Demonstrating the use of population level data to investigate trends in the rate, radiation dose and cost of Computed Tomography across clinical groups: Are there any areas of concern?

INTRODUCTION: Increases in computed tomography (CT) use may not always reflect clinical need or improve outcomes. This study aimed to demonstrate how population level data can be used to identify variations in care between patient groups, by analysing system-level changes in CT use around the diagnosis of new conditions. METHODS: Retrospective repeated cross-sectional observational study using West Australian linked administrative records, including 504,723 adults diagnosed with different conditions in 2006, 2012 and 2015. For 90 days pre/post diagnosis, CT use (any and 2+ scans), effective dose (mSv), lifetime attributable risk (LAR) of cancer incidence and mortality from CT, and costs were assessed. RESULTS: CT use increased from 209.4 per 1000 new diagnoses in 2006 to 258.0 in 2015; increases were observed for all conditions except neoplasms. Healthcare system costs increased for all conditions but neoplasms and mental disorders. Effective dose increased substantially for respiratory (+2.5 mSv, +23.1%, P < 0.001) and circulatory conditions (+2.1 mSv, +15.4%, P < 0.001). The LAR of cancer incidence and mortality from CT increased for endocrine (incidence +23.4%, mortality +18.0%) and respiratory disorders (+21.7%, +23.3%). Mortality LAR increased for circulatory (+12.1%) and nervous system (+11.0%) disorders. The LAR of cancer incidence and mortality reduced for musculoskeletal system disorders, despite an increase in repeated CT in this group. CONCLUSIONS: Use and costs increased for most conditions except neoplasms and mental and behavioural disorders. More strategic CT use may have occurred in musculoskeletal conditions, while use and radiation burden increased for respiratory, circulatory and nervous system conditions. Using this high-level approach we flag areas requiring deeper investigation into appropriateness and value of care.

Use of CT, ED presentation and hospitalisations 12 months before and after a diagnosis of cancer in Western Australia: a population-based retrospective cohort study.

OBJECTIVE: To examine the use of CT, emergency department (ED)-presentation and hospitalisation and in 12 months before and after a diagnosis of cancer. DESIGN: Population-based retrospective cohort study. SETTING: West Australian linked administrative records at individual level. PARTICIPANTS: 104 009 adults newly diagnosed with cancer in 2004-2014. MAIN OUTCOME MEASURES: CT use, ED presentations, hospitalisations. RESULTS: As compared with the rates in the 12th month before diagnosis, the rate of CT scans started to increase from 2 months before diagnosis with an increase in both ED presentations and hospitalisation from 1 month before the diagnosis. These rates peaked in the month of diagnosis for CT scans (477 (95% CI 471 to 482) per 1000 patients), and for hospitalisations (910 (95% CI 902 to 919) per 1000 patients), and the month prior to diagnosis for ED (181 (95% CI 178 to 184) per 1000 patients) then rapidly reduced after diagnosis but remained high for the next 12 months. While the patterns of the health services used were similar between 2004 and 2014, the rate of the health services used during after diagnosis was higher in 2014 versus 2004 except for CT use in patients with lymphohaematopoietic cancer with a significant reduction. CONCLUSION: Our results showed an increase in demand for health services from 2 months before diagnosis of cancer. Increasing use of health services during and post cancer diagnosis may warrant further investigation to identify factors driving this change.

Patterns of computed tomography utilisation in injury management: latent classes approach using linked administrative data in Western Australia.

PURPOSE: Whilst computed tomography (CT) imaging has been a vital component of injury management, its increasing use has raised concern regarding ionising radiation exposure. This study aims to identify latent classes (underlying patterns) of CT use over a 3-year period following the incidence of injury and factors predicting the observed patterns. METHOD: A retrospective observational cohort study was conducted in 21,544 individuals aged 18 + years presenting to emergency departments (ED) of four tertiary public hospitals with new injury in Western Australia. Mixture modelling approach was used to identify latent classes of CT use over a 3-year period post injury. RESULTS: Amongst injured people with at least one CT scan, three latent classes of CT use were identified including a: temporarily high CT use (46.4%); consistently high CT use (2.6%); and low CT use class (51.1%). Being 65 + years or older, having 3 + comorbidities, history with 3 + hospitalisations and history of CT use before injury were associated with consistently high use of CT. Injury to the head, neck, thorax or abdomen, being admitted to hospital after the injury and arriving to ED by ambulance were predictors for the temporarily high use class. Living in areas of higher socio-economic disadvantage was a unique factor associated with the low CT use class. CONCLUSIONS: Instead of assuming a single pattern of CT use for all patients with injury, the advanced latent class modelling approach has provided more nuanced understanding of the underlying patterns of CT use that may be useful for developing targeted interventions.

Trend in CT utilisation and its impact on length of stay, readmission and hospital mortality in Western Australia tertiary hospitals: an analysis of linked administrative data 2003-2015.

OBJECTIVE: High use of CT scanning has raised concern due to the potential ionising radiation exposure. This study examined trends of CT during admission to tertiary hospitals and its associations with length of stay (LOS), readmission and mortality. DESIGN: Retrospective observational study from 2003 to 2015. SETTING: West Australian linked administrative records at individual level. PARTICIPANTS: 2 375 787 episodes of tertiary hospital admission in adults aged 18+ years. MAIN OUTCOME MEASURES: LOS, 30-day readmissions and mortality stratified by CT use status (any, multiple (CTs to multiple areas during episode), and repeat (repeated CT to the same area)). METHODS: Multivariable regression models were used to calculate adjusted rate of CT use status. The significance of changes since 2003 in the outcomes (LOS, 30-day readmission and mortality) was compared among patients with specific CT imaging status relative to those without. RESULTS: Between 2003 and 2015, while the rate of CT increased 3.4% annually, the rate of repeat CTs significantly decreased -1.8% annually and multiple CT showed no change. Compared with 2003 while LOS had a greater decrease in those with any CT, 30-day readmissions had a greater increase among those with any CT, while the probability of mortality remained unchanged between the any CT/no CT groups. A similar result was observed in patients with multiple and repeat CT scanning, except for a significant increase in mortality in the recent years in the repeat CT group. CONCLUSION: The observed pattern of increase in CT utilisation is likely to be activity-based funding policy-driven based on the discordance between LOS and readmissions. Meanwhile, the repeat CT reduction aligns with a more selective strategy of use based on clinical severity. Future research should incorporate in-hospital and out-of-hospital CT to better understand overall CT trends and potential shifts between settings over time.

The use of computed tomography in the management of injury in tertiary emergency departments in Western Australia: Evidence of overtesting?

BACKGROUND: This study investigated trends in computed tomography (CT) utilization across different triage categories of injury presentations to tertiary emergency departments (EDs) and associations with diagnostic yield measured by injury severity, hospitalization and length of stay (LOS), and mortality. METHODS: A total of 411,155 injury-related ED presentations extracted from linked records from Western Australia from 2004 to 2015 were included in the retrospective study. The use of CT scanning and diagnostic yield measured by rate of diagnosis with severe injury, hospitalizations and LOS, and mortality were captured annually for injury-related ED presentations. Multivariable regression models were used to calculate the annual adjusted rate of CT scanning for injury presentations and hospitalizations across triage categories, diagnosis with severe injury, LOS, and mortality. The significance of changes observed was compared among patients with CT imaging relative to those without CT. RESULTS: While the number of ED presentations with injury increased by 65% from 2004 to 2015, the use of CT scanning in these presentations increased by 176%. The largest increase in CT use was among ED presentations triaged as semi-/nonurgent (+256%). Injury presentations with CT, compared to those without, had a higher rate of diagnosis with moderate/severe injury and hospitalization but no difference in LOS and mortality. The probability/rate observed in the outcomes of interest had a greater decrease over time in those with CT scanning compared with those without CT scanning across triage categories. CONCLUSIONS: The reduction in diagnostic yield in terms of injury severity and hospitalization found in our study might indicate a shift toward overtesting using CT in ED for injury or a higher use of CT to assist in the management of injuries. This helps health care policymakers consider whether the current increase in CT use meets the desired levels of quality and efficient care.

Factors driving CT utilisation in tertiary hospitals: a decomposition analysis using linked administrative data in Western Australia.

OBJECTIVES: While CT scanning plays a significant role in healthcare, its increasing use has raised concerns about inappropriate use. This study investigated factors driving the changing use of CT among people admitted to tertiary hospitals in Western Australia (WA). DESIGN AND SETTING: A repeated cross-sectional study of CT use in WA in 2003-2005 and 2013-2015 using linked administrative heath data at the individual patient level. PARTICIPANTS: A total of 2 375 787 tertiary hospital admissions of people aged 18 years or older. MAIN OUTCOME MEASURE: Rate of CT scanning per 1000 hospital admissions. METHODS: A multivariable decomposition model was used to quantify the contribution of changes in patient characteristics and changes in the probability of having a CT over the study period. RESULTS: The rate of CT scanning increased by 112 CT scans per 1000 admissions over the study period. Changes in the distribution of the observed patient characteristics were accounted for 62.7% of the growth in CT use. However, among unplanned admissions, changes in the distribution of patient characteristics only explained 17% of the growth in CT use, the remainder being explained by changes in the probability of having a CT scan. While the relative probability of having a CT scan generally increased over time across most observed characteristics, it reduced in young adults (-2.8%), people living in the rural/remote areas (-0.8%) and people transferred from secondary hospitals (-0.8%). CONCLUSIONS: Our study highlights potential improvements in practice towards reducing medical radiation exposure in certain high risk population. Since changes in the relative probability of having a CT scan (representing changes in scope) rather than changes in the distribution of the patient characteristics (representing changes in need) explained a major proportion of the growth in CT use, this warrants more in-depth investigations in clinical practices to better inform health policies promoting appropriate use of diagnostic imaging tests.

Increasing use of CT requested by emergency department physicians in tertiary hospitals in Western Australia 2003-2015: an analysis of linked administrative data.

OBJECTIVE: This study aimed to examine trends in number of CT scans requested by tertiary emergency department (ED) physicians in Western Australia (WA) from 2003 to 2015 across broad demographic and presentation characteristics, anatomical areas and presented symptoms. DESIGN: An observational cross-sectional study over study period from 2003 to 2015. SETTING: Linked administrative health service data at individual level from WA. PARTICIPANTS: A total of 1 666 884 tertiary hospital ED presentations of people aged 18 years or older were included in this study MAIN OUTCOME MEASURE: Number of CT scans requested by tertiary ED physicians in an ED presentation. METHODS: Poisson regression models were used to assess variation and trends in number of CT scans requested by ED physicians across demographic characteristics, clinical presentation characteristics and anatomical areas. RESULTS: Over the entire study duration, 71 per 1000 ED episodes had a CT requested by tertiary ED physicians. Between 2003 and 2015, the rate of CT scanning almost doubled from 58 to 105 per 1000 ED presentations. After adjusted for all observed characteristics, the rate of CT scans showed a downward trend from 2009 to 2011 and subsequent increase. Males, older individuals, those attending ED as a result of pain, those with neurological symptoms or injury or with higher priority triage code were the most likely to have CT requested by tertiary ED physicians. CONCLUSIONS: Noticeable changes in the number of CTs requested by tertiary ED physicians corresponded to the time frame of major health reforms happening within WA and nationally.

Muscle and bone dose in paediatric limb digital radiography: a Monte Carlo evaluation.

The proliferation of digital radiography (DR) has led to a re-evaluation of exposure parameters and image quality. Currently, there is a move towards reducing X-ray tube voltage (kVp) in paediatric exposures down to 40 kVp to achieve better images. However, the effect on patient dose of these modifications is uncertain. The main aims of this phantom study were to evaluate the effect of reducing the kVp in paediatric limb DR exposures on contrast-to-noise ratio (CNR) and patient dose. For this purpose, Monte Carlo simulations of radiographic exposures on a paediatric limb phantom were performed. The phantom included muscle tissue and bone segments of five different densities in the range of 1.12 to 1.48 g/cm3. The overall thickness of the phantom varied between 1 and 12 cm. Dependence of the CNR at constant limb phantom muscle and bone doses and dependence of the CNR per unit of muscle and bone dose at constant detector dose on radiographic exposure factors and limb thickness were calculated. X-ray tube current-time product (mAs) values required to achieve equal detector dose versus limb thickness for different kVp were calculated, as well as muscle and bone doses for the limb phantom of varying thickness. Present work has shown that reducing the kVp in paediatric radiography of the extremities can result in a significant increase in radiation dose, particularly for thicker limbs. Low kVp radiography requires justification for use on the extremities.

How have advances in CT dosimetry software impacted estimates of CT radiation dose and cancer incidence? A comparison of CT dosimetry software: Implications for past and future research.

OBJECTIVE: Organ radiation dose from a CT scan, calculated by CT dosimetry software, can be combined with cancer risk data to estimate cancer incidence resulting from CT exposure. We aim to determine to what extent the use of improved anatomical representation of the adult human body "phantom" in CT dosimetry software impacts estimates of radiation dose and cancer incidence, to inform comparison of past and future research. METHODS: We collected 20 adult cases for each of three CT protocols (abdomen/pelvis, chest and head) from each of five public hospitals (random sample) (January-April inclusive 2010) and three private clinics (self-report). Organ equivalent and effective dose were calculated using both ImPACT (mathematical phantom) and NCICT (voxelised phantom) software. Bland-Altman plots demonstrate agreement and Passing-Bablok regression reports systematic, proportional or random differences between results. We modelled the estimated lifetime attributable risk of cancer from a single exposure for each protocol, using age-sex specific risk-coefficients from the Biologic Effects of Ionizing Radiation VII report. RESULTS: For the majority of organs used in epidemiological studies of cancer incidence, the NCICT software (voxelised) provided higher dose estimates. Across the lifespan NCICT resulted in cancer estimates 2.9%-6.6% and 14.8%-16.3% higher in males and females (abdomen/pelvis) and 7.6%-19.7% and 12.9%-26.5% higher in males and females respectively (chest protocol). For the head protocol overall cancer estimates were lower for NCICT, but with greatest disparity, >30% at times. CONCLUSION: When the results of previous studies estimating CT dose and cancer incidence are compared to more recent, or future, studies the dosimetry software must be considered. Any change in radiation dose or cancer risk may be attributable to the software and phantom used, rather than-or in addition to-changes in scanning practice. Studies using dosimetry software to estimate radiation dose should describe software comprehensively to facilitate comparison with past and future research.

Detection of maturity and ligament injury using magic angle directional imaging.

PURPOSE: To investigate whether magnetic field-related anisotropies of collagen may be correlated with postmortem findings in animal models. METHODS: Optimized scan planning and new MRI data-processing methods were proposed and analyzed using Monte Carlo simulations. Six caprine and 10 canine knees were scanned at various orientations to the main magnetic field. Image intensities in segmented voxels were used to compute the orientation vectors of the collagen fibers. Vector field and tractography plots were computed. The Alignment Index was defined as a measure of orientation distribution. The knees were subsequently assessed by a specialist orthopedic veterinarian, who gave a pathological diagnosis after having dissected and photographed the joints. RESULTS: Using 50% less scans than reported previously can lead to robust calculation of fiber orientations in the presence of noise, with much higher accuracy. The 6 caprine knees were found to range from very immature (< 3 months) to very mature (> 3 years). Mature specimens exhibited significantly more aligned collagen fibers in their patella tendons compared with the immature ones. In 2 of the 10 canine knees scanned, partial cranial caudal ligament tears were identified from MRI and subsequently confirmed with encouragingly high consistency of tractography, Alignment Index, and dissection results. CONCLUSION: This method can be used to detect injury such as partial ligament tears, and to visualize maturity-related changes in the collagen structure of tendons. It can provide the basis for new, noninvasive diagnostic tools in combination with new scanner configurations that allow less-restricted field orientations.

Comparison between diffusion-weighted MRI (DW-MRI) at 1.5 and 3 tesla: a phantom study.

PURPOSE: To compare DW-MRI between 1.5 and 3 Tesla (T) in terms of image quality, apparent diffusion coefficient (ADC), reproducibility, lesion-to-background contrast and signal-to-noise ratio (SNR), using a test object. MATERIALS AND METHODS: A spherical diffusion phantom was used for qualitatively assessing image quality and performing quantitative measurements between the two field strengths. RESULTS: Distortions and signal losses degraded image quality at 3T even when the protocols were optimized for minimum TE. The ADC, in the majority of the phantom compartments, was significantly different between 1.5T and 3T (P < 0.009), while the average coefficient of variation, excluding the phantom compartments affected by artifacts, was <1.3% at both field strengths. The lesion-to-background contrast was improved at 1.5T for images acquired with b = 1000 s/mm(2) and comparable contrast was achieved at 3T with higher b-values. The SNR gain at 3T could, in theory, be balanced by the increased number of signal excitations one can accommodate at 1.5T to perform DW-MRI within the same acquisition time and possibly improved image quality, when 3T systems with no parallel transmission are used. CONCLUSION: Further phantom and in vivo studies are required to investigate the utility of DW-MRI at 3T, if image quality and acquisition times comparable to the ones from 1.5T are assumed.

A phantom for diffusion-weighted MRI (DW-MRI).

PURPOSE: To develop tissue-equivalent diffusivity materials and build a spherical diffusion phantom which mimics the conditions typically found in biological tissues. Also, to assess the reproducibility of ADC measurements from a whole-body diffusion protocol. MATERIALS AND METHODS: Nickel-doped agarose/sucrose gels were manufactured and used to build a spherical diffusion phantom with tissue-equivalent relaxation and diffusion compartments. The temporal stability of the gels was monitored for a period of 8 weeks and, using the same measurements, the reproducibility of ADC was assessed in a 1.5 Tesla (T) clinical system. RESULTS: The temporal stability of the nickel-doped agarose/sucrose gels diffusion properties was excellent (average coefficient of variation [CV] for ADC in all phantom compartments = 1.27%). The average CV for ADC measurements, excluding the phantom compartments affected by artifacts, was 0.76% showing that the reproducibility of ADC measurements using an EPI DW-MRI protocol is very good. CONCLUSION: Nickel-doped agarose/sucrose gels can be used as reference materials for MRI diffusion measurements and show excellent short-term stability with respect to ADC. A phantom made of these materials can be invaluable in optimizing DW-MRI protocols, developing novel pulse sequences for DW-MRI, or comparing ADC values among field strengths, vendors, and imaging centers.

Pseudotumors in association with well-functioning metal-on-metal hip prostheses: a case-control study using three-dimensional computed tomography and magnetic resonance imaging.

INTRODUCTION: Many papers have been published recently on the subject of pseudotumors surrounding metal-on-metal hip resurfacing and replacement prostheses. These pseudotumors are sterile, inflammatory lesions within the periprosthetic tissues and have been variously termed masses, cysts, bursae, collections, or aseptic lymphocyte-dominated vasculitis-associated lesions (ALVAL). The prevalence of pseudotumors in patients with a well-functioning metal-on-metal hip prosthesis is not well known. The purpose of this study was to quantify the prevalence of pseudotumors adjacent to well-functioning and painful metal-on-metal hip prostheses, to characterize these lesions with use of magnetic resonance imaging, and to assess the relationship between their presence and acetabular cup position with use of three-dimensional computed tomography. METHODS: We performed a case-control study to compare the magnetic resonance imaging findings of patients with a well-functioning unilateral metal-on-metal hip prosthesis and patients with a painful prosthesis (defined by either revision arthroplasty performed because of unexplained pain or an Oxford hip score of <30 of 48 possible points). Thirty patients with a painful hip prosthesis and twenty-eight controls with a well-functioning prosthesis were recruited consecutively. All patients also underwent computed tomography to assess the position of the acetabular component. RESULTS: Thirty-four patients were diagnosed with a pseudotumor. However, the prevalence of pseudotumors in patients with a painful hip (seventeen of thirty, 57%) was not significantly different from the prevalence in the control group (seventeen of twenty-eight, 61%). No objective differences in pseudotumor characteristics between the groups were identified. No clear association between the presence of a pseudotumor and acetabular component position was identified. The Oxford hip score in the group with a painful hip (mean, 20.2; 95% confidence interval [CI], 12.7 to 45.8) was poorer than that in the control group (mean, 41.2; 95% CI, 18.5 to 45.8; p ≤ 0.0001). CONCLUSIONS: A periprosthetic cystic pseudotumor was diagnosed commonly (in thirty-four [59%] of the entire study cohort) with use of metal artifact reduction sequence (MARS) magnetic resonance imaging in this series of patients with a metal-on-metal hip prosthesis. The prevalence of pseudotumors was similar in patients with a well-functioning hip prosthesis and patients with a painful hip. Pseudotumors were also diagnosed commonly in patients with a well-positioned acetabular component. Although magnetic resonance imaging is useful for surgical planning, the presence of a cystic pseudotumor may not necessarily indicate the need for revision arthroplasty. Further correlation of clinical and imaging data is needed to determine the natural history of pseudotumors to guide clinical practice.

Return of spinal reflex after spinal cord surgery for brachial plexus avulsion injury.

Motor but not sensory function has been described after spinal cord surgery in patients with brachial plexus avulsion injury. In the featured case, motor-related nerve roots as well as sensory spinal nerves distal to the dorsal root ganglion were reconnected to neurons in the ventral and dorsal horns of the spinal cord by implanting nerve grafts. Peripheral and sensory functions were assessed 10 years after an accident and subsequent spinal cord surgery. The biceps stretch reflex could be elicited, and electrophysiological testing demonstrated a Hoffman reflex, or Hreflex, in the biceps muscle when the musculocutaneous nerve was stimulated. Functional MR imaging demonstrated sensory motor cortex activities on active as well as passive elbow flexion. Quantitative sensory testing and contact heat evoked potential stimulation did not detect any cutaneous sensory function, however. To the best of the authors' knowledge, this case represents the first time that spinal cord surgery could restore not only motor function but also proprioception completing a spinal reflex arch.

Numerical simulation of SAR induced around Co-Cr-Mo hip prostheses in situ exposed to RF fields associated with 1.5 and 3 T MRI body coils.

When patients with metallic prosthetic implants undergo an MR procedure, the interaction between the RF field and the prosthetic device may lead to an increase in specific absorption rate (SAR) in tissues surrounding the prosthesis. In this work, the distribution of SAR(10g) around bilateral CoCrMo alloy hip prostheses in situ in anatomically realistic voxel models of an adult male and female due to RF fields from a generic birdcage coil driven at 64 or 128 MHz are predicted using a time-domain finite integration technique. Results indicate that the spatial distribution and maximum values of SAR(10g) are dependent on body model, frequency, and the position of the coil relative to the body. Enhancement of SAR(10g) close to the extremities of a prosthesis is predicted. Values of SAR(10g) close to the prostheses are compliant with recommended limits if the prostheses are located outside the coil. However, caution is required when the prostheses are within the coil since the predicted SAR(10g) close to an extremity of a prosthesis exceeds recommended limits when the whole body averaged SAR is 2 W kg(-1) . Compliance with recommended limits is likely to require a reduction in the time averaged input power.

Functional MRI brain imaging studies using the Contact Heat Evoked Potential Stimulator (CHEPS) in a human volunteer topical capsaicin pain model.

Acute application of topical capsaicin produces spontaneous burning and stinging pain similar to that seen in some neuropathic states, with local hyperalgesia. Use of capsaicin applied topically or injected intradermally has been described as a model for neuropathic pain, with patterns of activation in brain regions assessed using functional magnetic resonance imaging (fMRI) and positron emission tomography. The Contact Heat Evoked Potential Stimulator (CHEPS) is a noninvasive clinically practical method of stimulating cutaneous A-delta nociceptors. In this study, topical capsaicin (1%) was applied to the left volar forearm for 15 minutes of twelve adult healthy human volunteers. fMRI scans and a visual analog pain score were recorded during CHEPS stimulation precapsaicin and postcapsaicin application. Following capsaicin application there was a significant increase in visual analog scale (mean ± standard error of the mean; precapsaicin 26.4 ± 5.3; postcapsaicin 48.9 ± 6.0; P < 0.0001). fMRI demonstrated an overall increase in areas of activation, with a significant increase in the contralateral insular signal (mean ± standard error of the mean; precapsaicin 0.434 ± 0.03; postcapsaicin 0.561 ± 0.07; P = 0.047). The authors of this paper recently published a study in which CHEPS-evoked A-delta cerebral potential amplitudes were found to be decreased postcapsaicin application. In patients with neuropathic pain, evoked pain and fMRI brain responses are typically increased, while A-delta evoked potential amplitudes are decreased. The protocol of recording fMRI following CHEPS stimulation after topical application of capsaicin could be combined with recording of evoked potentials to provide a simple, rapid, and robust volunteer model to develop novel drugs for neuropathic pain.

Biasing visual selection: functional neuroimaging of the interplay between spatial cueing and feature memory guidance.

The authors investigate the interplay between spatial attention and memory-based feature guidance of visual selection. Three types of guidance were tested: working memory, spatial cueing and passive memory. In all cases the memory-cue was not relevant to a subsequent search task, whilst the spatial cue always provided valid information. Behaviourally, search performance was influenced by spatial cueing and by feature-based cueing from the contents of working memory; both forms of guidance interacted, with feature guidance being more effective when the target's location was not pre-cued. Spatial cueing recruited the dorsal fronto-parietal network which was silent during the WM-only condition. Memory guidance of selection was reflected in activity in a frontal-temporal-occipital network. Interestingly, when spatial and memory guidance were pitted against each other, neural activity in this latter network was greatly attenuated. Connectivity analysis showed that the posterior parietal cortices inhibit the responses of occipital and temporal regions to the onset of memory-items in the search display. In the presence of a reliable spatial cue the posterior parietal cortex resumes control of attentional deployment. These results illustrate how different forms of attention guidance interact to optimise visual selection.

In vivo-in vitro correlations: predicting pulmonary drug deposition from pharmaceutical aerosols.

In order to answer the question "what research remains to be done?" we review the current state of the art in pharmaceutical aerosol deposition modeling and explore possible in vivo- in vitro correlations (IVIVC) linking drug deposition in the human lung to predictions made using in vitro physical airway models and in silico computer models. The use of physical replicas of portions of the respiratory tract is considered, alongside the advantages and disadvantages of the different imaging methods used to obtain their dimensions. The use of airway replicas to determine drug deposition in vitro is discussed and compared with the predictions from different empirical curve fits to long-standing in vivo deposition data for monodisperse aerosols. The use of improved computational models and three-dimensional computational fluid dynamics (CFD) to predict aerosol deposition within the respiratory tract is examined. CFD's ability to predict both drug deposition from pharmaceutical aerosol sprays and powder behavior in dry powder inhalers is examined; both were highlighted as important areas for future research. Although the authors note the abilities of current in vitro and in silico methods to predict in vivo data, a number of limitations remain. These include our present inability to either image or replicate all but the most proximal airways in sufficient spatial and temporal detail to allow full capture of the fluid and aerosol mechanics in these regions. In addition, the highly complex microscale behavior of aerosols within inhalers and the respiratory tract places extreme computational demands on in silico methods. When the complexity of variations in respiratory tract geometry is associated with additional factors such as breathing pattern, age, disease state, postural position, and patient-device interaction are all considered, it is clear that further research is required before the prediction of all aspects of inhaled pharmaceutical aerosol deposition is possible.