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Background: The growth in multi-center neuroimaging studies generated a need for methods that mitigate the differences in hardware and acquisition protocols across sites i.e., scanner effects. ComBat harmonization methods have shown promise but have not yet been tested on all the data types commonly studied with magnetic resonance imaging (MRI). This study aimed to validate neuroCombat, longCombat and gamCombat on both structural and diffusion metrics in both cross-sectional and longitudinal data., Methods: We used a travelling subject design whereby 73 healthy volunteers contributed 161 scans across two sites and four machines using one T1 and five diffusion MRI protocols. Scanner was defined as a composite of site, machine and protocol. A common pipeline extracted two structural metrics (volumes and cortical thickness) and two diffusion tensor imaging metrics (mean diffusivity and fractional anisotropy) for seven regions of interest including gray and (except for cortical thickness) white matter regions., Results: Structural data exhibited no significant scanner effect and therefore did not benefit from harmonization in our particular cohort. Indeed, attempting harmonization obscured the true biological effect for some regions of interest. Diffusion data contained marked scanner effects and was successfully harmonized by all methods, resulting in smaller scanner effects and better detection of true biological effects. LongCombat less effectively reduced the scanner effect for cross-sectional white matter data but had a slightly lower probability of incorrectly finding group differences in simulations, compared to neuroCombat and gamCombat. False positive rates for all methods and all metrics did not significantly exceed 5%., Conclusions: Statistical harmonization of structural data is not always necessary and harmonization in the absence of a scanner effect may be harmful. Harmonization of diffusion MRI data is highly recommended with neuroCombat, longCombat and gamCombat performing well in cross-sectional and longitudinal settings., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David Menon received personal fees from Lantmannen AB, 10.13039/100004330GlaxoSmithKline plc, Calico Life Sciences LLC, PresSura Neuro, Integra Neurosciences, and NeuroTrauma Sciences, LLC; grants from 10.13039/100004330GlaxoSmithKline plc; and a shared 10.13039/100000002National Institutes of Health grant from Gryphon Collaborators on a grant application outside the presented work. Virginia Newcombe holds grants from F. Hoffman–La Roche Ltd and received personal fees from Neurodiem Honorarium for a talk put into the 10.13039/501100000735University of Cambridge research fund outside the presented work., (© 2022 The Authors.)

Objective: To determine the effect of extracranial injury (ECI) on 6-month outcome in patients with mild traumatic brain injury (TBI) versus moderate-to-severe TBI., Participants/setting: Patients with TBI (n = 135) or isolated orthopedic injury (n = 25) admitted to a UK major trauma center and healthy volunteers (n = 99)., Design: Case-control observational study., Main Measures: Primary outcomes: (a) Glasgow Outcome Scale Extended (GOSE), (b) depression, (c) quality of life (QOL), and (d) cognitive impairment including verbal fluency, episodic memory, short-term recognition memory, working memory, sustained attention, and attentional flexibility., Results: Outcome was influenced by both TBI severity and concomitant ECI. The influence of ECI was restricted to mild TBI; GOSE, QOL, and depression outcomes were significantly poorer following moderate-to-severe TBI than after isolated mild TBI (but not relative to mild TBI plus ECI). Cognitive impairment was driven solely by TBI severity. General health, bodily pain, semantic verbal fluency, spatial recognition memory, working memory span, and attentional flexibility were unaffected by TBI severity and additional ECI., Conclusion: The presence of concomitant ECI ought to be considered alongside brain injury severity when characterizing the functional and neurocognitive effects of TBI, with each presenting challenges to recovery.

Background: Previous secondhand smoke (SHS) reduction interventions have provided only delayed feedback on reported smoking behaviour, such as coaching, or presenting results from child cotinine assays or air particle counters., Design: This SHS reduction trial assigned families at random to brief coaching and continuous real-time feedback (intervention) or measurement-only (control) groups., Participants: We enrolled 298 families with a resident tobacco smoker and a child under age 14., Intervention: We installed air particle monitors in all homes. For the intervention homes, immediate light and sound feedback was contingent on elevated indoor particle levels, and up to four coaching sessions used prompts and praise contingent on smoking outdoors. Mean intervention duration was 64 days., Measures: The primary outcome was 'particle events' (PEs) which were patterns of air particle concentrations indicative of the occurrence of particle-generating behaviours such as smoking cigarettes or burning candles. Other measures included indoor air nicotine concentrations and participant reports of particle-generating behaviour., Results: PEs were significantly correlated with air nicotine levels (r=0.60) and reported indoor cigarette smoking (r=0.51). Interrupted time-series analyses showed an immediate intervention effect, with reduced PEs the day following intervention initiation. The trajectory of daily PEs over the intervention period declined significantly faster in intervention homes than in control homes. Pretest to post-test, air nicotine levels, cigarette smoking and e-cigarette use decreased more in intervention homes than in control homes., Conclusions: Results suggest that real-time particle feedback and coaching contingencies reduced PEs generated by cigarette smoking and other sources., Trial Registration Number: NCT01634334; Post-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Traumatic brain injury (TBI) is not a single insult with monophasic resolution, but a chronic disease, with dynamic processes that remain active for years. We aimed to assess patient trajectories over the entire disease narrative, from ictus to late outcome., Methods: Twelve patients with moderate-to-severe TBI underwent magnetic resonance imaging in the acute phase (within 1 week of injury) and twice in the chronic phase of injury (median 7 and 21 months), with some undergoing imaging at up to 2 additional time points. Longitudinal imaging changes were assessed using structural volumetry, deterministic tractography, voxel-based diffusion tensor analysis, and region of interest analyses (including corpus callosum, parasagittal white matter, and thalamus). Imaging changes were related to behavior., Results: Changes in structural volumes, fractional anisotropy, and mean diffusivity continued for months to years postictus. Changes in diffusion tensor imaging were driven by increases in both axial and radial diffusivity except for the earliest time point, and were associated with changes in reaction time and performance in a visual memory and learning task (paired associates learning). Dynamic structural changes after TBI can be detected using diffusion tensor imaging and could explain changes in behavior., Conclusions: These data can provide further insight into early and late pathophysiology, and begin to provide a framework that allows magnetic resonance imaging to be used as an imaging biomarker of therapy response. Knowledge of the temporal pattern of changes in TBI patient populations also provides a contextual framework for assessing imaging changes in individuals at any given time point., (© The Author(s) 2015.)

Introduction: Secondhand smoke contains a mixture of pollutants that can persist in air, dust, and on surfaces for months or longer. This persistent residue is known as thirdhand smoke (THS). Here, we detail a simple method of wipe sampling for nicotine as a marker of accumulated THS on surfaces., Methods: We analyzed findings from 5 real-world studies to investigate the performance of wipe sampling for nicotine on surfaces in homes, cars, and hotels in relation to smoking behavior and smoking restrictions., Results: The intraclass correlation coefficient for side-by-side samples was 0.91 (95% CI: 0.87-0.94). Wipe sampling for nicotine reliably distinguished between private homes, private cars, rental cars, and hotels with and without smoking bans and was significantly positively correlated with other measures of tobacco smoke contamination such as air and dust nicotine. The sensitivity and specificity of possible threshold values (0.1, 1, and 10 μg/m(2)) were evaluated for distinguishing between nonsmoking and smoking environments. Sensitivity was highest at a threshold of 0.1 μg/m(2), with 74%-100% of smoker environments showing nicotine levels above threshold. Specificity was highest at a threshold of 10 μg/m(2), with 81%-100% of nonsmoker environments showing nicotine levels below threshold. The optimal threshold will depend on the desired balance of sensitivity and specificity and on the types of smoking and nonsmoking environments., Conclusions: Surface wipe sampling for nicotine is a reliable, valid, and relatively simple collection method to quantify THS contamination on surfaces across a wide range of field settings and to distinguish between nonsmoking and smoking environments.

Traumatic brain injury (TBI) is often exacerbated by events that lead to secondary brain injury, and represent potentially modifiable causes of mortality and morbidity. Diffusion tensor imaging was used to characterize tissue at-risk in a group of 35 patients scanned at a median of 50 hours after injury. Injury progression was assessed in a subset of 16 patients with two scans. All contusions within the first few days of injury showed a core of restricted diffusion, surrounded by an area of raised apparent diffusion coefficient (ADC). In addition to these two well-defined regions, a thinner rim of reduced ADC was observed surrounding the region of increased ADC in 91% of patients scanned within the first 3 days after injury. In patients who underwent serial imaging, the rim of ADC hypointensity was subsumed into the high ADC region as the contusion enlarged. Overall contusion enlargement tended to be more frequent with early lesions, but its extent was unrelated to the time of initial imaging, initial contusion size, or the presence of hemostatic abnormalities. This rim of hypointensity may characterize a region of microvascular failure resulting in cytotoxic edema, and may represent a 'traumatic penumbra' which may be rescued by effective therapy.

To unravel the mechanism of chloroperoxidase (CPO)-catalyzed regioselective oxidation of indole, we studied the structure of the CPO-indole complex using nuclear magnetic resonance (NMR) relaxation measurements and computational techniques. The dissociation constant (KD) of the CPO-indole complex was calculated to be approximately 21 mM. The distances (r) between protons of indole and the heme iron calculated via NMR relaxation measurements and molecular docking revealed that the pyrrole ring of indole is oriented toward the heme with its 2-H pointing directly at the heme iron. Both KD and r values are independent of pH in the range of 3.0-6.5. The stability and structure of the CPO-indole complex are also independent of the concentration of chloride or iodide ion. Molecular docking suggests the formation of a hydrogen bond between the NH group of indole and the carboxyl O of Glu 183 in the binding of indole to CPO. Simulated annealing of the CPO-indole complex using r values from NMR experiments as distance restraints reveals that the van der Waals interactions were much stronger than the Coulomb interactions in the binding of indole to CPO, indicating that the association of indole with CPO is primarily governed by hydrophobic rather than electrostatic interactions. This work provides the first experimental and theoretical evidence of the long-sought mechanism that leads to the "unexpected" regioselectivity of the CPO-catalyzed oxidation of indole. The structure of the CPO-indole complex will serve as a lighthouse in guiding the design of CPO mutants with tailor-made activities for biotechnological applications.

Background: Secondhand smoke exposure (SHSe) poses health risks to children living with smokers. Most interventions to protect children from SHSe have coached adult smokers. This trial determined whether coaching and cotinine feedback provided to preteens can reduce their SHSe., Methods: Two hundred one predominantly low-income families with a resident smoker and a child aged 8 to 13 years who was exposed to two or more cigarettes per day or had a urine cotinine concentration ≥ 2.0 ng/mL were randomized to control or SHSe reduction coaching groups. During eight in-home sessions over 5 months, coaches presented to the child graphic charts of cotinine assay results as performance feedback and provided differential praise and incentives for cotinine reductions. Generalized estimating equations were used to determine the differential change in SHSe over time by group., Results: For the baseline to posttest period, the coaching group had a greater decrease in both urine cotinine concentration (P = .039) and reported child SHSe in the number of cigarettes exposed per day (child report, P = .003; parent report, P = .078). For posttest to month 12 follow-up, no group or group by time differences were obtained, and both groups returned toward baseline., Conclusions: Coaching preteens can reduce their SHSe, although reductions may not be sustained without ongoing counseling, feedback, and incentives. Unlike interventions that coach adults to reduce child SHSe, programs that increase child avoidance of SHSe have the potential to reduce SHSe in all settings in which the child is exposed, without requiring a change in adult smoking behavior.

Background: Traumatic brain injury is a major cause of morbidity and mortality worldwide. Ameliorating the neurocognitive and physical deficits that accompany traumatic brain injury would be of substantial benefit, but the mechanisms that underlie them are poorly characterized. This study aimed to use diffusion tensor imaging to relate clinical outcome to the burden of white matter injury., Methodology/principal Findings: Sixty-eight patients, categorized by the Glasgow Outcome Score, underwent magnetic resonance imaging at a median of 11.8 months (range 6.6 months to 3.7 years) years post injury. Control data were obtained from 36 age-matched healthy volunteers. Mean fractional anisotropy, apparent diffusion coefficient (ADC), and eigenvalues were obtained for regions of interest commonly affected in traumatic brain injury. In a subset of patients where conventional magnetic resonance imaging was completely normal, diffusion tensor imaging was able to detect clear abnormalities. Significant trends of increasing ADC with worse outcome were noted in all regions of interest. In the white matter regions of interest worse clinical outcome corresponded with significant trends of decreasing fractional anisotropy., Conclusions/significance: This study found that clinical outcome was related to the burden of white matter injury, quantified by diffusivity parameters late after traumatic brain injury. These differences were seen even in patients with the best outcomes and patients in whom conventional magnetic resonance imaging was normal, suggesting that diffusion tensor imaging can detect subtle injury missed by other techniques. An improved in vivo understanding of the pathology of traumatic brain injury, including its distribution and extent, may enhance outcome evaluation and help to provide a mechanistic basis for deficits that remain unexplained by other approaches.

Introduction: Smoking cigarettes in the enclosed environment of a car leads to the contamination of a car's microenvironment with residual tobacco smoke pollution (TSP)., Methods: Surface wipe, air, and dust samples were collected in used cars sold by nonsmokers (n = 40) and smokers (n = 87) and analyzed for nicotine. Primary drivers were interviewed about smoking behavior and restrictions, and car interiors were inspected to investigate (a) differences in car dustiness, signs of past smoking, ventilation use, mileage, and passenger cabin volume among nonsmokers and smokers with and without in-car smoking bans and (b) factors that contribute to the contamination of cars with residual TSP, such as ventilation use, cleaning behaviors, signs of past smoking, and holding the cigarette near/outside the car window while smoking., Results: Smokers reported using air conditioning less (p < .05) and driving with windows down more often than nonsmokers (p = .05); their cars were also dustier (p < .01) and exhibited more ash and burn marks than nonsmokers' cars (p < .001). Number of cigarettes smoked by the primary driver was the strongest predictor of residual TSP indicators (R(2) = .10 - .16, p = .001). This relationship was neither mediated by ash or burn marks nor moderated by efforts to remove residual TSP from the vehicle (i.e., cleaning, ventilation) or attempts to prevent tobacco smoke pollutants from adsorbing while smoking (e.g., holding the cigarette near/outside window)., Discussion: Findings suggest that smokers can prevent their cars from becoming contaminated with residual TSP by reducing or ceasing smoking; however, commonly used cleaning and ventilation methods did not successfully decrease contamination levels. Disclosure requirements and smoke-free certifications could help protect buyers of used cars and empower them to request nonsmoking environments or a discount on cars that have been smoked in previously.

Regular tobacco use in the enclosed environment of a car raises concerns about longer-term contamination of a car's microenvironment with residual secondhand smoke pollutants. This study (a) developed and compared methods to measure residual contamination of cars with secondhand smoke, (b) examined whether cars of smokers and nonsmokers were contaminated by secondhand smoke, and (c) how smoking behavior and restrictions affected contamination levels. Surface wipe, dust, and air samples were collected in used cars sold by nonsmokers (n = 20) and smokers (n = 87) and analyzed for nicotine. Sellers were interviewed about smoking behavior and restrictions, and car interiors were inspected for signs of tobacco use. Cars of smokers who smoked in their vehicles showed significantly elevated levels of nicotine (p < .001) in dust, on surfaces, and in the air compared with nonsmoker cars with smoking ban. When smokers imposed car smoking bans, air nicotine levels were significantly lower (p < .01), but dust and surface contamination levels remained at similar levels. Smoking more cigarettes in the car and overall higher smoking rate of the seller were significantly associated with higher secondhand smoke contamination of the car (p < .001). Use of a cutpoint for nicotine levels from surface wipe samples correctly identified 82% of smoker cars without smoking bans, 75% of smoker cars with bans, and 100% of nonsmoker cars. Surface nicotine levels provide a relatively inexpensive and accurate method to identify cars and other indoor environments contaminated with residual secondhand smoke. Disclosure requirements and smoke-free certifications could help protect nonsmoking buyers of used cars.

Secondhand smoke (SHS) causes premature death and disease in children and adults, and the scientific evidence indicates that there is no risk-free level of exposure to SHS. Smoking tobacco in a car can pollute the microenvironment of the car with residual SHS, leaving telltale signs to potential buyers (e.g., odor, used ash tray). This study examined (a) the proportion of used cars sold in the private party market that may be polluted with tobacco smoke and (b) whether asking prices of smoker and nonsmoker cars differed for cars of otherwise equivalent value. A random sample of 1,642 private party sellers were interviewed by telephone, and content analyses of print advertisements were conducted. Findings indicate that 22% of used cars were advertised by smokers or had been smoked in during the previous year. Among nonsmokers, 94% did not allow smoking in their car during the past year. Only 33% of smokers had the same restrictions. The smoking status of the seller and tobacco use in the car were significantly (p < .01) associated with the asking price independent of a car's Kelley Blue Book value (KBB). Used nonsmoker cars were offered at a considerable premium above their KBB value (>11%) and above comparable smoker cars (7-9%). These findings suggest that community preferences are affecting the value of smoke-free cars. New directions for research, tobacco control policies, and health education are discussed to further reduce smoking behavior, to help consumers make informed purchasing decisions, and to protect nonsmokers from SHS exposure.

Background: Serum albumin level is correlated with outcome in various clinical situations. Albumin has multiple physiologic properties that could be beneficial in brain injury. The Lund therapy for elevated intracranial pressure uses albumin as part of its protocol and demonstrates favorable outcome. We sought to find out if albumin is associated with outcome after traumatic brain injury to justify conducting a randomized trial., Methods: A retrospective study of traumatic brain injury patients was conducted. Characteristics known to influence outcome were included in a multiple logistic regression model to analyze predictors of poor outcome at 6 months., Results: Data were available for 138 patients. The majority of patients (65%) had a severe injury (Glasgow Coma Scale score <9). Seventy percent of patients had a favorable outcome. Albumin levels decrease considerably from normal values in the first few days after injury irrespective of outcome. Albumin remained <25 g/L for a longer period of time in patient with an unfavorable outcome (6 days vs. 3 days, p = 0.012). Multiple logistic regression analysis identified albumin levels, age, Glasgow Coma Scale score at admission, and Injury Severity Score as predictors of poor outcome., Conclusion: Serum albumin level seems to be an independent predictor of poor outcome. The model also identified classic predictors of poor outcome that tends to strengthen its adequacy. Because albumin level is the only modifiable factor influencing outcome, it seems justified to carry out a randomized trial of the use of albumin in the treatment of brain injury.

Objective: The objective was to study the anatomical changes in the pituitary gland following acute moderate or severe traumatic brain injury (TBI)., Design: Retrospective, observational, case-control study., Setting: Neurosciences Critical Care Unit of a university hospital., Patients: Forty-one patients with moderate or severe TBI who underwent magnetic resonance imaging (MRI) during the acute phase (less than seven days) of TBI. MRI scans of 43 normal healthy volunteers were used as controls., Interventions: None., Measurements and Main Results: Patient demographics, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Injury Severity Score (ISS), post-resuscitation Glasgow Coma Score (GCS), Glasgow Outcome Score (GOS), mean intracranial pressure (ICP), mean cerebral perfusion pressure (CPP), computed tomography (CT) data, pituitary gland volumes and structural lesions in the pituitary on MRI scans. The pituitary glands were significantly enlarged in the TBI group (the median and interquartile range were as follows: cases 672 mm3 (range 601-783 mm3) and controls 552 mm3 (range 445-620 mm3); p value<0.0001). APACHE II, GCS, GOS and ICP were not significantly correlated with the pituitary volume. Twelve of the 41 cases (30%) demonstrated focal changes in the pituitary gland (haemorrhage/haemorrhagic infarction (n=5), swollen gland with bulging superior margin (n=5), heterogeneous signal intensities in the anterior lobe (n=2) and partial transection of the infundibular stalk (n=1)., Conclusions: Acute TBI is associated with pituitary gland enlargement with specific lesions, which are seen in approximately 30% of patients. MRI of the pituitary may provide useful information about the mechanisms involved in post-traumatic hypopituitarism.

While computed tomography (CT) is the appropriate technique for the urgent detection of hematomas and contusions in the cerebral hemispheres, it is much less effective at documenting diffuse injury and posterior fossa lesions, and is therefore only partially predictive of outcome. More recently, magnetic resonance imaging (MRI) has been used, particularly to examine posterior fossa structures, but the relationship between brainstem injury and outcome is unclear and the types of brainstem injury are poorly understood. The aim of this study was to use acute MRI to examine the types of brainstem injury following severe traumatic brain injury (TBI) and their relationship to supratentorial injury. We also aimed to correlate these findings with outcome at 6 months (Glasgow Outcome Scale [GOS] score). Forty-six patients (mean age, 34 years, range, 16-70 years; 76% male) admitted to a regional neurocritical care unit with TBI requiring ventilation underwent CT and MRI (T2, FLAIR, gradient echo) scanning within 3 days (median, 1 day) of injury. GOS was ascertained by outpatient interview. Brainstem lesions were detected in 13 patients by MRI, only two of which were detected by CT. Eleven out of 13 patients with brainstem injury had an unfavorable outcome (death, vegetative state, or severe disability), of whom five died. Of the 33 patients without brainstem lesions, 18 had an unfavorable outcome, of whom four died. The direct relationship between brainstem lesions and unfavorable outcome was statistically significant (p < 0.05, chi-squared test). With regard to supratentorial injury, all but two brainstem lesions were seen either in the context of severe diffuse axonal injury or a significant mass lesion, and all of these patients had a poor outcome. However, the two patients with brainstem injury and good outcome had relatively few supratentorial abnormalities. From these observations, we have devised a simple classification system that is useful clinically and has potential associations with outcome. Poor prognosis is common following major TBI but is more common in those with brainstem injury. However, brainstem injury is not an absolute indicator of poor outcome. Understanding the anatomy and extent of brainstem injury, as well as its relationship to supratentorial abnormalities, will facilitate a more accurate use of early MRI as a prognostic tool and assist in the counseling of families.

Objective: Hyperglycemia occurring after head injury is associated with poor neurological outcome. We tested the hypothesis that blood glucose levels are associated with brain tissue pH (pH(b)) and that the correction of hyperglycemia would result in an improvement in pH(b)., Methods: This is a retrospective analysis of a prospectively collected database. Thirty-four patients in a tertiary care neuroscience critical care unit with major traumatic brain injury underwent pH(b) monitoring., Results: A total of 428 glucose measurements were recorded during pH(b) monitoring. Mean glucose level was 7.1 mmol/L (range, 2.8-21.7 mmol/L) and median (interquartile range) pH(b) was 7.11 mmol/L (7.00-7.19 mmol/L). To account for the correlated, unbalanced nature of the data, a linear generalized estimating equation model was created. This model predicted that for each 1 mmol/L increase in blood glucose, pH(b) changed by -0.011 mmol/L (95% confidence interval, -0.016 to -0.005 mmol/L; P < 0.001). This relationship remained significant in a multivariable model that included cerebral perfusion pressure, brain tissue oxygen and carbon dioxide tension, and brain temperature. Twenty-one episodes of significant hyperglycemia (>or=11.1 mmol/L) treated with intravenous insulin were identified. Insulin therapy significantly reduced blood glucose concentration from a median (interquartile range) of 11.9 mmol/L (range, 11.4-13.6 mmol/L) to 8.8 mmol/L (range, 7.3-9.6 mmol/L; P < 0.001). Baseline pH(b) was not significantly different from pH(b) associated with the subsequent glucose reading of less than 11.1 mmol/L (P = 0.29), but there was a suggestion of improvement if the change in blood glucose was large., Conclusion: Blood glucose is associated with brain tissue acidosis in patients with major head injury. Prospective studies are required to confirm these results and to determine whether treatment of hyperglycemia improves outcome.

There is evidence that fractures heal more rapidly in patients with head injury. We measured the circulating level of interleukin-6 (IL-6) and its soluble receptor (sIL-6R) and soluble glycoprotein 130 (sgp130) in serum from patients who had sustained a head injury with and without fracture and compared these with levels found in control subjects. Within 12 hours of injury the serum level of IL-6 was significantly higher in patients with head injury and fracture compared with the control group. Levels of IL-6 were also significantly higher in patients with head injury and fracture compared with fracture only. While there was no significant difference in circulating levels of sIL-6R in the initial samples they were increased one week after surgery in patients with head injury and fracture and with head injury only. In addition, reduced levels of sgp130 in patients with head injury with and without fracture indicated a possible reduction of the inhibitory effect of this protein on the activity of IL-6. Our study suggests that IL-6 may be involved in altered healing of a fracture after head injury.

The ability to measure brain tissue chemistry has led to valuable information regarding pathophysiological changes in patients with traumatic brain injury (TBI). Over the last few years, the focus has been on monitoring changes in brain tissue oxygen to determine thresholds of ischemia that affect outcome. However, the variability of this measurement suggests that it may not be a robust method. We have therefore investigated the relationship of brain tissue pH (pH(b)) and outcome in patients with TBI. We retrospectively analyzed prospectively collected data of 38 patients admitted to the Neurosciences Critical Care Unit with TBI between 1998 and 2003, and who had a multiparameter tissue gas sensor inserted into the brain. All patients were managed using an evidence-based protocol targeting CPP > 70 mm Hg. Physiological variables were averaged over 4 min and analyzed using a generalized least squares random effects model to determine the temporal profile of pH(b) and its association with outcome. Median (IQR) minimum pH(b) was 7.00 (6.89, 7.08), median (IQR) maximum pH(b) was 7.25 (7.18, 7.33), and median (IQR) patient averaged pH(b) was 7.13 (7.07, 7.17). pH(b) was significantly lower in those who did not survive their hospital stay compared to those that survived. In addition, those with unfavorable neurological outcome had lower pH(b) values than those with favorable neurological outcome. pH(b) differentiated between survivors and non-survivors. Measurement of pH(b) may be a useful indicator of outcome in patients with TBI.

Objective: To investigate the effect of hyperventilation on cerebral blood flow in traumatic brain injury., Design: A prospective interventional study., Setting: A specialist neurocritical care unit., Patients: Fourteen healthy volunteers and 33 patients within 7 days of closed head injury., Interventions: All subjects underwent positron emission tomography imaging of cerebral blood flow. In patients, PaCO2 was reduced from 36 +/- 1 to 29 +/- 1 torr (4.8 +/- 0.1 to 3.9 +/- 0.1 kPa) and measurements repeated. Jugular venous saturation (SjvO2 ) and arteriovenous oxygen content differences (AVDO2 ) were monitored in 25 patients and values related to positron emission tomography variables., Measurements and Main Results: The volumes of critically hypoperfused and hyperperfused brain (HypoBV and HyperBV, in milliliters) were calculated based on thresholds of 10 and 55 mL.100g(-1).min(-1), respectively. Whereas baseline HypoBV was significantly higher in patients ( p<.05), baseline HyperBV was similar to values in healthy volunteers. Hyperventilation resulted in increases in cerebral perfusion pressure (p <.0001) and reductions in intracranial pressure (p <.001), whereas SjvO2 (>50%) and AVDO2 (<9 mL/mL) did not exceed global ischemic thresholds. However, despite these beneficial effects, hyperventilation shifted the cerebral blood flow distribution curve toward the hypoperfused range, with a decrease in global cerebral blood flow (31 +/- 1 to 23 +/- 1 mL.100g(-1).min(-1); p<.0001) and an increase in HypoBV (22 [1-141] to 51 [2-428] mL; p<.0001). Hyperventilation-induced increases in HypoBV were apparently nonlinear, with a threshold value between 34 and 38 torr (4.5-5 kPa)., Conclusions: Hyperventilation increases the volume of severely hypoperfused tissue within the injured brain, despite improvements in cerebral perfusion pressure and intracranial pressure. Significant hyperperfusion is uncommon, even at a time when conventional clinical management includes a role for modest hyperventilation. These reductions in regional cerebral perfusion are not associated with ischemia, as defined by global monitors of oxygenation, but may represent regions of potentially ischemic brain tissue.

There is evidence to suggest that fractures heal more rapidly in patients with a head injury as a result of systemic factors released from the site of this injury. We have measured the circulating level of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) in serum because of their known involvement in the stimulation of the activity of osteoblasts and the healing of fractures. The serum level of IGF-1 was significantly lower in patients with both head injury and fracture and fracture only compared with that in healthy volunteers (p < 0.01 and p < 0.02, respectively). The level of IGFBP-3 was also significantly lower in patients with both head injury and fracture (p < 0.01). Our findings showed, however, that the level of IGF-1 and IGFBP-3 varied from week to week in both the patients and healthy control subjects. These results indicate that the levels of circulating IGF-1 and IGFBP-3 are unlikely to be responsible for the altered healing of fractures seen in conjunction with head injury.

Objectives: To define optimal cerebral perfusion pressure (CPPOPT) in individual head-injured patients using continuous monitoring of cerebrovascular pressure reactivity. To test the hypothesis that patients with poor outcome were managed at a cerebral perfusion pressure (CPP) differing more from their CPPOPT than were patients with good outcome., Design: Retrospective analysis of prospectively collected data., Setting: Neurosciences critical care unit of a university hospital., Patients: A total of 114 head-injured patients admitted between January 1997 and August 2000 with continuous monitoring of mean arterial blood pressure (MAP) and intracranial pressure (ICP)., Measurements and Main Results: MAP, ICP, and CPP were continuously recorded and a pressure reactivity index (PRx) was calculated online. PRx is the moving correlation coefficient recorded over 4-min periods between averaged values (6-sec periods) of MAP and ICP representing cerebrovascular pressure reactivity. When cerebrovascular reactivity is intact, PRx has negative or zero values, otherwise PRx is positive. Outcome was assessed at 6 months using the Glasgow Outcome Scale. A total of 13,633 hrs of data were recorded. CPPOPT was defined as the CPP where PRx reaches its minimum value when plotted against CPP. Identification of CPPOPT was possible in 68 patients (60%). In 22 patients (27%), CPPOPT was not found because it presumably lay outside the studied range of CPP. Patients' outcome correlated with the difference between CPP and CPPOPT for patients who were managed on average below CPPOPT (r =.53, p <.001) and for patients whose mean CPP was above CPPOPT (r = -.40, p <.05)., Conclusions: CPPOPT could be identified in a majority of patients. Patients with a mean CPP close to CPPOPT were more likely to have a favorable outcome than those whose mean CPP was more different from CPPOPT. We propose use of the criterion of minimal achievable PRx to guide future trials of CPP oriented treatment in head injured patients.

Collaborative interdisciplinary research can contribute to bridging the gap between research and practice. This paper by Leslie Gelling and Dot Chatfield considers the nature of collaborative research, describes three models of collaboration and suggests some potential benefits of successful research collaboration to individuals, groups, organisations and consumers.