A Mediation Analysis Examining High Risk, Anticholinergic Medication Use, Delirium, and Dementia After Major Surgery.

INTRODUCTION: Anticholinergic medications are known to cause adverse cognitive effects in community-dwelling older adults and medical inpatients, including dementia. The prevalence with which such medications are prescribed in older adults undergoing major surgery is not well described nor is their mediating relationship with delirium and dementia. We sought to determine the prevalence of high-risk medication use in major surgery patients and their relationship with the subsequent development of dementia. METHODS: This was a retrospective cohort study which used data between January 2013 and December 2019, in a large midwestern health system, including sixteen hospitals. All patients over age 50 undergoing surgery requiring an inpatient stay were included. The primary exposure was the number of doses of anticholinergic medications delivered during the hospital stay. The primary outcome was a new diagnosis of Alzheimer's disease and related dementias at 1-y postsurgery. Regression methods and a mediation analysis were used to explore relationships between anticholinergic medication usage, delirium, and dementia. RESULTS: There were 39,665 patients included, with a median age of 66. Most patients were exposed to anticholinergic medications (35,957/39,665; 91%), and 7588/39,665 (19.1%) patients received six or more doses during their hospital stay. Patients with at least six doses of these medications were more likely to be female, black, and with a lower American Society of Anesthesiologists class. Upon adjusted analysis, high doses of anticholinergic medications were associated with increased odds of dementia at 1 y relative to those with no exposure (odds ratio 2.7; 95% confidence interval 2.2-3.3). On mediation analysis, postoperative delirium mediated the effect of anticholinergic medications on dementia, explaining an estimated 57.6% of their association. CONCLUSIONS: High doses of anticholinergic medications are common in major surgery patients and, in part via a mediating relationship with postoperative delirium, are associated with the development of dementia 1 y following surgery. Strategies to decrease the use of these medications and encourage the use of alternatives may improve long-term cognitive recovery.

"Ethical Care in Secret": Qualitative Data from an International Survey of Exploratory Therapists Working with Gender-Questioning Clients.

This is a mixed methods international survey of therapists (n = 89) belonging to Therapy First, an organization supporting the use of exploratory therapy, rather than gender affirmative therapy, with gender-questioning clients. The method used was an electronic questionnaire, producing a 33% response rate from members. Responses were analyzed using thematic analysis. This article reports qualitative responses relating to therapists' experiences of anxiety in working in a hostile professional environment, and their adoption of strategies to minimize risk of allegations of conversion therapy. Therapist strategies included refining existing marketing approaches to serve preferred client groups, and reliance on proven therapy models.

Emergency Department Pediatric Readiness Among US Trauma Centers: A Machine Learning Analysis of Components Associated With Survival.

OBJECTIVE: We used machine learning to identify the highest impact components of emergency department (ED) pediatric readiness for predicting in-hospital survival among children cared for in US trauma centers. BACKGROUND: ED pediatric readiness is associated with improved short-term and long-term survival among injured children and part of the national verification criteria for US trauma centers. However, the components of ED pediatric readiness most predictive of survival are unknown. METHODS: This was a retrospective cohort study of injured children below 18 years treated in 458 trauma centers from January 1, 2012, through December 31, 2017, matched to the 2013 National ED Pediatric Readiness Assessment and the American Hospital Association survey. We used machine learning to analyze 265 potential predictors of survival, including 152 ED readiness variables, 29 patient variables, and 84 ED-level and hospital-level variables. The primary outcome was in-hospital survival. RESULTS: There were 274,756 injured children, including 4585 (1.7%) who died. Nine ED pediatric readiness components were associated with the greatest increase in survival: policy for mental health care (+8.8% change in survival), policy for patient assessment (+7.5%), specific respiratory equipment (+7.2%), policy for reduced-dose radiation imaging (+7.0%), physician competency evaluations (+4.9%), recording weight in kilograms (+3.2%), life support courses for nursing (+1.0%-2.5%), and policy on pediatric triage (+2.5%). There was a 268% improvement in survival when the 5 highest impact components were present. CONCLUSIONS: ED pediatric readiness components related to specific policies, personnel, and equipment were the strongest predictors of pediatric survival and worked synergistically when combined.

A Pilot Study to Assess the Performance of Phase-Sensitive Breast Tomosynthesis.

Background A new modality, phase-sensitive breast tomosynthesis (PBT), may have similar diagnostic performance to conventional breast tomosynthesis but with a reduced radiation dose. Purpose To perform a pilot study of the performance of a novel PBT system compared with conventional digital breast tomosynthesis (DBT) in patients undergoing additional diagnostic imaging workup for breast lesions. Materials and Methods In a prospective study from June 2020 to March 2021, participants with suspicious breast lesions detected at screening DBT or MRI were recruited for additional PBT imaging before additional diagnostic workup or biopsy. In this pilot study, nine radiologists independently evaluated image quality and assessed the likelihood of lesion malignancy by retrospectively evaluating DBT and PBT images in two separate reading sessions. Image quality was rated subjectively using a Likert scale from 1 to 5. Areas under the receiver operating characteristic curve (AUCs) were used to compare the lesion classification (malignant vs benign) performance of the radiologists. Results Images in 50 patients (mean age, 56 years ± 12 [SD]; 49 women) with 52 evaluable lesions (28 malignant) were assessed. For image appearance and general feature visibility, DBT images had a higher total mean image quality score (3.8) than PBT images (2.9), with P < .002 for each comparison. For classification of lesions as benign or malignant, the AUCs were 0.74 for both PBT and DBT. PBT images were acquired at a 24% mean radiation dose reduction (mean, 1.78 mGy vs 2.34 mGy for DBT; P < .001). Conclusion The phase-sensitive breast tomosynthesis system had a 24% lower mean radiation dose compared with digital breast tomosynthesis, although with lower image quality. Diagnostic performance of the system remains to be determined in larger studies. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Gao and Moy in this issue.

Assessing Outcomes for Cost-Utility Analysis in Children and Adolescents With Mental Health Problems: Are Multiattribute Utility Instruments Fit for Purpose?

OBJECTIVES: The objective of this study was to compare the concurrent and construct validity, as well as the sensitivity of 5 multiattribute utility instruments (MAUIs), including the Assessment of Quality of Life-6D (AQoL-6D), EQ-5D-Y, Health Utilities Index (HUI)-2 and HUI-3, and the Child Health Utility 9D, 1 generic pediatric quality of life instrument, with 3 routinely collected outcome measures in Australian mental health services (Strengths and Difficulties Questionnaire, Clinical Global Assessment Scale [CGAS] and the Health of the Nation Outcome Scale for Children and Adolescents) in children and adolescents diagnosed of internalizing (eg, anxiety/depression), externalizing (eg, attention deficit hyperactivity disorder/conduct disorders), and trauma/stress related mental disorders. METHODS: A cross-sectional survey of measures, including demographic and basic treatment information, in children/adolescents recruited via 5 child and youth mental health services in Queensland and Victoria, Australia. Measures were either proxy or self-report completed, the CGAS and the Health of the Nation Outcome Scale for Children and Adolescents were clinician completed. RESULTS: The sample included 426 participants and had a mean age of 13.7 years (range 7-18 years). Utilities (as calculated from MAUIs) were generally lower in older adolescents and those with internalizing disorders. All MAUIs and self-reported clinical measures significantly correlated with each other (absolute correlation range 0.40-0.90), with the AQoL-6D showing generally higher levels of correlations. Correlations between the MAUIs and clinician/proxy-reported measures were weak, regardless of diagnosis (absolute correlation range 0.09-0.47). Generally, EQ-5D-Y, HUI-2, and AQoL-6D were more sensitive than Child Health Utility 9D and HUI-3 when distinguishing between different severities according to clinician-assessed CGAS (effect size range 0.17-0.84). CONCLUSIONS: The study showed that the commonly used MAUIs had good concurrent and construct validity compared with routinely used self-complete measures but poor validity when compared with clinician/proxy-completed measures. These findings generally held across different diagnoses.

Reframing postconcussional syndrome as an interface disorder of neurology, psychiatry and psychology.

Persistent symptoms following a minor head injury can cause significant morbidity, yet the underlying mechanisms for this are poorly understood. The shortcomings of the current terminology that refer to non-specific symptom clusters is discussed. This update considers the need for a multi-dimensional approach for the heterogenous mechanisms driving persistent symptoms after mild traumatic brain injury. Relevant pathophysiology is discussed to make the case for mild traumatic brain injury to be conceptualized as an interface disorder spanning neurology, psychiatry and psychology. The relevance of pre-injury factors, psychological co-morbidities and their interaction with the injury to produce persistent symptoms are reviewed. The interplay with psychiatric diagnoses, functional and somatic symptom disorder presentations and the influence of the medicolegal process is considered. The judicious use and interpretation of investigations given the above complexity is discussed, with suggestions of how the explanation of the diagnostic formulation to the patient can be tailored, including insight into the above processes, to aid recovery. Moving beyond the one-dimensional concept of 'postconcussional syndrome' and reframing the cause of persistent symptoms following mild traumatic brain injury in a bio-psycho-socio-ecological model will hopefully improve understanding of the underlying contributory mechanistic interactions and facilitate treatment.

Extending Trauma Quality Improvement Beyond Trauma Centers: Hospital Variation in Outcomes Among Nontrauma Hospitals.

OBJECTIVE: The American College of Surgeons (ACS) conducts a robust quality improvement program for ACS-verified trauma centers, yet many injured patients receive care at non-accredited facilities. This study tested for variation in outcomes across non-trauma hospitals and characterized hospitals associated with increased mortality. SUMMARY BACKGROUND DATA: The study included state trauma registry data of 37,670 patients treated between January 1, 2013, and December 31, 2015. Clinical data were supplemented with data from the American Hospital Association and US Department of Agriculture, allowing comparisons among 100 nontrauma hospitals. METHODS: Using Bayesian techniques, risk-adjusted and reliability-adjusted rates of mortality and interfacility transfer, as well as Emergency Departments length-of-stay (ED-LOS) among patients transferred from EDs were calculated for each hospital. Subgroup analyses were performed for patients ages >55 years and those with decreased Glasgow coma scores (GCS). Multiple imputation was used to address missing data. RESULTS: Mortality varied 3-fold (0.9%-3.1%); interfacility transfer rates varied 46-fold (2.1%-95.6%); and mean ED-LOS varied 3-fold (81-231 minutes). Hospitals that were high and low statistical outliers were identified for each outcome, and subgroup analyses demonstrated comparable hospital variation. Metropolitan hospitals were associated increased mortality [odds ratio (OR) 1.7, P = 0.004], decreased likelihood of interfacility transfer (OR 0.7, P ≤ 0.001), and increased ED-LOS (coef. 0.1, P ≤ 0.001) when compared with nonmetropolitan hospitals and risk-adjusted. CONCLUSIONS: Wide variation in trauma outcomes exists across nontrauma hospitals. Efforts to improve trauma quality should include engagement of nontrauma hospitals to reduce variation in outcomes of injured patients treated at those facilities.

Laboratory coagulation tests and recombinant porcine factor VIII: A United Kingdom Haemophilia Centre Doctors' Organisation guideline.

INTRODUCTION: Acquired haemophilia A (AHA) is a rare bleeding disorder caused by development of auto-antibodies to endogenous coagulation factor VIII (FVIII). Recombinant porcine factor VIII (rpFVIII) is currently licensed only for the management of bleeding in patients with AHA. Regular monitoring of rpFVIII is recommended to assess treatment effectiveness. AIM: This guideline from the United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) examines the current publications in the area and aims to offer advice for the laboratory monitoring of rpFVIII in patients with AHA. METHODS: A review of the current literature was undertaken followed by critical review by the authors. RESULTS/CONCLUSIONS: A validated one-stage clotting FVIII assay is recommended for the measurement and regular monitoring of rpFVIII. Assessment of cross-reacting rpFVIII inhibitors by one-stage porcine Bethesda assay should be performed as part of the initial diagnosis of AHA or prior to treatment with rpFVIII. Available data show that chromogenic FVIII assays underestimate rpFVIII and this should be considered if measurement of rpFVIII is required in patients receiving Emicizumab.

Post-traumatic amnesia.

Post-traumatic amnesia is the transient state of altered brain function that may follow a traumatic brain injury. At a practical level, an individual has emerged from post-traumatic amnesia when he or she is fully orientated and with return of continuous memory. However, the clinical manifestations are often more complex, with numerous cognitive domains commonly affected, as well as behaviour. In the acute setting, post-traumatic amnesia may easily go unrecognised; this is problematic as it has important implications for both immediate management and for longer-term prognosis. We therefore recommend its careful clinical assessment and prospective evaluation using validated tools. Patients in post-traumatic amnesia who have behavioural disturbance can be particularly challenging to manage. Behavioural and environmental measures form the mainstay of its treatment while avoiding pharmacological interventions where possible, as they may worsen agitation. Patients need assessing regularly to determine their need for further rehabilitation and to facilitate safe discharge planning.

Dissemination of cancer survivorship care plans: who is being left out?

OBJECTIVES: The Institute of Medicine (IOM) and the American College of Surgeons Commission on Cancer (CoC) recommend a clear and effectively explained comprehensive survivorship care plan (SCP) be given to all cancer survivors. The objective of this study is to understand the relationship between social determinants of health (SDOH) and self-reported receipt of SCP by cancer survivors in the USA. METHODS: We analyzed an adult population of cancer survivors in the 2016 Behavioral Risk Factor Surveillance System's (BRFSS) Survivorship modules. Weighted multivariable logistic regression was used to analyze the association of SDOH and reported receipt of SCP. RESULTS: There were 7061 cancer patients eligible for an SCP. The probability of reporting receipt of SCP decreased with lower educational achievement (high school/some college: AOR = 0.82, 95% CI: 0.70-0.97, p = 0.02; < high school: AOR = 0.68, 95% CI: 0.47-0.97, p = 0.03) compared to those with at least one college degree. Additionally, being widowed/divorced/separated (widowed/divorced/separated: AOR = 0.72, 95% CI: 0.61-0.86, p < 0.01 vs. married/cohabiting) and uninsured (uninsured: AOR = 0.52, 95% CI: 0.0.34-0.80, p < 0.01 vs. insured) increased the odds of not receiving an SCP. Younger patients were more likely to receive an SCP than those over 65 (18-24 years: AOR = 6.62, 95% CI: 1.87-24.49, p < 0.01 vs. 65+ years). CONCLUSION: Among cancer survivors, SDOH such as low educational achievement, widowed/divorced/separated marital status, and being uninsured were associated with a lower likelihood of receiving an SCP. Future studies should evaluate how omission of SCP in these patients influences the quality of care during the transition from oncologists to primary care.

Distinct dopaminergic abnormalities in traumatic brain injury and Parkinson's disease.

OBJECTIVE: Traumatic brain injury (TBI) and rapid eye movement sleep behavioural disorder (RBD) are risk factors for Parkinson's disease (PD). Dopaminergic abnormalities are often seen after TBI, but patients usually lack parkinsonian features. We test whether TBI, PD and RBD have distinct striatal dopamine abnormalities using dopamine transporter (DaT) imaging. METHODS: 123I-ioflupane single-photon emission CT scans were used in a cross-sectional study to measure DaT levels in moderate/severe TBI, healthy controls, patients with early PD and RBD. Caudate and putamen DaT, putamen to caudate ratios and left-right symmetry of DaT were compared. RESULTS: 108 participants (43 TBI, 26 PD, 8 RBD, 31 controls) were assessed. Patients with early PD scored significantly higher on the Unified Parkinson's Disease Rating Scale motor subscale than other groups. Patients with TBI and PD had reduced DaT levels in the caudate (12.2% and 18.7%, respectively) and putamen (9.0% and 42.6%, respectively) compared with controls. Patients with RBD had reduced DaT levels in the putamen (12.8%) but not in the caudate compared with controls. Patients with PD and TBI showed distinct patterns of DaT reduction, with patients with PD showing a lower putamen to caudate ratio. DaT asymmetry was greater in the PD group than other groups. CONCLUSIONS: The results show that patients with early PD and TBI have distinct patterns of striatal dopamine abnormalities. Patients with early PD and moderate/severe TBI showed similar reductions in caudate DaT binding, but patients with PD showed a greater reduction in putamen DaT and a lower putamen to caudate ratio. The results suggest that parkinsonian motor signs are absent in these patients with TBI because of relatively intact putaminal dopamine levels.

Stratifying drug treatment of cognitive impairments after traumatic brain injury using neuroimaging.

Cognitive impairment is common following traumatic brain injury. Dopaminergic drugs can enhance cognition after traumatic brain injury, but individual responses are highly variable. This may be due to variability in dopaminergic damage between patients. We investigate whether measuring dopamine transporter levels using 123I-ioflupane single-photon emission computed tomography (SPECT) predicts response to methylphenidate, a stimulant with dopaminergic effects. Forty patients with moderate-severe traumatic brain injury and cognitive impairments completed a randomized, double-blind, placebo-controlled, crossover study. 123I-ioflupane SPECT, MRI and neuropsychological testing were performed. Patients received 0.3 mg/kg of methylphenidate or placebo twice a day in 2-week blocks. Subjects received neuropsychological assessment after each block and completed daily home cognitive testing during the trial. The primary outcome measure was change in choice reaction time produced by methylphenidate and its relationship to stratification of patients into groups with normal and low dopamine transporter binding in the caudate. Overall, traumatic brain injury patients showed slow information processing speed. Patients with low caudate dopamine transporter binding showed improvement in response times with methylphenidate compared to placebo [median change = -16 ms; 95% confidence interval (CI): -28 to -3 ms; P = 0.02]. This represents a 27% improvement in the slowing produced by traumatic brain injury. Patients with normal dopamine transporter binding did not improve. Daily home-based choice reaction time results supported this: the low dopamine transporter group improved (median change -19 ms; 95% CI: -23 to -7 ms; P = 0.002) with no change in the normal dopamine transporter group (P = 0.50). The low dopamine transporter group also improved on self-reported and caregiver apathy assessments (P = 0.03 and P = 0.02, respectively). Both groups reported improvements in fatigue (P = 0.03 and P = 0.007). The cognitive effects of methylphenidate after traumatic brain injury were only seen in patients with low caudate dopamine transporter levels. This shows that identifying patients with a hypodopaminergic state after traumatic brain injury can help stratify the choice of cognitive enhancing therapy.

Dopaminergic abnormalities following traumatic brain injury.

Traumatic brain injury can reduce striatal dopamine levels. The cause of this is uncertain, but is likely to be related to damage to the nigrostriatal system. We investigated the pattern of striatal dopamine abnormalities using 123I-Ioflupane single-photon emission computed tomography (SPECT) scans and their relationship to nigrostriatal damage and clinical features. We studied 42 moderate-severe traumatic brain injury patients with cognitive impairments but no motor parkinsonism signs and 20 healthy controls. 123I-Ioflupane scanning was used to assess dopamine transporter levels. Clinical scan reports were compared to quantitative dopamine transporter results. Advanced MRI methods were used to assess the nigrostriatal system, including the area through which the nigrostriatal projections pass as defined from high-resolution Human Connectome data. Detailed clinical and neuropsychological assessments were performed. Around 20% of our moderate-severe patients had clear evidence of reduced specific binding ratios for the dopamine transporter in the striatum measured using 123I-Ioflupane SPECT. The caudate was affected more consistently than other striatal regions. Dopamine transporter abnormalities were associated with reduced substantia nigra volume. In addition, diffusion MRI provided evidence of damage to the regions through which the nigrostriatal tract passes, particularly the area traversed by dopaminergic projections to the caudate. Only a small percentage of patients had evidence of macroscopic lesions in the striatum and there was no relationship between presence of lesions and dopamine transporter specific binding ratio abnormalities. There was also no relationship between reduced volume in the striatal subregions and reduced dopamine transporter specific binding ratios. Patients with low caudate dopamine transporter specific binding ratios show impaired processing speed and executive dysfunction compared to patients with normal levels. Taken together, our results suggest that the dopaminergic system is affected by a moderate-severe traumatic brain injury in a significant proportion of patients, even in the absence of clinical motor parkinsonism. Reduced dopamine transporter levels are most commonly seen in the caudate and this is likely to reflect the pattern of nigrostriatal tract damage produced by axonal injury and associated midbrain damage.

Altered caudate connectivity is associated with executive dysfunction after traumatic brain injury.

Traumatic brain injury often produces executive dysfunction. This characteristic cognitive impairment often causes long-term problems with behaviour and personality. Frontal lobe injuries are associated with executive dysfunction, but it is unclear how these injuries relate to corticostriatal interactions that are known to play an important role in behavioural control. We hypothesized that executive dysfunction after traumatic brain injury would be associated with abnormal corticostriatal interactions, a question that has not previously been investigated. We used structural and functional MRI measures of connectivity to investigate this. Corticostriatal functional connectivity in healthy individuals was initially defined using a data-driven approach. A constrained independent component analysis approach was applied in 100 healthy adult dataset from the Human Connectome Project. Diffusion tractography was also performed to generate white matter tracts. The output of this analysis was used to compare corticostriatal functional connectivity and structural integrity between groups of 42 patients with traumatic brain injury and 21 age-matched controls. Subdivisions of the caudate and putamen had distinct patterns of functional connectivity. Traumatic brain injury patients showed disruption to functional connectivity between the caudate and a distributed set of cortical regions, including the anterior cingulate cortex. Cognitive impairments in the patients were mainly seen in processing speed and executive function, as well as increased levels of apathy and fatigue. Abnormalities of caudate functional connectivity correlated with these cognitive impairments, with reductions in right caudate connectivity associated with increased executive dysfunction, information processing speed and memory impairment. Structural connectivity, measured using diffusion tensor imaging between the caudate and anterior cingulate cortex was impaired and this also correlated with measures of executive dysfunction. We show for the first time that altered subcortical connectivity is associated with large-scale network disruption in traumatic brain injury and that this disruption is related to the cognitive impairments seen in these patients.

Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration.

Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using 11C-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, 11C-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater 11C-PBR28 binding. Minocycline reduced 11C-PBR28 binding (mean Δwhite matter binding = -23.30%, 95% confidence interval -40.9 to -5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury.

Serum insulin-like growth factor-I levels are associated with improved white matter recovery after traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin-like growth factor-I (IGF-I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF-I concentrations on WM tract and neuropsychological recovery after TBI. METHODS: Thirty-nine adults after TBI (84.6% male, median age = 30.5 years, 87.2% moderate-severe, median time since TBI = 16.3 months, n = 4 with GHD) were scanned twice, 13.3 months (range = 12.1-14.9) apart, and 35 healthy controls were scanned once. Symptom and quality of life questionnaires and cognitive assessments were completed at both visits (n = 33). Our main outcome measure was fractional anisotropy (FA), a measure of WM tract integrity, in a priori regions of interest: splenium of corpus callosum (SPCC) and posterior limb of internal capsule (PLIC). RESULTS: At baseline, FA was reduced in many WM tracts including SPCC and PLIC following TBI compared to controls, indicating axonal injury, with longitudinal increases indicating axonal recovery. There was a significantly greater increase in SPCC FA over time in patients with serum IGF-I above versus below the median for age. Only the higher IGF-I group had significant improvements in immediate verbal memory recall over time. INTERPRETATION: WM recovery and memory improvements after TBI were greater in patients with higher serum IGF-I at baseline. These findings suggest that the growth hormone/IGF-I system may be a potential therapeutic target following TBI. Ann Neurol 2017;82:30-43.

Computed Tomography Scans in Patients With Young Adult Hip Pain Carry a Lifetime Risk of Malignancy.

PURPOSE: To calculate the lifetime risk of malignancy in young adult patients with hip pain using 5 different imaging and radiation dose protocols with or without pre- and postoperative computed tomography (CT). METHODS: Radiographic and CT patient radiation doses were retrospectively reviewed. Imaging protocols for hip pain composed of radiographs with or without pre- and postoperative CT scans were modeled and radiation doses were estimated using the PCXMC computer code. Based on these radiation doses, lifetime attributable risks of cancer and mortality for a 10- through 60-year-old male and female were calculated as published by the committee on the Biological Effects of Ionizing Radiation (BEIR) in the BEIR VII report. Relative risks and number needed to harm (NNH) were calculated for each protocol. RESULTS: Based on a review of our institutional database, 2 CT scan doses were used for this study: a high 5.06 mSv and a low 2.86 mSv. Effective doses of radiation ranged from 0.59 to 0.66 mSv for radiographs alone to 10.71 to 10.78 mSv for radiographs and CT both pre- and postoperatively at the higher dose. Lifetime attributable risk of cancer for radiographs alone was 0.006% and 0.011% for a 20-year-old male and female, respectively. Lifetime attributable risk of cancer for radiographs along with pre- and postoperative CT scans at higher dose was 0.105% and 0.177% for a 20-year-old male and female, respectively. Radiographs alone lead to an NNH of 16,667 for males and 9,090 for females, whereas the protocol with pre- and postoperative CT scans at the higher dose led to an NNH of 952 for males and 564 for females. The relative risk of this protocol compared to radiographs alone was 17.5 for males and 16.1 for females. CONCLUSION: Protocols with CT scans of the hip/pelvis pose a small lifetime attributable risk (0.034%-0.177% for a 20-year-old) but a large relative risk (5-17 times) of cancer compared with radiographs alone in the imaging evaluation for hip pain that decreases with increasing age. CLINICAL RELEVANCE: This study illustrates the need for clinicians to understand the imaging protocols used at their institution to understand the risks and benefits of using those protocols in their practice.

Catecholamines and cognition after traumatic brain injury.

Cognitive problems are one of the main causes of ongoing disability after traumatic brain injury. The heterogeneity of the injuries sustained and the variability of the resulting cognitive deficits makes treating these problems difficult. Identifying the underlying pathology allows a targeted treatment approach aimed at cognitive enhancement. For example, damage to neuromodulatory neurotransmitter systems is common after traumatic brain injury and is an important cause of cognitive impairment. Here, we discuss the evidence implicating disruption of the catecholamines (dopamine and noradrenaline) and review the efficacy of catecholaminergic drugs in treating post-traumatic brain injury cognitive impairments. The response to these therapies is often variable, a likely consequence of the heterogeneous patterns of injury as well as a non-linear relationship between catecholamine levels and cognitive functions. This individual variability means that measuring the structure and function of a person's catecholaminergic systems is likely to allow more refined therapy. Advanced structural and molecular imaging techniques offer the potential to identify disruption to the catecholaminergic systems and to provide a direct measure of catecholamine levels. In addition, measures of structural and functional connectivity can be used to identify common patterns of injury and to measure the functioning of brain 'networks' that are important for normal cognitive functioning. As the catecholamine systems modulate these cognitive networks, these measures could potentially be used to stratify treatment selection and monitor response to treatment in a more sophisticated manner.

Disconnection between the default mode network and medial temporal lobes in post-traumatic amnesia.

SEE BIGLER DOI101093/AWW277 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-traumatic amnesia is very common immediately after traumatic brain injury. It is characterized by a confused, agitated state and a pronounced inability to encode new memories and sustain attention. Clinically, post-traumatic amnesia is an important predictor of functional outcome. However, despite its prevalence and functional importance, the pathophysiology of post-traumatic amnesia is not understood. Memory processing relies on limbic structures such as the hippocampus, parahippocampus and parts of the cingulate cortex. These structures are connected within an intrinsic connectivity network, the default mode network. Interactions within the default mode network can be assessed using resting state functional magnetic resonance imaging, which can be acquired in confused patients unable to perform tasks in the scanner. Here we used this approach to test the hypothesis that the mnemonic symptoms of post-traumatic amnesia are caused by functional disconnection within the default mode network. We assessed whether the hippocampus and parahippocampus showed evidence of transient disconnection from cortical brain regions involved in memory processing. Nineteen patients with traumatic brain injury were classified into post-traumatic amnesia and traumatic brain injury control groups, based on their performance on a paired associates learning task. Cognitive function was also assessed with a detailed neuropsychological test battery. Functional interactions between brain regions were investigated using resting-state functional magnetic resonance imaging. Together with impairments in associative memory, patients in post-traumatic amnesia demonstrated impairments in information processing speed and spatial working memory. Patients in post-traumatic amnesia showed abnormal functional connectivity between the parahippocampal gyrus and posterior cingulate cortex. The strength of this functional connection correlated with both associative memory and information processing speed and normalized when these functions improved. We have previously shown abnormally high posterior cingulate cortex connectivity in the chronic phase after traumatic brain injury, and this abnormality was also observed in patients with post-traumatic amnesia. Patients with post-traumatic amnesia showed evidence of widespread traumatic axonal injury measured using diffusion magnetic resonance imaging. This change was more marked within the cingulum bundle, the tract connecting the parahippocampal gyrus to the posterior cingulate cortex. These findings provide novel insights into the pathophysiology of post-traumatic amnesia and evidence that memory impairment acutely after traumatic brain injury results from altered parahippocampal functional connectivity, perhaps secondary to the effects of axonal injury on white matter tracts connecting limbic structures involved in memory processing.

Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial.

BACKGROUND: The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial. METHODS: We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336. FINDINGS: Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19-1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy. INTERPRETATION: Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. FUNDING: Research for Patient Benefit Programme from the UK National Institute for Health Research.