The retrospective nature of this study limits the conclusions that can be determined as the methodology was not able to ascertain any measure of acute versus chronic marijuana use. Urine toxicology screens, such as those used in the ED, detectable levels of THC can be present for up to 4.6 days after the last noted use for individuals who do not use marijuana frequently, or up to 15.4 days after last use for those who are frequent users . Therefore, the presence of marijuana at the time of exposure may not correlate with recent use. Timing of exposure may be a factor and is an important limitation in this study. Additionally, study findings are based on patients with TBI that have had a urine THC test performed. Since not all patients with moderate or severe TBI were tested for the presence of THC, bias is thus introduced. There was a large percentage of study participants who were not tested or had missing test results for THC . Consequently, a more accurate analysis of THC prevalence and association was not possible as there was no way to determine which of those cases that were not tested or had no results documented were positive for THC. It is important to note that despite there being a small percentage of THC prevalence, this study reflects only one year worth of data, from 2017, and that establishing previous prevalence rates for comparison from the NTDB cannot be calculated. This is because the presence of THC was never abstracted nor documented in the data set prior to 2017. Future studies examining prevalence rates for a series of years is warranted. Observational research has been shown to provide mis-estimations of the outcome of interest. Data analyzed from the NTDB is extracted from various trauma registries across the United States and Canada.
Each hospital employs its own registry abstractors who input the data collected from the electronic medical record into the registry which then feeds into the NTDB. This is an important limitation as the documentation and accuracy of data inputted may be inaccurate, incomplete, or inconsistent. This can result in information bias. Furthermore, indoor vertical farming system systematic under reporting of data by participating hospitals can result in selection bias and create an inconsistent database. An example of this was the lack of consistency in the measurement and documentation of blood alcohol levels at time of hospital admission, and the missed opportunities for urine testing. This contributed to a large percentage of missing data which may have also introduced informational bias. Additionally, this variation in reporting results in incomplete data, as seen in this study, as well as conflicting data. There were two occasions where participants were documented as having not being tested for any substances yet were each found to have been positive for THC and/or cocaine. Outcomes of such practices and variations between trauma registries leads to a lack of confidence regarding data accuracy and resulting analyses. Successful viral suppression from combination antiretroviral therapy has led to an increase in life expectancy among persons living with HIV . While severe HIV associated neurocognitive disorder is less prevalent in the cART era, mild to moderate HAND persists despite virologic suppression. HAND affects up to 50% of HIV-positive persons, with older HIV-positive adults at greater risk for neurocognitive impairment than their younger counterparts.Among neurocognitive domains affected by HAND, complex motor skills are consistently compromised across time. Complex motor skills refer to a combination of cognitive and perceptual-motor abilities, including perception, planning, continuous tracking, and sequential movements. Although the prevalence of complex motor impairment has receded in comparison to the pre-cART era, deficits in complex motor functioning are still observed in approximately 30% of those with HAND.
Complex motor impairment is related to everyday functioning impairment, including driving ability, highlighting the clinical relevance in understanding mechanistic pathways underlying HIV-associated motor dysfunction. A recent longitudinal study found that complex motor function is particularly vulnerable to the effects of age and stage of HIV infection, and implicated the basal ganglia as a neural correlate of interest. The effects of acute HIV infection on the basal ganglia are well documented, with greater atrophy associated with psychomotor slowing. Inflammatory processes are one putative factor that may contribute to central nervous system injury, including deficits in complex motor skills. Biomarkers of inflammation, such as cytokines and monocytes, are elevated in the context of HIV infection. HIV, viral products, and activated immune cells are able to cross the blood brain barrier and contribute to inflammation in the CNS. Neuroimaging studies have shown that peripheral inflammatory biomarkers are able to alter neural activity in the basal ganglia, including dopaminergic activity, which is reflected by psychomotor slowing in HIV-negative adults. Among HIV-positivepersons, global neurocognitive impairment is associated with elevation of various peripheral biomarkers of inflammation and coagulation . Taken together, deficits in complex motor performance are commonly observed among HIV-positive persons, and elevation in peripheral biomarkers of inflammation may be a contributing factor. Thus, we hypothesize that HIV will have negative direct and indirect effects via inflammation on complex motor performance. Comparisons of demographic, neuromedical, psychiatric, and biomarker data between the HIV-positive and HIV-negative groups were performed with two-tailed t-test, Wilcoxon rank-sum test, likelihood ratio 2 test, or Fisher Exact Tests , as appropriate. FET and Kruskal-Wallis tests were conducted to examine whether complex motor performance, inflammatory biomarkers, and HIV disease characteristics differed by age decade. When appropriate, the biomarker values were log10 transformed for group comparisons. Hedge’s g statistic for continuous variables and odds ratios for binary variables were used to generate effect sizes for group comparisons. To adjust for multiple comparisons, the Benjamini-Hochberg method was used to limit false discovery rate to 5%. Group comparisons were performed with JMP 11.0.0 .
Path analysis was used to test the indirect effect of HIV on complex motor performance through the pathway of inflammation. To conduct the path analysis, we calculated biascorrected 95% confidence intervals using bootstrapping with the Process Procedure. The Process Procedure calculates the unstandardized path coefficients for all paths in the model. Covariates were selected based on which variables in Table 1 demonstrated univariable associations with the primary dependent variable at a critical α = .10. The following covariates were identified as having met our criterion for inclusion in the analysis as control variables: hypertension, hyperlipidemia, diabetes mellitus, lifetime cannabis use disorder, and lifetime methamphetamine use disorder. Given that demographic variables were accounted for in the adjusted T-scores for complex motor performance,indoor vertical farming technology we did not include demographic variables as covariates for analyses involving complex motor performance as the outcome variable of interest. Path analyses were performed using IBM SPSS Statistics for Windows, Version 24. Although neurologic findings commonly associated with HIV infection have been suggested to largely remit with initiation of cART, our cross-sectional study observed worse complex motor skills across the adult age continuum of HIV-positive, relative to HIV-negative, adults. Inflammation burden was higher among HIV-positive adults, compared to the HIVnegative comparison group. Consistent with our hypothesis, HIV infection was observed to have both direct and indirect effects via inflammation on complex motor performance, such thatinflammation burden accounted for 15.1% of the effect of HIV infection on motor performance when controlling for relevant covariates. These results indicate that inflammatory processes may contribute to worse complex motor skills in the context of cART-treated HIV. Our sample consisted of virally suppressed, chronic HIV-positive patients; however, impairment in complex motor skills was still observed among 20% of the HIV-positive sample. This observed impairment rate is consistent with motor impairment rates reported in previous literature e.g. Some evidence indicates a higher impairment rate in complex motor performance among persons with chronic HIV compared to persons with acute or early HIV infection, which may reflect a history of immunosuppression and/or greater inflammation burden. For example, persons with AIDS performed significantly worse on a fine motor speed test than those without AIDS. Deficits in motor skills may indicate injury to the basal ganglia, which are part of the motor control pathways. The basal ganglia appears to be particularly vulnerable to alterations in BBB permeability, immune cellular infiltration, and accumulation of HIV viral RNA. Neuropathological studies have observed higher concentrations of macrophages, microglia, and viral proteins in the basal ganglia. Our path analyses indicate that inflammation burden may play a role in the association between HIV infection and worse complex motor performance. This finding is consistent with previous research demonstrating the detrimental impact of HIV and its proteins on the brain through peripheral and CNS pathways. Monocytes and macrophages are observed to infiltrate the CNS in HIV infection. Elevations in soluble markers of monocyte and cytokine activation, including sCD14, MCP-1/CCL2 and IL-6, have been observed among HIV-positive adults with neurocognitive impairment.Expression of MCP-1/CCL2 may contribute to upregulation of HIV-1 replication, thereby contributing to an increased risk of neurocognitive impairment.
In addition to inflammation, coagulation imbalance, which includes upregulation of D-dimer, is associated with global neurocognitive functioning among HIV-positive adults. In the current analysis, D-dimer was included in the inflammation burden composite given the bidirectional relationship between inflammation and coagulation . Multiple factors likely contribute to activation of inflammatory and coagulation pathways observed among HIV-positive persons on cART, such as viral replication, excess levels of translocated microbial products and other chronic pathogens , and loss of immunoregulatory responses. HIV was observed to have both direct and indirect effects via inflammation burden on complex motor performance; however, inflammation burden only accounted for 15.1% of the effect of HIV on complex motor performance. These results suggest there are additional mechanisms by which HIV may have deleterious effects on complex motor performance. Other factors contributing to neurocognitive impairment may include vascular remodeling , metabolic disorders , and co-infections. The present study evaluated a model that identified one plausible indirect pathway between HIV and worse complex motor performance; future research may build upon this work by evaluating models with multiple pathways in order to estimate the relative contribution of various plausible mediators. A better understanding of the interplay of factors contributing to neurologic dysfunction in HIV may lead to more accurate prognosis and and/or risk stratification of HIV-positive adults in regard to neurologic dysfunction. Although some brain metabolite abnormalities may improve after initiating cART, some abnormalities persist, including ongoing inflammatory processes. A long-term prospective cohort study found interacting effects of aging and HIV disease stage, such that the magnitude of motor performance impairment was greater than the sum of the independent effects of age and HIV disease stage. The interaction between aging and HIV disease stage suggest that complex motor skills may be particularly susceptible to aging-related progression of neurocognitive impairment among HIV-positive adults. The Grooved Pegboard Test appears to be particularly sensitive to detecting neurocognitive decline among HIV-positive persons.Our study findings should be considered in light of its limitations. First, although we used path analysis, this study was cross-sectional in nature, which precludes us from making inferences in regard to causation or mediation. Our results are also consistent with the alternative hypothesis that both inflammatory processes and complex motor skills may be mediated by an unobserved third variable. Given that the parent study involves repeated assessment of neurocognitive functioning and inflammation over five years, future analyses will examine whether changes in inflammation are associated with changes in complex motor functioning. Second, our study could not rule out other pathology underlying complex motor performance deficits . Third, it is unclear how to best conceptualize inflammation burden as normative standards regarding biomarker measurement and conceptualization have not been established. However, our calculation of a composite inflammation burden score may be a viable method compared to reliance on a single biomarker given our analysis indicated that complex motor performance was significantly associated with the composite but not any individual biomarker. Furthermore, conceptualization of an inflammation burden composite adds to the body of research aimed at developing clinically relevant risk indices . Fourth, our HIV-negative comparison group was relatively healthy and differed from the HIV-positive group on multiple characteristics. Fifth, our HIV-positive group consisted of mostly non-Hispanic white males with some college education, which is not fully representative of HIV-positive persons in the United States. Sixth, prior research indicates multitasks may better detect motor impairment compared to a single motor task ; the Grooved Pegboard Test, however, involves the use of many complex operations and is correlated with a range of cognitive functions. In summary, HIV has a deleterious impact on complex motor skills, which may be partially explained by inflammatory processes.