Corticotropin-Releasing Factor Release From a Unique Subpopulation of Accumbal Neurons Constrains Action-Outcome Acquisition in Reward Learning.

Background: The nucleus accumbens (NAc) mediates reward learning and motivation. Despite an abundance of neuropeptides, peptidergic neurotransmission from the NAc has not been integrated into current models of reward learning. The existence of a sparse population of neurons containing corticotropin-releasing factor (CRF) has been previously documented.

CRF release from a unique subpopulation of accumbal neurons constrains action-outcome acquisition in reward learning.

Background: The nucleus accumbens (NAc) mediates reward learning and motivation. Despite an abundance of neuropeptides, peptidergic neurotransmission from the NAc has not been integrated into current models of reward learning. The existence of a sparse population of neurons containing corticotropin releasing factor (CRF) has been previously documented.

Chronic Loss of Muscarinic M5 Receptor Function Manifests Disparate Impairments in Exploratory Behavior in Male and Female Mice despite Common Dopamine Regulation.

There are five cloned muscarinic acetylcholine receptors (M1-M5). Of these, the muscarinic type 5 receptor (M5) is the only one localized to dopamine neurons in the ventral tegmental area and substantia nigra. Unlike M1-M4, the M5 receptor has relatively restricted expression in the brain, making it an attractive therapeutic target.

Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity.

Chimeric antigen receptor (CAR) T cell therapy is revolutionizing cancer immunotherapy for patients with B cell malignancies and is now being developed for solid tumors and chronic viral infections. Although clinical trials have demonstrated the curative potential of CAR T cell therapy, a substantial and well-established limitation is the heightened contraction and transient persistence of CAR T cells during prolonged antigen exposure. The underlying mechanism(s) for this dysfunctional state, often termed CAR T cell exhaustion, remains poorly defined.

23.4% Hypertonic Saline: A Tactical Option for the Management of Severe Traumatic Brain Injury With Impending or Ongoing Herniation.

There are limited options available to the combat medic for management of traumatic brain injury (TBI) with impending or ongoing herniation. Current pararescue and Tactical Combat Casualty Care (TCCC) guidelines prescribe a bolus of 3% or 5% hypertonic saline. However, this fluid bears a tactical burden of weight (~570g) and pack volume (~500cm3).

Social Experience Interacts with Serotonin to Affect Functional Connectivity in the Social Behavior Network following Playback of Social Vocalizations in Mice.

Past social experience affects the circuitry responsible for producing and interpreting current behaviors. The social behavior network (SBN) is a candidate neural ensemble to investigate the consequences of early-life social isolation. The SBN interprets and produces social behaviors, such as vocalizations, through coordinated patterns of activity (functional connectivity) between its multiple nuclei.

Access and Continuity: A Multidisciplinary Education Workshop to Teach Patient-Centered Medical Home (PCMH) Principles.

Introduction: As more practices move to patient-centered medical home (PCMH) models, future health care professionals must train to work in collaborative settings. We implemented a 3-hour workshop for multidisciplinary trainees on the PCMH principles of access and continuity based on the EFECT framework (eliciting a patient-centered narrative, facilitating an interprofessional team discussion, evaluating the clinical evidence, creating a shared care plan, and tracking outcomes).

Methods: Participants included internal medicine residents and medical, physician assistant (PA), and clinical psychology students.

Ophidiomycosis, an emerging fungal disease of snakes: Targeted surveillance on military lands and detection in the western US and Puerto Rico.

Wildlife disease surveillance and pathogen detection are fundamental for conservation, population sustainability, and public health. Detection of pathogens in snakes is often overlooked despite their essential roles as both predators and prey within their communities. Ophidiomycosis (formerly referred to as Snake Fungal Disease, SFD), an emergent disease on the North American landscape caused by the fungus Ophidiomyces ophiodiicola, poses a threat to snake population health and stability.

Management of Critically Injured Burn Patients During an Open Ocean Parachute Rescue Mission.

Best practices and training for prolonged field care (PFC) are evolving. The New York Pararescue Team has used part task training, cadaver labs, clinical rotations, and a complicated sim lab to prepare for PFC missions including critical care. This report details an Atlantic Ocean nighttime parachute insertion to provide advanced burn care to two sailors with 50% and 60% body surface area burns.

Ketamine Administration by Special Operations Medical Personnel During Training Mishaps.

Background: Opioids can have adverse effects on casualties in hemorrhagic shock. In 2014, the Committee on Tactical Combat Casualty Care (CoTCCC) recommended the use of ketamine at the point of injury (POI). Despite these recommendations the adherence is moderate at best.

Seasonal patterns of melatonin alter aggressive phenotypes of female Siberian hamsters.

Many animal species exhibit year-round aggression, a behaviour that allows individuals to compete for limited resources in their environment (eg, food and mates). Interestingly, this high degree of territoriality persists during the non-breeding season, despite low levels of circulating gonadal steroids (ie, testosterone [T] and oestradiol [E ]). Our previous work suggests that the pineal hormone melatonin mediates a 'seasonal switch' from gonadal to adrenal regulation of aggression in Siberian hamsters (Phodopus sungorus); solitary, seasonally breeding mammals that display increased aggression during the short, 'winter-like' days (SDs) of the non-breeding season.

Serotonergic innervation of the auditory midbrain: dorsal raphe subregions differentially project to the auditory midbrain in male and female mice.

In the auditory inferior colliculus (IC), serotonin reflects features of context including the valence of social interactions, stressful events, and prior social experience. However, within the dorsal raphe nucleus (DRN; B6 + B7), the source of serotonergic projections to the IC has not been resolved at the level of DRN subregions. Additionally, few studies have investigated which DRN subregions are engaged during naturalistic, sensory-driven social behaviors.

CHANGE-seq reveals genetic and epigenetic effects on CRISPR-Cas9 genome-wide activity.

Current methods can illuminate the genome-wide activity of CRISPR-Cas9 nucleases, but are not easily scalable to the throughput needed to fully understand the principles that govern Cas9 specificity. Here we describe 'circularization for high-throughput analysis of nuclease genome-wide effects by sequencing' (CHANGE-seq), a scalable, automatable tagmentation-based method for measuring the genome-wide activity of Cas9 in vitro. We applied CHANGE-seq to 110 single guide RNA targets across 13 therapeutically relevant loci in human primary T cells and identified 201,934 off-target sites, enabling the training of a machine learning model to predict off-target activity.

Vasoplegic syndrome following cardiothoracic surgery-review of pathophysiology and update of treatment options.

Vasoplegic syndrome is a common occurrence following cardiothoracic surgery and is characterized as a high-output shock state with poor systemic vascular resistance. The pathophysiology is complex and includes dysregulation of vasodilatory and vasoconstrictive properties of smooth vascular muscle cells. Specific bypass machine and patient factors play key roles in occurrence.

Next Generation CAR T Cells for the Immunotherapy of High-Grade Glioma.

High grade gliomas (HGG) comprise a heterogeneous group of brain malignancies with dismal prognosis. Current standard-of-care includes radiation, chemotherapy, and surgical resection when possible. Despite advances in each of these treatment modalities, survival rates for pediatric and adult HGG patients has remained largely unchanged over the course of several years.

Oligoclonal T Cells Transiently Expand and Express Tim-3 and PD-1 Following Anti-CD19 CAR T Cell Therapy: A Case Report.

Clinical trials of chimeric antigen receptor (CAR) T cells in hematologic malignancy associate remissions with two profiles of CAR T cell proliferation kinetics, which differ based upon costimulatory domain. Additional T cell intrinsic factors that influence or predict clinical response remain unclear. To address this gap, we report the case of a 68-year-old woman with refractory/relapsed diffuse large B cell lymphoma (DLBCL), treated with tisagenlecleucel (anti-CD19), with a CD137 costimulatory domain (4-1BB) on an investigational new drug application (#16944).

The Role of Magnetic Resonance Imaging in Optimizing Injury Management in Air Force Pararescuemen, Combat Rescue Officers, and Survival Specialists.

Operators perform physically demanding jobs associated with a variety of overuse and acute musculoskeletal injuries. The current management of musculoskeletal complaints in the Air Force includes plane radiographs and 6 weeks of physical therapy (PT) before consideration of orthopedic consultation and magnetic resonance imaging (MRI); however, MRI shows a clear advantage compared with plane radiographs. We conducted a performance improvement project and conclude that (1) MRI allowed for definitive diagnosis as well as definitive triage for care in a timely manner, (2) guidelines for ordering lumbosacral MRIs should be followed and not ordered for pain that is not progressive and severe or not associated with a neurological finding, and (3) because of the risk of X-ray exposure in patients in their 20 and 30s, X-rays should be avoided in this setting unless definitely indicated.

Successful Use of Ketamine as a Prehospital Analgesic by Pararescuemen During Operation Enduring Freedom.

Effective analgesia is a crucial part of the care and resuscitation of a traumatically injured patient. These secondary effects of pain may increase morbidity and mortality in the acutely injured patient. When ketamine is administered appropriately in the clinical setting, it can provide analgesia, anxiolysis, and amnesia for patients with less respiratory depression and hypotension than equivalent doses of opioid analgesics.

Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists.

Adoptive therapy with ex vivo-expanded genetically modified antigen-specific T cells can induce remissions in patients with relapsed/refractory cancer. The clinical success of this therapy depends upon efficient transduction and expansion of T cells ex vivo and their homing, persistence and cytotoxicity following reinfusion. Lower rates of ex vivo expansion and clinical response using anti-CD19 chimeric antigen receptor (CAR) T cells have been seen in heavily pretreated lymphoma patients compared with B-cell acute lymphoblastic leukemia patients and motivate the development of novel strategies to enhance ex vivo T cell expansion and their persistence in vivo.

Activation of VIP signaling enhances immunosuppressive effect of MDSCs on CMV-induced adaptive immunity.

Vasoactive intestinal peptide (VIP) is recognized as a potent anti-inflammatory factor which affects both the innate and adaptive arms of the immune system. These effects include, but are not limited to, inhibition of T cell proliferation and disruption of immune homeostasis. Myeloid-derived suppressor cells (MDSC) are an immune regulatory cell type that has been described in settings of cancer and infectious disease.

Putting it in Context: Linking Auditory Processing with Social Behavior Circuits in the Vertebrate Brain.

Context is critical to the adaptive value of communication. Sensory systems such as the auditory system represent an important juncture at which information on physiological state or social valence can be added to communicative information. However, the neural pathways that convey context to the auditory system are not well understood.

Optimization of Simulation and Moulage in Military-Related Medical Training.

Preparation of Special Operations Forces (SOF) Medics as first responders for the battle space and austere environments is critical to optimize survival and quality of life for our Operators who may sustain serious and complex wounding patterns and illnesses. In the absence of constant clinical exposure for these medics, it is necessary to maximize all available training opportunities. The incorporation of scenario-based training helps weave together teamwork and the ability to practice treatment protocols in a tactical, controlled training environment to reproduce, to some degree, the environment in and stressors under which care will need to be delivered.

Administration of a vasoactive intestinal peptide antagonist enhances the autologous anti-leukemia T cell response in murine models of acute leukemia.

Vasoactive intestinal peptide (VIP) is a neuroendocrine peptide hormone that has potent anti-inflammatory activities. VIP signaling through its receptor VPAC1 on T cells leads to reduced proliferation and a reduction in pro-inflammatory cytokine secretion. We report here that inhibition of the VIP pathway with a peptide antagonist significantly enhances a T-cell-dependent, autologous anti-leukemia response in murine models of acute myeloid leukemia and T lymphoblastic leukemia.

Modulation of Immune Checkpoints and Graft-versus-Leukemia in Allogeneic Transplants by Antagonizing Vasoactive Intestinal Peptide Signaling.

The goal of allogeneic bone marrow transplantation (allo-BMT) is elimination of leukemia cells through the graft-versus-leukemia (GvL) activity of donor cells, while limiting graft-versus-host disease (GvHD). Immune checkpoint pathways regulate GvL and GvHD activities, but blocking antibodies or genetic inactivation of these pathways can cause lethal GVHD. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide that regulates coinhibitory pathways; its role in allo-BMT has not been studied.