SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma.

End stage liver disease is marked by portal hypertension, systemic elevations in ammonia, and development of hepatocellular carcinoma (HCC). While these clinical consequences of cirrhosis are well described, it remains poorly understood whether hepatic insufficiency and the accompanying elevations in ammonia contribute to HCC carcinogenesis. Using preclinical models, we discovered that ammonia entered the cell through the transporter SLC4A11 and served as a nitrogen source for amino acid and nucleotide biosynthesis. Elevated ammonia promoted cancer stem cell properties in vitro and tumor initiation in vivo. Enhancing ammonia clearance reduced HCC stemness and tumor growth. In patients, elevations in serum ammonia were associated with an increased incidence of HCC. Taken together, this study forms the foundation for clinical investigations using ammonia lowering agents as potential therapies to mitigate HCC incidence and aggressiveness.

Potentiating the radiation-induced type I interferon antitumoral immune response by ATM inhibition in pancreatic cancer.

Radiotherapy induces a type I interferon-mediated (T1IFN-mediated) antitumoral immune response that we hypothesized could be potentiated by a first-in-class ataxia telangiectasia mutated (ATM) inhibitor, leading to enhanced innate immune signaling, T1IFN expression, and sensitization to immunotherapy in pancreatic cancer. We evaluated the effects of AZD1390 or a structurally related compound, AZD0156, on innate immune signaling and found that both inhibitors enhanced radiation-induced T1IFN expression via the POLIII/RIG-I/MAVS pathway. In immunocompetent syngeneic mouse models of pancreatic cancer, ATM inhibitor enhanced radiation-induced antitumoral immune responses and sensitized tumors to anti-PD-L1, producing immunogenic memory and durable tumor control. Therapeutic responses were associated with increased intratumoral CD8+ T cell frequency and effector function. Tumor control was dependent on CD8+ T cells, as therapeutic efficacy was blunted in CD8+ T cell-depleted mice. Adaptive immune responses to combination therapy provided systemic control of contralateral tumors outside of the radiation field. Taken together, we show that a clinical candidate ATM inhibitor enhances radiation-induced T1IFN, leading to both innate and subsequent adaptive antitumoral immune responses and sensitization of otherwise resistant pancreatic cancer to immunotherapy.

Impact of immune tolerance mechanisms on the efficacy of immunotherapy in primary and secondary liver cancers.

The liver is a functionally unique organ with an immunosuppressive microenvironment. The liver is the sixth most common site of primary cancer in humans and is a frequent site of metastasis from other solid tumors. The development of effective therapies for primary and metastatic liver cancer has been challenging due to the complex metabolic and immune microenvironment of the liver. The liver tumor microenvironment (TME) in primary and secondary (metastatic) liver cancers is heterogenous and consists of unique immune and stromal cell populations. Crosstalk between these cell populations and tumor cells creates an immunosuppressive microenvironment within the liver which potentiates cancer progression. Immune checkpoint inhibitors (ICIs) are now clinically approved for the management of primary and secondary liver cancer and can partially overcome liver immune tolerance, but their efficacy is limited. In this review, we describe the liver microenvironment and the use of immunotherapy in primary and secondary liver cancer. We discuss emerging combination strategies utilizing locoregional and systemic therapy approaches which may enhance efficacy of immunotherapy in primary and secondary liver cancer. A deeper understanding of the immunosuppressive microenvironment of the liver will inform novel therapies and therapeutic combinations in order to improve outcomes of patients with primary and secondary liver cancer.

High-content CRISPR screening in tumor immunology.

CRISPR screening is a powerful tool that links specific genetic alterations to corresponding phenotypes, thus allowing for high-throughput identification of novel gene functions. Pooled CRISPR screens have enabled discovery of innate and adaptive immune response regulators in the setting of viral infection and cancer. Emerging methods couple pooled CRISPR screens with parallel high-content readouts at the transcriptomic, epigenetic, proteomic, and optical levels. These approaches are illuminating cancer immune evasion mechanisms as well as nominating novel targets that augment T cell activation, increase T cell infiltration into tumors, and promote enhanced T cell cytotoxicity. This review details recent methodological advances in high-content CRISPR screens and highlights the impact this technology is having on tumor immunology.

Updates in combined approaches of radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer.

Breast cancer is the most prevalent non-skin cancer diagnosed in females and developing novel therapeutic strategies to improve patient outcomes is crucial. The immune system plays an integral role in the body's response to breast cancer and modulating this immune response through immunotherapy is a promising therapeutic option. Although immune checkpoint inhibitors were recently approved for the treatment of breast cancer patients, not all patients respond to immune checkpoint inhibitors as a monotherapy, highlighting the need to better understand the biology underlying patient response. Additionally, as radiotherapy is a critical component of breast cancer treatment, understanding the interplay of radiation and immune checkpoint inhibitors will be vital as recent studies suggest that combined therapies may induce synergistic effects in preclinical models of breast cancer. This review will discuss the mechanisms supporting combined approaches with radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer. Moreover, this review will analyze the current clinical trials examining combined approaches of radiotherapy, immunotherapy, chemotherapy, and targeted therapy. Finally, this review will evaluate data regarding treatment tolerance and potential biomarkers for these emerging therapies aimed at improving breast cancer outcomes.

Centrin-deficient Leishmania mexicana confers protection against New World cutaneous leishmaniasis.

Leishmaniasis is a neglected protozoan disease affecting over 12 million people globally with no approved vaccines for human use. New World cutaneous leishmaniasis (CL) caused by L. mexicana is characterized by the development of chronic non-healing skin lesions. Using the CRISPR/Cas9 technique, we have generated live attenuated centrin knockout L. mexicana (LmexCen-/-) parasites. Centrin is a cytoskeletal protein important for cellular division in eukaryotes and, in Leishmania, is required only for intracellular amastigote replication. We have investigated the safety and immunogenicity characteristics of LmexCen-/- parasites by evaluating their survival and the cytokine production in bone-marrow-derived macrophages (BMDMs) and dendritic cells (BMDCs) in vitro. Our data shows that LmexCen-/- amastigotes present a growth defect, which results in significantly lower parasitic burdens and increased protective cytokine production in infected BMDMs and BMDCs, compared to the wild type (WT) parasites. We have also determined the safety and efficacy of LmexCen-/- in vivo using experimental murine models of L. mexicana. We demonstrate that LmexCen-/- parasites are safe and do not cause lesions in susceptible mouse models. Immunization with LmexCen-/- is also efficacious against challenge with WT L. mexicana parasites in genetically different BALB/c and C57BL/6 mouse models. Vaccinated mice did not develop cutaneous lesions, displayed protective immunity, and showed significantly lower parasitic burdens at the infection site and draining lymph nodes compared to the control group. Overall, we demonstrate that LmexCen-/- parasites are safe and efficacious against New World cutaneous leishmaniasis in pre-clinical models.

A forced marriage of IL-2 and PD-1 antibody nurtures tumor-infiltrating T cells.

IL-2 is a pleiotropic cytokine. In this issue of the JCI, Ren et al. report on the development of a low-affinity IL-2 paired with anti-PD-1 (PD-1-laIL-2) that reactivates intratumoral CD8+ T cells, but not CD4+ Treg cells. PD-1-laIL-2 treatment synergized with anti-PD-L1 therapy to overcome tumor resistance to immune checkpoint blockade (ICB) in tumor-bearing mice. Rejection of rechallenged tumors following PD-1-laIL-2 therapy demonstrated the establishment of a potent T cell memory response. Furthermore, PD-1-laIL-2 therapy manifested no obvious toxicity. These findings suggest the potential of PD-1-laIL-2 therapy in treating patients with cancer.

Older age and online health information search behaviors: The mediating influence of executive functions.

INTRODUCTION: Searching the internet for health-related information is a complex and dynamic goal-oriented process that ostensibly places demands on executive functions, which are higher-order cognitive abilities that can deteriorate with older age. This study examined the effects of older age on electronic health (eHealth) search behavior and the potential mediating influence of executive functions. METHOD: Fifty younger adults (≤ 35 years) and 41 older adults (≥50 years) completed naturalistic eHealth search tasks involving fact-finding (Fact Search) and symptom determination (Symptom Search), a neurocognitive battery, and a series of self-report questionnaires. RESULTS: Multiple regression models controlling for potentially confounding psychiatric symptoms, health conditions, literacy, and demographic variables revealed that older adults were slower and less accurate than younger adults on the eHealth Fact Search task, but not on the eHealth Symptom Search task. Executive functions mediated the relationship between age and Fact and Symptom Search accuracy, independent of basic processing speed and attention. Parallel mediation models showed that episodic memory was not an independent mediator of age and search accuracy for either eHealth task once speed/attention and executive functions were included. CONCLUSIONS: Older adults can experience difficulty searching the internet for some health-related information, which is at least partly attributable to executive dysfunction. Future studies are needed to determine the benefits of training in the organizational and strategic aspects of internet search for older adults and whether these findings are applicable to clinical populations with executive dysfunction.

From infection to vaccination: reviewing the global burden, history of vaccine development, and recurring challenges in global leishmaniasis protection.

INTRODUCTION: Leishmaniasis is a major public health problem and the second most lethal parasitic disease in the world due to the lack of effective treatments and vaccines. Even when not lethal, leishmaniasis significantly affects individuals and communities through life-long disabilities, psycho-sociological trauma, poverty, and gender disparity in treatment. AREAS COVERED: This review discusses the most relevant and recent research available on Pubmed and GoogleScholar highlighting leishmaniasis' global impact, pathogenesis, treatment options, and lack of effective control strategies. An effective vaccine is necessary to prevent morbidity and mortality, lower health care costs, and reduce the economic burden of leishmaniasis for endemic low- and middle-income countries. Since there are several forms of leishmaniasis, a pan-Leishmania vaccine without geographical restrictions is needed. This review also focuses on recent advances and common challenges in developing prophylactic strategies against leishmaniasis. EXPERT OPINION: Despite advances in pre-clinical vaccine research, approval of a human leishmaniasis vaccine still faces major challenges - including manufacturing of candidate vaccines under Good Manufacturing Practices, developing well-designed clinical trials suitable in endemic countries, and defined correlates of protection. In addition, there is a need to explore Challenge Human Infection Model to avoid large trials because of fluctuating incidence and prevalence of leishmanasis.

MicroRNA-21 Deficiency Promotes the Early Th1 Immune Response and Resistance toward Visceral Leishmaniasis.

MicroRNA-21 (miR-21) inhibits IL-12 expression and impairs the Th1 response necessary for control of Leishmania infection. Recent studies have shown that Leishmania infection induces miR-21 expression in dendritic cells and macrophages, and inhibition of miR-21 restores IL-12 expression. Because miR-21 is known to be expressed due to inflammatory stimuli in a wide range of hematopoietic cells, we investigated the role of miR-21 in regulating immune responses during visceral leishmaniasis (VL) caused by Leishmania donovani infection. We found that miR-21 expression was significantly elevated in dendritic cells, macrophages, inflammatory monocytes, polymorphonuclear neutrophils, and in the spleen and liver tissues after L. donovani infection, concomitant with an increased expression of disease exacerbating IL-6 and STAT3. Bone marrow dendritic cells from miR-21 knockout (miR-21KO) mice showed increased IL-12 production and decreased production of IL-10. On L. donovani infection, miR-21KO mice exhibited significantly greater numbers of IFN-γ- and TNF-α-producing CD4+ and CD8+ T cells in their organs that was associated with increased production of Th1-associated IFN-γ, TNF-α, and NO from the splenocytes. Finally, miR-21KO mice displayed significantly more developing and mature hepatic granulomas leading to reduction in organ parasitic loads compared with wild type counterparts. Similar results were noted in L. donovani-infected wild type mice after transient miR-21 depletion. These observations indicate that miR-21 plays a critical role in pathogenesis of VL by suppressing IL-12- and Th1-associated IFN-γ and also inducing disease-promoting induction of the IL-6 and STAT-3 signaling pathway. miR-21 could therefore be used as a potential target for developing host-directed treatment for VL.

Mechanisms of Immunopathogenesis in Cutaneous Leishmaniasis And Post Kala-azar Dermal Leishmaniasis (PKDL).

Leishmaniasis is a neglected tropical disease that affects 12 million people worldwide. The disease has high morbidity and mortality rates and is prevalent in over 80 countries, leaving more than 300 million people at risk of infection. Of all of the manifestations of this disease, cutaneous leishmaniasis (CL) is the most common form and it presents as ulcerating skin lesions that can self-heal or become chronic, leading to disfiguring scars. This review focuses on the different pathologies and disease manifestations of CL, as well as their varying degrees of severity. In particular, this review will discuss self-healing localized cutaneous leishmaniasis (LCL), leishmaniasis recidivans (LR), mucocutaneous leishmaniasis (MCL), anergic diffuse cutaneous leishmaniasis (ADCL), disseminated leishmaniasis (DL), and Post Kala-azar Dermal Leishmaniasis (PKDL), which is a cutaneous manifestation observed in some visceral leishmaniasis (VL) patients after successful treatment. The different clinical manifestations of CL are determined by a variety of factors including the species of the parasites and the host's immune response. Specifically, the balance between the pro and anti-inflammatory mediators plays a vital role in the clinical presentation and outcome of the disease. Depending upon the immune response, Leishmania infection can also transition from one form of the disease to another. In this review, different forms of cutaneous Leishmania infections and their immunology are described.

The role of vascular endothelium and exosomes in human protozoan parasitic diseases.

The vascular endothelium is a vital component in maintaining the structure and function of blood vessels. The endothelial cells (ECs) mediate vital regulatory functions such as the proliferation of cells, permeability of various tissue membranes, and exchange of gases, thrombolysis, blood flow, and homeostasis. The vascular endothelium also regulates inflammation and immune cell trafficking, and ECs serve as a replicative niche for many bacterial, viral, and protozoan infectious diseases. Endothelial dysfunction can lead to vasodilation and pro-inflammation, which are the hallmarks of many severe diseases. Exosomes are nanoscale membrane-bound vesicles that emerge from cells and serve as important extracellular components, which facilitate communication between cells and maintain homeostasis during normal and pathophysiological states. Exosomes are also involved in gene transfer, inflammation and antigen presentation, and mediation of the immune response during pathogenic states. Protozoa are a diverse group of unicellular organisms that cause many infectious diseases in humans. In this regard, it is becoming increasingly evident that many protozoan parasites (such as Plasmodium, Trypanosoma, Leishmania, and Toxoplasma) utilize exosomes for the transfer of their virulence factors and effector molecules into the host cells, which manipulate the host gene expression, immune responses, and other biological activities to establish and modulate infection. In this review, we discuss the role of the vascular endothelium and exosomes in and their contribution to pathogenesis in malaria, African sleeping sickness, Chagas disease, and leishmaniasis and toxoplasmosis with an emphasis on their actions on the innate and adaptive immune mechanisms of resistance.

Ibrutinib treatment inhibits breast cancer progression and metastasis by inducing conversion of myeloid-derived suppressor cells to dendritic cells.

BACKGROUND: Ibrutinib is a Bruton's tyrosine kinase (BTK) and interleukin-2-inducible kinase (ITK) inhibitor used for treating chronic lymphocytic leukaemia (CLL) and other cancers. Although ibrutinib is known to inhibit the growth of breast cancer cell growth in vitro, its impact on the treatment and metastasis of breast cancer is unclear. METHODS: Using an orthotopic mouse breast cancer model, we show that ibrutinib inhibits the progression and metastasis of breast cancer. RESULTS: Ibrutinib inhibited proliferation of cancer cells in vitro, and Ibrutinib-treated mice displayed significantly lower tumour burdens and metastasis compared to controls. Furthermore, the spleens and tumours from Ibrutinib-treated mice contained more mature DCs and lower numbers of myeloid-derived suppressor cells (MDSCs), which promote disease progression and are linked to poor prognosis. We also confirmed that ex vivo treatment of MDSCs with ibrutinib switched their phenotype to mature DCs and significantly enhanced MHCII expression. Further, ibrutinib treatment promoted T cell proliferation and effector functions leading to the induction of antitumour TH1 and CTL immune responses. CONCLUSIONS: Ibrutinib inhibits tumour development and metastasis in breast cancer by promoting the development of mature DCs from MDSCs and hence could be a novel therapeutic agent for the treatment of breast cancer.

Assessment of sleep after traumatic brain injury (TBI).

BACKGROUND: Individuals who have sustained a TBI often present with complaints of disturbed sleep. Identifying sleep disorders in the TBI population has not been standardized. Much of the confusion may come from the heterogeneity of the research that has been conducted on sleep problems after traumatic brain injury. This review focused attention to current research findings in order to develop an evidenced-based approach to assessment of sleep disturbances within this unique population. OBJECTIVES: To review various methods used in the assessment of disorders of sleep after TBI and offer recommendations for best approaches for clinical assessment of sleep. METHODS: The authors describe various methods such as history, questionnaires, physical examination and objective sleep measurement, their usefulness and limitations based on the available evidence and experience for assessment of sleep in individuals who have sustained a TBI. RESULTS: An evidence-driven method for the assessment of sleep disorders following TBI is discussed. CONCLUSIONS: Through skilled assessment, clinicians can assess sleep following TBI and the most applicable interventions can be chosen with the hopes of reducing additional symptom burden and optimizing functioning.

Implementation of Actigraphy in Acute Traumatic Brain Injury (TBI) Neurorehabilitation Admissions: A Veterans Administration TBI Model Systems Feasibility Study.

BACKGROUND: Sleep problems and disorders are prevalent in patients with traumatic brain injury (TBI) and are associated with negative outcomes. Incidence varies because of challenges including differences in assessment methods, particularly in the acute stages of recovery when patients are cognitively impaired and unable to complete traditional self-report methods. Actigraphy (ACG) recently has been validated in the acute TBI rehabilitation setting and may serve as a superior method of assessing sleep-wake patterns at this stage of recovery. Although a few studies with small sample sizes have described the use of ACG, none have described feasibility and implementation protocols. OBJECTIVE: To describe the feasibility and implementation protocol of ACG to evaluate sleep-wake patterns and white-light exposure data in patients with acute TBI during inpatient rehabilitation. Sleep-wake patterns and light exposure data are presented to characterize the sample using these methods to inform future research. DESIGN: Retrospective study. SETTING: Acute inpatient rehabilitation unit at a Veterans' Affairs Polytrauma Rehabilitation Center. PARTICIPANTS: Veterans (age ≥18 years) admitted to inpatient rehabilitation and enrolled in the Traumatic Brain Injury Model Systems study who were admitted and discharged in the calendar year 2013. METHODS: Veterans underwent actigraph watch placement as soon as possible after admission. Records from the calendar year 2013 were reviewed to determine the number of admissions that met study criteria and what percentage of those patients had 3 days of continuous ACG data collected. The barriers to successful watch placement in this population were reviewed. Average sleep, light, and wake data from available records were collected for the study sample. MAIN OUTCOME MEASUREMENTS: Percentage of patients who met study criteria and who had 72 hours of continuous ACG data collected. The barriers to successful watch placement in this population were reviewed. Average sleep, light, and wake data from available records were collected. RESULTS: Of 22 eligible Traumatic Brain Injury Model Systems admissions, 3 consecutive nights of ACG data were successfully obtained for 86% (n = 19) of the sample. Barriers to data collection included patient access due to abbreviated lengths of stay, staff availability for ACG placement, and data collection protocols to prevent loss of data in Veterans' Affairs computing systems. CONCLUSIONS: ACG is feasible for collecting data about sleep, wake, and light exposure in patients who are in acute TBI inpatient rehabilitation settings. LEVEL OF EVIDENCE: III.

Incidence, Characterization, and Predictors of Sleep Apnea in Consecutive Brain Injury Rehabilitation Admissions.

OBJECTIVE: To prospectively examine the incidence and risk factors for sleep apnea in consecutive brain injury rehabilitation admissions. SETTING: Inpatient neurorehabilitation hospital. PARTICIPANTS: Participants (n = 86) were consecutive neurorehabilitation admissions. DESIGN: Retrospective analysis of prospectively collected data. MAIN MEASURES: Polysomnography. RESULTS: Half (49%) of the sample was diagnosed with sleep apnea. For the full sample, univariate logistic regression revealed age (odds ratio: 1.08; 95% confidence interval: 1.04-1.11) and hypertension (odds ratio: 7.77; 95% confidence interval: 2.81-21.47) as significant predictors of sleep apnea diagnosis. Results of logistic regression conducted within the traumatic brain injury group revealed age (odds ratio: 1.07; 95% confidence interval: 1.02-1.13) as the only significant predictor of apnea diagnosis after adjustment for other variables. Hierarchical generalized linear regression models for the prediction of apnea severity (ie, apnea-hypopnea index found that Functional Independence Measure Cognition Score (P = .01) and age (P < .01) were significant predictors. Following adjustment for all other terms, only age (P < .01) remained significant. CONCLUSION: Sleep apnea is prevalent in acute neurorehabilitation admissions and traditional risk profiles for sleep apnea may not effectively screen for the disorder. Given the progressive nature of obstructive sleep apnea and morbidity associated with even mild obstructive sleep apnea, early identification and intervention may address comorbidities influencing acute and long-term outcome.

Embedded Measures of Performance Validity in the Rey Complex Figure Test in a Clinical Sample of Veterans.

The purpose of this study was to determine how well scores from the Rey Complex Figure Test (RCFT) could serve as embedded measures of performance validity in a large, heterogeneous clinical sample at an urban-based Veterans' Affairs hospital. Participants were divided into credible performance (n = 244) and noncredible performance (n = 87) groups based on common performance validity tests during their respective clinical evaluations. We evaluated how well preselected RCFT scores could discriminate between the 2 groups using cut scores from single indexes as well as multivariate logistic regression prediction models. Additionally, we evaluated how well memory error patterns (MEPs) could discriminate between the 2 groups. Optimal discrimination occurred when indexes from the Copy and Recognition trials were simultaneous predictors in logistic regression models, with 91% specificity and at least 53% sensitivity. Logistic regression yielded superior discrimination compared with individual indexes and compared with the use of MEPs. Specific scores on the RCFT, including the Copy and Recognition trials, can serve as adequate indexes of performance validity, when using both cut scores and logistic regression prediction models. We provide logistic regression equations that can be applied in similar clinical settings to assist in determining performance validity.

The Relationship Between Sleep-Wake Cycle Disturbance and Trajectory of Cognitive Recovery During Acute Traumatic Brain Injury.

OBJECTIVE: Following traumatic brain injury, both sleep dysfunction and cognitive impairment are common. Unfortunately, little is known regarding the potential associations between these 2 symptoms during acute recovery. This study sought to prospectively examine the relationship between ratings of sleep dysfunction and serial cognitive assessments among traumatic brain injury acute neurorehabilitation admissions. METHODS: Participants were consecutive admissions to a free-standing rehabilitation hospital following moderate to severe traumatic brain injury (Median Emergency Department Glasgow Coma Scale = 7). Participants were assessed for sleep-wake cycle disturbance (SWCD) and cognitive functioning at admission and with subsequent weekly examinations. Participants were grouped on the basis of presence (SWCD+) or absence (SWCD-) of sleep dysfunction for each examination; groups were equivalent on demographic and injury variables. Individual Growth Curve modeling was used to examine course of Cognitive Test for Delirium performance across examinations. RESULTS: Individual Growth Curve modeling revealed a significant interaction between examination number (ie, time) and SWCD group (ß = -4.03, P < .001) on total Cognitive Test for Delirium score. The SWCD+ ratings on later examinations were predicted to result in lower Cognitive Test for Delirium scores and greater cognitive impairment over time. CONCLUSIONS: This study has implications for improving neurorehabilitation treatment, as targeting sleep dysfunction for early intervention may facilitate cognitive recovery.

Comorbid disease in persons with traumatic brain injury: descriptive findings using the modified cumulative illness rating scale.

OBJECTIVE: To provide descriptive findings regarding the overall health status and prevalence of medical comorbidities experienced by traumatic brain injury (TBI) patients. DESIGN: Inception cohort design with cross-sectional follow-up at 1 to 15 years. SETTING: Rehabilitation hospital. PARTICIPANTS: Adults (N=258) with moderate to severe TBI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The Modified Cumulative Illness Rating Scale is a 14-item rating scale used to indicate health status by rating impairment across 14 different domains. RESULTS: The TBI sample had lower rates of comorbidities compared with other rehabilitation populations, including stroke and orthopedic samples. The most commonly encountered medical conditions within our sample were eyes, ears, nose, and throat problems, psychiatric or behavioral disturbances, hypertension, and musculoskeletal injury at mild to moderate severity. Prevalence of conditions did not differ by sex, race, or cause of TBI. CONCLUSIONS: The current TBI sample was relatively healthy with few medical comorbidities. Further, the Modified Cumulative Illness Rating Scale may better be used as a standardized checklist to assess for the presence of co-occurring conditions, given the near absence of conditions in the higher range of severity.