So You Want to Do Trauma Research? A Practical Guide to Creating a Research Program at Your Home Institution.

BACKGROUND: There are 3 pillars upon which the foundation of a teaching program in health care is founded: research, education, and clinical care. However, in a busy academic trauma practice, the unfortunate reality is that research is often a low priority in the frenzy of mandates for clinical productivity. OBJECTIVE: The purpose of this report is to advise hospitals on how to create a modest trauma research program that supports research interests without significantly impacting the overall clinical productivity of the department. METHODS: Relevant literature related to the development of an academic trauma research department was reviewed. Relevant articles were then compared to this manuscript to assess the novelty of the topic. RESULTS: There are 4 essential components of a trauma research program: (1) a zealot, (2) institutional commitment and support, (3) a statistician, and (4) registry data access. CONCLUSION: The creation of a trauma research program may seem like a herculean effort, but this work is necessary for institutions hoping to achieve status as a Level I/II trauma center. Following the steps outlined in this report, trauma providers can create a robust research program at their institution without sacrificing clinical productivity.

Application of a Novel Endpoint Staging Framework: Proof of Concept in the AMBAR Study.

Background: A theoretical endpoint staging framework was previously developed and published, aligning outcomes (i.e., memory) to the stage of Alzheimer's disease (AD) in which a given outcome is most relevant (i.e., has the greatest risk of degradation). The framework guides the selection of endpoints measuring outcomes relevant within a target AD population. Here, a proof of concept is presented via post-hoc analyses of the Alzheimer Management by Albumin Replacement (AMBAR) Phase 2b clinical trial in patients with AD (NCT01561053, 2012). Objective: To evaluate whether aligning endpoints measuring cognition, function, and quality of life to hypothesized 'target' stages of AD yields magnitudes of treatment efficacy greater than those reported in the AMBAR full analysis set (FAS). Methods: Three endpoints were tested: ADAS-Cog 12, ADCS-ADL, and QoL-AD. The magnitude of treatment efficacy was hypothesized to be maximized in the target stages of mild, mild-to-moderate, and very mild AD, respectively, compared to the full analysis set (FAS) and non-target stages. Results: For ADAS-Cog 12, the magnitude of treatment efficacy was largest in the non-target stage (-4.0, p = 0.0760) compared to target stage and FAS. For ADCS-ADL and QoL-AD, the magnitude of treatment efficacy was largest in the target stage (14.2, p = 0.0003; 2.4, p < 0.0001, respectively) compared to non-target stage and FAS. Conclusions: Findings indicated that evaluating endpoints in the most relevant AD stage can increase the magnitude of the observed treatment efficacy. Evidence provides preliminary proof of concept for the endpoint staging framework.

A choroid plexus apocrine secretion mechanism shapes CSF proteome and embryonic brain development.

We discovered that apocrine secretion by embryonic choroid plexus (ChP) epithelial cells contributes to the cerebrospinal fluid (CSF) proteome and influences brain development in mice. The apocrine response relies on sustained intracellular calcium signaling and calpain-mediated cytoskeletal remodeling. It rapidly alters the embryonic CSF proteome, activating neural progenitors lining the brain's ventricles. Supraphysiological apocrine secretion induced during mouse development by maternal administration of a serotonergic 5HT2C receptor agonist dysregulates offspring cerebral cortical development, alters the fate of CSF-contacting neural progenitors, and ultimately changes adult social behaviors. Critically, exposure to maternal illness or to the psychedelic drug LSD during pregnancy also overactivates the ChP, inducing excessive secretion. Collectively, our findings demonstrate a new mechanism by which maternal exposure to diverse stressors disrupts in utero brain development.

Brain Death/Death by Neurologic Criteria: What You Need to Know.

ABSTRACT: Since the beginning of time, man has been intrigued with the question of when a person is considered dead. Traditionally, death has been considered the cessation of all cardiorespiratory function. At the end of the last century a new definition was introduced into the lexicon surrounding death in addition to cessation of cardiac and respiratory function: Brain Death/Death by Neurologic Criteria (BD/DNC). There are medical, legal, ethical, and even theological controversies that surround this diagnosis. In addition, there is no small amount of confusion among medical practitioners regarding the diagnosis of BD/DNC. For families enduring the devastating development of BD/DNC in their loved one, it is the duty of the principal caregiver to provide a transparent presentation of the clinical situation and clear definitive explanation of what constitutes BD/DNC. In this report, we present a historical outline of the development of BD/DNC as a clinical entity, specifically how one goes about making a determination of BD/DNC, what steps are taken once a diagnosis of BD/DNC is made, a brief discussion of some of the ethical/moral issues surrounding this diagnosis, and finally the caregiver approach to the family of a patient who had been declared with BD/DNC. It is our humble hope that with a greater understanding of the myriad of complicated issues surrounding the diagnosis of BD/DNC that the bedside caregiver can provide needed closure for both the patient and the family enduring this critical time in their life.

The State of the Union: Trauma System Development in the United States.

Injury is both a national and international epidemic that affects people of all age, race, religion, and socioeconomic class. Injury was the fourth leading cause of death in the United States (U.S.) in 2021 and results in an incalculable emotional and financial burden on our society. Despite this, when prevention fails, trauma centers allow communities to prepare to care for the traumatically injured patient. Using lessons learned from the military, trauma care has grown more sophisticated in the last 50 years. In 1966, the first civilian trauma center was established, bringing management of injury into the new age. Now, the American College of Surgeons recognizes 4 levels of trauma centers (I-IV), with select states recognizing Level V trauma centers. The introduction of trauma centers in the U.S. has been proven to reduce morbidity and mortality for the injured patient. However, despite the proven benefits of trauma centers, the U.S. lacks a single, unified, trauma system and instead operates within a "system of systems" creating vast disparities in the level of care that can be received, especially in rural and economically disadvantaged areas. In this review we present the history of trauma system development in the U.S, define the different levels of trauma centers, present evidence that trauma systems and trauma centers improve outcomes, outline the current state of trauma system development in the U.S, and briefly mention some of the current challenges and opportunities in trauma system development in the U.S. today.

American Trauma Care: A System of Systems.

OBJECTIVE: The benefits of organized trauma systems have been well-documented during 50 years of trauma system development in the United States. Unfortunately, despite this evidence, trauma system development has occurred only sporadically in the 50 states. METHODS: The relevant literature related to trauma system design and development was reviewed based on relevance to the study. Information from these sources was summarized into a SWOT (strengths, weaknesses, opportunities, and threats) analysis. RESULTS: Strengths discovered were leadership brought forth by the American College of Surgeons Committee on Trauma and meaningful change generated from The National Academy of Sciences, Engineering, and Medicine report addressing the fractionation of the nation's trauma systems, whereas weaknesses included patient outcome disparities due to the lack of a national governing authority, undertriage, underresourced rural trauma, and underfunded trauma research. Opportunities included the creation of level IV trauma centers; telemedicine; the development of rural trauma management courses; air medical transport to bring high-intensity care to the patient, particularly in rural areas; trauma research; and trauma prevention through outreach and educational programs. The following threats were determined: mass casualty incidents, motor vehicle collisions because of the high rate of motor vehicle collision deaths in the United States relative to other developed countries, and underfunded trauma systems. CONCLUSION: Much work remains to be done in the development of an American trauma system. Recommendations include implementation of trauma care governance at the federal level; national oversight and support of emergency medical services systems, particularly in rural areas with strict reporting processes for emergency medical services programs; national organization of our mass casualty response; increased federal and state funding allocated to trauma centers; a consistent model for trauma system development; and trauma research.

A collaboration between immune cells and the choroid plexus epithelium in brain inflammation.

The choroid plexus (ChP) is a vital brain barrier and source of cerebrospinal fluid (CSF). Here, we use chronic two-photon imaging in awake mice and single-cell transcriptomics to demonstrate that in addition to these roles, the ChP is a complex immune organ that regulates brain inflammation. In a mouse meningitis model, neutrophils and monocytes accumulated in ChP stroma and surged across the epithelial barrier into the CSF. Bi-directional recruitment of monocytes from the periphery and, unexpectedly, macrophages from the CSF to the ChP helped eliminate neutrophils and repair the barrier. Transcriptomic analyses detailed the molecular steps accompanying this process, including the discovery of epithelial cells that transiently specialized to nurture immune cells, coordinate their recruitment, survival, and differentiation, and ultimately, control the opening/closing of the ChP brain barrier. Collectively, we provide a new conceptual understanding and comprehensive roadmap of neuroinflammation at the ChP brain barrier.

Prolonged cytopenia following CD19 CAR T cell therapy is linked with bone marrow infiltration of clonally expanded IFNγ-expressing CD8 T cells.

Autologous anti-CD19 chimeric antigen receptor T cell (CAR T) therapy is highly effective in relapsed/refractory large B cell lymphoma (rrLBCL) but is associated with toxicities that delay recovery. While the biological mechanisms of cytokine release syndrome and neurotoxicity have been investigated, the pathophysiology is poorly understood for prolonged cytopenia, defined as grade ≥3 cytopenia lasting beyond 30 days after CAR T infusion. We performed single-cell RNA sequencing of bone marrow samples from healthy donors and rrLBCL patients with or without prolonged cytopenia and identified significantly increased frequencies of clonally expanded CX3CR1hi cytotoxic T cells, expressing high interferon (IFN)-γ and cytokine signaling gene sets, associated with prolonged cytopenia. In line with this, we found that hematopoietic stem cells from these patients expressed IFN-γ response signatures. IFN-γ deregulates hematopoietic stem cell self-renewal and differentiation and can be targeted with thrombopoietin agonists or IFN-γ-neutralizing antibodies, highlighting a potential mechanism-based approach for the treatment of CAR T-associated prolonged cytopenia.

Development of ADS051, an oral, gut-restricted, small molecule neutrophil modulator for the treatment of neutrophil-mediated inflammatory diseases.

Neutrophils are an essential component of the innate immune system; however, uncontrolled neutrophil activity can lead to inflammation and tissue damage in acute and chronic diseases. Despite inclusion of neutrophil presence and activity in clinical evaluations of inflammatory diseases, the neutrophil has been an overlooked therapeutic target. The goal of this program was to design a small molecule regulator of neutrophil trafficking and activity that fulfilled the following criteria: (a) modulates neutrophil epithelial transmigration and activation, (b) lacks systemic exposure, (c) preserves protective host immunity, and (d) is administered orally. The result of this discovery program was ADS051 (also known as BT051), a low permeability, small molecule modulator of neutrophil trafficking and activity via blockade of multidrug resistance protein 2 (MRP2)- and formyl peptide receptor 1 (FPR1)-mediated mechanisms. ADS051, based on a modified scaffold derived from cyclosporine A (CsA), was designed to have reduced affinity for calcineurin with low cell permeability and, thus, a greatly reduced ability to inhibit T-cell function. In cell-based assays, ADS051 did not inhibit cytokine secretion from activated human T cells. Furthermore, in preclinical models, ADS051 showed limited systemic absorption (<1% of total dose) after oral administration, and assessment of ADS051 in human, cell-based systems demonstrated inhibition of neutrophil epithelial transmigration. In addition, preclinical toxicology studies in rats and monkeys receiving daily oral doses of ADS051 for 28 days did not reveal safety risks or ADS051-related toxicity. Our results to date support the clinical development of ADS051 in patients with neutrophil-mediated inflammatory diseases.

Defining diurnal fluctuations in mouse choroid plexus and CSF at high molecular, spatial, and temporal resolution.

Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components. Using ChP and CSF metabolomics and blood-CSF barrier analyses, we observed diurnal changes in metabolites and cellular junctions. We then focused on transthyretin (TTR), a diurnally regulated thyroid hormone chaperone secreted by the ChP. Diurnal variation in ChP TTR depended on Bmal1 clock gene expression. We achieved real-time tracking of CSF-TTR in awake TtrmNeonGreen mice via multi-day intracerebroventricular fiber photometry. Diurnal changes in ChP and CSF TTR levels correlated with CSF thyroid hormone levels. These datasets highlight an integrated platform for investigating diurnal control of brain states by the ChP and CSF.

Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus.

Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K+] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly. Excessive CSF [K+] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting targeted gene therapy as a potential treatment to mitigate intracranial fluid accumulation following hemorrhage.

Comprehensive Review of Current Pain Management in Rib Fractures With Practical Guidelines for Clinicians.

Rib fractures are present in 15% of all traumas and 60% of patients with chest traumas. Rib fractures are not life-threatening in isolation, but they can be quite painful which leads to splinting and compromise of respiratory function. Splinting limits the ability of a patient to take a deep breath, which leads to atelectasis, atelectasis to poor secretion removal, and poor secretion removal leads to pneumonia. Pneumonia is the common pathway to respiratory failure in patients with rib fractures. It is noted that in the elderly, each rib fracture increases developing pneumonia by 27% and the risk of dying by 19%. From a public health perspective, rib fractures have long-term implications with only 59% of patients returning to work at 6 months. In this review we will examine the state of art as it currently exists with regard to the management of pain associated with rib fractures. Included in this overview will be a brief review of the anatomy of the thorax and some important physiologic concepts, the latest trends in pharmacologic and noninvasive means of managing rib pain, a special section on epidural anesthesia, some other alternative invasive methods of pain control, and a review of the recent literature on rib plating. Finally, a practical, easy to follow guideline, to manage the patient with pain from rib fractures will be presented.

Long-term outcomes after using retrievable vena cava filters in major trauma patients with contraindications to prophylactic anticoagulation.

PURPOSE: To investigate the long-term outcomes of using vena cava filters to prevent symptomatic pulmonary embolism (PE) in major trauma patients who have contraindications to prophylactic anticoagulation. METHODS: This was an a priori sub-study of a randomized controlled trial (RCT) involving long-term outcome data of 223 patients who were enrolled in Western Australia. State-wide clinical information system, radiology database and death registry were used to assess long-term outcomes, including incidences of venous thromboembolism, venous injury and mortality beyond day-90 follow-up. RESULTS: The median follow-up time of 198 patients (89%) who survived beyond 90 days was 65 months (interquartile range 59-73). Ten patients (5.1%) died after day-90 follow-up; and four patients developed venous thromboembolism, including two with symptomatic PE, all allocated to the control group (0 vs 4%, p = 0.043). Inferior vena cava injuries were not recorded in any patients. The mean total hospitalization cost, including the costs of the filter and its insertion and removal, to prevent one short- or long-term symptomatic PE was A$284,820 (€193,678) when all enrolled patients were considered. The number of patients needed to treat (NNT = 5) and total hospitalization cost to prevent one symptomatic PE (A$1,205 or €820) were, however, substantially lower when the filter was used only for patients who could not be anticoagulated within seven days of injury. CONCLUSION: Long-term complications related to retrievable filters were rare, and the cost of using filters to prevent symptomatic PE was acceptable when restricted to those who could not be anticoagulated within seven days of severe injury.

Relationship of Impairments in Associative Learning With Intellectual Disability and Cerebellar Hypoplasia in Autistic Children.

BACKGROUND AND OBJECTIVES: The severity of autism spectrum disorder (ASD) varies widely and is associated with intellectual disability (ID) and brain dysmorphology. We tested the hypothesis that the heterogeneity of ASD can be accounted for, in part, by altered associative learning measured by eye-blink conditioning (EBC) paradigms, used to test for forebrain and cerebellar dysfunction across the full range of ASD severity and intellectual ability. METHODS: Children in this cohort study were diagnosed with ASD or typical development (TD); most children were recruited from a 10-year longitudinal study. Outcome measures were the percentage and timing of conditioned eye-blink responses (CRs) acquired to a tone, recorded photometrically and related to measures of ASD severity, IQ, and age 2 brain morphometry by MRI. A sequence of trace and delay EBC was used. Analysis of variance, t test, and logistic regression (LR) were used. RESULTS: Sixty-two children were studied at school age. Nine children with ASD with ID since age 2 (ASD + ID; IQ = 49 ± 6; 11.9 ± 0.2 years old [±SD]) learned more slowly than 30 children with TD (IQ = 120 ± 16; 10.5 ± 1.5 years old [±SD]) during trace EBC and showed atypically early-onset CRs (1.4 SD pre-TD) related to hypoplasia of the cerebellum at age 2 but not of the amygdala, hippocampus, or cerebral cortex. Conversely, 16 children with ASD with robust intellectual development since age 2 (IQ = 100 ± 3; 12.0 ± 0.4 years old [±SD]) learned typically but showed early-onset CRs only during long-delay EBC (0.8 SD pre-TD) unrelated to hypoplasia of any measured brain area. Using 16 EBC measures, binary LR classified ASD and TD with 80% accuracy (95% CI = 72-88%), 81% sensitivity (95% CI = 69-92%), and 79% specificity (95% CI = 68-91%); multinomial LR more accurately classified children based on ID (94% accuracy, 95% CI = 89-100%) than ASD severity (85% accuracy, 95% CI = 77-93%). Separate analyses of 39 children with MRI (2.1 ± 0.3 years old [±SD]) indicated that cerebellar hypoplasia did not predict ASD + ID over ages 2-4 (Cohen d = 0.3) compared with early-onset CRs during age 11 trace EBC (Cohen d = -1.3). DISCUSSION: Trace EBC reveals the relationship between cerebellar hypoplasia and ASD + ID likely by engaging cerebrocerebellar circuits involved in intellectual ability and implicit timing. Follow-up prospective studies using associative learning can determine whether ID can be predicted in children with early ASD diagnoses.

The Predictive Performance of Contemporary Guideline Recommendations for Helicobacter pylori Testing in a United States Population.

BACKGROUND: The Houston Consensus Conference and American College of Gastroenterology (ACG) have recommended Helicobacter pylori screening in United States populations with specific risk factors. However, the performance of these guidelines in clinical practice is not known. METHODS: We identified consecutive patients undergoing upper endoscopy with gastric biopsies for any indication in a safety-net hospital in Houston, TX during January 2015-December 2016. We tested the association between the presence of H pylori (histopathology, stool antigen, urea breath test, immunoglobulin G serology, or prior treatment) and H pylori risk factors using logistic regression models, reported as odds ratios and 95% confidence intervals (CIs). We evaluated the area under the receiver operating characteristic (AUROC) curve for predictive ability of individual risk factors identified by the Houston Consensus Conference and ACG. RESULTS: Of 942 patients, the prevalence of H pylori infection was 51.5%. The risk factors with the highest predictive performance included first-generation immigrant (AUROC, 0.59) and Hispanic or black race/ethnicity (AUROC, 0.57), whereas the remaining 7 risk factors/statements had low predictive value. A model that combined first-generation immigrant status, black or Hispanic race/ethnicity, dyspepsia, and reflux had higher predictive ability for H pylori infection (AUROC, 0.64; 95% CI, 0.61-0.68) than any individual risk factor. CONCLUSIONS: In this contemporary U.S. cohort, the performance of individual risk factors identified by the Houston Consensus Conference and ACG was generally low for predicting H pylori infection except for black or Hispanic race/ethnicity and first-generation immigrant status. A risk prediction model combining several risk factors had improved diagnostic performance and should be validated in future studies.

Trigeminal afferents sense locomotion-related meningeal deformations.

The trigeminal sensory innervation of the cranial meninges is thought to serve a nociceptive function and mediate headache pain. However, the activity of meningeal afferents under natural conditions in awake animals remains unexplored. Here, we used two- and three-dimensional two-photon calcium imaging to track the activity of meningeal afferent fibers in awake mice. Surprisingly, a large subset of afferents was activated during non-noxious conditions such as locomotion. We estimated locomotion-related meningeal deformations and found afferents with distinct dynamics and tuning to various levels of meningeal expansion, compression, shearing, and Z-axis motion. Further, these mechanosensitive afferents were often tuned to distinct directions of meningeal expansion or compression. Thus, in addition to their role in headache-related pain, meningeal sensory neurons track the dynamic mechanical state of the meninges under natural conditions.