Fourth Controlled Human Infection Model (CHIM) meeting - CHIMs in endemic countries, May 22-23, 2023.

Earlier meetings laid the foundations for Controlled Human Infection Models (CHIMs), also known as human challenge studies and human infection studies, including Good Manufacturing Practice (GMP) production of the challenge agent, CHIM ethics, environmental safety in CHIM, recruitment, community engagement, advertising and incentives, pre-existing immunity, and clinical, immunological, and microbiological endpoints. The fourth CHIM meeting focused on CHIM studies being conducted in endemic countries. Over the last ten years we have seen a vast expansion of the number of countries in Africa performing CHIM studies, as well as a growing number of different challenge organisms being used. Community and public engagement with assiduous ethical and regulatory oversight has been central to successful introductions and should be continued, in more community-led or community-driven models. Valuable initiatives for regulation of CHIMs have been undertaken but further capacity building remains essential.

The relationship between resilience and neurophysiological stress in Special Operations Forces combat service members.

Military resilience research is increasing due to the growing literature associating resilience with stress adaptation. This study aimed to investigate which physiological stress adaptation components were associated with resilience in Special Operations Forces combat service members. Special Operations Forces combat service members (n = 117) self-reported resilience (ER89) and lifetime clinician-confirmed mild traumatic brain injury history. Participants also underwent transcranial Doppler ultrasonography to measure middle cerebral artery velocity during rest and a breath-holding task. Neither resilience nor mild traumatic brain injury history was significantly associated with middle cerebral artery velocity percent increase following breath-holding; younger Special Operations Forces combat service members had a higher percent increase in middle cerebral artery velocity following a breath-holding task. Resilience was negatively associated with time to return to baseline middle cerebral artery velocity following peak velocity; whereas, mild traumatic brain injury history did not have a significant association. The Special Operations Forces combat service members that scored higher in resilience tended to return to baseline middle cerebral artery velocity following peak velocity faster than their less resilient counterparts. More resilient Special Operations Forces combat service members recovered faster from physiological stress (breath-holding) than less resilient counterparts. This is the first study to investigate resilience and cerebrovascular stress response and recovery in this population. Our initial findings indicated that the Ego Resiliency Scale may be an optimal resilience psychometric and should be used to evaluate effective military resilience trainings, which aim to improve performance and mental health.

Neuroinflammatory Biomarkers Associated With Mild Traumatic Brain Injury History in Special Operations Forces Combat Soldiers.

BACKGROUND: Special Operations Forces (SOF) combat soldiers are frequently exposed to blast and blunt neurotrauma, most often classified as mild traumatic brain injury (mTBI). Repetitive mTBI may increase the risk of developing long-term neurological sequelae. Identifying changes in neuroinflammatory biomarkers before chronic conditions emerge could serve as preliminary evidence of developing neuropathology. OBJECTIVE: To determine the effects of mTBI history, lifetime mTBI incidence, and recency on blood biomarker concentrations of axonal protein neurofilament light (NfL), glycolytic enzyme neuron-specific enolase (NSE), astrocyte-expressed S100 calcium-binding protein B (S100B), and neurotrophic cytokine interleukin-6 (IL-6) in healthy, active duty SOF combat soldiers. METHODS: Self-reported mTBI history/recency and fasted blood samples were collected in this cross-sectional study of 104 asymptomatic SOF combat soldiers. Biomarker concentrations were quantified using commercial enzyme-linked immunosorbent assays. Mann-Whitney U and Kruskal-Wallis tests were used to compare groups. Post hoc tests with appropriate corrections were conducted as warranted. RESULTS: Soldiers with mTBI history had higher NSE concentrations than those without (z = -2.60, P = .01). We also observed significant main effects of lifetime mTBI incidence on NSE (χ(3) = 9.52, P = .02) and S100B (χ(3) = 8.21, P = .04) concentrations and a significant main effect of mTBI recency on NfL concentration (χ(2) = 6.02, P = .049). CONCLUSION: The SOF combat soldiers with mTBI history had increased NSE. Longitudinal studies in this population are needed due to between-subject heterogeneity in biomarker concentrations. The NfL concentrations in our SOF combat soldiers-regardless of mTBI history or recency-were similar to values previously reported in civilian acute TBI patients.

Effects of deployment on diet quality and nutritional status markers of elite U.S. Army special operations forces soldiers.

BACKGROUND: Special Operations Forces (SOF) Soldiers deploy frequently and require high levels of physical and cognitive performance. Nutritional status is linked to cognitive and physical performance. Studies evaluating dietary intake and nutritional status in deployed environments are lacking. Therefore, this study assessed the effects of combat deployment on diet quality and serum concentrations of nutritional status markers, including iron, vitamin D, parathyroid hormone (PTH), glucose, and lipids, among elite United States (U.S.) Army SOF Soldiers. METHODS: Changes from baseline to post-deployment were determined with a repeated measure within-subjects design for Healthy Eating Index-2010 (HEI-2010) scores, intake of foods, food groups, key nutrients, and serum nutritional status markers. Dietary intake was assessed with a Block Food Frequency Questionnaire. The association between post-deployment serum 25-hydroxy vitamin D (25-OH vitamin D) and PTH was determined. Analyses of serum markers were completed on 50 participants and analyses of dietary intake were completed on 33 participants. RESULTS: In response to deployment, HEI-2010 scores decreased for total HEI-2010 (70.3 ± 9.1 vs. 62.9 ± 11.1), total fruit (4.4 ± 1.1 vs. 3.7 ± 1.5), whole fruit (4.6 ± 1.0 vs. 4.2 ± 1.4), dairy (6.2 ± 2.7 vs. 4.8 ± 2.4), and empty calories (14.3 ± 3.2 vs. 11.1 ± 4.5) (P ≤ 0.05). Average daily intakes of foods and food groups that decreased included total dairy (P < 0.01), milk (P < 0.01), and non-juice fruit (P = 0.03). Dietary intake of calcium (P = 0.05) and vitamin D (P = 0.03) decreased. PTH increased from baseline (3.4 ± 1.6 vs. 3.8 ± 1.4 pmol/L, P = 0.04), while there was no change in 25-OH vitamin D. Ferritin decreased (385 ± 173 vs. 354 ± 161 pmol/L, P = 0.03) and soluble transferrin receptor increased (16.3 ± 3.7 vs. 17.1 ± 3.5 nmol/L, P = 0.01). There were no changes in glucose or lipids. Post-deployment, serum 25-OH vitamin D was inversely associated with PTH (r = -0.43, P < 0.01). CONCLUSIONS: HEI-2010 scores and dietary intake of milk, calcium, and vitamin D decreased following deployment. Serum PTH increased and iron stores were degraded. No Soldiers were iron deficient. Personnel that deploy frequently should maintain a high diet quality in the U.S. and while deployed by avoiding empty calories and consuming fruits, vegetables, and adequate sources of calcium, vitamin D, and iron. Improving availability and quality of perishable food during deployment may improve diet quality.

Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML.

CD33 is a valid target for acute myeloid leukemia (AML) but has proven challenging for antibody-drug conjugates. Herein, we investigated the cellular determinants for the activity of the novel CD33/CD3-directed bispecific T-cell engager antibody, AMG 330. In the presence of T cells, AMG 330 was highly active against human AML cell lines and primary AML cells in a dose- and effector to target cell ratio-dependent manner. Using cell lines engineered to express wild-type CD33 at increased levels, we found a quantitative relationship between AMG 330 cytotoxicity and CD33 expression; in contrast, AMG 330 cytotoxicity was neither affected by common CD33 single nucleotide polymorphisms nor expression of the adenosine triphosphate-binding cassette (ABC) transporter proteins, P-glycoprotein or breast cancer resistance protein. Unlike bivalent CD33 antibodies, AMG 330 did not reduce surface CD33 expression. The epigenetic modifier drugs, panobinostat and azacitidine, increased CD33 expression in some cell lines and augmented AMG 330-induced cytotoxicity. These findings demonstrate that AMG 330 has potent CD33-dependent cytolytic activity in vitro, which can be further enhanced with other clinically available therapeutics. As it neither modulates CD33 expression nor is affected by ABC transporter activity, AMG 330 is highly promising for clinical exploration as it may overcome some limitations of previous CD33-targeted agents.

Homeostasis of human NK cells is not IL-15 dependent.

IL-15 is a proinflammatory cytokine that plays an important role in the development and activation of NK cells and is a potential target for inflammatory disease therapy. Studies conducted in IL-15- and IL-15R knockout mice identified IL-15 as an important cytokine for NK cell homeostasis. Consistent with this information derived from genetically modified mice, we demonstrated that neutralizing IL-15 with a mouse anti-mouse IL-15 mAb (M96) depletes C57BL/6 mouse NK cells. An mAb directed against macaque IL-15 (Hu714MuXHu) was manufactured and demonstrated to block IL-15-induced activation of nonhuman primate (NHP) NK cells in vitro. Neutralization of macaque IL-15 by parenteral administration of Hu714MuXHu reduces (>95%) circulating NK cell counts in NHPs. A blocking mAb directed against human IL-15 (huIL-15; AMG 714) was manufactured. Unexpectedly, when human subjects were treated with the blocking anti-IL-15 Ab AMG 714 in clinical trials, no reductions in circulating NK cell counts were observed despite achieving significantly higher exposures than the levels of Hu714MuXHu needed to cause NK cell count reductions in NHPs in vivo. Both AMG 714 and Hu714MuXHu are able to block huIL-15 activity in a human T cell blast proliferation and IFN-γ production assay. Both Abs block huIL-15-mediated Stat5 activation and CD69 expression in human NK cells. Collectively, these results demonstrate that NK cell homeostasis is obligatorily dependent upon IL-15 in both mice and NHPs, but that IL-15 is dispensable for maintenance of circulating human NK cells.

Platelet-Rich Plasma Injections for the Treatment of Degenerative Orthopedic Conditions.

Platelet-rich plasma injections for the treatment of degenerative orthopedic conditions have good evidence for safety, pain relief, and functional improvement. The U.S. Military is providing platelet-rich plasma services for military services members and TRICARE beneficiaries. The use of this safe and effective treatment should be continued and expanded.

Reversible Increased Anxiety Following Left-Sided Stellate Ganglion Block to Treat Posttraumatic Stress Disorder: A Case Report.

Describe a 2-patient case report of a rare occurrence of significantly increased anxiety after a left-sided stellate ganglion block (SGB) and the subsequent improvement of that anxiety through a right-sided SGB. Right-sided SGB to treat post-traumatic stress disorder (PTSD) has over 23 supporting publications in the peer-reviewed medical literature, including level 1 evidence. A published case series of 285 patients showed that two-level SGB may improve anxiety-related symptoms in patients. However, a recently published study indicates that some patients only respond to a left-sided SGB. The patients had an ultrasound-guided right-sided SGB for the treatment of PTSD and experienced a reduction in anxiety symptoms based on Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) scores. Later, a left-sided SGB was performed. Clinically, the addition of a left-sided SGB is typically associated with further anxiety reduction, but in these 2 cases, the patients had a significant reversal of the improvements experienced after a right-sided SGB. Following this unusual response to a left-sided SGB, these patients were offered another right-sided SGB, after which, they experienced a significant and durable improvement in anxiety symptoms beyond the original baseline PCL-score. In rare cases and for unknown reasons, a left-sided SGB may result in acute worsening of anxiety symptoms, which can be addressed and significantly improved with the application of a subsequent right-sided SGB.

Cumulative Blast Impulse Is Predictive for Changes in Chronic Neurobehavioral Symptoms Following Low Level Blast Exposure during Military Training.

INTRODUCTION: Cumulative low-level blast exposure during military training may be a significant occupational hazard, increasing the risk of poor long-term outcomes in brain function. US Public Law 116-92 section 717 mandates that US Department of Defense agencies document the blast exposure of each Service member to help inform later disability and health care decisions. However, which empirical measures of training blast exposure, such as the number of incidents, peak overpressure, or impulse, best inform changes in the neurobehavioral symptoms reflecting brain health have not been established. MATERIALS AND METHODS: This study was approved by the US Army Special Operations Command, the University of North Carolina at Chapel Hill, and the VA Puget Sound Health Care System. Using methods easily deployable across different organizational structures, this study sought to identify and measure candidate risk factors related to career occupational blast exposure predictive of changes in neurobehavioral symptom burden. Blast dosimetry-symptom relationships were first evaluated in mice and then tested in a military training environment. In mice, the righting time neurobehavioral response was measured after exposure to a repetitive low-level blast paradigm modeled after Special Operations training. In the military training environment, 23 trainees enrolled in a 6-week explosive breaching training course, 13 instructors, and 10 Service member controls without blast exposure participated in the study (46 total). All participants provided weekly Neurobehavioral Symptom Inventory (NSI) surveys. Peak blast overpressure, impulse, total number of blasts, Time in Low-Level Blast Occupation, and Time in Service were analyzed by Bayesian analysis of regression modeling to determine their probability of influence on the post-training symptoms reported by participants. RESULTS: We tested the hypothesis that cumulative measures of low-level blast exposure were predictive of changes in neurobehavioral symptoms. In mice, repetitive blast resulted in reduced righting times correlated with cumulative blast impulse. In Service members, peak blast overpressure, impulse, total number of blasts, Time in Low-Level Blast Occupation, and Time in Service all showed strong evidence of influence on NSI scores after blast exposure. However, only models including baseline NSI scores and cumulative blast impulse provided significant predictive value following validation. CONCLUSIONS: These results indicate that measures of cumulative blast impulse may have utility in predicting changes in NSI scores. Such paired dosimetry-symptom measures are expected to be an important tool in safely guiding Service members' occupational exposure and optimizing force readiness and lethality.

Mild Traumatic Brain Injury and Career Stage Associate with Visible Perivascular Spaces in Special Operations Forces Soldiers.

Mild traumatic brain injury (mTBI) and occupational blast exposure in military Service Members may lead to impaired brain waste clearance which increases neurological disease risk. Perivascular spaces (PVS) are a key part of the glymphatic system which supports brain waste clearance, preferentially during sleep. Visible PVS on clinical magnetic resonance imaging have been previously observed in patients with neurodegenerative diseases and animal neurotrauma models. The purpose of this study was to determine associations between PVS morphological characteristics, military career stage, and mTBI history in Special Operations Forces (SOF) Soldiers. Participants underwent T2-weighed neuroimaging to capture three-dimensional whole brain volumes. Segmentation was performed using a previously validated, multi-scale deep convolutional encoder-decoder neural network. Only PVS clusters within the white matter mask were quantified for analyses. Due to non-normal PVS metric distribution, non-parametric Mann-Whitney U tests were used to determine group differences in PVS outcomes. In total, 223 healthy SOF combat Soldiers (age = 33.1 ± 4.3yrs) were included, 217 reported career stage. Soldiers with mTBI history had greater PVS number (z = 2.51, P = 0.013) and PVS volume (z = 2.42, P = 0.016). In-career SOF combat Soldiers had greater PVS number (z = 2.56, P = 0.01) and PVS volume (z = 2.28, P = 0.02) compared to a baseline cohort. Mild TBI history is associated with increased PVS burden in SOF combat Soldiers that are clinically recovered from mTBI. This may indicate ongoing physiological changes that could lead to impaired waste clearance via the glymphatic system. Future studies should determine if PVS number and volume are meaningful neurobiological outcomes for neurodegenerative disease risk and if clinical interventions such as improving sleep can reduce PVS burden.

Increased [18F]Fluorodeoxyglucose Uptake in the Left Pallidum in Military Veterans with Blast-Related Mild Traumatic Brain Injury: Potential as an Imaging Biomarker and Mediation with Executive Dysfunction and Cognitive Impairment.

Blast-related mild traumatic brain injury (blast-mTBI) can result in a spectrum of persistent symptoms leading to substantial functional impairment and reduced quality of life. Clinical evaluation and discernment from other conditions common to military service can be challenging and subject to patient recall bias and the limitations of available assessment measures. The need for objective biomarkers to facilitate accurate diagnosis, not just for symptom management and rehabilitation but for prognostication and disability compensation purposes is clear. Toward this end, we compared regional brain [18F]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) intensity-scaled uptake measurements and motor, neuropsychological, and behavioral assessments in 79 combat Veterans with retrospectively recalled blast-mTBI with 41 control participants having no lifetime history of TBI. Using an agnostic and unbiased approach, we found significantly increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI versus control participants, p < 0.0001; q = 3.29 × 10-9 [Cohen's d, 1.38, 95% confidence interval (0.96, 1.79)]. The degree of left pallidum [18F]FDG-uptake correlated with the number of self-reported blast-mTBIs, r2 = 0.22; p < 0.0001. Greater [18F]FDG-uptake in the left pallidum provided excellent discrimination between Veterans with blast-mTBI and controls, with a receiver operator characteristic area under the curve of 0.859 (p < 0.0001) and likelihood ratio of 21.19 (threshold:SUVR ≥ 0.895). Deficits in executive function assessed using the Behavior Rating Inventory of Executive Function-Adult Global Executive Composite T-score were identified in Veterans with blast-mTBI compared with controls, p < 0.0001. Regression-based mediation analyses determined that in Veterans with blast-mTBI, increased [18F]FDG-uptake in the left pallidum-mediated executive function impairments, adjusted causal mediation estimate p = 0.021; total effect estimate, p = 0.039. Measures of working and prospective memory (Auditory Consonant Trigrams test and Memory for Intentions Test, respectively) were negatively correlated with left pallidum [18F]FDG-uptake, p < 0.0001, with mTBI as a covariate. Increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI compared with controls did not covary with dominant handedness or with motor activity assessed using the Unified Parkinson's Disease Rating Scale. Localized increased [18F]FDG-uptake in the left pallidum may reflect a compensatory response to functional deficits following blast-mTBI. Limited imaging resolution does not allow us to distinguish subregions of the pallidum; however, the significant correlation of our data with behavioral but not motor outcomes suggests involvement of the ventral pallidum, which is known to regulate motivation, behavior, and emotions through basal ganglia-thalamo-cortical circuits. Increased [18F]FDG-uptake in the left pallidum in blast-mTBI versus control participants was consistently identified using two different PET scanners, supporting the generalizability of this finding. Although confirmation of our results by single-subject-to-cohort analyses will be required before clinical deployment, this study provides proof of concept that [18F]FDG-PET bears promise as a readily available noninvasive biomarker for blast-mTBI. Further, our findings support a causative relationship between executive dysfunction and increased [18F]FDG-uptake in the left pallidum.

Mild traumatic brain injury history is associated with lower brain network resilience in soldiers.

Special Operations Forces combat soldiers sustain frequent blast and blunt neurotrauma, most often classified as mild traumatic brain injuries. Exposure to repetitive mild traumatic brain injuries is associated with persistent behavioural, cognitive, emotional and neurological symptoms later in life. Identifying neurophysiological changes associated with mild traumatic brain injury exposure, in the absence of present-day symptoms, is necessary for detecting future neurological risk. Advancements in graph theory and functional MRI have offered novel ways to analyse complex whole-brain network connectivity. Our purpose was to determine how mild traumatic brain injury history, lifetime incidence and recency affected whole-brain graph theoretical outcome measures. Healthy male Special Operations Forces combat soldiers (age = 33.2 ± 4.3 years) underwent multimodal neuroimaging at a biomedical research imaging centre using 3T Siemens Prisma or Biograph MRI scanners in this cross-sectional study. Anatomical and functional scans were preprocessed. The blood-oxygen-level-dependent signal was extracted from each functional MRI time series using the Big Brain 300 atlas. Correlations between atlas regions were calculated and Fisher z-transformed to generate subject-level correlation matrices. The Brain Connectivity Toolbox was used to obtain functional network measures for global efficiency (the average inverse shortest path length), local efficiency (the average global efficiency of each node and its neighbours), and assortativity coefficient (the correlation coefficient between the degrees of all nodes on two opposite ends of a link). General linear models were fit to compare mild traumatic brain injury lifetime incidence and recency. Nonparametric ANOVAs were used for tests on non-normally distributed data. Soldiers with a history of mild traumatic brain injury had significantly lower assortativity than those who did not self-report mild traumatic brain injury (t148 = 2.44, P = 0.016). The assortativity coefficient was significantly predicted by continuous mild traumatic brain injury lifetime incidence [F1,144 = 6.51, P = 0.012]. No differences were observed between recency groups, and no global or local efficiency differences were observed between mild traumatic brain injury history and lifetime incidence groups. Brain networks with greater assortativity have more resilient, interconnected hubs, while those with lower assortativity indicate widely distributed, vulnerable hubs. Greater lifetime mild traumatic brain injury incidence predicted lower assortativity in our study sample. Less resilient brain networks may represent a lack of physiological recovery in mild traumatic brain injury patients, who otherwise demonstrate clinical recovery, more vulnerability to future brain injury and increased risk for accelerated age-related neurodegenerative changes. Future longitudinal studies should investigate whether decreased brain network resilience may be a predictor for long-term neurological dysfunction.

Early Initiation of Vestibular Therapy Following Sports-Related Concussions: A Retrospective Cohort Study.

BACKGROUND: Vestibular dysfunction is common following sports-related concussions (SRC). Within the current practice, it is theorized that patients with vestibular dysfunction as sequelae of sports-related concussion have a prolonged recovery time compared to those without vestibular dysfunction. STUDY METHOD:  A retrospective, cohort investigation of 282 subjects with sports-related concussions with vestibular dysfunction was conducted at The Sports Medicine Concussion Clinic, Duke University. The primary endpoint was the return-to-play (RTP) date. RESULTS: For every one-day increase in time from injury to initial vestibular therapy, the geometric mean time from injury to RTP increases by 1.02 days (exp{ß}=1.02 days; 95% CI: 1.01, 1.02 days; p<0.001). CONCLUSION:  Our data suggest an association between the timing of vestibular therapy in SRC and a direct relationship to earlier recovery and return to sport.

Relationship between Anterior Pituitary Volume and IGF-1 Serum Levels in Soldiers with Mild Traumatic Brain Injury History.

PURPOSE: A high mild traumatic brain injury (mTBI) incidence rate exists in military and sport. Hypopituitarism is an mTBI sequela; however, few studies have examined this phenomenon in those with an mTBI history. This cross-sectional study of Special Operations Forces combat soldiers aimed 1) to relate anterior pituitary gland volumes (actual and normalized) to insulin-like growth factor 1 (IGF-1) concentrations, 2) to examine the effect of mTBI history on anterior pituitary gland volumes (actual and normalized) and IGF-1 concentrations, and 3) to measure the odds of demonstrating lower anterior pituitary gland volumes (actual and normalized) or IGF-1 concentrations if self-reporting mTBI history. METHODS: Anterior pituitary gland volumes were manually segmented from T1-weighted 3D brain MRI sequences; IGF-1 serum concentrations were quantified using commercial enzyme-linked immunosorbent assays. Correlations and linear regression were used to determine the association between IGF-1 serum concentration and anterior pituitary gland volume (n = 74). Independent samples t-tests were used to compare outcomes between mTBI groups and logistic regression models were fit to test the odds of demonstrating IGF-1 concentration or anterior pituitary volume less than sample median based on mTBI group (n = 54). RESULTS: A significant linear relationship between the subjects' anterior pituitary gland volumes and IGF-1 concentrations (r72 = 0.35, P = 0.002) was observed. Soldiers with mTBI history had lower IGF-1 concentrations (P < 0.001) and lower anterior pituitary gland volumes (P = 0.037) and were at greater odds for IGF-1 serum concentrations less than the sample median (odds ratio = 5.73; 95% confidence interval = 1.77-18.55). CONCLUSIONS: Anterior pituitary gland volume was associated with IGF-1 serum concentrations. Mild TBI history may be adversely associated with anterior pituitary gland volumes and IGF-1 concentrations. Longitudinal IGF-1 and anterior pituitary gland monitoring may be indicated in those who report one or more mTBI.

Active Warfighter Mental Health Lower in Mid-Career.

PURPOSE: The present study investigated Special Operations Forces (SOF) combat Servicemember mental health at different SOF career stages in association with resilience. METHODS: Fifty-eight SOF combat Service Members either entering SOF (career start; n=38) or multiple years with their SOF organization (mid-career; n=20) self-reported mild traumatic brain injury (TBI) history, resilience, subjective well-being, depression, anxiety, and posttraumatic stress. Poisson regression analyses were employed to test SOF career stage differences in each mental health symptom using resilience, while accounting for other pertinent military factors. RESULTS: There were significant interaction effects of SOF career stage and resilience on mental health symptoms. SOF career start combat Servicemembers endorsed lower depression and posttraumatic stress and higher subjective well-being with higher resilience, but these associations between resilience and mental health symptoms were not seen in SOF mid-career Servicemembers. CONCLUSIONS: Although preliminary, the adaptive association between resilience and mental health seemed to be blunted in combat Servicemembers having served multiple years in SOF. This information informs research to provide evaluation tools to support prophylactic performance and long-term health preservation in military populations.

Warfighter Resilience.

PURPOSE: Our aim in this study was to psychometrically test resilience assessments (Ego Resiliency Scale [ER89], Connor-Davidson Resilience Scale [CD-RISC 25], Responses to Stressful Experiences Scale [RSES short-form]) and describe resilience levels in a Special Operations Forces (SOF) combat sample. METHODS: Fifty-eight SOF combat Servicemembers either entering SOF (career start; n = 38) or having served multiple years with their SOF organization (mid-career; n = 20) self-reported resilience, mild traumatic brain injury (mTBI) history, and total military service. RESULTS: All resilience metrics demonstrated acceptable internal consistency, but ceiling effects were found for CD-RISC and RSES scores. ER89 scores were moderate on average. ER89 scores were higher in SOF career start than mid-career Servicemembers (ηρ2 = 0.07) when accounting for the interaction between SOF career stage and total military service (ηρ2 = 0.07). DISCUSSION: SOF mid-career Servicemembers had similar ER89 resilience scores with more total military service. The SOF career start combat Servicemembers had higher ER89 measured resilience with less total military service only, potentially showing a protective effect of greater service before entering SOF. CONCLUSION: The ER89 may be a more optimal military resilience metric than the other metrics studied; longitudinal research on SOF combat Servicemember resilience is warranted.

Behavioral health clinicians endorse stellate ganglion block as a valuable intervention in the treatment of trauma-related disorders.

The stellate ganglion block (SGB) procedure has been used successfully for over 10 years to treat post-traumatic stress symptoms in thousands of US military service members, civilians, and veterans in select hospitals in Europe and North America. Primarily through targeting the autonomic nervous system, the SGB procedure serves as an invaluable adjunct to trauma-focused psychotherapy. Without published best practices for emerging therapies, clinicians are left on their own to determine how best to apply new treatments to their patient populations. The aim of this qualitative research was to compile attitudes and recommendations from therapists with expertise in using SGB for treating symptoms of post-traumatic stress disorder, so that their experiences could be disseminated widely to clinicians without SGB expertise. An 18-item survey was developed and distributed electronically to a group of behavioral health professionals of various specialties between May and June 2020. Of surveyed behavioral health clinicians with personal experience incorporating SGB into their trauma-focused psychotherapy, 95% of respondents would recommend SGB to a colleague as a useful tool for the treatment of trauma-related disorders. SGB was rated at least as useful as the most valuable interventions listed in the American Psychological Association Clinical Practice Guideline for the Treatment of Post-traumatic Stress Disorder with 100% of respondents characterizing SGB as 'Very Beneficial' or 'Somewhat Beneficial', and 0 respondents characterizing SGB as 'Not Helpful' or 'Harmful'. Given the feedback from this study, behavioral health providers should consider using SGB in conjunction with standard trauma-focused care.

First-in-human study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of ALPN-101, a dual CD28/ICOS antagonist, in healthy adult subjects.

ALPN-101 (ICOSL vIgD-Fc) is an Fc fusion protein of a human inducible T cell costimulatory ligand (ICOSL) variant immunoglobulin domain (vIgD) designed to inhibit the cluster of differentiation 28 (CD28) and inducible T cell costimulator (ICOS) pathways simultaneously. A first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ALPN-101 in healthy adult subjects. ALPN-101 was generally well-tolerated with no evidence of cytokine release, clinically significant immunogenicity, or severe adverse events following single subcutaneous (SC) doses up to 3 mg/kg or single intravenous (IV) doses up to 10 mg/kg or up to 4 weekly IV doses of up to 1 mg/kg. ALPN-101 exhibited a dose-dependent increase in exposure with an estimated terminal half-life of 4.3-8.6 days and SC bioavailability of 60.6% at 3 mg/kg. Minimal to modest accumulation in exposure was observed with repeated IV dosing. ALPN-101 resulted in a dose-dependent increase in maximum target saturation and duration of high-level target saturation. Consistent with its mechanism of action, ALPN-101 inhibited cytokine production in whole blood stimulated by Staphylococcus aureus enterotoxin B ex vivo, as well as antibody responses to keyhole limpet hemocyanin immunization, reflecting immunomodulatory effects upon T cell and T-dependent B cell responses, respectively. In conclusion, ALPN-101 was well-tolerated in healthy subjects with dose-dependent PK and PD consistent with the known biology of the CD28 and ICOS costimulatory pathways. Further clinical development of ALPN-101 in inflammatory and/or autoimmune diseases is therefore warranted.

Neurovascular Coupling in Special Operations Forces Combat Soldiers.

The purpose of this study was to investigate how concussion history affects neurovascular coupling in Special Operations Forces (SOF) combat Soldiers. We studied 100 SOF combat Soldiers [age = 33.5 ± 4.3 years; height = 180.4 ± 6.0 cm; 55 (55.0%) with self-reported concussion history]. We employed transcranial Doppler (TCD) ultrasound to assess neurovascular coupling (NVC) via changes in posterior cerebral artery (PCA) velocity in response to a reading and a visual search task. Baseline TCD data were collected for 2 min. NVC was quantified by the percent change in overall PCA response curves. We employed linear mixed effect models using a linear spline with one knot to assess group differences in percent change observed in the PCA velocity response curves between SOF combat Soldiers with and without a concussion history. Baseline PCA velocity did not significantly differ (t98 = 1.28, p = 0.20) between those with and without concussion history. Relative PCA velocity response curves did not differ between those with and without a concussion history during the reading task (F1,98 = 0.80, p = 0.37) or the visual search task (F1,98 = 0.52, p = 0.47). When assessing only SOF combat Soldiers with a concussion history, differential response to task was significantly greater in those with 3 or more concussions (F1,4341 = 27.24, p < 0.0001) relative to those with 1-2 concussions. Despite no main effect of concussion history on neurovascular coupling response in SOF combat Soldiers, we observed a dose-response based on lifetime concussion incidence. While long-term neurophysiological effects associated with head impact and blast-related injury are currently unknown, assessing NVC response may provide further insight into cerebrovascular function and overall physiological health.

Evidence for endotoxin contamination in plastic Na+-heparin blood collection tube lots.

BACKGROUND: Biomarker assays are often conducted on whole blood samples in the course of drug development studies. Because bacterial lipopolysaccharide (LPS) (endotoxin) contamination is known to cause spontaneous cytokine production by monocytes, contamination of blood collection tubes may interfere with biomarker assay results. METHODS: Whole blood from healthy donors was collected into plastic or glass sodium (Na(+))-heparin Vacutainer() blood collection tubes and heparinized syringes. Samples were analyzed for phosphoprotein response, cytokine production, and RNA expression. Tubes were tested for endotoxin contamination by use of the limulus amoebocyte lysate assay. RESULTS: Results of phospho-flow cytometry, branched DNA (bDNA), and ELISA assays indicated that a specific lot (#5339582) of plastic Na(+)-heparin Vacutainer tubes was highly contaminated with an endotoxinlike substance, and contamination was confirmed by the limulus amoebocyte lysate assay. Analysis of multiple-analyte panels revealed that analytes whose changed expression was predictive of LPS stimulation were increased when whole blood was incubated in contaminated tubes for 6 or 18 h. Two additional lots of plastic tubes tested had detectable amounts of endotoxin sufficient to strongly alter phospho-flow cytometry analyses, as determined by the fold change in phosphorylation of p38 mitogen-activated protein kinase in response to tumor necrosis factor alpha and LPS. In contrast, 3 lots of glass tubes had substantially lower levels of spontaneous blood activation. CONCLUSIONS: Endotoxin contamination associated with tubes from 3 lots of a particular type of plastic Na(+)-heparin Vacutainer tube dramatically affected biomarker assay measurements. Prescreening these tubes is suggested before their use in clinical sample analysis.