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1.  Patient-reported outcome measures: an on-line system empowering patient choice 
An innovative web-based system was developed to allow patient-reported outcome measures (PROMs) to be easily administered. Stakeholders guided the design and implementation. The software gives patients access to their current and previous scores. This pilot study focused on patients undergoing arthroscopic subacromial decompression, evaluated using the Oxford shoulder score (OSS). Patients showing good improvement in their OSS were offered the choice to return for routine follow-up clinic appointments, or continue rehabilitation, reassured by their improved score. Thirty-six of 117 patients were eligible. Thirty of these (83%) were opted to avoid further clinics. PROMs 2.0 can be used for any medical intervention with a validated PROM. Evolution and refinement is ongoing. Funding has been granted for 12 primary and secondary healthcare trusts to implement PROMs 2.0. Further work is needed to assess economic impact, patient views and satisfaction with the process.
PMCID: PMC4078267  PMID: 24013090
Innovation; Outcome; Measure; eHealth; Patient Choice; clinical decision support
2.  The Role of Rumination in Elevating Perceived Stress in Posttraumatic Stress Disorder 
Journal of interpersonal violence  2013;29(10):1953-1962.
Rumination has been shown to be important in both the maintenance and severity of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Increased rumination has also been linked to perceptions of increased stress, which in turn are significantly associated with increased PTSD severity. The present study sought to examine this relationship in more detail by means of a mediation analysis. Forty-nine female survivors of interpersonal violence who met Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) criteria for PTSD were administered the Clinician-Administered PTSD Scale (CAPS), the Ruminative Thought Style Questionnaire (RTS), the Perceived Stress Scale (PSS), and the Beck Depression Inventory–II (BDI-II). Results indicated that perceived stress mediates the relationship between rumination and PTSD, but did not do so after controlling for depression. Such results provide further evidence for the overlap between PTSD and MDD, and, in broader clinical practice, translate to a sharper focus on rumination and perceived stress as maintenance factors in both disorders.
PMCID: PMC4119088  PMID: 24346652
PTSD; domestic violence; child abuse; sexual assault
3.  Piezo2 is the major transducer of mechanical forces for touch sensation in mice 
Nature  2014;516(7529):121-125.
The sense of touch provides critical information about our physical environment by transforming mechanical energy into electrical signals1. It is postulated that mechanically activated (MA) cation channels initiate touch sensation, but the identity of these molecules in mammals has been elusive2. Piezo2 is a rapidly adapting (RA) MA ion channel expressed in a subset of sensory neurons of the dorsal root ganglion (DRG) and in cutaneous mechanoreceptors known as Merkel cell-neurite complexes3,4. Merkel cells have been demonstrated to play a role in vertebrate mechanosensation using Piezo2, particularly in shaping the type of current sent by its innervating sensory neuron4-6. However, major aspects of touch sensation remain intact without Merkel cell activity4,7. Here, we show that mice lacking Piezo2 in both adult sensory neurons and Merkel cells exhibit a profound loss of touch sensation. We precisely localize Piezo2 to the peripheral endings of a broad range of low threshold mechanoreceptors (LTMRs) that innervate both hairy and glabrous skin. Most RA MA currents in DRG neuronal cultures are absent in Piezo2CKO mice, and ex vivo skin nerve preparation studies show that mechanosensitivity of LTMRs strongly depends on Piezo2. This striking cellular phenotype correlates with an unprecedented behavioral phenotype: an almost complete deficit in light touch sensation in multiple behavioral assays, without affecting other somatosensory functions. Our results highlight that a single ion channel that displays RA MA currents in vitro is responsible for the mechanosensitivity of most LTMR subtypes involved in innocuous touch sensation. Interestingly, we find that touch and pain sensation are separable, suggesting that yet-unknown MA ion channel(s) must account for noxious (painful) mechanosensation.
PMCID: PMC4380172  PMID: 25471886
4.  Application of high-dimensional feature selection: evaluation for genomic prediction in man 
Scientific Reports  2015;5:10312.
In this study, we investigated the effect of five feature selection approaches on the performance of a mixed model (G-BLUP) and a Bayesian (Bayes C) prediction method. We predicted height, high density lipoprotein cholesterol (HDL) and body mass index (BMI) within 2,186 Croatian and into 810 UK individuals using genome-wide SNP data. Using all SNP information Bayes C and G-BLUP had similar predictive performance across all traits within the Croatian data, and for the highly polygenic traits height and BMI when predicting into the UK data. Bayes C outperformed G-BLUP in the prediction of HDL, which is influenced by loci of moderate size, in the UK data. Supervised feature selection of a SNP subset in the G-BLUP framework provided a flexible, generalisable and computationally efficient alternative to Bayes C; but careful evaluation of predictive performance is required when supervised feature selection has been used.
PMCID: PMC4437376  PMID: 25988841
5.  Can Patient Comorbidities Be Included in Clinical Performance Measures for Radiation Oncology? 
Journal of Oncology Practice  2014;10(3):e175-e181.
ACE-27 is predictive of treatment modifications for patients with cancers of the breast, cervix, lung, prostate, and stomach who receive radiation as part of their care.
Patient comorbidities may affect the applicability of performance measures that are inherent in multidisciplinary cancer treatment guidelines. This article describes the distribution of common comorbid conditions by disease site and by patient and facility characteristics in patients who received radiation therapy as part of treatment for cancer of the breast, cervix, lung, prostate, and stomach, and investigates the association of comorbidities with treatment decisions.
Materials and Methods:
Stratified two-stage cluster sampling provided a random sample of radiation oncology facilities. Eligible patients were randomly sampled from each participating facility for each disease site, and data were abstracted from medical records. The Adult Comorbidity Evaluation Index (ACE-27) was used to measure comorbid conditions and their severity. National estimates were calculated using SUDAAN statistical software.
Multivariable logistic regression models predicted the dependent variable “treatment changed or contraindicated due to comorbidities.” The final model showed that ACE-27 was highly associated with change in treatment for patients with severe or moderate index values compared to those with none or mild (P < .001). Two other covariates, age and medical coverage, had no (age) or little (medical coverage) significant contribution to predicting treatment change in the multivariable model. Disease site was associated with treatment change after adjusting for other covariates in the model.
ACE-27 is highly predictive of treatment modifications for patients treated for these cancers who receive radiation as part of their care. A standardized tool identifying patients who should be excluded from clinical performance measures allows more accurate use of these measures.
PMCID: PMC4018459  PMID: 24643573
6.  Oral bacterial community dynamics in paediatric patients with malignancies in relation to chemotherapy-related oral mucositis: a prospective study 
Clinical Microbiology and Infection  2013;19(12):E559-E567.
The role of oral bacteria in the development of chemotherapy-related oral mucositis has not been fully elucidated. This study aimed to investigate oral bacterial community diversity and dynamics in paediatric patients with malignancies in relation to the occurrence of oral mucositis. Patients with malignancies (n = 37) and reference individuals without known systemic disorders (n = 38) were recruited. For patients, oral bacterial samples were taken from mucosal surfaces both at the time of malignancy diagnosis and during chemotherapy. If oral mucositis occurred, samples were taken from the surface of the mucositis lesions. Oral mucosal bacterial samples were also taken from reference individuals. All samples were assessed using a 16S ribosomal RNA gene 454 pyrosequencing method. A lower microbial diversity (p < 0.01) and a higher intersubject variability (p < 0.001) were found in patients as compared with reference individuals. At the time of malignancy diagnosis (i.e. before chemotherapy) patients that later developed mucositis showed a higher microbial diversity (p < 0.05) and a higher intersubject variability (p < 0.001) compared with those without mucositis. The change of bacterial composition during chemotherapy was more pronounced in patients who later developed mucositis than those without mucositis (p < 0.01). In conclusion, we found a higher microbial diversity at the time of malignancy diagnosis in patients who later develop oral mucositis and that these patients had a more significant modification of the bacterial community by chemotherapy before the occurrence of mucositis. These findings may possibly be of clinical importance in developing better strategies for personalized preventive management.
PMCID: PMC4413823  PMID: 23829394
16S rRNA gene; 454 pyrosequencing; cancer; oral microflora; stomatitis
7.  Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949) 
Davies, G | Armstrong, N | Bis, J C | Bressler, J | Chouraki, V | Giddaluru, S | Hofer, E | Ibrahim-Verbaas, C A | Kirin, M | Lahti, J | van der Lee, S J | Le Hellard, S | Liu, T | Marioni, R E | Oldmeadow, C | Postmus, I | Smith, A V | Smith, J A | Thalamuthu, A | Thomson, R | Vitart, V | Wang, J | Yu, L | Zgaga, L | Zhao, W | Boxall, R | Harris, S E | Hill, W D | Liewald, D C | Luciano, M | Adams, H | Ames, D | Amin, N | Amouyel, P | Assareh, A A | Au, R | Becker, J T | Beiser, A | Berr, C | Bertram, L | Boerwinkle, E | Buckley, B M | Campbell, H | Corley, J | De Jager, P L | Dufouil, C | Eriksson, J G | Espeseth, T | Faul, J D | Ford, I | Scotland, Generation | Gottesman, R F | Griswold, M E | Gudnason, V | Harris, T B | Heiss, G | Hofman, A | Holliday, E G | Huffman, J | Kardia, S L R | Kochan, N | Knopman, D S | Kwok, J B | Lambert, J-C | Lee, T | Li, G | Li, S-C | Loitfelder, M | Lopez, O L | Lundervold, A J | Lundqvist, A | Mather, K A | Mirza, S S | Nyberg, L | Oostra, B A | Palotie, A | Papenberg, G | Pattie, A | Petrovic, K | Polasek, O | Psaty, B M | Redmond, P | Reppermund, S | Rotter, J I | Schmidt, H | Schuur, M | Schofield, P W | Scott, R J | Steen, V M | Stott, D J | van Swieten, J C | Taylor, K D | Trollor, J | Trompet, S | Uitterlinden, A G | Weinstein, G | Widen, E | Windham, B G | Jukema, J W | Wright, A F | Wright, M J | Yang, Q | Amieva, H | Attia, J R | Bennett, D A | Brodaty, H | de Craen, A J M | Hayward, C | Ikram, M A | Lindenberger, U | Nilsson, L-G | Porteous, D J | Räikkönen, K | Reinvang, I | Rudan, I | Sachdev, P S | Schmidt, R | Schofield, P R | Srikanth, V | Starr, J M | Turner, S T | Weir, D R | Wilson, J F | van Duijn, C | Launer, L | Fitzpatrick, A L | Seshadri, S | Mosley, T H | Deary, I J
Molecular Psychiatry  2015;20(2):183-192.
General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.
PMCID: PMC4356746  PMID: 25644384
8.  Identifying Risk Factors for Disparities in Breast Cancer Mortality among African-American and Hispanic Women 
This study evaluated the risk factors associated with racial disparities in female breast cancer mortality for African-American and Hispanic women at the census tract level in Texas from 1995 to 2005.
Data on female breast cancer cases were obtained from the Texas Cancer Registry. Socioeconomic and demographic data were collected from Census 2000. Network distance and driving times to mammography facilities were estimated using Geographic Information System techniques. Demographic, poverty and spatial accessibility factors were constructed using principal component analysis. Logistic regression models were developed to predict the census tracts with significant racial disparities in breast cancer mortality based on racial disparities in late-stage diagnosis and structured factors from the principal component analysis.
Late-stage diagnosis, poverty factors, and demographic factors were found to be significant predictors of a census tract showing significant racial disparities in breast cancer mortality. Census tracts with higher poverty status were more likely to display significant racial disparities in breast cancer mortality for both African Americans (odds ratio [OR], 2.43; 95% confidence interval [CI], 1.95–3.04) and Hispanics (OR, 5.30; 95% CI, 4.26–6.59). Spatial accessibility was not a consistent predictor of racial disparities in breast cancer mortality for African-American and Hispanic women.
Physical access to mammography facilities does not necessarily reflect a greater utilization of mammogram screening, possibly owing to financial constraints. Therefore, a metric measuring access to health care facilities is needed to capture all aspects of access to preventive care. Despite easier physical access to mammography facilities in metropolitan areas, great resources and efforts should also be devoted to these areas where racial disparities in breast cancer mortality are often found.
PMCID: PMC4338013  PMID: 22265181
9.  Competition as a source of constraint on life history evolution in natural populations 
Heredity  2013;112(1):70-78.
Competition among individuals is central to our understanding of ecology and population dynamics. However, it could also have major implications for the evolution of resource-dependent life history traits (for example, growth, fecundity) that are important determinants of fitness in natural populations. This is because when competition occurs, the phenotype of each individual will be causally influenced by the phenotypes, and so the genotypes, of competitors. Theory tells us that indirect genetic effects arising from competitive interactions will give rise to the phenomenon of ‘evolutionary environmental deterioration', and act as a source of evolutionary constraint on resource-dependent traits under natural selection. However, just how important this constraint is remains an unanswered question. This article seeks to stimulate empirical research in this area, first highlighting some patterns emerging from life history studies that are consistent with a competition-based model of evolutionary constraint, before describing several quantitative modelling strategies that could be usefully applied. A recurrent theme is that rigorous quantification of a competition's impact on life history evolution will require an understanding of the causal pathways and behavioural processes by which genetic (co)variance structures arise. Knowledge of the G-matrix among life history traits is not, in and of itself, sufficient to identify the constraints caused by competition.
PMCID: PMC3860166  PMID: 23443060
indirect genetic effects; evolutionary constraint; behaviour; personality; G-matrix
11.  The Minimal Preprocessing Pipelines for the Human Connectome Project 
NeuroImage  2013;80:105-124.
The Human Connectome Project (HCP) faces the challenging task of bringing multiple magnetic resonance imaging (MRI) modalities together in a common automated preprocessing framework across a large cohort of subjects. The MRI data acquired by the HCP differ in many ways from data acquired on conventional 3 Tesla scanners and often require newly developed preprocessing methods. We describe the minimal preprocessing pipelines for structural, functional, and diffusion MRI that were developed by the HCP to accomplish many low level tasks, including spatial artifact/distortion removal, surface generation, cross-modal registration, and alignment to standard space. These pipelines are specially designed to capitalize on the high quality data offered by the HCP. The final standard space makes use of a recently introduced CIFTI file format and the associated grayordinates spatial coordinate system. This allows for combined cortical surface and subcortical volume analyses while reducing the storage and processing requirements for high spatial and temporal resolution data. Here, we provide the minimum image acquisition requirements for the HCP minimal preprocessing pipelines and additional advice for investigators interested in replicating the HCP’s acquisition protocols or using these pipelines. Finally, we discuss some potential future improvements for the pipelines.
PMCID: PMC3720813  PMID: 23668970
Human Connectome Project; Image Analysis Pipeline; Surface-based Analysis; CIFTI; Grayordinates; Multi-modal Data Integration
12.  Human Connectome Project Informatics: quality control, database services, and data visualization 
NeuroImage  2013;80:10.1016/j.neuroimage.2013.05.077.
The Human Connectome Project (HCP) has developed protocols, standard operating and quality control procedures, and a suite of informatics tools to enable high throughput data collection, data sharing, automated data processing and analysis, and data mining and visualization. Quality control procedures include methods to maintain data collection consistency over time, to measure head motion, and to establish quantitative modality-specific overall quality assessments. Database services developed as customizations of the XNAT imaging informatics platform support both internal daily operations and open access data sharing. The Connectome Workbench visualization environment enables user interaction with HCP data and is increasingly integrated with the HCP's database services. Here we describe the current state of these procedures and tools and their application in the ongoing HCP study.
PMCID: PMC3845379  PMID: 23707591
13.  Mylotarg has potent anti-leukaemic effect: a systematic review and meta-analysis of anti-CD33 antibody treatment in acute myeloid leukaemia 
Annals of Hematology  2014;94:361-373.
Conventional chemotherapy is ineffective in the majority of patients with acute myeloid leukaemia (AML), and monoclonal antibodies recognising CD33 expressed on myeloid progenitors (e.g. gemtuzumab ozogamicin (GO)) have been reported to improve outcome in patients with AML. Reports of excess toxicity have resulted in GO’s licence being withdrawn. As a result, the role of these agents remains unclear. A systematic review and meta-analysis included studies of patients with AML who had entered a randomised control trial (RCT), where one arm included anti-CD33 antibody therapy. Fixed effect meta-analysis was used, involving calculation of observed minus expected number of events, and variance for each endpoint in each trial, with the overall treatment effect expressed as Peto’s odds ratio with 95 % confidence interval. Meta-analysis of 11 RCTs with 13 randomisations involving GO was undertaken. Although GO increased induction deaths (p = 0.02), it led to a reduction in resistant disease (p = 0.0009); hence, there was no improvement in complete remission. Whilst GO improved relapse-free survival (hazard ratio (HR) = 0.90, 95 % confidence interval (CI) = 0.84–0.98, p = 0.01), there was no overall benefit of GO in overall survival (OS) (HR = 0.96, 95 % CI = 0.90–1.02, p = 0.2). GO improved OS in patients with favourable cytogenetics, with no evidence of benefit in patients with intermediate or adverse cytogenetics (test for heterogeneity between subtotals p = 0.01). GO has a potent clinically detectable anti-leukaemic effect. Further trials to investigate its optimum delivery and identification of patient populations who may benefit are needed.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-014-2218-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4317519  PMID: 25284166
Acute myeloid leukaemia; CD33 antigen; Systematic review; Meta-analysis; Randomised clinical trials; Gemtuzumab; Mylotarg; Humanised monoclonal antibodies
14.  The Application of Functional Imaging Techniques to Personalise Chemoradiotherapy in Upper Gastrointestinal Malignancies 
Functional imaging gives information about physiological heterogeneity in tumours. The utility of functional imaging tests in providing predictive and prognostic information after chemoradiotherapy for both oesophageal cancer and pancreatic cancer will be reviewed. The benefit of incorporating functional imaging into radiotherapy planning is also evaluated. In cancers of the upper gastrointestinal tract, the vast majority of functional imaging studies have used 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Few studies in locally advanced pancreatic cancer have investigated the utility of functional imaging in risk-stratifying patients or aiding target volume definition. Certain themes from the oesophageal data emerge, including the need for a multiparametric assessment of functional images and the added value of response assessment rather than relying on single time point measures. The sensitivity and specificity of FDG-PET to predict treatment response and survival are not currently high enough to inform treatment decisions. This suggests that a multimodal, multiparametric approach may be required. FDG-PET improves target volume definition in oesophageal cancer by improving the accuracy of tumour length definition and by improving the nodal staging of patients. The ideal functional imaging test would accurately identify patients who are unlikely to achieve a pathological complete response after chemoradiotherapy and would aid the delineation of a biological target volume that could be used for treatment intensification. The current limitations of published studies prevent integrating imaging-derived parameters into decision making on an individual patient basis. These limitations should inform future trial design in oesophageal and pancreatic cancers.
PMCID: PMC4150923  PMID: 24998430
Functional imaging; oesophageal cancer; pancreatic cancer; radiotherapy treatment planning; response assessment; target volume delineation
15.  Robot-assisted intraocular surgery: development of the IRISS and feasibility studies in an animal model 
Eye  2013;27(8):972-978.
The aim of this study is to develop a novel robotic surgical platform, the IRISS (Intraocular Robotic Interventional and Surgical System), capable of performing both anterior and posterior segment intraocular surgery, and assess its performance in terms of range of motion, speed of motion, accuracy, and overall capacities.
Patients and methods
To test the feasibility of performing ‘bimanual' intraocular surgical tasks using the IRISS, we defined four steps out of typical anterior (phacoemulsification) and posterior (pars plana vitrectomy (PPV)) segment surgery. Selected phacoemulsification steps included construction of a continuous curvilinear capsulorhexis and cortex removal in infusion–aspiration (I/A) mode. Vitrectomy steps consisted of performing a core PPV, followed by aspiration of the posterior hyaloid with the vitreous cutter to induce a posterior vitreous detachment (PVD) assisted with triamcinolone, and simulation of the microcannulation of a temporal retinal vein. For each evaluation, the duration and the successful completion of the task with or without complications or involuntary events was assessed.
Intraocular procedures were successfully performed on 16 porcine eyes. Four eyes underwent creation of a round, curvilinear anterior capsulorhexis without radialization. Four eyes had I/A of lens cortical material completed without posterior capsular tear. Four eyes completed 23-gauge PPV followed by successful PVD induction without any complications. Finally, simulation of microcannulation of a temporal retinal vein was successfully achieved in four eyes without any retinal tears/perforations noted.
Robotic-assisted intraocular surgery with the IRISS may be technically feasible in humans. Further studies are pending to improve this particular surgical platform.
PMCID: PMC3740307  PMID: 23722720
intraocular surgery; robot; phacoemulsification; vitrectomy
16.  Brucellosis as an Emerging Threat in Developing Economies: Lessons from Nigeria 
Nigeria is the most populous country in Africa, has a large proportion of the world's poor livestock keepers, and is a hotspot for neglected zoonoses. A review of the 127 accessible publications on brucellosis in Nigeria reveals only scant and fragmented evidence on its spatial and temporal distribution in different epidemiological contexts. The few bacteriological studies conducted demonstrate the existence of Brucella abortus in cattle and sheep, but evidence for B. melitensis in small ruminants is dated and unclear. The bulk of the evidence consists of seroprevalence studies, but test standardization and validation are not always adequately described, and misinterpretations exist with regard to sensitivity and/or specificity and ability to identify the infecting Brucella species. Despite this, early studies suggest that although brucellosis was endemic in extensive nomadic systems, seroprevalence was low, and brucellosis was not perceived as a real burden; recent studies, however, may reflect a changing trend. Concerning human brucellosis, no studies have identified the Brucella species and most reports provide only serological evidence of contact with Brucella in the classical risk groups; some suggest brucellosis misdiagnoses as malaria or other febrile conditions. The investigation of a severe outbreak that occurred in the late 1970s describes the emergence of animal and human disease caused by the settling of previously nomadic populations during the Sahelian drought. There appears to be an increasing risk of re-emergence of brucellosis in sub-Saharan Africa, as a result of the co-existence of pastoralist movements and the increase of intensive management resulting from growing urbanization and food demand. Highly contagious zoonoses like brucellosis pose a threat with far-reaching social and political consequences.
PMCID: PMC4109902  PMID: 25058178
17.  Evaluation of a modified Fitts law BCI target acquisition task in able and motor disabled individuals 
Journal of neural engineering  2009;6(5):056002.
A brain-computer interface (BCI) is a communication system that takes recorded brain signals and translates them into real-time actions, in this case movement of a cursor on a computer screen. This work applied Fitts’ law to the evaluation of performance on a target acquisition task during sensorimotor rhythm-based BCI training. Fitts’ law, which has been used as a predictor of movement time in studies of human movement, was used here to determine the information transfer rate, which was based on target acquisition time and target difficulty. The information transfer rate was used to make comparisons between control modalities and subject groups on the same task. Data were analyzed from eight able-bodied and five motor disabled participants who wore an electrode cap that recorded and translated their electroencephalogram (EEG) signals into computer cursor movements. Direct comparisons were made between able-bodied and disabled subjects and between EEG and joystick cursor control in able-bodied subjects. Fitts’ law aptly described the relationship between movement time and index of difficulty for each task movement direction when evaluated separately and averaged together. This study showed that Fitts’ law can be successfully applied to computer cursor movement controlled by neural signals.
PMCID: PMC4075430  PMID: 19700814
18.  Non-steroidal anti-inflammatory drug and aspirin use and the risk of head and neck cancer 
British Journal of Cancer  2013;108(5):1178-1181.
Evidence for non-steroidal anti-inflammatory drugs (NSAIDs) preventing head and neck cancer (HNC) is inconclusive; however, there is some suggestion that aspirin may exert a protective effect.
Using data from the United States National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, we examined the association between aspirin and ibuprofen use and HNC.
Regular aspirin use was associated with a significant 22% reduction in HNC risk. No association was observed with regular ibuprofen use.
Aspirin may have potential as a chemopreventive agent for HNC, but further investigation is warranted.
PMCID: PMC3619083  PMID: 23449358
head and neck cancer; ibuprofen; aspirin; cohort study
19.  Penetration of Recommended Procedures for Lung Cancer Staging and Management in the United States over 10 Years: A Quality Research in Radiation Oncology Survey 
To document the penetration of clinical trial results, practice guidelines, and appropriateness criteria into national practice, we compared the use of components of staging and treatment for lung cancer among patients treated in 2006–2007 versus in 1998–1999.
Patient, staging work-up, and treatment characteristics were extracted from the process survey database of the Quality Research in Radiation Oncology (QRRO), comprising records from 340 patients with locally advanced non-small cell lung cancer (LA-NSCLC) at 44 institutions and 144 patients with limited-stage small cell lung cancer (LS-SCLC) at 39 institutions. Data were compared for patients treated in 2006–2007 versus patients treated in 1998–1999.
Use of all recommended procedures for staging and treatment was more common in 2006–2007. Specifically, disease was staged with brain imaging (magnetic resonance imaging or computed tomography) and whole-body imaging (positron emission tomography or bone scanning) in 66% of patients with LA-NSCLC in 2006–2007 (vs. 42% in 1998–1999, p=0.0001) and in 84% of patients with LS-SCLC in 2006–2007 (vs. 58.3% in 1998–1999, p=0.0011). Concurrent chemoradiation was used for 77% of LA-NSCLC patients (vs. 45% in 1998–1999, p<0.0001) and for 90% of LS-SCLC patients (vs. 62.5% in 1998–1999, p<0.0001). Use of the recommended radiation dose (59–74 Gy for NSCLC and 60–70 Gy as once-daily therapy for SCLC) did not change appreciably, being 88% for NSCLC in both periods and 51% (2006–2007) vs. 43% (1998–1999) for SCLC. Twice-daily radiation for SCLC was used for 21% of patients in 2006–2007 vs. 8% in 1998–1999. Finally, 49% of patients with LS-SCLC received prophylactic cranial irradiation (PCI) in 2006–2007 (vs. 21% in 1998–1999).
Although adherence to all quality indicators improved over time, brain imaging and recommended radiation doses for stage III NSCLC were used in <90% of cases. Use of full thoracic doses and PCI for LS-SCLC also require improvement.
PMCID: PMC3897271  PMID: 23273996
lung cancer; QRRO; quality indicators; clinical performance measures; healthcare management; standard of care; patterns of care
This study detailed the sequence of recurring inflammatory events associated with episodic allergen exposures of mice resulting in airway hyperreactivity, sustained inflammation, goblet cell hyperplasia, and fibrogenesis that characterize a lung with chronic asthma. Ovalbumin (OVA)-sensitized female Balb/c mice were exposed to saline-control or OVA aerosols for 1hr per day for episodes of 3 days every week for up to 8 weeks. Lung inflammation was assessed by inflammatory cell recoveries using bronchoalveolar lavages (BAL) and tissue collagenase dispersions. Cell accumulations were observed within airway submucosal and associated perivascular spaces using immunohistochemical and tinctorial staining methods. Airway responsiveness to methacholine aerosols were elevated after 2 weeks and further enhanced to a sustained level after the 4th and 8th weeks. Although by the 8th week, diminished OVA-induced accumulations of eosinophils, neutrophils and monocyte-macrophages were observed, suggesting diminished responsiveness, the BAL recovery of lymphocytes remained elevated. Airway but not perivascular lesions persisted with a proliferating cell population, epithelial goblet cell hyperplasia and evidence of enhanced collagen deposition. Examination of lung inflammatory cell content before the onset of the 1st, 2nd and 4th OVA exposure episodes demonstrated enhancements in residual BAL lymphocyte and BAL and tissue eosinophil recoveries with each exposure episode. Although tissue monocyte-macrophage numbers returned to baseline prior to each exposure episode, the greatest level of accumulation was observed after the 4th week. These results provide the basis for establishing the inflammatory and exposure criteria by which episodic environmental exposures to allergen might result in the development of a remodeled lung in asthma.
PMCID: PMC3558838  PMID: 23356647
ovalbumin; airway reactivity; eosinophils; neutrophils; lymphocytes; macrophages
22.  Evaluation of Adherence to Quality Measures for Prostate Cancer Radiotherapy in the United States: Results from the Quality Research in Radiation Oncology (QRRO) Survey 
To test the feasibility of using proposed quality indicators to assess radiotherapy quality in prostate cancer management based on a 2007 stratified random survey of treating academic and non-academic US institutions.
Methods and Materials
414 patients with clinically localized prostate cancer treated with external beam radiotherapy (EBRT) or brachytherapy were selected from 45 institutions. Indicators used as specific measurable clinical performance measures to represent surrogates for quality of radiotherapy delivery included established measures, such as the use of prescription doses ≥75 Gy for intermediate- and high-risk EBRT patients and androgen-deprivation therapy (ADT) in conjunction with EBRT for patients with high-risk disease, and emerging measures, including daily target localization (image-guidance) to correct for organ motion for EBRT patients.
167 patients (47%) were treated with 6 MV photons, 31 (9%) were treated with 10 MV, 65 (18%) received 15 MV, and the remaining 90 (26%) 16–23 MV. For intermediate- plus high-risk patients (n=181), 78% were treated to ≥75 Gy. Among favorable-risk patients, 72% were treated to ≥75 Gy. Among high-risk EBRT patients, 60 (87%) were treated with ADT in conjunction with EBRT and 13% (n=9) with radiotherapy alone. Among low- and intermediate-risk patients, 10% and 42%, respectively, were treated with ADT plus EBRT. For 24% of EBRT patients (85/354), weekly electronic portal imaging was obtained as verification films without daily target localization and the remaining 76% were treated with daily localization of the target using various methods.
Adherence to defined quality indicators was observed in a majority of patients. ≈90% of high-risk patients are treated with ADT plus EBRT and ≈80% of intermediate- and high-risk patients receive prescription doses >=75 Gy, consistent with the published results of randomized trials.
PMCID: PMC3587045  PMID: 23471563
external beam radiotherapy; quality indicators; androgen deprivation therapy; dose escalation; prostate cancer
23.  Prone Whole-Breast Irradiation Using Three-Dimensional Conformal Radiotherapy in Women Undergoing Breast Conservation for Early Disease Yields High Rates of Excellent to Good Cosmetic Outcomes in Patients With Large and/or Pendulous Breasts 
International journal of radiation oncology, biology, physics  2011;83(3):10.1016/j.ijrobp.2011.08.020.
To report our institution’s experience using prone positioning for three-dimensional conformal radiotherapy (3D-CRT) to deliver post-lumpectomy whole breast irradiation (WBI) in a cohort of women with large and/or pendulous breasts, to determine the rate of acute and late toxicities and, more specifically, cosmetic outcomes. We hypothesized that using 3D-CRT for WBI in the prone position would reduce or eliminate patient and breast size as negative prognostic indicators for toxicities associated with WBI.
Methods and Materials
From 1998 to 2006, 110 cases were treated with prone WBI using 3D-CRT. The lumpectomy, breast target volumes, heart, and lung were contoured on all computed tomography scans. A dose of 45–50 Gy was prescribed to the breast volume using standard fractionation schemes. The planning goals were ≥95% of prescription to 95% of the breast volume, and 100% of boost dose to 95% of lumpectomy planning target volume. Toxicities and cosmesis were prospectively scored using the Common Terminology Criteria for Adverse Effects Version 3.0 and the Harvard Scale. The median follow-up was 40 months.
The median body mass index (BMI) was 33.6 kg/m2, and median breast volume was 1396 cm3. The worst toxicity encountered during radiation was Grade 3 dermatitis in 5% of our patient population. Moist desquamation occurred in 16% of patients, with only 2% of patients with moist desquamation outside the inframammary/axillary folds. Eleven percent of patients had Grade ≥2 late toxicities, including Grade 3 induration/fibrosis in 2%. Excellent to good cosmesis was achieved in 89%. Higher BMI was associated with moist desquamation and breast pain, but BMI and breast volume did not impact fibrosis or excellent to good cosmesis.
In patients with higher BMI and/or large–pendulous breasts, delivering prone WBI using 3D-CRT results in favorable toxicity profiles and high excellent to good cosmesis rates. Higher BMI was associated with moist desquamation, but prone positioning removed BMI and breast size as factors for poorer cosmetic outcomes. This series adds to the growing literature demonstrating that prone WBI may be advantageous in select patients.
PMCID: PMC3845369  PMID: 22208973
Prone; Breast; Radiation; Body mass index; Cosmesis
24.  Multiplex Cytological Profiling Assay to Measure Diverse Cellular States 
PLoS ONE  2013;8(12):e80999.
Computational methods for image-based profiling are under active development, but their success hinges on assays that can capture a wide range of phenotypes. We have developed a multiplex cytological profiling assay that “paints the cell” with as many fluorescent markers as possible without compromising our ability to extract rich, quantitative profiles in high throughput. The assay detects seven major cellular components. In a pilot screen of bioactive compounds, the assay detected a range of cellular phenotypes and it clustered compounds with similar  annotated protein targets or chemical structure based on cytological profiles. The results demonstrate that the assay captures subtle patterns in the combination of morphological labels, thereby detecting the effects of chemical compounds even though their targets are not stained directly. This image-based assay provides an unbiased approach to characterize compound- and disease-associated cell states to support future probe discovery.
PMCID: PMC3847047  PMID: 24312513
25.  Nitric Oxide-Mediated Regulation of β-Amyloid Clearance via Alterations of MMP-9/TIMP-1 
Journal of neurochemistry  2012;123(5):736-749.
Fibrillar amyloid plaques are largely composed of amyloid-beta (Aβ) peptides that are metabolized into products, including Aβ1-16, by proteases including matrix metalloproteinase 9 (MMP-9). The balance between production and degradation of Aβ proteins is critical to amyloid accumulation and resulting disease. Regulation of MMP-9 and its endogenous inhibitor TIMP-1 by nitric oxide (NO) has been shown. We hypothesize that NOS2 protects against AD pathology by increasing amyloid clearance through NO regulation of MMP-9/TIMP-1 balance. We show NO-mediated increased MMP-9/TIMP-1 ratios enhanced the degradation of fibrillar Aβ in vitro, which was abolished when silenced for MMP-9 protein translation. The in vivo relationship between MMP-9, NO and Aβ degradation was examined by comparing an AD mouse model that expresses NOS2 with a model lacking NOS2. To quantitate MMP-9 mediated changes, we generated an antibody recognizing the Aβ1-16 fragment, and used mass spectrometry multi-reaction monitoring (MRM) assay for detection of immunoprecipitated Aβ1-16 peptides. Aβ1-16 levels decreased in brain lysates lacking NOS2 when compared to strains that express human APP on the NOS2 background. TIMP-1 increased in the APPSwDI/NOS2−/− mice with decreased MMP activity and increased amyloid burden, thereby supporting roles for NO in the regulation of MMP/TIMP balance and plaque clearance.
PMCID: PMC3614913  PMID: 23016931
matrix metalloproteinase-9; tissue inhibitor of metalloproteinase-1; NOS2; nitric oxide; amyloid; mass spectrophotometry; microglia; mouse models; immunity

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