfunction. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization addresses the surgical challenges and relevant cardiac involvement in the perioperative, operative, and postoperative management in patients with CTD.

Harmonization of training, training program requirements, board certification, and the practice of cytopathology: data from the American Board of Pathology surveys.

INTRODUCTION: The American Board of Pathology (ABPath) has ongoing efforts to better align certification with graduate medical education, training program requirements, and pathology practice. The present study focused on the subspecialty of cytopathology. We evaluated the current content and scope of fellowship programs, practice patterns and needs of diplomates, and program director (PD) and diplomate perceptions of the ABPath certification examination to identify gaps and provide an evidence base to guide harmonization in these areas. METHODS: Two surveys were administered: one directed to PDs of all 93 Accreditation Council for Graduate Medical Education (ACGME) cytopathology fellowship programs and the other to cytopathology diplomates submitting continuing certification reporting to the ABPath. RESULTS: Most (86%) cytopathology diplomates work in smaller groups. Only 11% do >50% cytopathology in practice. Diplomates' cytopathology-related practice tasks varied, as did their perception of the content of fellowship training aligning with practice needs. In fellowship training programs, the specimen types, volumes, techniques of specimen acquisition, and graduated responsibility varied significantly. We identified areas in which current training and certification requirements are challenging for some programs. Diplomates and PDs had differing perceptions of the cytopathology examination; diplomates regarded image-based and microscopic glass slide questions as the best assessment of their knowledge. CONCLUSIONS: First, fellowship training programs could benefit from shared resources and should provide more graduated responsibility for fellows. Second, the ACGME Review Committee could consider this data in future program requirement revisions. Finally, information from these surveys will be useful as the ABPath adjusts certification examination content and delivery.

Association of Pain With Atrial Fibrillation and Delirium After Cardiac Surgery: A DECADE Sub-Study.

OBJECTIVE: The authors aimed to evaluate the effects of postoperative pain on the incidence of atrial fibrillation and delirium in patients having surgery with cardiopulmonary bypass (CPB). DESIGN: Post hoc analysis of the (An investigator-initiated, multicentre, double-blind trial (ClinicalTrials NCT02004613) (DECADE)), a randomized, placebo-controlled trial. SETTING: Tertiary, academic hospital. PARTICIPANTS: Six hundred five adults from the DECADE enrolled at Cleveland Clinic Main Campus, who had had surgery with CPB. INTERVENTIONS: Dexmedetomidine versus placebo started before surgical incision and postoperatively was maintained until 24 hours. MEASUREMENTS: Primary outcomes were atrial fibrillation, diagnosed by clinicians in the intensive care unit (ICU), presence of delirium assessed with the Confusion Assessment Method for the ICU, data on pain scores, and opioid consumption, occurring between ICU admission and the earlier of postoperative day five or hospital discharge. RESULTS: Postoperative pain levels were similar among patients with or without atrial fibrillation. Two hundred six (34%) patients had atrial fibrillation and ninety-two (15%) had delirium before hospital discharge within the first five postoperative days. The risk of atrial fibrillation was not significantly different between groups (hazard ratio: 1.09; 97.5% confidence interval [CI]: 0.99, 1.20, p = 0.039); there were no associations between postoperative pain and the risk of postoperative delirium (hazard ratio: 0.96; 97.5% CI: 0.84-1.11; p = 0.57). Postoperative opioid consumption was neither significantly associated with postoperative atrial fibrillation nor delirium. CONCLUSIONS: Atrial fibrillation and delirium was not associated with pain after cardiac surgery. Opioid use was not associated with atrial fibrillation and delirium. Because both atrial fibrillation and delirium have a multifactorial nature, further studies should be focused on other plausible mechanisms.

Distinct metabolic programs established in the thymus control effector functions of γδ T cell subsets in tumor microenvironments.

Metabolic programming controls immune cell lineages and functions, but little is known about γδ T cell metabolism. Here, we found that γδ T cell subsets making either interferon-γ (IFN-γ) or interleukin (IL)-17 have intrinsically distinct metabolic requirements. Whereas IFN-γ+ γδ T cells were almost exclusively dependent on glycolysis, IL-17+ γδ T cells strongly engaged oxidative metabolism, with increased mitochondrial mass and activity. These distinct metabolic signatures were surprisingly imprinted early during thymic development and were stably maintained in the periphery and within tumors. Moreover, pro-tumoral IL-17+ γδ T cells selectively showed high lipid uptake and intracellular lipid storage and were expanded in obesity and in tumors of obese mice. Conversely, glucose supplementation enhanced the antitumor functions of IFN-γ+ γδ T cells and reduced tumor growth upon adoptive transfer. These findings have important implications for the differentiation of effector γδ T cells and their manipulation in cancer immunotherapy.

Harmonization of Training, Training Requirements, Board Certification, and Practice of Hematopathology.

OBJECTIVES: Hematopathology (HP) is a rapidly changing field with insufficient data to provide guidance to program directors (PDs), the Accreditation Council for Graduate Medical Education, or the American Board of Pathology. METHODS: Two surveys were performed-one for HP PDs and one, given twice, for HP diplomates doing Maintenance of Certification/Continuing Certification reporting in 2017 to 2018. RESULTS: Bone marrow (BM), lymph node (LN), and flow cytometry interpretations and peripheral blood/fluid reviews are performed by more than 80% of hematopathologists and are the areas with the greatest amount of training. A smaller proportion of hematopathologists is involved in other HP-related activities. Most PDs believed fellows should perform BM procedures. Interpretation of 400 or more LNs and 500 BMs was PDs' median expectations for fellows. PDs and HP diplomates considered coagulation and benign RBC disorders overemphasized on the certification examination. CONCLUSIONS: These results highlight how varied the practice of HP is and can provide guidance to HP PDs, those responsible for assessing HP programs, and the American Board of Pathology.

Recent advances in perioperative anesthetic management update in the perioperative support of patients with septic shock and the effect on outcomes.

Septic shock during the perioperative period imparts significant challenges for anesthetic management. There is increasing support for standardization of care using evidence-based, international consensus guidelines, such as the Surviving Sepsis Campaign. This review will highlight practices in the supportive management relevant to the perioperative care of patients with severe sepsis or septic shock and their effect on clinical outcomes. It will address the epidemiological data of sepsis, the diagnostic criteria, and the role of routine, goal-directed hemodynamic resuscitation. Furthermore, it will review other options for support, including antibiotics, intensive insulin therapy, and intensive care sedation in this high risk patient population.