Inhibition of Aurora-A/N-Myc Protein-Protein Interaction Using Peptidomimetics: Understanding the Role of Peptide Cyclization.

Using N-Myc61-89 as a starting template we showcase the systematic use of truncation and maleimide constraining to develop peptidomimetic inhibitors of the N-Myc/Aurora-A protein-protein interaction (PPI); a potential anticancer drug discovery target. The most promising of these - N-Myc73-94-N85C/G89C-mal - is shown to favour a more Aurora-A compliant binding ensemble in comparison to the linear wild-type sequence as observed through fluorescence anisotropy competition assays, circular dichroism (CD) and nuclear magnetic resonance (NMR) experiments. Further in silico investigation of this peptide in its Aurora-A bound state, by molecular dynamics (MD) simulations, imply (i) the bound conformation is more stable as a consequence of the constraint, which likely suppresses dissociation and (ii) the constraint may make further stabilizing interactions with the Aurora-A surface. Taken together this work unveils the first orthosteric N-Myc/Aurora-A inhibitor and provides useful insights on the biophysical properties and thus design of constrained peptides, an attractive therapeutic modality.

Low resilience is associated with worse health-related quality of life in caregivers of service members and veterans with traumatic brain injury: a longitudinal study.

PURPOSE: To examine [a] the association of caregiver health-related quality of life (HRQOL) and service member/veteran (SMV) neurobehavioral outcomes with caregiver resilience; [b] longitudinal change in resilience at the group and individual level; and [c] the magnitude of change at the individual level. METHODS: Caregivers (N = 232) of SMVs with traumatic brain injury completed a resilience measure, and 18 caregiver HRQOL and SMV neurobehavioral outcome measures at a baseline evaluation and follow-up evaluation three years later. Caregivers were divided into two resilience groups at baseline and follow-up: [1] Low Resilience (≤ 45 T, baseline n = 99, follow-up n = 93) and [2] High Resilience (> 45 T, baseline n = 133, follow-up n = 139). RESULTS: At baseline and follow-up, significant effects were found between Low and High Resilience groups for the majority of outcome measures. There were no significant differences in resilience from baseline to follow-up at the group-mean level. At the individual level, caregivers were classified into four longitudinal resilience groups: [1] Persistently Low Resilience (Baseline + Follow-up = Low Resilience, n = 60), [2] Reduced Resilience (Baseline = High Resilience + Follow-up = Low Resilience, n = 33), [3] Improved Resilience (Baseline = Low Resilience + Follow-up = High Resilience, n = 39), and [4] Persistently High Resilience (Baseline + Follow-up = High Resilience, n = 100). From baseline to follow-up, approximately a third of the Reduced and Improved Resilience groups reported a meaningful change in resilience (≥ 10 T). Nearly all of the Persistently High and Persistently Low Resilience groups did not report meaningful change in resilience (< 10 T). CONCLUSION: Resilience was not a fixed state for all caregivers. Early intervention may stall the negative caregiving stress-health trajectory and improve caregiver resilience.

Chemical biology tools for protein labelling: insights into cell-cell communication.

Multicellular organisms require carefully orchestrated communication between and within cell types and tissues, and many unicellular organisms also sense their context and environment, sometimes coordinating their responses. This review highlights contributions from chemical biology in discovering and probing mechanisms of cell-cell communication. We focus on chemical tools for labelling proteins in a cellular context and how these can be applied to decipher the target receptor of a signalling molecule, label a receptor of interest in situ to understand its biology, provide a read-out of protein activity or interactions in downstream signalling pathways, or discover protein-protein interactions across cell-cell interfaces.

Health outcomes before and during the COVID-19 pandemic in caregivers of service members and veterans with traumatic brain injury.

PURPOSE: To examine change in health-related quality of life (HRQOL) during the COVID-19 pandemic in caregivers of service members/veterans (SMVs) with traumatic brain injury (TBI), by comparing HRQOL during the first year of the pandemic to HRQOL 12 months pre-pandemic. METHODS: Caregivers (N = 246) were classified into three COVID-19 Pandemic Impact groups based on impact ratings of the pandemic on HRQOL: No Impact (n = 50), Mild Impact (n = 117), and Moderate-Severe Impact (n = 79). Caregivers completed 19 measures across physical, social, caregiving, and economic HRQOL domains, and a measure of SMV Adjustment. T-scores were used to determine individual symptom trajectories for each measure as follows: Asymptomatic (pre + during < 60 T); Developed (pre < 60 + during ≥ 60 T); Improved (pre ≥ 60 T + during < 60 T); and Persistent (pre + during ≥ 60 T). RESULTS: Using ANOVA, during the pandemic, the Moderate-Severe Impact group reported worse scores on 19 measures (d = 0.41-0.89) compared to the No Impact group and 18 measures (d = 0.31-0.62) compared to the Mild Impact group (d = 0.31-0.38). The Mild Impact group reported worse scores on two measures compared to the No Impact group (d = 0.42-0.43). Using the entire sample, the majority of HRQOL measures were classified as Asymptomatic (47.2-94.7%), followed by Persistent (2.4-27.2%). Few were classified as Developed (0.4-12.6%) or Improved (2.4-13.8%). Using repeated measures ANOVA, no meaningful effects sizes were found for mean scores on all measures completed pre-pandemic compared to during the pandemic (d ≤ 0.17). CONCLUSION: The vast majority of caregivers reported stability in HRQOL pre-pandemic compared to during the pandemic. The COVID-19 pandemic was not associated with a high prevalence of decline in caregiver HRQOL.

Subject and Family Perspectives from the Central Thalamic Deep Brain Stimulation Trial for Traumatic Brain Injury: Part II.

This is the second paper in a two-part series describing subject and family perspectives from the CENTURY-S (CENtral Thalamic Deep Brain Stimulation for the Treatment of Traumatic Brain InjURY-Safety) first-in-human invasive neurological device trial to achieve cognitive restoration in moderate to severe traumatic brain injury (msTBI). To participate, subjects were independently assessed to formally establish decision-making capacity to provide voluntary informed consent. Here, we report on post-operative interviews conducted after a successful trial of thalamic stimulation. All five msTBI subjects met a pre-selected primary endpoint of at least a 10% improvement in completion time on Trail-Making-Test Part B, a marker of executive function. We describe narrative responses of subjects and family members, refracted against that success. Interviews following surgery and the stimulation trial revealed the challenge of adaptation to improvements in cognitive function and emotional regulation as well as altered (and restored) relationships and family dynamics. These improvements exposed barriers to social reintegration made relevant by recoveries once thought inconceivable. The study's success sparked concerns about post-trial access to implanted devices, financing of device maintenance, battery replacement, and on-going care. Most subjects and families identified the need for supportive counseling to adapt to the new trajectory of their lives.

Pain interference and health-related quality of life in caregivers of service members and veterans with traumatic brain injury and mental health comorbidity.

PURPOSE: To examine (1) the relationship between caregiver pain interference with caregiver health-related quality of life (HRQOL), caregiver age, and service member/veteran (SMV) functional ability, and (2) change in caregiver pain interference longitudinally over 5 years. METHOD: Participants were 347 caregivers of SMVs diagnosed with traumatic brain injury (TBI). Caregivers completed the SF-12v2 Health Survey Bodily Pain scale at an initial baseline evaluation and up to four annual follow-up evaluations. Caregivers were divided into three pain interference groups: High Pain Interference (n = 104), Neutral Pain Interference (n = 117), and Low Pain Interference (n = 126). Caregivers also completed 15 HRQOL measures and a measure of SMV functional ability. RESULTS: The High Pain Interference group reported more clinically elevated scores on 13 measures compared to the Low Pain Interference group, and seven measures compared to the Neutral Pain Interference group. The Neutral Pain Interference group had more clinically elevated scores on three measures compared to the Low Pain Interference group. The High and Neutral Pain Interference groups were older than the Low Pain Interference group. Parent caregivers were older than intimate partner/sibling caregivers, but did not report worse pain interference. Caregiver age, and measures of Fatigue, Strain, Perceived Rejection, and Economic QOL were the strongest predictors of pain interference (p < .001), accounting for 28.2% of the variance. There was minimal change in Bodily Pain scores over five years. The interaction of time and age was not significant (X2 = 2.7, p = .61). CONCLUSION: It is important to examine pain in the context of HRQOL in caregivers, regardless of age.

Is Traumatic Brain Injury Severity in Service Members and Veterans Related to Health-Related Quality of Life in Their Caregivers?

OBJECTIVE: To examine the relationship between service member/veteran (SM/V) traumatic brain injury (TBI) severity with caregiver health-related quality of life (HRQOL). SETTING: Military treatment facility. PARTICIPANTS: Caregivers ( N = 316) of SM/Vs following a TBI divided into 2 groups based on SM/V TBI severity: (1) caregivers of SM/Vs following an uncomplicated mild TBI (UnMTBI Caregiver group, n = 246), and (2) caregivers of SM//Vs following a complicated mild, moderate, severe, or penetrating TBI (STBI Caregiver group, n = 70). The STBI Caregiver group was further divided into 2 subgroups: Parent ( n = 21) versus Intimate Partner ( n = 49). The UnMTBI Caregiver group consisted of intimate partners. DESIGN: Prospective cohort. MAIN MEASURES: Caregivers completed 15 HRQOL measures. RESULTS: Using analysis of variance and chi-square analysis, the UnMTBI Caregiver group reported worse scores on 12 HRQOL measures and more clinically elevated scores for 6 of 15 comparisons than the STBI Caregiver group. The UnMTBI Caregiver group also reported worse scores on 10 HRQOL measures than intimate partners in the STBI Caregiver group and 5 measures than parents in the STBI Caregiver group. Parents reported worse scores on 3 measures than intimate partners in the STBI Caregiver group. The UnMTBI Caregiver group reported more clinically elevated scores for 7 of 15 comparisons than intimate partners in the STBI Caregiver group. CONCLUSION: Intimate partner caregivers of an SM/V following a remote uncomplicated MTBI reported worse HRQOL than intimate partners and parent caregivers of an SM/V following a more severe TBI, mostly likely due to SM/V physical and mental health comorbidities. Interventions that focus on the SM/V's TBI and other comorbidities, the caregiver's behavioral health problems, and the relationship and family factors that interact with each other will likely have the most success in improving individual and family outcomes for military families.

Dignity of Risk, Reemergent Agency, and the Central Thalamic Stimulation Trial for Moderate to Severe Brain Injury.

This article discusses the utility of Perske's "dignity of risk" as a useful heuristic to explain the consent process for a study to evaluate central thalamic deep brain stimulation as a means to restore cognitive function in moderate to severe brain injury. Narratives of interviews with subjects and their families from a related BRAIN Initiative study reveal discordant views on risk, with subjects being more risk-tolerant than their loved ones. This is a challenge for families who remain protective of subjects who have recovered to the point that they are capable of independent decision-making. While the legal threshold for consent has been met, normative and psychological challenges remain as families accommodate themselves to the reemergent agency of the subject. Dignity of risk is a constructive framework to apprehend how families come to appreciate the primacy of the subject's voice and affirm their reemergent agency following a devastating brain injury.

Relationship satisfaction among spouse caregivers of service members and veterans with comorbid mild traumatic brain injury and post-traumatic stress disorder.

This study examined relationship satisfaction and health-related quality of life (HRQOL) among spouse caregivers assisting service members and veterans (SMV) with comorbid uncomplicated mild traumatic brain injury (MTBI) and post-traumatic stress disorder (PTSD). Spouse caregivers (N = 205) completed the Couples Satisfaction Index (CSI), 12 HRQOL measures, and the Mayo-Portland Adaptability Inventory 4th Edition (MPAI-4). T-scores were classified as "clinically elevated" using a cutoff of ≥60T. The sample was also classified into "Satisfied" (≥13.5, n = 113, 55.0%) or "Dissatisfied" (<13.5, n = 92, 44.0%) relationship categories. Using stepwise regression analysis, Anxiety, Family Disruption, Vigilance, Emotional Support, Feeling Trapped, and MPAI-4 Adjustment were identified as the strongest predictors of CSI total scores (p < 0.001), accounting for 41.6% of the variance. Squared semi-partial correlations revealed that 18.1% of the variance was shared across all six measures, with 7.8% to 1.5% of unique variance accounted for by each measure separately. When comparing the number of clinically elevated measures simultaneously, the Dissatisfied group consistently had a higher number of clinically elevated scores compared to the Satisfied group (e.g., 3-or-more clinically elevated scores: Dissatisfied = 40.2%, Satisfied = 8.8%, OR = 6.93, H = 0.76). Caring for a SMV with comorbid TBI and PTSD can have a profound impact on the spouse caregiver's HRQOL, relationship satisfaction, and family functioning. The findings from the current study continue to support the need for family involvement in the SMV's treatment plan, but more effort is needed to integrate behavioral health treatment that focuses on the family member's own issues into military TBI and PTSD systems of care.

En este estudio se analizó la satisfacción con la relación y la calidad de vida relacionada con la salud entre cónyuges cuidadores que asisten a miembros del servicio militar y veteranos con lesión cerebral traumática leve sin complicaciones concomitante con trastorno por estrés postraumático. Los cónyuges cuidadores (N=205) completaron el Índice de satisfacción de las parejas (Couples Satisfaction Index, CSI), la Encuesta de 12 ítems sobre la calidad de vida relacionada con la salud (12 HRQQL) y la Encuesta de Adaptabilidad Mayo-Portland 4.ª edición (Mayo-Portland Adaptability Inventory 4th Edition, MPAI-4). Los puntajes T se clasificaron en "clínicamente elevados" usando un valor de corte de ≥60T. La muestra también se clasificó en categorías de relaciones "satisfechas" (>13.5, n=113, 55.0%) o "insatisfechas" (<13.5, n=92, 44.0%). Utilizando un análisis de regresión paso a paso, se identificaron la ansiedad, la interrupción familiar, la vigilancia, el apoyo emocional, la sensación de estar atrapado y la adaptación de la MPAI-4 como los factores pronósticos más fuertes de los puntajes totales del CSI (p<.001), que representaron el 41.6% de la varianza. Las correlaciones semiparciales al cuadrado revelaron que el 18.1% de la varianza se compartió entre las seis medidas, con una varianza única de 7.8% a 1.5% representada por cada medida separadamente. Cuando se comparó el número de medidas clínicamente elevadas de manera simultánea, el grupo insatisfecho tuvo sistemáticamente un número más alto de puntajes clínicamente elevados en comparación con el grupo satisfecho (p. ej.: 3 o más puntajes clínicamente elevados: insatisfecho=40.2%, satisfecho=8.8%, OR=6.93, H=.76). cuidar a un miembro del servicio militar o a un veterano con lesión cerebral traumática leve y trastorno por estrés postraumático concomitantes puede afectar enormemente la calidad de vida relacionada con la salud del cónyuge cuidador, la satisfacción con la relación y el funcionamiento familiar. Los resultados del presente estudio continúan respaldando la necesidad de la participación familiar en el plan de tratamiento del miembro del servicio militar o veterano, pero se necesita más esfuerzo para integrar un tratamiento de salud conductual que se centre en los problemas propios del familiar en los sistemas de atención de militares con lesión cerebral traumática leve y trastorno por estrés postraumático.

Subject and Family Perspectives from the Central Thalamic Deep Brain Stimulation for Traumatic Brain Injury Study: Part I.

This is the first article in a two-part series describing subject and family perspectives from the central thalamic deep brain stimulation for the treatment of traumatic brain injury using the Medtronic PC + S first-in-human invasive neurological device trial to achieve cognitive restoration in moderate to severe traumatic brain injury, with subjects who were deemed capable of providing voluntary informed consent. In this article, we report on interviews conducted prior to surgery wherein we asked participants about their experiences recovering from brain injury and their perspectives on study enrollment and participation. We asked how risks and benefits were weighed, what their expectations and fears were, and how decisions were reached about trial participation. We found that informed consent and enrollment decisions are fraught. Subjects and families were often split, with subjects more focused on putative benefits and families concerned about incremental risk. Both subjects and families viewed brain injury as disruptive to personal identity and relationships. As decisions were made about study enrollment, families struggled with recognizing the re-emergent agency of subjects and ceding decision-making authority to subjects who had previously been dependent upon them for protection and guidance. Subjects and family members reported a hope for the relief of cognitive disabilities, improved quality of life, normalization of interpersonal interactions, and a return to work or school as reasons for study participation, along with altruism and a desire to advance science. Despite these aspirations, both subjects and families appreciated the risks of the intervention and did not suffer from a therapeutic misconception. A second essay to be published in the next issue of Cambridge Quarterly of Healthcare Ethics-Clinical Neuroethics will describe interviews conducted after surgery, the effects of cognitive restoration for subjects, families, and challenges presented to the social structures they will call upon to support them through recovery. This subsequent article will be available online prior to its formal publication in October 2023.

Respiratory axon regeneration in the chronically injured spinal cord.

Promoting the combination of robust regeneration of damaged axons and synaptic reconnection of these growing axon populations with appropriate neuronal targets represents a major therapeutic goal following spinal cord injury (SCI). A key impediment to achieving this important aim includes an intrinsic inability of neurons to extend axons in adult CNS, particularly in the context of the chronically-injured spinal cord. We tested whether an inhibitory peptide directed against phosphatase and tensin homolog (PTEN: a central inhibitor of neuron-intrinsic axon growth potential) could restore inspiratory diaphragm function by reconnecting critical respiratory neural circuitry in a rat model of chronic cervical level 2 (C2) hemisection SCI. We found that systemic delivery of PTEN antagonist peptide 4 (PAP4) starting at 8 weeks after C2 hemisection promoted substantial, long-distance regeneration of injured bulbospinal rostral Ventral Respiratory Group (rVRG) axons into and through the lesion and back toward phrenic motor neurons (PhMNs) located in intact caudal C3-C5 spinal cord. Despite this robust rVRG axon regeneration, PAP4 stimulated only minimal recovery of diaphragm function. Furthermore, re-lesion through the hemisection site completely removed PAP4-induced functional improvement, demonstrating that axon regeneration through the lesion was responsible for this partial functional recovery. Interestingly, there was minimal formation of putative excitatory monosynaptic connections between regrowing rVRG axons and PhMN targets, suggesting that (1) limited rVRG-PhMN synaptic reconnectivity was responsible at least in part for the lack of a significant functional effect, (2) chronically-injured spinal cord presents an obstacle to achieving synaptogenesis between regenerating axons and post-synaptic targets, and (3) addressing this challenge is a potentially-powerful strategy to enhance therapeutic efficacy in the chronic SCI setting. In conclusion, our study demonstrates a non-invasive and transient pharmacological approach in chronic SCI to repair the critically-important neural circuitry controlling diaphragmatic respiratory function, but also sheds light on obstacles to circuit plasticity presented by the chronically-injured spinal cord.

LAR inhibitory peptide promotes recovery of diaphragm function and multiple forms of respiratory neural circuit plasticity after cervical spinal cord injury.

Chondroitin sulfate proteoglycans (CSPGs), up-regulated in and around the lesion after traumatic spinal cord injury (SCI), are key extracellular matrix inhibitory molecules that limit axon growth and consequent recovery of function. CSPG-mediated inhibition occurs via interactions with axonal receptors, including leukocyte common antigen- related (LAR) phosphatase. We tested the effects of a novel LAR inhibitory peptide in rats after hemisection at cervical level 2, a SCI model in which bulbospinal inspiratory neural circuitry originating in the medullary rostral ventral respiratory group (rVRG) becomes disconnected from phrenic motor neuron (PhMN) targets in cervical spinal cord, resulting in persistent partial-to-complete diaphragm paralysis. LAR peptide was delivered by a soaked gelfoam, which was placed directly over the injury site immediately after C2 hemisection and replaced at 1 week post-injury. Axotomized rVRG axons originating in ipsilateral medulla or spared rVRG fibers originating in contralateral medulla were separately assessed by anterograde tracing via AAV2-mCherry injection into rVRG. At 8 weeks post-hemisection, LAR peptide significantly improved ipsilateral hemidiaphragm function, as assessed in vivo with electromyography recordings. LAR peptide promoted robust regeneration of ipsilateral-originating rVRG axons into and through the lesion site and into intact caudal spinal cord to reach PhMNs located at C3-C5 levels. Furthermore, regenerating rVRG axons re-established putative monosynaptic connections with their PhMNs targets. In addition, LAR peptide stimulated robust sprouting of both modulatory serotonergic axons and contralateral-originating rVRG fibers within the PhMN pool ipsilateral/caudal to the hemisection. Our study demonstrates that targeting LAR-based axon growth inhibition promotes multiple forms of respiratory neural circuit plasticity and provides a new peptide-based therapeutic strategy to ameliorate the devastating respiratory consequences of SCI.

Peroxiredoxin-1 Tyr194 phosphorylation regulates LOX-dependent extracellular matrix remodelling in breast cancer.

BACKGROUND: Peroxiredoxin 1 (PRDX1) belongs to an abundant family of peroxidases whose role in cancer is still unresolved. While mouse knockout studies demonstrate a tumour suppressive role for PRDX1, in cancer cell xenografts, results denote PRDX1 as a drug target. Probably, this phenotypic discrepancy stems from distinct roles of PRDX1 in certain cell types or stages of tumour progression. METHODS: We demonstrate an important cell-autonomous function for PRDX1 utilising a syngeneic mouse model (BALB/c) and mammary fibroblasts (MFs) obtained from it. RESULTS: Loss of PRDX1 in vivo promotes collagen remodelling known to promote breast cancer progression. PRDX1 inactivation in MFs occurs via SRC-induced phosphorylation of PRDX1 TYR194 and not through the expected direct oxidation of CYS52 in PRDX1 by ROS. TYR194-phosphorylated PRDX1 fails to bind to lysyl oxidases (LOX) and leads to the accumulation of extracellular LOX proteins which supports enhanced collagen remodelling associated with breast cancer progression. CONCLUSIONS: This study reveals a cell type-specific tumour suppressive role for PRDX1 that is supported by survival analyses, depending on PRDX1 protein levels in breast cancer cohorts.

On the move: redox-dependent protein relocation in plants.

Compartmentation of proteins and processes is a defining feature of eukaryotic cells. The growth and development of organisms is critically dependent on the accurate sorting of proteins within cells. The mechanisms by which cytosol-synthesized proteins are delivered to the membranes and membrane compartments have been extensively characterized. However, the protein complement of any given compartment is not precisely fixed and some proteins can move between compartments in response to metabolic or environmental triggers. The mechanisms and processes that mediate such relocation events are largely uncharacterized. Many proteins can in addition perform multiple functions, catalysing alternative reactions or performing structural, non-enzymatic functions. These alternative functions can be equally important functions in each cellular compartment. Such proteins are generally not dual-targeted proteins in the classic sense of having targeting sequences that direct de novo synthesized proteins to specific cellular locations. We propose that redox post-translational modifications (PTMs) can control the compartmentation of many such proteins, including antioxidant and/or redox-associated enzymes.

AAV2-BDNF promotes respiratory axon plasticity and recovery of diaphragm function following spinal cord injury.

More than half of spinal cord injury (SCI) cases occur in the cervical region, leading to respiratory dysfunction due to damaged neural circuitry that controls critically important muscles such as the diaphragm. The C3-C5 spinal cord is the location of phrenic motor neurons (PhMNs) that are responsible for diaphragm activation; PhMNs receive bulbospinal excitatory drive predominately from supraspinal neurons of the rostral ventral respiratory group (rVRG). Cervical SCI results in rVRG axon damage, PhMN denervation, and consequent partial-to-complete paralysis of hemidiaphragm. In a rat model of C2 hemisection SCI, we expressed the axon guidance molecule, brain-derived neurotrophic factor (BDNF), selectively at the location of PhMNs (ipsilateral to lesion) to promote directed growth of rVRG axons toward PhMN targets by performing intraspinal injections of adeno-associated virus serotype 2 (AAV2)-BDNF vector. AAV2-BDNF promoted significant functional diaphragm recovery, as assessed by in vivo electromyography. Within the PhMN pool ipsilateral to injury, AAV2-BDNF robustly increased sprouting of both spared contralateral-originating rVRG axons and serotonergic fibers. Furthermore, AAV2-BDNF significantly increased numbers of putative monosynaptic connections between PhMNs and these sprouting rVRG and serotonergic axons. These findings show that targeting circuit plasticity mechanisms involving the enhancement of synaptic inputs from spared axon populations is a powerful strategy for restoring respiratory function post-SCI.-Charsar, B. A., Brinton, M. A., Locke, K., Chen, A. Y., Ghosh, B., Urban, M. W., Komaravolu, S., Krishnamurthy, K., Smit, R., Pasinelli, P., Wright, M. C., Smith, G. M., Lepore, A. C. AAV2-BDNF promotes respiratory axon plasticity and recovery of diaphragm function following spinal cord injury.

Resilience is associated with health-related quality of life in caregivers of service members and veterans following traumatic brain injury.

PURPOSE: To examine factors related to resilience in military caregivers across caregiver health-related quality of life (HRQOL), caregiver sociodemographic variables, and service member/veteran (SMV) injury and health status. METHODS: Caregivers (N = 346, Female = 96.2%; Spouse = 91.0%; Age: M = 40.6 years, SD = 9.3) of SMVs following a mild, moderate, severe, or penetrating TBI were recruited from U.S. military treatment facilities and via community outreach. Caregivers completed select TBI-CareQOL and NIH Toolbox scales, the Caregiver Appraisal Scale, Caregiver Questionnaire, and Mayo-Portland Adaptability Inventory-4. Caregivers were divided into three groups using the TBI-QOL Resilience scale: (1) Low-Moderate Resilience (n = 125), (2) Moderate Resilience (n = 122), and (3) Moderate-High Resilience (n = 99). RESULTS: Factors related to low caregiver resilience were strain on employment, financial burden from out-of-pocket expenses, caring for children, less personal time, caring for both verbal and physical irritability, anger, and aggression, and lower SMV functional ability (all p's < .05). The Low-Moderate Resilience group had consistently worse HRQOL scores compared to the Moderate and Moderate-High Resilience groups (ps < .001; d = .50-1.60), with the exception of Caregiving Ideology. CONCLUSION: Lower resilience among caregivers of SMVs following TBI is associated with poorer caregiver HRQOL. Programs aimed at promoting and maintaining resilience in military caregivers long-term is important for their own health, the health of the SMV, and the health of their children.

Long-term neurobehavioural symptom reporting following mild, moderate, severe, and penetrating traumatic brain injury in U.S. military service members.

The purpose of this study was to examine long-term neurobehavioural symptom reporting following mild, moderate, severe, or penetrating TBI in U.S. military service members and veterans (SMV). Participants were 445 SMVs divided into four groups: 158 uncomplicated mild TBI ("unMTBI" group), 105 penetrating, severe, moderate, or complicated mild TBI ("smcTBI" group), 101 injured controls (IC), and 81 non-injured controls (NIC). Two independent cohorts were examined that included participants 5-years or 10-year post-injury. Participants completed the TBI-Quality of Life, Neurobehavioural Symptom Inventory, and Post-traumatic Stress Disorder Checklist. At 5-years and 10-years post-injury, there were significant main effects for the majority of measures (all p's < .005). At 10-years post-injury, the NIC group had consistently better scores compared to the IC, unMTBI, and smcTBI groups. At 5-years post-injury, either (a) the IC and NIC group had better scores compared to both TBI groups, or (b) the NIC group had better scores compared to the IC, unMTBI, and smcTBI groups. A high proportion of SMVs reported poor long-term neurobehavioural symptoms following TBI or bodily injury without TBI. Injured SMVs (regardless of injury type) can have long-term symptoms that impact mental health and overall quality of life requiring long-term follow-up and care.

Impact of Endocrinology eConsults on Access to Endocrinology Care for Medicaid Patients.

Background: Access to endocrinologists is a particular challenge for medically underserved populations. Introduction: Electronic consultations (eConsults) are a promising tool to help address this problem. Materials and Methods: This retrospective cohort study compared two groups: (1) Medicaid patients referred to an endocrinologist 1 year before the implementation of eConsults and (2) those referred in the 1 year after implementation. Data included patient demographics, dates of referral requests, appointment dates, eConsult response dates and times, diagnosis codes, and consultants' recommendations. Provider perspectives of eConsults were determined by using a survey. Results: Before eConsult implementation, only 138 out of 365 (37.8%) of referrals to endocrinology were completed. Postimplementation, 281 out of 469 (59.9%) of referrals were completed either by a confirmed face-to-face visit with an endocrinologist or by an eConsult, of whom 194 (41.4%) did not require a face-to-face visit. Thyroid conditions were the most common reason for a consult, accounting for roughly 40% of all consults. Overall, 32 out of 36 (89%) primary care providers (PCPs) indicated that they were satisfied with eConsults and 19 out of 36 (53%) felt that the process did not create additional work or burden for them. Discussion: These findings demonstrate that eConsult use can help address poor access to specialty care for Medicaid-insured patients. eConsults were able to significantly decrease the need for face-to-face visits and enabled PCPs to address specialty-related issues in primary care. Conclusions: Widespread adoption of eConsults could be a potential solution for major challenges that our health care system faces today.

Using Drosophila Motor Mutants to Teach Neurodevelopment in an Undergraduate Neurobiology Lab.

Most undergraduate neuroscience courses include a neurodevelopment component. Typically, the focus is on development of the mammalian central nervous system, including the concepts of neurulation, patterning of the neural tube, and differentiation of the various cells required to build a functional nervous system. However, it can be challenging to design an affordable undergraduate laboratory exercise to reinforce these concepts for students outside of lecture. Here we describe a laboratory exercise that takes advantage of the high level of conservation in neurodevelopmental pathways using Drosophila as a model organism to illuminate the connection between cell differentiation and nervous system function. Following a lesson discussing spinal cord development, students use Drosophila larvae to assess the effects of mutations in highly conserved motor neuron differentiation genes on motor behaviors such as crawling. As outcomes of this laboratory, students are able to master important neurodevelopmental concepts, connect neurodevelopment to nervous system function, and gain experience with experimental design and data analysis.

Caring for a service member or Veteran following traumatic brain injury influences caregiver mental health.

This study examined factors related to poor mental health in caregivers assisting service members and Veterans (SMV) following traumatic brain injury (TBI). Participants were 201 military caregivers (96.0% female; Age: M = 39.2 years, SD = 10.2) of SMVs following a mild, moderate, severe, or penetrating TBI. The SF-36v2 Health Survey, Caregiver Appraisal Scale, Mayo-Portland Adaptability Inventory-4, and Caregiver Questionnaire were completed. Caregivers were divided into two mental health groups: Poor Mental Health (n = 108) and Good Mental Health (n = 93). Factors related to poor caregiver mental health were worse general health and stress appraisal, less personal time, unmet needs, and greater financial and employment strain. Factors also related to poor caregiver mental health included assisting a SMV who had sustained a mild TBI, did not have significant hospital care, had post-traumatic stress disorder, depression, and/or anxiety, was experiencing greater functional disability, and was experiencing physical expressions of irritability, anger, and aggression (all p's<.05; d =.29 to d =.64; OR = 1.911 to OR = 4.984). For many military caregivers, poor mental health may be related to the SMVs ongoing comorbid mental health symptoms and less so neurological impairment related to the brain injury. TBI treatment programs require a holistic approach that addresses the behavioral health concerns of both SMVs and their caregivers.