A mathematical model of neuroinflammation in severe clinical traumatic brain injury.

BACKGROUND: Understanding the interdependencies among inflammatory mediators of tissue damage following traumatic brain injury (TBI) is essential in providing effective, patient-specific care. Activated microglia and elevated concentrations of inflammatory signaling molecules reflect the complex cascades associated with acute neuroinflammation and are predictive of recovery after TBI. However, clinical TBI studies to date have not focused on modeling the dynamic temporal patterns of simultaneously evolving inflammatory mediators, which has potential in guiding the design of future immunomodulation intervention studies. METHODS: We derived a mathematical model consisting of ordinary differential equations (ODE) to represent interactions between pro- and anti-inflammatory cytokines, M1- and M2-like microglia, and central nervous system (CNS) tissue damage. We incorporated variables for several cytokines, interleukin (IL)-1ß, IL-4, IL-10, and IL-12, known to have roles in microglial activation and phenotype differentiation. The model was fit to cerebrospinal fluid (CSF) cytokine data, collected during the first 5 days post-injury in n = 89 adults with severe TBI. Ensembles of model fits were produced for three patient subgroups: (1) a favorable outcome group (GOS = 4,5) and (2) an unfavorable outcome group (GOS = 1,2,3) both with lower pro-inflammatory load, and (3) an unfavorable outcome group (GOS = 1,2,3) with higher pro-inflammatory load. Differences in parameter distributions between subgroups were ranked using Bhattacharyya metrics to identify mechanistic differences underlying the neuroinflammatory patterns of patient groups with different TBI outcomes. RESULTS: Optimal model fits to data showed different microglial and damage responses by patient subgroup. Upon comparison of model parameter distributions, unfavorable outcome groups were characterized by either a prolonged, pathophysiological or a transient, sub-physiological course of neuroinflammation. CONCLUSION: By developing a mathematical characterization of inflammatory processes informed by clinical data, we have created a system for exploring links between acute neuroinflammatory components and patient outcome in severe TBI.

Longitudinal sex and stress hormone profiles among reproductive age and post-menopausal women after severe TBI: A case series analysis.

PRIMARY OBJECTIVES: To describe hormone profiles for pre-/post-menopausal women, to monitor time to resumption of menstruation among pre-menopausal women and to describe cortisol associated LH suppression and phasic variation in other sex hormones over timeMethods and procedures: This study determined amenorrhea duration and characterized acute (days 0-7) and chronic (months 1-6) gonadotropins [luteinizing hormone and follicle stimulating hormone (LH, FSH)], sex hormones (progesterone, estradiol) and stress hormone (cortisol) profiles. Women were pre-menopausal (n = 3) or post-menopausal (n = 3). Among pre-menopausal women, menstrual cycle resolution and phase association (luteal/follicular) was monitored using self-report monthly reproductive history questionnaires. This study compared post-TBI hormone profiles, stratified by menopausal status, to hormone levels from seven controls and described 6- and 12-month outcomes for these women. MAIN OUTCOMES AND RESULTS: Consistent with functional hypothalamic amenorrhea (FHA), menstruation resumption among pre-menopausal women occurred when serum cortisol normalized to luteal phase control levels. For post-menopausal women, serum cortisol reductions corresponded with resolution of suppressed LH levels. CONCLUSIONS: The stress of TBI results in anovulation and central hypothalamic-pituitary-ovarian (HPG) axis suppression. Future work will examine acute/chronic consequences of post-TBI hypercortisolemia and associated HPG suppression, the temporal association of HPG suppression with other neuroendocrine adaptations and how HPG suppression impacts multidimensional recovery for women with TBI.

Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients: A Randomized Clinical Trial.

Importance: Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA) therapy. Few studies of anemia treatment in an incident dialysis (ID) population have been reported. Objective: To evaluate the efficacy and safety of daprodustat vs darbepoetin alfa in treating anemia of chronic kidney disease in ID patients. Design, Setting, and Participants: This prospective, randomized, open-label clinical trial was conducted from May 11, 2017, through September 24, 2020, in 90 centers across 14 countries. Patients with advanced CKD were eligible if they planned to start dialysis within 6 weeks from screening or had started and received hemodialysis (HD) or peritoneal dialysis (PD) within 90 days before randomization, had a screening hemoglobin (Hb) concentration of 8.0 to 10.5 g/dL (to convert to grams per liter, multiply by 10) and a randomization Hb of 8.0 to 11.0 g/dL, were ESA-naive or had received limited ESA treatment, and were iron-replete. Interventions: Randomized 1:1 to daprodustat or darbepoetin alfa. Main Outcomes and Measures: The primary analysis in the intent-to-treat population evaluated the mean change in Hb concentration from baseline to evaluation period (weeks 28-52) to assess noninferiority of daprodustat vs darbepoetin alfa (noninferiority margin, -0.75 g/dL). The mean monthly intravenous (IV) iron dose from baseline to week 52 was the principal secondary end point. Rates of treatment-emergent and serious adverse events (AEs) were also compared between treatment groups to assess safety and tolerability. Results: A total of 312 patients (median [IQR] age, 55 [45-65] years; 194 [62%] male) were randomized to either daprodustat (157 patients; median [IQR] age, 52.0 [45-63] years; 96 [61%] male) or darbepoetin alfa (155 patients; median [IQR] age, 56.0 [45-67] years; 98 [63%] male); 306 patients (98%) completed the trial. The mean (SD) Hb concentration during the evaluation period was 10.5 (1.0) g/dL for the daprodustat and 10.6 (0.9) g/dL for the darbepoetin alfa group, with an adjusted mean treatment difference of -0.10 g/dL (95% CI, -0.34 to 0.14 g/dL), indicating noninferiority. There was a reduction in mean monthly IV iron use from baseline to week 52 in both treatment groups; however, daprodustat was not superior compared with darbepoetin alfa in reducing monthly IV iron use (adjusted mean treatment difference, 19.4 mg [95% CI, -11.0 to 49.9 mg]). Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa. Conclusions and Relevance: This randomized clinical trial found that daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD and may represent a potential oral alternative to a conventional ESA in the ID population. Trial Registration: ClinicalTrials.gov Identifier: NCT03029208.

Estradiol to Androstenedione Ratios Moderate the Relationship between Neurological Injury Severity and Mortality Risk after Severe Traumatic Brain Injury.

Early declines in gonadotropin production, despite elevated serum estradiol, among some individuals with severe traumatic brain injury (TBI) suggests amplified systemic aromatization occurs post-injury. Our previous work identifies estradiol (E2) as a potent mortality marker. Androstenedione (A), a metabolic precursor to E2, estrone (E1), and testosterone (T), is a steroid hormone substrate for aromatization that has not been explored previously as a biomarker in TBI. Here, we evaluated serum A, E1, T, and E2 values for 82 subjects with severe TBI. Daily hormone values were calculated, and E2:A and E1:T ratios were generated and then averaged for days 0-3 post-injury. After data inspection, mean E2:A values were categorized as above (high aromatization) and below (low aromatization) the 50th percentile for 30-day mortality assessment using Kaplan-Meier survival analysis and a multivariable Cox proportional hazard model adjusting for age, and Glasgow Coma Scale (GCS) to predict 30-day mortality status. Daily serum T, E1, and E2 were graphed by E2:A category. Serum E1 and E2 significantly differed over time (p < 0.05); the high aromatization group had elevated levels and a significantly lower probability of survival within the first 30 days (p = 0.0274). Multivariable Cox regression showed a significant E2:A*GCS interaction (p = 0.0129), wherein GCS predicted mortality only among those in the low aromatization group. E2:A may be a useful mortality biomarker representing enhanced aromatization after TBI. E2:A ratios may represent non-neurological organ dysfunction after TBI and may be useful in defining injury subgroups in which GCS has variable capacity to serve as an accurate early prognostic marker.

Systemic Estrone Production and Injury-Induced Sex Hormone Steroidogenesis after Severe Traumatic Brain Injury: A Prognostic Indicator of Traumatic Brain Injury-Related Mortality.

Extensive pre-clinical studies suggest that sex steroids are neuroprotective in experimental traumatic brain injury (TBI). However, clinical trials involving sex hormone administration have not shown beneficial results, and our observational cohort studies show systemic estradiol (E2) production to be associated with adverse outcomes. Systemic E2 is produced via aromatization of testosterone (T) or reduction of estrone (E1). E1, also produced via aromatization of androstenedione (Andro) and is a marker of T-independent E2 production. We hypothesized that E1 would be (1) associated with TBI-related mortality, (2) the primary intermediate for E2 production, and (3) associated with adipose tissue-specific aromatase transcription. We assessed 100 subjects with severe TBI and 8 healthy controls. Serum levels were measured on days 0-3 post-TBI for key steroidogenic precursors (progesterone), aromatase pathway intermediates (E1, E2, T, Andro), and the adipose tissue-specific aromatase transcription factors cortisol, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). E1 was elevated after TBI versus controls. High E1 was associated with higher progesterone, cortisol, and IL-6 (p < 0.05). Multivariable logistic regression demonstrated that those in the highest E1 tertile had increased odds for mortality (adjusted OR = 5.656, 95% CI = 1.102-29.045, p = 0.038). Structural equation models show that early serum E2 production is largely T independent, occurring predominantly through E1 metabolism. Acute serum E1 functions as a mortality marker for TBI through aromatase-dependent E1 production and T-independent E2 production. Further work should evaluate risk factors for high E2 production and how systemic E2 and its key intermediate E1 contribute to the extracerebral consequences of severe TBI.