Application of the International Interocular Difference Thresholds into Practice: Localising the Patient Experience.

Demyelinating diseases of the central nervous system (CNS) often have neuro-ophthalmological manifestations, and retinal examination can be helpful in making the diagnosis. The latest iteration of optical coherence tomography (OCT)-based criteria for optic neuritis in multiple sclerosis has been developed in the research realm, but its application to clinical practice, and to the more uncommon demyelinating diseases requires further study. The ability to use OCT data to distinguish between various CNS demyelinating disorders could provide additional paraclinical tools to accurately diagnose patients. Furthermore, neuro-ophthalmological testing can define the extent of inflammatory damage in the CNS, independent of patient-reported history. New referrals for OCT at a tertiary multiple sclerosis and neuro-immunology referral centre (n = 167) were analysed retrospectively for the self-reporting of optic neuritis, serological test results, and diagnosis. Only approximately 30% of patients with a clinical history of unilateral optic neuritis solely had a unilateral optic neuropathy, nearly 40% of those subjects actually having evidence of bilateral optic neuropathies. Roughly 30% of patients reporting a history of bilateral optic neuritis did not have any evidence of structural disease, with 20% of these patients having a separate, intervenable diagnosis noted on macular scans. OCT is a useful adjunct diagnostic tool in the evaluation of demyelinating disease and has the ability to aid in a more accurate diagnosis for patients. Application of the international interocular difference thresholds to a clinical patient population generally reproduces the original results, emphasising their appropriateness. The analysis distinguishing the demyelinating diseases needs to be replicated in a blinded, multi-centre setting.

Understanding the relationship between cognitive performance and function in daily life after traumatic brain injury.

OBJECTIVE: Cognitive impairment is a key cause of disability after traumatic brain injury (TBI) but relationships with overall functioning in daily life are often modest. The aim is to examine cognition at different levels of function and identify domains associated with disability. METHODS: 1554 patients with mild-to-severe TBI were assessed at 6 months post injury on the Glasgow Outcome Scale-Extended (GOSE), the Short Form-12v2 and a battery of cognitive tests. Outcomes across GOSE categories were compared using analysis of covariance adjusting for age, sex and education. RESULTS: Overall effect sizes were small to medium, and greatest for tests involving processing speed (ηp 2 0.057-0.067) and learning and memory (ηp 2 0.048-0.052). Deficits in cognitive performance were particularly evident in patients who were dependent (GOSE 3 or 4) or who were unable to participate in one or more major life activities (GOSE 5). At higher levels of function (GOSE 6-8), cognitive performance was surprisingly similar across categories. There were decreases in performance even in patients reporting complete recovery without significant symptoms. Medium to large effect sizes were present for summary measures of cognition (ηp 2 0.111), mental health (ηp 2 0.131) and physical health (ηp 2 0.252). CONCLUSIONS: This large-scale study provides novel insights into cognitive performance at different levels of disability and highlights the importance of processing speed in function in daily life. At upper levels of outcome, any influence of cognition on overall function is markedly attenuated and differences in mental health are salient.

Acute Management of Optic Neuritis: An Evolving Paradigm.

The current management of acute optic neuritis (ON) is focused on expediting visual recovery through the use of high-dose intravenous corticosteroids. The recent identification of specific autoantibodies associated with central nervous system inflammatory disorders has provided novel insights into immune targets and mechanisms that impact the prognosis, treatment, and recurrence of ON. Therefore, neurologists and ophthalmologists need to be aware of clinical, laboratory, and imaging findings that may provide important clues to the etiology of ON and the potential need for aggressive management. Moving forward, rapid and accurate diagnosis of inflammatory ON will likely be critical for implementing clinical care that optimizes short-term and long-term therapeutic outcomes.

Generative artificial intelligence versus clinicians: Who diagnoses multiple sclerosis faster and with greater accuracy?

BACKGROUND: Those receiving the diagnosis of multiple sclerosis (MS) over the next ten years will predominantly be part of Generation Z (Gen Z). Recent observations within our clinic suggest that younger people with MS utilize online generative artificial intelligence (AI) platforms for personalized medical advice prior to their first visit with a specialist in neuroimmunology. The use of such platforms is anticipated to increase given the technology driven nature, desire for instant communication, and cost-conscious nature of Gen Z. Our objective was to determine if ChatGPT (Generative Pre-trained Transformer) could diagnose MS in individuals earlier than their clinical timeline, and to assess if the accuracy differed based on age, sex, and race/ethnicity. METHODS: People with MS between 18 and 59 years of age were studied. The clinical timeline for people diagnosed with MS was retrospectively identified and simulated using ChatGPT-3.5 (GPT-3.5). Chats were conducted using both actual and derivatives of their age, sex, and race/ethnicity to test diagnostic accuracy. A Kaplan-Meier survival curve was estimated for time to diagnosis, clustered by subject. The p-value testing for differences in time to diagnosis was accomplished using a general Wilcoxon test. Logistic regression (subject-specific intercept) was used to capture intra-subject correlation to test the accuracy prior to and after the inclusion of MRI data. RESULTS: The study cohort included 100 unique people with MS. Of those, 50 were members of Gen Z (38 female; 22 White; mean age at first symptom was 20.6 years (y) (standard deviation (SD)=2.2y)), and 50 were non-Gen Z (34 female; 27 White; mean age at first symptom was 37.0y (SD=10.4y)). In addition, a total of 529 people that represented digital simulations of the original cohort of 100 people (333 female; 166 White; 136 Black/African American; 107 Asian; 120 Hispanic, mean age at first symptom was 31.6y (SD=12.4y)) were generated allowing for 629 scripted conversations to be analyzed. The estimated median time to diagnosis in clinic was significantly longer at 0.35y (95% CI=[0.28, 0.48]) versus that by ChatGPT at 0.08y (95% CI=[0.04, 0.24]) (p<0.0001). There was no difference in the diagnostic accuracy between ages and by race/ethnicity prior to the inclusion of MRI data. However, prior to including the MRI data, males had a 47% less likely chance of a correct diagnosis relative to females (p=0.05). Post-MRI data inclusion within GPT-3.5, the odds of an accurate diagnosis was 4.0-fold greater for Gen Z participants, relative to non-Gen Z participants (p=0.01) with the diagnostic accuracy being 68% less in males relative to females (p=0.009), and 75% less for White subjects, relative to non-White subjects (p=0.0004). CONCLUSION: Although generative AI platforms enable rapid information access and are not principally designed for use in healthcare, an increase in use by Gen Z is anticipated. However, the obtained responses may not be generalizable to all users and bias may exist in select groups.

Disparities by Race in Pregnancy Care and Clinical Outcomes in Women With Multiple Sclerosis: A Diverse Multicenter Cohort

BACKGROUND AND OBJECTIVES: Racial disparities exist in both neurologic and obstetric populations, underscoring the importance of evaluating pregnancy outcomes in diverse women with multiple sclerosis (MS). The objective of this multicenter retrospective study was to compare pregnancy care and outcomes between Black and Hispanic (underrepresented) and White women with MS. METHODS: Demographic and clinical data were extracted from medical records of 9 US MS centers for women with MS/clinically isolated syndrome who delivered live births between 2010 and 2021. Sites identified at last 15 consecutive Black/Hispanic women and a matching number of White women. Socioeconomic factors, pregnancy, and MS care/outcomes were compared between groups (underrepresented and White and then Black and Hispanic) using Wilcoxon rank sum (U statistic and effect size r reported), χ2, t tests and logistic regressions as appropriate to data type. Multiple imputation by chained equation was used to account for missing data. RESULTS: Overall, 294 pregnancies resulting in live births were analyzed ( 81 Black, 67 Hispanic, and 146 White mothers). Relative to underrepresented women, White women lived in areas of higher median (interquartile range [IQR]) Child Opportunity Index (79 [45.8] vs 22 [45.8], U = 3,824, r = 0.56, p < 0.0001) and were more often employed (84.9% vs 75%, odds ratio [OR] 2.57, CI 1.46-4.50, p = 0.0008) and privately insured (93.8% vs 56.8%, OR 11.6, CI 5.5-24.5, p < 0.0001) and more received a 14-week ultrasound (98.6% vs 93.9%, OR 4.66, CI 0.99-21.96, p = 0.027). Mode of delivery was significantly different between the three groups (X2(10,294) = 20.38, p = 0.03); notably, Black women had the highest rates of emergency cesarean deliveries, and Hispanic women highest rates of uncomplicated vaginal deliveries. Babies born to underrepresented women had lower median (IQR) birthweights than babies born to White women (3,198 g [435.3 g] vs 3,275 g [412.5 g], U = 9,255, r = 0.12, p = 0.04) and shorter median (IQR) breastfeeding duration (4.5 [3.3] vs 6.0 [4.2] months, U = 8,184, r = 0.21, p = 0.003). While underrepresented women were younger than White women (mean [SD] 30.9 [4.8] vs 33.8 [4.0], t = 1.97, CI 1.96-3.98, p < 0.0001), their median (Q1-Q3, IQR) Expanded Disability Status Scale was higher (1.5 [1-2.5, 1.5] vs 1 [0-1.5, 1.5], U = 7,260, r = 0.29, p < 0.0001) before pregnancy. Finally, medical records were missing more key data for Black women (19.7% missing vs 8.9% missing, OR 2.54, CI 1.25-5.06, p = 0.008). DISCUSSION: In this geographically diverse multicenter cohort, underrepresented women entered pregnancy with higher disability and fewer health care resources. Pregnancy represents a pivotal window where structural factors affect maternal and fetal health and neurologic trajectories; it is a critical period to optimize care and health outcomes.

A narrative review of neuro-ophthalmologic disease in African Americans and Hispanics with multiple sclerosis.

Multiple sclerosis (MS) is the most common non-traumatic cause of disability in young people, with vision loss in the disease representing the second largest contributor to disability. In particular, African-American patients with MS are noted to have lower vision than their Caucasian counterparts. In this review, we examine the disparities in eye diseases in the MS population with our gaps in knowledge and discuss the underlying nature of pathological disparities.

Understanding humoral immunity and multiple sclerosis severity in Black, and Latinx patients.

People identified with Black/African American or Hispanic/Latinx ethnicity are more likely to exhibit a more severe multiple sclerosis disease course relative to those who identify as White. While social determinants of health account for some of this discordant severity, investigation into contributing immunobiology remains sparse. The limited immunologic data stands in stark contrast to the volume of clinical studies describing ethnicity-associated discordant presentation, and to advancement made in our understanding of MS immunopathogenesis over the past several decades. In this perspective, we posit that humoral immune responses offer a promising avenue to better understand underpinnings of discordant MS severity among Black/African American, and Hispanic/Latinx-identifying patients.

Disease associations of excessive daytime sleepiness in multiple sclerosis: A prospective study.

Background: Excessive daytime sleepiness (EDS) in multiple sclerosis (MS) can be a significant source of disability. Despite this, its prevalence as a patient-reported outcome in this condition has not been well established, and its causes are not well understood. Methods: We prospectively assessed EDS as part of an observational study for patients referred for diagnostic neuro-ophthalmological testing. EDS was evaluated by the Epworth Sleepiness Scale (ESS), and visual data were also collected as part of a research protocol. Analysis with patient data was performed following the exclusion of patients with known primary sleep disorders. Results: A total of 69 patients with MS were included in the analysis. The mean ESS was 6.5 with a SD of 4.3. ESS ≥ 10 was present in 23% of the cohort even in the presence of minimal mean neurological disability (Patient Determined Disease Steps (PDDS) = 1.5). The ESS score was not associated with age, sex, disease-related disability, retinal nerve fiber layer (RNFL), or optic neuritis (ON), but displayed an association with visual dysfunction. Conclusions: There is an increased prevalence of EDS in MS. The increased values of the ESS are not explained by other sleep disorders, suggesting separate mechanisms. Further study of the underlying mechanisms is warranted.

Tailoring Multi-Dimensional Outcomes to Level of Functional Recovery after Traumatic Brain Injury.

There is increasing emphasis on assessing multi-dimensional outcomes in traumatic brain injury (TBI), but achieving this aim is hampered by a plethora of overlapping assessment tools. There is a clear need for advice on the choice of outcomes and we examined level of functional recovery as a framework to guide selection of assessments. In this cohort study we analysed cross-sectional data from 2604 patients enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) project. Patients were followed up 6 months after injury and assessed on the Glasgow Outcome Scale-Extended (GOSE), cognitive tests, and patient-reported outcomes. We describe assessment completeness and prevalence of impairment. Relationships between outcomes were visualized using UpSet plots and hierarchical cluster analysis. GOSE categories varied markedly for both completion rates, 34-91% for patient-reported outcomes and 9-81% for cognitive tests, and prevalence of impairment, 3-82% for patient-reported outcomes and 9-59% for cognitive tests. In complete case samples, the GOSE identified impairment in 59-61%, whereas the most impaired patient-reported outcome was the Short Form-12 version 2 (SF-12v2) Physical Component Summary (28% overall), and the most impaired cognitive test was Trail Making Test (TMT) Part A (19% overall). The findings show that degree of disability is a key context of use for cognitive tests and patient-reported outcomes. Level of functional recovery provides a guide to the feasibility of different types of assessment and the likelihood of impairment, and can help tailor suitable assessment approaches in clinical practice and research studies.

Questionnaires vs Interviews for the Assessment of Global Functional Outcomes After Traumatic Brain Injury.

Importance: An interview is considered the gold standard method of assessing global functional outcomes in clinical trials among patients with acute traumatic brain injury (TBI). However, several multicenter clinical trials have used questionnaires completed by a patient or caregiver to assess the primary end point. Objective: To examine agreement between interview and questionnaire formats for assessing TBI outcomes and to consider whether an interview has advantages. Design, Setting, and Participants: This cohort study used data from patients enrolled in the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) project from December 2014 to December 2017. Data were analyzed from December 2020 to April 2021. Included patients were aged 16 years or older with TBI and a clinical indication for computed tomography imaging. Outcome assessments were completed using both an interview and a questionnaire at follow-up 3 and 6 months after injury. Exposures: Traumatic brain injury of all severities. Main Outcomes and Measures: Ratings on the Glasgow Outcome Scale-Extended (GOSE) administered as a structured interview rated by an investigator and as a questionnaire completed by patients or caregivers and scored centrally were compared, and the strength of agreement was evaluated using weighted κ statistics. Secondary outcomes included comparison of different sections of the GOSE assessments and the association of GOSE ratings with baseline factors and patient-reported mental health, health-related quality of life, and TBI symptoms. Results: Among the 3691 eligible individuals in the CENTER-TBI study, both GOSE assessment formats (interview and questionnaire) were completed by 994 individuals (26.9%) at 3 months after TBI (654 [65.8%] male; median age, 53 years [IQR, 33-66 years]) and 628 (17.0%) at 6 months (409 [65.1%] male; median age, 51 years [IQR, 31-64 years]). Outcomes of the 2 assessment methods agreed well at both 3 months (weighted κ, 0.77; 95% CI, 0.73-0.80) and 6 months (weighted κ, 0.82; 95% CI, 0.78-0.86). Furthermore, item-level agreement between the 2 methods was good for sections regarding independence in everyday activities (κ, 0.70-0.79 across both time points) and moderate for sections regarding subjective aspects of functioning such as relationships and symptoms (κ, 0.41-0.51 across both time points). Compared with questionnaires, interviews recorded more problems with work (294 [30.5%] vs 233 [24.2%] at 3 months and 161 [26.8%] vs 136 [22.7%] at 6 months), fewer limitations in social and leisure activities (330 [33.8%] vs 431 [44.1%] at 3 months and 179 [29.7%] vs 219 [36.4%] at 6 months), and more symptoms (524 [53.6%] vs 324 [33.1%] at 3 months and 291 [48.4%] vs 179 [29.8%] at 6 months). Interviewers sometimes assigned an overall rating based on judgment rather than interview scoring rules, particularly for patients with potentially unfavorable TBI outcomes. However, for both formats, correlations with baseline factors (ρ, -0.13 to 0.42) and patient-reported outcomes (ρ, 0.29 to 0.65) were similar in strength. Conclusions and Relevance: In this cohort study, GOSE ratings obtained by questionnaire and interview methods were in good agreement. The similarity of associations of the ratings obtained by both GOSE methods with baseline factors and other TBI outcome measures suggests that despite some apparent differences, the core information collected by both interviews and questionnaires was similar. The findings support the use of questionnaires in studies in which this form of contact may offer substantial practical advantages compared with interviews.

Randomized Controlled Trials in Adult Traumatic Brain Injury: A Systematic Review on the Use and Reporting of Clinical Outcome Assessments.

As part of efforts to improve study design, the use of outcome measures in randomized controlled trials (RCTs) in traumatic brain injury (TBI) is receiving increasing attention. This review aimed to assess how clinical outcome assessments (COAs) have been used and reported in RCTs in adult TBI. Systematic literature searches were conducted to identify medium to large (n ≥ 100) acute and post-acute TBI trials published since 2000. Data were extracted independently by two reviewers using a set of structured templates. Items from the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement and CONSORT patient-reported outcomes (PROs) extension were used to evaluate reporting quality of COAs. Glasgow Outcome Scale/Extended (GOS/GOSE) data were extracted using a checklist developed specifically for the review. A total of 126 separate COAs were identified in 58 studies. The findings demonstrate heterogeneity in the use of TBI outcomes, limiting comparisons and meta-analyses of RCT findings. The GOS/GOSE was included in 39 studies, but implemented in a variety of ways, which may not be equivalent. Multi-dimensional outcomes were used in 30 studies, and these were relatively more common in rehabilitation settings. The use of PROs was limited, especially in acute study settings. Quality of reporting was variable, and key information concerning COAs was often omitted, making it difficult to know how precisely outcomes were assessed. Consistency across studies would be increased and future meta-analyses facilitated by (a) using common data elements (CDEs) recommendations for TBI outcomes and (b) following CONSORT guidelines when publishing RCTs.

Genetic dissection of mouse distal chromosome 1 reveals three linked BMD QTLs with sex-dependent regulation of bone phenotypes.

UNLABELLED: Genetic analyses with mouse congenic strains for distal Chr1 have identified three closely linked QTLs regulating femoral vBMD, mid-diaphyseal cortical thickness, and trabecular microstructure in a sex-dependent fashion. The homologous relationship between distal mouse Chr 1 and human 1q21-24 offers the possibility of finding common regulatory genes for cortical and trabecular bone. INTRODUCTION: The distal third of mouse chromosome 1 (Chr 1) has been shown to carry a major quantitative trait locus (QTL) for BMD from several inbred mouse strain crosses. Genetic and functional analyses are essential to identify genes and cellular mechanisms for acquisition of peak bone mass. MATERIALS AND METHODS: Nested congenic sublines of mice were developed with a C57BL/6J (B6) background carrying <1- to 9-Mbp-sized segments donated from C3H/HeJ (C3H). Isolated femurs from 16-wk-old female and male mice were measured by pQCT and microCT40 for volumetric (v)BMD, mid-diaphyseal cortical thickness, and distal trabecular phenotypes. Static and dynamic histomorphologic data were obtained on selected females and males at 16 wk. RESULTS AND CONCLUSIONS: We found that the original BMD QTL, Bmd5, mapped to distal Chr 1 consists of three QTLs with different effects on vBMD and trabecular bone in both sexes. Compared with B6 controls, femoral vBMD, BMD, and cortical thickness (p < 0.0001) were significantly increased in congenic subline females, but not in males, carrying C3H alleles at QTL-1. Both females and males carrying C3H alleles at QTL-1 showed marked increases in BV/TV by microCT compared with B6 mice (p < 0.0001). Females increased BV/TV by increasing trabecular thickness, whereas males increased trabecular number. In addition, the microCT40 data showed two unique QTLs for male trabecular bone, QTL-2 and QTL-3, which may interact to regulate trabecular thickness and number. These QTLs are closely linked with and proximal to QTL-1. The histomorphometric data revealed sex-specific differences in cellular and bone formation parameters. Mice and humans share genetic homology between distal mouse Chr 1 and human Chr 1q20-24 that is associated with adult human skeletal regulation. Sex- and compartment-specific regulatory QTLs in the mouse suggest the need to partition human data by sex to improve accuracy of mapping and genetic loci identification.

A chromosomal inversion within a quantitative trait locus has a major effect on adipogenesis and osteoblastogenesis.

We mapped a quantitative trait locus (QTL) for BMD to mid-distal chromosome (Chr) 6 in a cross between C57BL/6J (B6) and C3H/HeJ (C3H). The B6.C3H-6T (6T) congenic was developed to map candidate genes in this QTL. Recently, a 25 cM paracentric inversion was discovered on Chr 6 in C3H/HeJ; we found 6T also carries this inversion. Microarrays from the liver of B6 and 6T uncovered two narrow bands of decreased gene expression in close proximity to the predicted locations of the inversion breakpoints. Changes in specific gene expression in 6T were consistent with its phenotype of low trabecular bone volume and marrow adipogenesis. The BXH recombinant inbred (RI) strains do not carry the C3H/HeJ inversion. To test if the inversion, or allelic effects, were responsible for the 6T phenotype, we made a new congenic, B.H-6, developed by introgressing a 30 Mb region of C3H genomic sequence from BXH6 onto a B6 background. While genetically identical to 6T, this new congenic had a distinct metabolic and skeletal phenotype, with more body fat and greater trabecular BV/TV compared to B6 or 6T. We conclude that the phenotype of 6Tcannot be explained by simple allelic differences in one or more genes from C3H. Rather, 6T demonstrates that disordered regulation of gene expression by genomic rearrangement can have a profound effect on a complex trait, such as BMD, and that genomic rearrangement can supersede the effects of various alleles.

Distal Chr 4 harbors a genetic locus (Gct1) fundamental for spontaneous ovarian granulosa cell tumorigenesis in a mouse model.

The spontaneous development of juvenile-onset ovarian granulosa cell tumors in mice of the SWXJ-9 recombinant inbred strain is a model for juvenile-type granulosa cell tumors that appear in very young girls. To expedite gene discovery in this mouse model of childhood cancer, we did a gene mapping study with the SWXJ-9 recombinant inbred strain and the evolutionarily divergent Mus musculus castaneus (CAST/Ei) strain as a mapping partner. Our mapping strategy focused on autosomal determinants of susceptibility with a backcross scheme that exploited a paternal, parent-of-origin effect for a X-linked gene (Gct4) that strongly supports granulosa cell tumor development. Of 1,968 backcross females examined, we detected 81 granulosa cell tumor-bearing animals and compared their allelic inheritance patterns to non-tumor-bearing siblings in a case-control analysis. The results of our study have confirmed an important locus on mouse chromosome (Chr) 4 (Gct1) and have revealed new loci for granulosa cell tumor susceptibility (Gct7-Gct9) on Chrs 1, 2, and 13 with susceptibility alleles contributed by the SWXJ-9 progenitor. Two novel gene-gene interactions supportive for granulosa cell tumor development were also observed between loci on Chrs 17 and 18 and loci on Chrs 2 and 10. Our data substantiate the evidence that Gct1 on Chr 4 is a fundamental oncogene for granulosa cell tumorigenesis in mice and has identified additional interacting autosomal loci that support tumor development.

The Role of EGFR-Met Interactions in the Pathogenesis of Glioblastoma and Resistance to Treatment.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. It is a devastating and intractable disease with a poor outcome. Aberrant receptor tyrosine kinase signaling is a key driver in gliomagenesis and resistance to treatment. EGFR gene amplification and mutations are an important genetic alteration in GBM resulting in increased expression of EGFR wild type (EGFRwt) as well as mutant oncogenic forms of the EGFR. EGFRvIII is the most common oncogenic mutant in GBM and is usually co-expressed with EGFRwt. EGFRvIII does not bind ligand and is constitutively active. Recent studies have also highlighted a key role for Met in gliomagenesis and the EGFR and Met may act in concert to promote the malignant phenotype. Met is transactivated by EGFRvIII and plays a key role in EGFRvIII-mediated resistance to targeted treatment. HGF, a Met ligand, is highly expressed in GBM. HGF and Met create an important autocrine signaling loop that promotes GBM invasion. In addition, HGF/Met is able to induce EGFR activation, leading to enhanced activation of oncogenic signaling in GBM. In this review, we discuss the evidence for EGFR and Met interaction in GBM and discuss the mechanisms and biological consequences of transactivation between the two kinases. Additionally, we discuss the therapeutic potential of targeting both EGFR and Met signaling for the treatment of GBM.

The chronic and evolving neurological consequences of traumatic brain injury.

Traumatic brain injury (TBI) can have lifelong and dynamic effects on health and wellbeing. Research on the long-term consequences emphasises that, for many patients, TBI should be conceptualised as a chronic health condition. Evidence suggests that functional outcomes after TBI can show improvement or deterioration up to two decades after injury, and rates of all-cause mortality remain elevated for many years. Furthermore, TBI represents a risk factor for a variety of neurological illnesses, including epilepsy, stroke, and neurodegenerative disease. With respect to neurodegeneration after TBI, post-mortem studies on the long-term neuropathology after injury have identified complex persisting and evolving abnormalities best described as polypathology, which includes chronic traumatic encephalopathy. Despite growing awareness of the lifelong consequences of TBI, substantial gaps in research exist. Improvements are therefore needed in understanding chronic pathologies and their implications for survivors of TBI, which could inform long-term health management in this sizeable patient population.

Congenic mice with low serum IGF-I have increased body fat, reduced bone mineral density, and an altered osteoblast differentiation program.

Targeted gene studies have demonstrated the importance of insulin-like growth factor-I (IGF-I) for osteoblast (OB) differentiation and the acquisition of peak bone mineral density (BMD). The skeletal response to allelic differences in IGF-I expression can also be measured in vivo, using congenic mice. We created a congenic strain with reduced (approximately 20%) circulating IGF-I (C3H.B6-6T [6T]) by backcrossing a small genomic region (30 cM) of Chromosome 6 (Chr6) from C3H/HeJ (C3H) onto a C57Bl/6J (B6) background. 6T female mice have lower serum IGF-I (P<0.001 vs. B6) but similar growth hormone (GH) and serum IGF binding protein (IGFBP) concentrations as B6. At 16 weeks of age, congenics have greater body fat (P<0.02 vs. B6) despite less total body weight, and exhibit smaller femoral cross-sectional size (P=0.001), reduced cortical thickness (P<0.001) and lower trabecular BV/TV (P<0.05) than B6. 6T mice also have suppressed serum leptin (P<0.01), but compared to B6 have similar markers of bone resorption (i.e., urine CTx and serum TRAP 5B). At 8 weeks of age, skeletal IGF-I mRNA from long bones was reduced by 40% (P<0.05) as were liver mRNA transcripts (i.e., 50%, P<0.01). Osteoblast progenitors from the bone marrow of 6T mice formed less colony forming unit fibroblasts by crystal violet staining than B6 (P<0.007) and had significantly reduced alkaline phosphatase-positive colonies than B6(P<0.0001). In addition, staining of bone marrow with oil red O revealed greater numbers of adipocytes in 6T than B6. Several candidate genes in the Chr6 QTL were excluded by lack of strain-related expression differences in bone, but genes positively regulating adipocyte differentiation including Alox 5 and PPAR-gamma require further study as either "pathway" or candidate genes. In summary, allelic differences in a QTL on Chr6 result in altered IGF-I gene expression, changes in OB lineage allocation, and reduced peak bone mass. Congenic mice are useful models not only for mapping genes related to bone mass but also for elucidating the biology underlying various skeletal phenotypes associated with more subtle manipulation of the mouse genome.

Effect of 4-aminopyridine on vision in multiple sclerosis patients with optic neuropathy.

OBJECTIVE: The objective of this randomized, double-blind, placebo-controlled, crossover study was to examine if patients with optic neuropathy would derive a therapeutic benefit from 4-aminopyridine (4-AP) treatment. Furthermore, the study was intended to determine if patients with certain P100 latencies or retinal nerve fiber layer (RNFL) measures would be more likely to respond to therapy. METHODS: Patients were enrolled in a randomized, placebo-controlled, double-blind, crossover study of 10 weeks duration. Patients underwent visual evoked potentials (VEP), optical coherence tomography (OCT), and visual acuity before starting 5 weeks of either placebo or 4-AP. After 5 weeks, they completed a second evaluation (VEP, OCT, and visual acuity) and were crossed over between treatment arms. Five weeks later, they had their final evaluation. All investigators were blinded to treatment arm until after data analysis. RESULTS: On average, patients had faster P100s on 4-AP when compared to placebo. A subset of patients had distinct responses to 4-AP as measured by improvements in visual acuity. Finally, eyes with an RNFL measure between 60 and 80 µm had the highest response rate. CONCLUSIONS: 4-Aminopyridine is useful for improving vision in patients with demyelinating optic neuropathy. Future clinical trials may be able to enrich a patient population for potential responders using OCT and VEP measures. Selecting patients for future trials should use RNFL measures as part of inclusion/exclusion criteria. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence supporting the use of 4-AP in certain patients with optic neuropathy to improve visual function (patients with RNFL between 60 and 80 µm).

Multiple quantitative trait loci for cortical and trabecular bone regulation map to mid-distal mouse chromosome 4 that shares linkage homology to human chromosome 1p36.

The mid-distal region of mouse chromosome 4 (Chr 4) is homologous with human Chr 1p36. Previously, we reported that mouse Chr 4 carries a quantitative trait locus (QTL) with strong regulatory effect on volumetric bone mineral density (vBMD). The intent of this study is to utilize nested congenic strains to decompose the genetic complexity of this gene-rich region. Adult females and males from 18 nested congenic strains carrying discrete C3H sequences were phenotyped for femoral mineral and volume by pQCT and for trabecular bone volume (BV), tissue volume (TV), trabecular number (Trab.no), and trabecular thickness (Trab.thk) by MicroCT 40. Our data show that the mouse Chr 4 region consists of at least 10 regulatory QTL regions that affected either or both pQCT and MicroCT 40 phenotypes. The pQCT phenotypes were typically similar between sexes, whereas the MicroCT 40 phenotypes were divergent. Individual congenic strains contained one to seven QTL regions. These regions conferred large positive or negative effects in some congenic strains, depending on the particular bone phenotype. The QTL regions II to X are syntenic with human 1p36, containing from 1 to 102 known genes. We identified 13 candidate genes that can be linked to bone within these regions. Six of these genes were linked to osteoblasts, three linked to osteoclasts, and two linked to skeletal development. Three of these genes have been identified in Genome Wide Association Studies (GWAS) linked to 1p36. In region III, there is only one gene, Lck, which conferred negative pQCT and MicroCT 40 phenotypes in both sexes. This gene is important to development and functioning of T cells, has been associated with osteoclast activity, and represents a novel bone regulatory gene that merits further experimental evaluation. In summary, congenic strains are powerful tools for identifying regulatory regions that influence bone biology and offer models for testing hypotheses about gene-gene and gene-environment interactions that are not available to experimental work in humans.