Cognitive behavior therapy (CBT) is an effective treatment for social anxiety disorder (SAD), but many patients do not respond sufficiently and a substantial proportion relapse after treatment has ended. Predicting an individual's long-term clinical response therefore remains an important challenge. This study aimed at assessing neural predictors of long-term treatment outcome in participants with SAD 1 year after completion of Internet-delivered CBT (iCBT). Twenty-six participants diagnosed with SAD underwent iCBT including attention bias modification for a total of 13 weeks. Support vector machines (SVMs), a supervised pattern recognition method allowing predictions at the individual level, were trained to separate long-term treatment responders from nonresponders based on blood oxygen level-dependent (BOLD) responses to self-referential criticism. The Clinical Global Impression-Improvement scale was the main instrument to determine treatment response at the 1-year follow-up. Results showed that the proportion of long-term responders was 52% (12/23). From multivariate BOLD responses in the dorsal anterior cingulate cortex (dACC) together with the amygdala, we were able to predict long-term response rate of iCBT with an accuracy of 92% . This activation pattern was, however, not predictive of improvement in the continuous Liebowitz Social Anxiety Scale—Self-report version. Follow-up psychophysiological interaction analyses revealed that lower dACC–amygdala coupling was associated with better long-term treatment response. Thus, BOLD response patterns in the fear-expressing dACC–amygdala regions were highly predictive of long-term treatment outcome of iCBT, and the initial coupling between these regions differentiated long-term responders from nonresponders. The SVM-neuroimaging approach could be of particular clinical value as it allows for accurate prediction of treatment outcome at the level of the individual. Klumpp et al.,10 using a similar task, found that pretreatment reactivity in the inferior frontal and the superior and middle temporal gyri was associated with reduced social anxiety following CBT. However, both studies evaluated the short-term treatment response only. In a previous positron emission tomography study from our lab, the initial attenuation (pre–post) of anxiety-related amygdala activity in treated SAD participants was associated with clinical improvement 1 year later, but as the sample was small the study could not discriminate properly between the effects of CBT and selective serotonin reuptake inhibitors (SSRIs).11Recent functional magnetic resonance imaging (fMRI) studies suggest that neural biomarkers add substantial value to predictions of CBT outcome. In SAD participants, Doehrmann 12 In pattern recognition, a statistical model is estimated on a subset of the data (‘training') and then applied to predict the diagnostic or prognostic label of novel unseen data (‘testing'). This is usually achieved within a cross-validation procedure, whereby the model is repeatedly retrained, withholding a different partition of data each time. This approach is standard within the statistical literature and is well known to provide approximately unbiased estimates of generalizability to new samples, and helps to minimize the possibility of ‘over-fitting' the data. Of crucial importance, and in contrast to voxel-wise group statistics, pattern recognition analyses can make predictions at the level of the individual based on the pattern within the data, for example, treatment responder status or diagnostic category for a new unseen participant.13Mass-univariate voxel-wise methods, seeking pretreatment brain voxels that correlate with symptom improvement or differ between responders and nonresponders, have so far been the most common approach in psychiatric prediction studies. However, such studies may not be easily translated to clinical settings when the concern is whether or not a certain patient will respond to a specific treatment. In contrast, supervised pattern recognition methods constitute a novel approach in clinical neuroimaging, utilizing patterns of information across many voxels, for example, to separate responders from nonresponders.13 was recently successful in separating SAD from panic disorder participants, and from healthy controls.14 In addition, we recently demonstrated the utility of SVM and accurately discriminated SAD participants from healthy controls based on the multivariate pattern of blood oxygen level-dependent (BOLD) response in the fear network,15 that is, the amygdala, hippocampus, anterior cingulate cortex (ACC) and insula, frequently demonstrated to be dysfunctional in SAD.16 Pretreatment reactivity in fear network regions has also been associated with subsequent treatment outcome in SAD and other anxiety disorders.18 The ACC in particular has been implicated in treatment prediction studies of depression,19 and anxiety.20 Moreover, cognitive control of emotion, involving prefrontal–limbic interactions,21 has been suggested to be impaired in participants with SAD and restored with CBT22 but it is not known whether such interactions are predictive of treatment response in SAD. Although the SVM approach has been successful in predicting treatment response in depression,23 there are, to our knowledge, no studies using SVM to predict CBT treatment outcome in anxiety disorders such as SAD. Also, neuroimaging prediction studies of long-term treatment effects are largely lacking in psychiatric research.24A supervised pattern recognition method called support vector machine (SVM)25 Adding ABM has not been shown to further improve outcome,26 and we refer to the present combined intervention as iCBT. Using a disorder-relevant fMRI paradigm, we entered BOLD responses to sentences with negative content about oneself, that is, self-referential criticism27 into linear SVMs to classify responder status at long-term follow-up. Our SVM analyses focused primarily on the fear network and brain regions associated with cognitive control of negative emotion, that is, the ACC, amygdala, hippocampus, insula, ventromedial prefrontal cortex and dorsolateral prefrontal cortex.The objective of the present study was to use SVM classification to evaluate neural predictors of long-term iCBT response 1 year after treatment of participants with SAD. In addition to iCBT, the participants underwent Internet-delivered attention bias modification (ABM) in a cross-over design.25 and the screening procedure was similar to our previous treatment studies.28 Briefly, participants reported interest on a webpage and answered self-report questionnaires via the Internet regarding social anxiety, depression and magnetic resonance safety. Participants had no neurological or major somatic disorder, no suicidal ideation, no other ongoing psychological treatment and they were not included if psychotropic medication  was recently initiated or changed, that is, a stable dose for 3 months was required. Applicants fulfilling the initial screening criteria were interviewed via telephone using the structured clinical interview for the 4th version of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) axis 1 (SCID-I).29 At baseline, 8  participants were currently on prescription medication, that is, SSRIs. Five participants had a history of SSRI treatment and 13 were medication-naive. One participant (deemed as nonresponder) increased the dose from 50–100 mg sertraline from posttreatment to 1-year follow-up. Three participants withdrew and did not take part in the 1-year follow-up.This study included 26 right-handed participants with a primary diagnosis of SAD .30 In accordance with prior studies,30 scores of 1 or 2 (very much or much improved) defined treatment responders, whereas participants scoring ⩾3  were classified as nonresponders. Two psychologists, blind to the experimental conditions, conducted the interviews. In addition, we predicted long-term clinical improvement (pre follow-up) using the continuous Liebowitz Social Anxiety Scale—Self-report version, LSAS-SR.31Treatment response at 1-year follow-up was assessed with the Clinical Global Impression-Improvement (CGI-I) interview scale.25 The guided iCBT protocol contained a 9-week intervention supported by a clinician and has been found effective in several randomized controlled trials.33 Previously, we showed that the short-term outcome in this sample was in favor of iCBT, that is, 66% of the iCBT participants, in comparison with 25% of the ABM group, were deemed as CGI-I responders.25 At the 1-year follow-up, we found no effect of the order  in which the two interventions were presented.This study included two forms of intervention for SAD. Both treatments were provided to all participants in a cross-over design where half of the participants started with iCBT and the other half started with ABM.3 The self-help text included information, exercises, homework assignments and ended with essay questions that were sent to the therapist. For more details, see Andersson et al.5 and 34 The Internet-delivered ABM used in this study was a web-based flash program displayed in full-screen mode at the participant's computer. E-mail and mobile phone SMS reminders prompted for each training session, scheduled on Tuesdays and Thursdays over the 4-week treatment course. The participant and therapist had no other communication during the treatment period.Briefly, the treatment program is based upon the cognitive model of SAD described by Clark and Wells.et al.,27 which was translated into Swedish. The sentences were split into three categories based on the referential target: self, other female or other male. The task included 216 sentences divided into three categories based on valence: negative , neutral  or positive  valences. Across valences, sentences were matched on number of letters and words, and appeared in randomized order. Participants were instructed to read the sentences and press a button with the right hand when they had read each sentence. Each sentence was presented for a maximum of 2500 ms. In addition, 96 fixation crosses (‘+') were randomly interspersed between the sentences and displayed for 2500 ms. Each sentence and fixation cross was separated by a cross or circle presented for 500 ms. Stimuli were demonstrated using the E-prime 2.0 software , projected on a screen and viewed through a tilted mirror attached to the head coil. The total duration of the task was 17 min and 20 s.We evaluated BOLD responses to self-referential criticism using a disorder-relevant paradigm developed by Blair 3) were collected prior to the functional images. BOLD contrast images (T2* weighted) were acquired using a 3T Discovery MR750  scanner equipped with a 32-channel head coil. The following scanning parameters were used: echo time: 30 ms, repetition time: 2000 ms, flip-angle: 80°, field of view: 25 × 25 cm2, matrix size: 96 × 96. Thirty-seven slices with a thickness of 3.4 mm (2.6 × 2.6 × 3.4 voxel size) were acquired every 2000 ms. Ten dummy scans were run before the image acquisition started to avoid signals resulting from progressive saturation. Preprocessing was done using Statistical Parametric Mapping Software 8  implemented in MATLAB . Functional scans were realigned to the mean image of each run to correct for head movements during image acquisition, after which slice timing correction was performed. The functional scans (3 × 3 × 3 mm3 voxel dimensions) were then co-registered to the structural scans. Structural scans were segmented into gray and white matter, and parameters for warping the scans to the Montreal Neurological Institute (MNI152) template were calculated using the unified segmentation procedure in SPM8. Functional scans were subsequently warped to MNI standard space by applying these parameters, and smoothed with an 8-mm isotropic Gaussian kernel.Structural high-resolution T1-weighted images  including the ACC, amygdala, hippocampus and insula. All regions were defined by the Automatic Anatomical Labeling ROI library within the Wake Forest University PickAtlas software.35 In follow-up analyses, the ACC was divided into the dorsal (dACC) and ventral (vACC) subdivisions by a split at the MNI-coordinate z=8, which corresponds to clusters 2 and 3 in Beckmann et al.36Functional brain imaging data were fitted to the general linear model using SPM8. First-level, within-subject, analyses included nine regressors of interest in the model, valence (3) × target (3), containing onset times of respective sentences, as well as the isx movement parameters from the realignment preprocessing step as nuisance regressors. The model was convolved with the canonical hemodynamic response function defined in SPM8 and filtered using a 128-s high-pass filter. The other-referred contrast consisted of both female and male targets, and the contrast of interest used in subsequent analyses was self-referential criticism (self-negative minus other negative). On the basis of previous CBT prediction studies,37 including the dorsolateral prefrontal cortex (Brodmann areas 9 and 46) and ventromedial prefrontal cortex .38 Behavioral treatment effects and initial responder/nonresponder differences on demographic and clinical data were calculated using the STATA statistical software, v. 13.1 .We also investigated the predictive value of regions involved in cognitive control of negative emotion,39 For each ROI or network, pretreatment contrast images of self-referential criticism were summarized using a dot-product kernel matrix, which was then used as input to a linear SVM. Each SVM was embedded within a leave-one-participant-out cross-validation framework and for each cross-validation fold, data were centered using the mean of the training data. The SVM soft margin parameter C was fixed to its default value 1.39 SVMs were trained to separate CGI-I responders from nonresponders at 1-year follow-up. We employed SVMs because they provide excellent performance for neuroimaging data relative to alternative approaches such as random forests.40 We tested the statistical significance of each classifier using permutation testing. This involved repeating the cross-validation procedure (1000 times) after randomly permuting the class labels. Significance of the classification accuracy was then derived by counting the number of times the permuted accuracy exceeded the true accuracy and dividing by 1000.SVM analyses were carried out using the Pattern Recognition for Neuroimaging Toolbox.39 and was achieved by mapping the predictive weights in the original voxel space. It is important to emphasize that the voxel weights should not be interpreted as describing focal differences between classes in the same way as in mass-univariate analysis. Instead, the weights should be interpreted as a multivariate pattern, where the weight indicates the direction and quantifies the contribution of each voxel to the classifier decision. They do not permit inference at the level of individual voxels.We used a discriminative mapping approach to visualize the relative contribution of the different brain regions to the classifier decision. This is a standard approach in SVM studies using neuroimaging data41 in Pattern Recognition for Neuroimaging Toolbox with the aim to predict improvement (pre follow-up) on the continuous LSAS-SR.As a complement to SVM analyses on the dichotomous CGI-I measure, we also conducted relevance vector regressions42 and because it is a functionally heterogeneous region, for example, with regard to control and expression of negative emotion,43 we analyzed the dACC and vACC subregions separately, and together with the amygdala. Furthermore, follow-up analyses (guided by the significant SVM classifications) using mass-univariate voxel-wise comparisons of initial BOLD response to self-referential criticism were performed between responders and nonresponders, and psychophysiological interactions44 were conducted using the dACC and vACC as seeds to evaluate couplings between these regions and the amygdala during self-referential criticism.In the main analyses we found the ACC to be highly predictive of long-term response. Because the ACC has strong anatomical connection with the amygdala,10 were evaluated, as well as whole-brain analysis. SVM prediction of SAD diagnostic status, assessed with the structured clinical interview for DSM-IV,29 was also performed. In addition, we checked for associations between descriptive variables =7.52, P<0.001, mean 75.37±19.1 to 44.67±22.8), and there was no significant change between the posttreatment and 1-year follow-up assessments (t(23)=0.70, P=0.489).25There were 12/23 (52%) responders at 1-year follow-up according to the clinical interview CGI-I. Participants improved on the LSAS-SR from pretreatment to follow-up (P>0.100).SVM analyses of pretreatment BOLD response to self-referential criticism (self>other referred criticism) showed that information from the ACC was highly accurate in classifying CGI-I responder status 1 year after treatment =0.97) and dACC together with the amygdala , but not the vACC, predicted 1-year treatment response. Furthermore, psychophysiological interaction analyses showed that the dACC, but not the vACC, was significantly  less coupled with the right amygdala during self-referential criticism at pretreatment . Also, pretreatment voxel-wise univariate analyses suggested that the dACC was less reactive to self-referential criticism in responders as compared with nonresponders, although this was significant only when participants on concurrent medication were excluded from the analysis .SVM analyses taking ACC subdivisions into account showed that the dACC alone . Also, voxel-wise univariate analyses suggested lower initial dACC–amygdala coupling, and arguably also lower initial dACC reactivity to self-referential criticism, in responders relative to nonresponders. Both the dACC and the amygdala have been associated with fear expression.49 For instance, Vogt et al.50 examined the whole cingulate cortex and showed that 60% of the fear-induced activity was located in the dorsal ACC subregion, suggesting that multivariate brain activation patterns particularly in fear-expressing regions may influence sustained success of CBT.Thus, in individuals with SAD, treatment response 1 year after iCBT was accurately predicted by initial multi-voxel patterns of BOLD response to self-referential criticism in the ACC . Our results are consistent with the notion that ACC-dependent self-referential processing is relevant for treatment outcome.51 The supplementary analyses in the present study showed that clinical and demographic variables, in contrast to SVM-fMRI, failed to predict iCBT long-term outcome, consistent with the notion that neuroimaging biomarkers add substantially to the predictive value of conventional factors for clinical treatment response.9 This was also noted in an fMRI random forest study on CBT outcome predictors in generalized anxiety disorder and panic disorder.52 The clinical utility of the multivariate SVM method may be substantial as it can predict accurately at the individual level. An important feature is that this method provides approximately unbiased estimates of generalizability to new cases. This was achieved by training the models on one sample and testing them on another independent sample, here realized using leave-one-out cross-validation. This represents a first step toward personalized treatment where therapeutic choice is guided by neuroimaging biomarkers. An important next step toward this objective is to validate the SVM models derived here using larger data sets, preferably derived from different sites and/or scanners.Prior studies using clinical predictors of treatment response, such as symptom severity, have reported mixed results in SAD.20 Unfortunately, reliability assessment of the CGI-I was not performed although the long-term clinical outcome is comparable to previous large-scale randomized controlled trials of iCBT for SAD (including 1-year follow-ups).28 In contrast to the CGI-I, we were not able to predict improvement on the LSAS-SR continuous outcome and prediction of SAD diagnostic status, using the structured clinical interview for DSM-IV, was also not significant, suggesting that treatment outcome measures should be carefully selected in SVM prediction studies. The dACC–amygdala activity may be predictive of change in global symptoms rather than specific social anxiety symptoms, although other reasons for the discrepancy should be noted, such as the use of categorical vs continuous measures, and SVM vs relevance vector regression machine-learning algorithms. Only 13 participants were treatment-naive at the first fMRI assessment, and possible drug × iCBT interactions cannot be ruled out entirely. However, the distribution of participants on concurrent psychotropic medication was not different between responders and nonresponders and, importantly, the accurate predictions from the ACC remained significant when participants on concurrent SSRI treatment were excluded from the main SVM analyses (see There are several limitations of this study. Because of the small sample size, the results should be interpreted with some caution even though our sample size is in the higher range in comparison with other neuroimaging treatment prediction studies in the anxiety disorders.yses see . Also, tIn conclusion, we demonstrate that the initial dACC–amygdala BOLD response pattern to self-referential criticism is predictive of long-term treatment response to iCBT, and that lower pretreatment coupling between these fear-expressing brain regions is associated with stable symptom improvement. In contrast, clinical or demographic variables were not associated with sustained treatment response, underscoring the importance of taking into account neuroimaging biomarkers in prediction studies. To our knowledge, this is the first study using the multivariate SVM–fMRI method to successfully predict long-term treatment response in an anxiety disorder. Although SVMs hold high promise, additional studies involving the integration of imaging and related data from more than one site will allow us to further evaluate the clinical utility of this approach.


However, the long-lasting effects of stressful events on brain structures remain unclear. Thus, this study examined the 1-year prognoses of subjects after a stressful event to clarify the long-term effects of stress on structural brain changes.Stressful events can have both short- and long-term effects on the brain.3 37 subjects =28/9, age=21.0±1.6 years) were recruited for a third time, and their structural magnetic resonance imaging (MRI) scans were evaluated 1 year after the earthquake. The optimized voxel-based morphometry (VBM) method for a brain structural data set  was applied, and rGMVs from before (Pre), soon after (Post) and at the 1-year follow-up (Follow-up) of the earthquake were compared using conjunction analyses. In addition, we also assessed the subjects' psychological characteristics, including anxiety, depression, posttraumatic growth and self-esteem. Furthermore, we collected longitudinal brain structural MRI data from 11 normal controls  obtained on at least two occasions before the earthquake , and right hippocampal volumes significantly decreased  from Pre and Post to Follow-up (Post hoc correlation analyses revealed that the increase in the volume of the left OFC from Post to Follow-up was significantly correlated with self-esteem scores at Post (r=0.43, P=0.007; At 1 year after the earthquake, none of the subjects in this study had developed clinical PTSD, whereas other psychological measures did not significantly change from Post to Follow-up see . In termollow-up , whereas3 but stress-induced structural and functional alterations in the OFC are reversible.4 Although the left OFC volume in our subjects experiencing PTSD symptoms soon after the earthquake decreased in the short term,3 the mean OFC volumes increased during this period (5 Moreover, the results provide an initial indication that the increased left OFC volume was caused by higher self-esteem. Given that higher self-esteem is one of the most important traits of resilience in the context of stressful life events,6 it is possible that self-esteem is a predictor of increased OFC volume, representing the successful regulation of emotional distress after the earthquake by healthy survivors.The increase in OFC volume identified in some subjects who reported stress indicates that recovery from emotional distress is possible following a stressful event. Previous neuroimaging findings have shown that a reduction in OFC volume is a sign of emotional distress following stressor,s period , which i7 and is observed even in subjects with subclinical depression after a disaster.5 Even if the hippocampal volume of young healthy adults were not significantly but slightly reduced as a function of aging (see 8 Together, these findings led us to hypothesize that both prolonged stress and aging affect a reduction in hippocampal volume over time, whereas short-term stress does not reduce hippocampal volume in the period immediately following stressful events such as earthquakes3 (see In contrast, stress related to the earthquake may persist even after 1 year. Psychological evaluations at 1 year revealed that even subclinical levels of depression and anxiety levels had not improved from soon after the earthquake. Hippocampal volume reduction is a robust finding in traumatized subjects,ging see , post-eakes3 see .The limitations of this study included the absence of psychological assessments and incomplete profiles for the control subjects see .10 have been reported soon after a disaster. Therefore, further longitudinal investigations using multimodal approaches are necessary to examine whether the stress-induced alterations in brain structure are reversible (see Despite these limitations, the present follow-up VBM study found that stressful events had long-lasting effects on various brain structures, suggesting that such changes are influenced by prolonged stress and self-esteem characteristics. Here, it was assumed that structural changes in the brain following stressful life events are not static, but dynamic, throughout one's lifetime. Recently, altered functional and structural connectivity, including in regions adjacent to the OFC and hippocampus as well as in the insula, basal ganglia and parietal lobe,ible see .


To describe the association between ex-prisoner primary care physician contact within 1 month of prison release and health service utilisation in the 6 months following release.A cohort from the Passports study with a mean follow-up of 219 (±44) days postrelease. Associations were assessed using a multivariate Andersen-Gill model, controlling for a range of other factors.Face-to-face, baseline interviews were conducted in a sample of prisoners within 6 weeks of expected release from seven prisons in Queensland, Australia, from 2008 to 2010, with telephone follow-up interviews 1, 3 and 6 months postrelease.From an original population-based sample of 1325 sentenced adult (≥18 years) prisoners, 478 participants were excluded due to not being released from prison during follow-up , loss to follow-up , or lacking exposure data . A total of 847 (63.9%) participants were included in the analyses.Primary care physician contact within 1 month of follow-up as a dichotomous measure.Adjusted time-to-event hazard rates for hospital, mental health, alcohol and other drug and subsequent primary care physician service utilisations assessed as multiple failure time-interval data.Primary care physician contact prevalence within 1 month of follow-up was 46.5%. One-month primary care physician contact was positively associated with hospital (adjusted HR (AHR)=2.07; 95% CI 1.39 to 3.09), mental health , alcohol and other drug  and subsequent primary care physician service utilisation  over 6 months of follow-up.Engagement with primary care physician services soon after prison release increases health service utilisation during the critical community transition period for ex-prisoners.Australian New Zealand Clinical Trials Registry (ACTRN12608000232336). This is the first study to examine the association between early primary care physician (PCP) contact and health service utilisation rates in a large prospective cohort of recently released ex-prisoners.Potential differences in participant characteristics between those excluded from analysis and the final study sample were empirically assessed.The fact that the Andersen-Gill model applied in analysis controls for both interparticipant and intraparticipant variability in event rates and the associations between early PCP contact and healthcare service utilisation remained significant after adjustment for covariates and the conservative Bonferroni adjustment further strengthens the inferences presented here.Cohort data used from the intervention and control arms of the Passports study were shown to influence primary care utilisation; however, these effects were controlled for in the final regression model, limiting differential bias between PCP-contact status groups.Other potential study limitations include a primary reliance on self-report from ex-prisoners; hospital utilisation was assessed as one broad category resulting in the inability to disaggregate emergency care from tertiary prevention contacts; a lack of data on the specific health conditions responsible for PCP-associated hospitalisations; and the contemporaneous assessment of 1-month PCP contact and other health service utilisation outcomes at 1 month follow-up.Prisoners experience disproportionate health burden with prevalence estimates being over twofold higher for chronic diseases, blood-borne viruses, alcohol and other drug (AOD) disorders, and severe mental illness, compared to the community.14Interrupted healthcare often compounds adverse health outcomes for ex-prisoners.30Currently, the effect of early PCP contact on subsequent health service utilisation in recently released ex-prisoners is poorly understood. Prior to inspection of the data presented here, we formed an a priori hypothesis that access to a PCP within 1 month of release from prison would be associated with increased utilisation of healthcare services in the community.In a large sample of ex-prisoners in Queensland, Australia, the aims of the current study were to (1) estimate the prevalence of PCP contact within 1 month of release, and (2) determine the association between PCP contact in the first month postrelease and utilisation of mental health, AOD, hospital and subsequent PCP services in the first 6 months postrelease.We used cohort data from the intervention and control arms of the Passports study, a randomised controlled trial of a service brokerage intervention, the design of which is described in more detail elsewhere.31A baseline interview was administered to 1325 sentenced adult (≥18 years) prisoners within 6 weeks of expected release from one of seven prisons in Queensland, Australia, during the period 1 August 2008 to 31 July 2010. Three follow-up telephone interviews were conducted approximately 1, 3 and 6 months postrelease. For participants reincarcerated at the scheduled follow-up, interviews were conducted in custody. Interviews were conducted by trained researchers (N=13) with prior experience interviewing marginalised populations. All participants provided informed, written consent prior to their participation.Baseline self-report measures included sociodemographic characteristics, lifetime chronic health conditions, lifetime hepatitis C exposure, social visits in the previous month while in prison, participation in transitional programmes, postrelease supervision status, and history of incarceration as a juvenile. The presence or absence of a lifetime chronic condition  and lifetime hepatitis C exposure  were assessed separately as dichotomous variables. Self-reported participation in transitional programmes, postrelease supervision orders , and incarceration history as a juvenile were assessed separately as binomial variables.Validated screeners administered at baseline included the Patient Activation Measure (PAM)34Current central nervous system (CNS) and non-CNS medication usage was extracted from prison medical records and assessed as separate dichotomous variables; these served as proxy measures for current mental and physical health disorders, respectively.The total number of self-reported PCP service utilisations within 1 month of release was dichotomised, indicating the presence or absence of PCP contact in this period.Outcomes were self-reported utilisation of mental health, AOD, hospital, and subsequent PCP services in the community. Each service utilisation type was assessed separately at each follow-up interview. Subsequent PCP service utilisation was assessed at 3-month and 6-month follow-up. Participants reported the number of type-specific service utilisations since baseline or the previous follow-up interview, creating three distinct follow-up time intervals. The total reported service utilisations for each time interval was dichotomised to indicate the presence or absence of service utilisation at each follow-up, for each service type.All analyses were conducted using STATA V.13.0.2 analyses were performed, comparing differences between PCP-contact and no-PCP-contact groups for continuous and categorical outcomes, respectively.Descriptive statistics were calculated for all variables. Independent samples t tests and χThe association between PCP contact at 1 month postrelease and health service utilisation over the 6-month follow-up period was estimated separately for each service type, controlling for baseline sociodemographic, behavioural, and cohort-specific characteristics (outlined below). A multivariate Andersen-Gill extension of a Cox proportional hazards model38Time at-risk began at the initial prison release date and was censored on the last recorded follow-up interview date in the community, or at death. If the last follow-up was conducted in prison, the censor date was the preceding QCS readmission. Prison sentences that occurred within the follow-up period were truncated , as the participants were not ‘at-risk’ of utilising health services in the community while incarcerated. Exploratory subgroup analyses were conducted between non-recidivists and recidivists during the follow-up period, and between first-time and repeat offenders as identified at baseline.All models were adjusted for age, gender, Indigenous status, receipt of the Passports intervention,Missing covariate data were replaced using multiple imputation (imputed datasets: N=30) applying multivariate chained equations as described for use in the Cox model.The Passports study was approved by the University of Queensland Behavioural and Social Sciences Ethical Review Committee (Project #2007000607), QCS Research Committee, and the Queensland Health Human Research Ethics Committee (HREC/11/QHC/40), and was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12608000232336).Seven individuals (0.5%) were excluded as they were not released from prison during the follow-up period due to parole rejection or being remanded in custody on new charges. A further 257 (19.4%) and 214 (16.2%) participants were excluded from analysis due to a complete lack of follow-up data and/or study ‘exposure’ data , respectively. The remaining participants  were included in the analyses.Compared with those excluded from analysis (N=478), this study sample was less likely to identify participants as Indigenous, significantly older, and was more likely to report social visits in prison, to have no history of juvenile incarceration, to screen negative for ID, to report having a postrelease supervisory order, to report current non-CNS medication use, to report a lifetime chronic condition, and to report no hepatitis C exposure .The mean (±SD) time to each follow-up was 39 (±15), 109 (±25) and 219 (±44) days postrelease for the 1, 3 and 6-month follow-up interviews, respectively.Overall, 394 participants (46.5%) reported PCP contact prior to the 1-month follow-up interview. Participant characteristics are presented overall and according to 1-month PCP contact in Unadjusted Kaplan-Meier survival curves comparing type-specific service utilisation rates between the PCP-contact and no-PCP-contact groups are displayed in The association between 1-month PCP contact status and health service utilisation over the follow-up period is shown in Exploratory subgroup analysis, stratified by repeat offending, revealed that PCP contact at 1-month follow-up predicted increased rates of utilisation of hospital , mental health , AOD , and subsequent PCP services  for the non-recidivist subgroup only . ConversAlmost half (46.5%) of the ex-prisoners in this study reported community PCP contact within 1 month of prison release. A recent Australian national survey found that 23% of prisoners had a referral or appointment with a medical practitioner on discharge, suggesting that a substantial proportion of the PCP-contact group in the current study accessed the service without prison facilitation.20et al, Low-intensity service brokerage increases contact with healthcare in recently released prisoners: a single-blinded, multi-site randomised controlled trial. under review), however these effects were controlled for in the final regression model, limiting possible differential bias between PCP status groups. Although we observed increased hospital utilisation among the PCP-contact group, we were unable to disaggregate this to test for differential effects on preventive healthcare  and emergency care utilisation. Additionally, we were unable to determine what health conditions were responsible for PCP-associated hospitalisations. The relative contribution of these unmeasured factors is an important focus for future research. The outcome investigated was health service utilisation. Although this is suggestive of health improvement, actual health outcomes were not assessed. Lastly, 1-month PCP contact and the utilisation of other health services at 1 month were assessed contemporaneously, further complicating the process of making causal inferences. However, the two subsequent follow-up periods (3-month and 6-month) are not similarly affected.To our knowledge, this is the first study to examine the association between early PCP contact and health service utilisation in a large sample of recently released ex-prisoners. The fact that associations between early PCP contact and healthcare service utilisation remained significant after adjustment for covariates and the conservative Bonferroni adjustment further strengthens this inference. However, the results presented here must be considered in the context of some study limitations. Approximately one-third of the original study group was excluded from analysis due to a lack of exposure and/or follow-up data. However, the Passports study cohort is generally representative of all prisoners released in Queensland during the same time periodGiven that nationally, 81% of Australians access a community PCP over a 12-month period,Compared to the no-PCP-contact group, the PCP-contact group had more chronic conditions, medication use and a greater risk of severe mental illness . It is possible that the increased service utilisation rates we observed may reflect increased morbidity or a general propensity to access healthcare services in the PCP-contact group, such that PCP contact had no causal effect on subsequent healthcare utilisation. However, potential differential influence from these factors was controlled for in the regression model. The increased rates of utilisation of specialised care , hospital and subsequent PCP services observed here suggest that early PCP contact postrelease facilitates referral to other health services, thus serving as a critical entry point into the health system for ex-prisoners reintegrating into the community. This gateway effect may be due to a combination of factors including low cost, low stigma, closer provider proximity, broader geographic distribution, easier appointment processes, pre-existing physician familiarity and reduced waiting times compared to other service types.In participants who reoffended during follow-up, there was no significant association between PCP contact and other health service utilisation, whereas we observed significant positive associations for ex-prisoners who stayed in the community. Previous research has demonstrated the benefits of mental health, AOD and PCP service utilisation specifically related to reduced recidivism in ex-prisoner populations.The association between 1-month PCP contact and other health service utilisation held for both first-time and repeat offenders, except that among first-time offenders the 1-month PCP contact did not predict increased AOD service utilisation. The reasons for this are unclear. First-time offenders may be less likely to identify their substance use as problematic or conversely, they may be more likely to perceive that they can maintain prison-initiated abstinence without postrelease community health service intervention. Therefore, early PCP contact may improve continuity of care for both first-time and repeat offenders, provided they remain in the community for at least 6 months postrelease.Prior studies have shown elevated service utilisation rates for ambulatory care-sensitive conditions in ex-prisoners54Affordable Care Act in the USA, represent a pivotal opportunity for PCPs to foster correctional healthcare partnerships, promote timely engagement and provide targeted interventions in this previously underserviced group.The current study provides previously unavailable evidence that early postrelease PCP contact increases health service utilisation in the community, especially during the period where ex-prisoners are at highest risk of poor health outcomes.Our results suggest that 1-month PCP service utilisation is associated with increased utilisation of mental health, AOD, hospital, and subsequent PCP services for at least 6 months after release from prison. Our findings provide new evidence that facilitating early postrelease PCP service contact may be an effective and practical way to improve ex-prisoner healthcare integration in the community. Future research should focus on understanding the factors underlying this positive association between early PCP contact and subsequent health service utilisation, in order to inform effective programmes to manage the health needs of this vulnerable population. Replication using a randomised design focused on establishing a causal relationship between early PCP contact and increased utilisation of health services by using more detailed administrative health data and evaluating the associated health outcomes, is feasible


In 2007, the Cameroon Baptist Convention Health Services (CBCHS) implemented a screen-and-treat cervical cancer prevention program using visual inspection with acetic acid enhanced by digital cervicography (VIA-DC).We retrospectively analyzed 46,048 medical records of women who received care through the CBCHS Women’s Health Program from 2007 through 2014 to determine the prevalence and predictors of positive VIA-DC, rates of same day treatment, and cohort prevalence of invasive cervical cancer (ICC).Of the 44,979 women who were screened for cervical cancer, 9.0% were VIA-DC-positive, 66.8% were VIA-DC-negative, 22.0% were VIA-DC-inadequate , and 2.2% were VIA-DC-uncertain . Risk factors significantly associated with VIA-DC-positive screen were HIV-positivity, young age at sexual debut, higher lifetime number of sexual partners, low education status and higher gravidity. In 2014, 31.1% of women eligible for cryotherapy underwent same day treatment. Among the 32,788 women screened from 2007 through 2013, 201 cases of ICC were identified corresponding to a cohort prevalence of 613 per 100,000.High rate of VIA-DC-positive screens suggests a significant burden of potential cervical cancer cases and highlights the need for expansion of cervical cancer screening and prevention throughout the 10 regions of Cameroon. VIA-DC-inadequate rates were also high, especially in older women, and additional screening methods are needed to confirm whether these results are truly negative. In comparison to similar screening programs in sub-Saharan Africa there was low utilization of same day cryotherapy treatment. Further studies are required to characterize possible program specific barriers to treatment, for example cultural demands, health system challenges and cost of procedure. The prevalence of ICC among women who presented for screening was high and requires further investigation. Invasive cervical cancer (ICC) is the leading cause of cancer mortality among women in sub-Saharan Africa (SSA) with approximately 99,000 new cases and 57,400 deaths in 2012 . In addiDespite their relative increased risk, less than 19% of women in developing countries have been screened for CIN even once in their lifetime . Many deCervical cancer screening is not provided routinely in the public health system utilized by the majority of the Cameroonian population . TherefoThe Institutional Review Boards at University of Massachusetts Medical School (UMMS) and Cameroon Baptist Convention Health Services approved this project. The informed consent requirement was waived for this retrospective chart review. The patient records were de-identified and analyzed anonymously.The WHP procedure for cervical cancer screening was modeled after the Cervical Cancer Prevention Program in Zambia (CCPPZ), a regional leader in implementing screening programs based on VIA-DC . This teWomen with VIA-DC-positive screens were considered eligible for cryotherapy treatment if the cervical lesion met all of the following criteria outlined in WHO guidelines , 35:Complete visualization of transformation zone (TZ) and acetowhite lesion (AWL) marginsAWL occupies <75% of the TZ and can be covered by the cryoprobeNo suspicion of cancerNo evidence of reproductive tract infection or pregnancyWith patient consent, cryotherapy eligible women were offered immediate treatment. Women who did not receive same day cryotherapy were given appointments to follow up for treatment. Clinicians had the option to use free text to record an explanation for lack of same day treatment. Women with cryotherapy ineligible AWL were referred to CBCHS hospitals for treatment with loop electrosurgical excision procedure (LEEP) if they met all of the following criteria:AWL extends into canal or covers >75% of TZ or cannot be covered by cryoprobeNo suspicion of cancerNo evidence of reproductive tract infection or pregnancyBiopsies were taken in cases of uncertainty or for lesions that were suspicious for ICC. Biopsy and LEEP specimens underwent histopathologic assessment by pathologists at Yaoundé Gyneco-Obstetric and Pediatric Hospital or Buea Regional Hospital. The histology results were reported according to the Richart CIN staging system . Nurses Cervical cancer screening was offered to women aged ≥25 years and to women less than age 25, if they were HIV positive. Pregnant women were excluded.The CBCHS WHP has minimal external funding and no governmental funding. Thus low cost fees, stratified based on the financial status of the community being served, were charged for screening and treatment in order to sustain the program. Often, women who could not afford to pay were screened and treated at no charge or asked to pay later. The WHP offered additional services including clinical breast exam, family planning and treatment of reproductive tract infection.Screening was conducted at seven WHP sites in hospitals or health centers located in North West, Littoral, Central and South West regions of Cameroon, encompassing urban , semi-urban , and rural referral  areas. The catchment area was further broadened through short-term outreach screening clinics.Nurses or peer educators collected patient data using a structured, paper-based, clinical record. All patient demographic, social, and medical history, including HIV-status, was self-reported. For biopsy and LEEP specimens, a pathology request form was filled at the time of collection and then the Richart CIN histopathologic diagnosis was recorded by a pathologist at the time of reading . All papΚ = 0.927, p ≤ 0.001); thus only VIA-DC outcomes were used for analysis. In order to identify factors associated with VIA-DC-positive versus VIA-DC-negative screen, we obtained adjusted odds ratios (AOR) and 95% confidence intervals (CI) from a multivariable logistic regression model with an exchangeable correlation structure to account for the clustering of patients within sites. The covariates included self-reported HIV status , age , years of education , marital status , occupation , screening location , gravidity , age at sexual debut  and number of lifetime sexual partners . Two-sided p<0.05 was considered to be significant for all tests. Due to low sample size, only descriptive statistics regarding histologic grade of the tissue specimens are presented. ICC prevalence was not calculated for women of unknown age because histopathology data and VIA-DC screening data were not linked due to inconsistency in recording of unique patient identifiers. Cases missing age/date of birth were not consistent between the two datasets. Statistical analysis was conducted using SPSS Version 22.0.We obtained summary measures  for all characteristics for the total sample as well as by VIA-DC status . Kappa statistic demonstrated that there was a strong agreement between VIA-DC and VILI-DC  underwent VIA-DC screening . DemograHIV-positive women were 1.36 (95%CI: 1.22–1.53) times more likely than HIV-negative women to screen VIA-DC-positive . Women wWomen who screened VIA-DC-positive were offered same day cryotherapy, biopsy or referral for LEEP depending upon the characteristics and severity of dysplasia of the observed lesion. Data from 2007 through 2013 did not include detailed information regarding eligibility for same day treatment, rates of uptake, or reasons for attrition. In 2014, the data collection form was updated to document eligibility for cryotherapy based on the previously described WHO guidelines. In 2014 alone, 12,191 women underwent VIA-DC screening, and 927 (7.6%) screened VIA-DC-positive . Of thesFrom March 2007 through December 2013, 32,788 women were screened with VIA-DC and 764 specimens were collected from women with VIA-DC-positive and -uncertain screens. Among biopsy and LEEP specimens 14 (1.8%) were negative, 246 (32.2%) were CIN1, 177 (23.2%) were CIN2, 126 (16.5%) were CIN3/carcinoma-in-situ and 201 (26.3%) were ICC . AssuminThe CBCHS WHP operates the largest cervical cancer screening program in Cameroon, a country with the highest HIV prevalence in Western and Central Africa and where ICC is a major contributor to cancer mortality , 6. FromThe prevalence of VIA-DC-positive screen from 2007 through 2014 was 9.0%. These findings are lower than or similar to two previous studies conducted in Cameroon. Specifically, one study performed from 2001 to 2002 screened 4,813 women, comparing VIA and cytology as screening methods for CIN/ICC, and reported a VIA-positive rate of 21.7%, higher than our finding . A possiThe rate of VIA-DC-uncertain screens due to suspected cervicitis, severe atrophic changes or difficult-to-diagnose abnormalities that confounded evaluation of the ectocervix was 2.2% and is overall consistent with other reports in African countries, including Botswana , Kenya , Côte d'The rate of VIA-DC-inadequate screens was high (22.0%). Although in these cases the ectocervix was negative, the clinician was unable to visualize the entire SCJ. Most screening programs do not include a VIA-DC-inadequate category. For example the CCPPZ classification includes only negative, positive, suspicious for cancer and VIA-uncertain/indeterminate which is designated for those with non-neoplastic cervical abnormalities confounding VIA-DC interpretation such as cervicitis or severe atrophic changes. Thus the CCPPZ classifies a negative ectocervix with a non-visible SCJ as negative  whereas The only study that included a category comparable to VIA-DC-inadequate was conducted in Côte d'Ivoire and documented a rate of 2.3% . The lowIn part due to the complications mentioned above, the WHO does not prioritize VIA screening for women over age 50 . In our Previous studies have shown that risk factors for VIA-positive screen in developing countries include HIV-positive status , 13, lowThe WHO screen-and-treat approach is recommended for cervical cancer prevention in developing countries due to its efficacy in decreasing cervical cancer related morbidity and mortality , 40. In The 5-year age-standardized prevalence of ICC in Cameroon, as estimated by GLOBOCAN 2012 analysis from the IARC, is 80.7 per 100,000 , 30. DesThe prevalence of ICC in women screened by the CBCHS WHP from 2007 through 2013 was 613 per 100,000. This result is not age-standardized and therefore not comparable with population level data from GLOBOCAN. Nevertheless, the cohort specific ICC prevalence is high. This is likely due in part to selection bias; women who self-presented or who were referred to cervical cancer screening were more likely to have gynecologic symptoms or risk factors for cervical cancer and thus do not represent the general population. In contrast, some women who presented for VIA-DC screening and had lesions eligible for LEEP or biopsy did not receive the recommended procedure and therefore we do not know their true cervical cancer status. Our analysis assumes that these women are cancer-free, but some percentage of these women may have had ICC. In this respect, the cohort prevalence of ICC reported in this manuscript may underestimate the true prevalence of ICC in Cameroon.Though high, the WHP prevalence of ICC was lower than that reported by the CCPPZ . This may be due in part to the difference in self reported HIV prevalence between the two screened groups (11% HIV-positive in Cameroon vs 28% in Zambia) , differeThe prevalence of ICC was associated with age, peaking in women aged over 50. This finding underscores the need for data regarding outcomes of treatment in women diagnosed with ICC in resource poor settings in order to determine whether screening women aged 50 and over is worthwhile.This analysis was a retrospective evaluation of a large-scale, grassroots, fee-for-service cervical cancer screening program. Although this serves as a strength because it provides striking insight into the realities of implementing a nearly self-sustaining program that did not rely on short-term grant funding or expert oversight from a research team, there are limitations that should be addressed to improve the quality of care. Some VIA-DC result categories changed over time and in some cases were not comparable to categories in other studies. The high rate of VIA-DC-inadequate results was in part dependent upon clinician expertise in VIA-DC technique. The HIV status of our patient population was self-reported. The data available regarding treatment uptake is limited. Outcome of treatment decision  was systematically documented beginning in 2014, but reasons for treatment choice were not systematically reported, leaving the question of specific barriers to treatment answerable only by anecdotal evidence per nurse clinician notes and informal discussion with WHP staff. Data regarding follow-up treatment of cryotherapy eligible lesions was also not available, precluding calculation of attrition rate among women referred for treatment at a later date.At the time of data analysis, histopathology data was available only for women screened from 2007 through 2013. We believe this delay is an honest reflection of the logistical difficulty of pathologic diagnosis, dissemination of findings and upkeep of an electronic database in this low-resource setting. Since ICC prevalence was calculated from women who self-presented for screening or were referred by other providers, selection bias may have caused over-estimation of the true prevalence. Additionally, removal of cases due to instances of duplicate patient identifiers and lack of pathology specimens on VIA-DC-positive and -uncertain women who did not consent to biopsy or LEEP and were thus lost to follow-up may have caused under-estimation of the true ICC prevalence.The high rate of VIA-DC-positive results in Cameroon suggests a significant impending burden of ICC cases. The rate of VIA-DC-inadequate  screens was high, especially in women aged 50 and over. Training clinicians on techniques to better visualize the SCJ and adding an additional screening method to the protocol in cases of VIA-DC-inadequate results are possible ways to confirm whether these cases are truly negative. In comparison to similar screening programs in SSA, we report low utilization of same day cryotherapy treatment. Further studies are required to characterize possible program specific barriers to treatment, for example cultural demands, health system challenges and cost of procedure. The prevalence of ICC among women who presented for screening was high and requires further investigation.


A variety of health-related data are commonly deposited into electronic health records (EHRs), including laboratory, diagnostic, and medication information. The digital nature of EHR data facilitates efficient extraction of these data for research studies, including genome-wide association studies (GWAS). Previous GWAS have identified numerous SNPs associated with variation in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). These findings have led to the development of specialized genotyping platforms that can be used for fine-mapping and replication in other populations. We have combined the efficiency of EHR data and the economic advantages of the Illumina Metabochip, a custom designed SNP chip targeted to traits related to coronary artery disease, myocardial infarction, and type 2 diabetes, to conduct an array-wide analysis of lipid traits in a population with extreme obesity. Our analyses identified associations with 12 of 21 previously identified lipid-associated SNPs with effect sizes similar to prior results. Association analysis using several approaches to account for lipid-lowering medication use resulted in fewer and less strongly associated SNPs. The availability of phenotype data from the EHR and the economic efficiency of the specialized Metabochip can be exploited to conduct multi-faceted genetic association analyses. Genome-wide association studies (GWAS) have been highly successful at identifying SNPs associated with a wide variety of phenotypes, including lipid disorders, although such studies require very large sample sizes , 22 loci for low-density lipoprotein cholesterol (LDL-C), 31 loci for high-density lipoprotein cholesterol (HDL-C), and 16 loci for triglycerides (TG)  “replication” SNPs corresponding to validated associations; (2) a set of 63,450 SNPs that were the most significantly associated with over 20 traits related to coronary artery disease or T2D, including lipids, (3) SNPs previously associated with BMI and waist circumference, as well as 122,241 SNPs to fine-map these loci; and (4) 16,992 other SNPs selected for a variety of reasons, including those that reached genome-wide significance in any GWAS  that were excluded, with the final cleaned dataset consisting of a total of 190,446 SNPs of which 63,134 SNPs had minor allele frequencies <0.01.p-value of 0.0024 (0.05/21) to be statistically significant. We additionally assessed associations of 21 SNPs previously associated with body mass index and waist circumference  to be statistically significant.Statistical association testing between individual SNPs and lipid phenotypes was conducted under an additive model by regressing the genotype score  against the outcome lipid variable. Age and sex were included in the model as covariates. Further analyses addressed the issue of use of lipid-lowering agents (see Results). Our initial aim was to assess associations with 21 SNPs present on the Metabochip previously associated with lipid levels in prior meta-analysis of GWAS results . We estimated that our final sample size of 1686 individuals provided 80% power to detect SNPs explaining 2–2.5% of the variation in lipid or BMI levels at this significance level.We performed a secondary analysis to assess associations of all Metabochip SNPs with lipid and body weight traits in which we adjusted for the total number of SNPs tested, defining the significance cut-off as The demographic, anthropometric, and lipid profiles of the population Table  were chap < 0.05, including 3 that remained significant following adjustment for multiple comparisons (p < 0.002). The loci marked by these three SNPs included GCKR (associated with TG levels at 5.3 × 10−4), LPL (associated with HDL-C levels at 1.4 × 10−5), and CETP (associated with HDL-C levels at 4.1 × 10−11). The directions of the observed effects for all of the 12 SNPs nominally or significantly associated with lipid levels were directionally consistent with those previously reported.Results from association testing of previously identified lipid loci  or TC , but was significantly associated with levels of HDL-C  and TG . The observed values TC, LDL-C, and TG levels would likely have been higher, and HDL-C levels lower, had they not been taking lipid-lowering medications. We therefore considered three additional analytic approaches to accommodate the effect of the medications. Our first approach was to repeat the association analyses after removing all subjects on lipid-lowering medications . Our second approach was to include use of lipid-lowering medications as a covariate (medication user vs. non-user) in the regression model . Our final approach was to restrict analysis to subjects taking lipid-lowering medications .Results of the association analyses of SNPs at known lipid loci using all three approaches to address the use of lipid-lowering medications are shown in Table p-values tended to be less significant in the sample with medication-users removed, consistent with a smaller sample size. The same trend, i.e., comparable effect sizes but lower statistical significance, was also observed when analyses were restricted to subjects taking lipid-lowering medications. Inclusion of medication use as a covariate in the model had virtually no effect on the genotype-lipid phenotype association at any of the tested SNPs.A significant proportion (46%) of subjects in this cohort were being treated with lipid-lowering medications. Medication use was not associated with levels of LDL-C , which has previously been associated with TC in multiple studies , apolipoprotein A1/C3/A4/A5 cluster (APOA5), cholesterol ester transfer protein (CETP), UDP-GalNAc transferase 2 (GALNT2), hepatic lipase (LIPC), endothelial lipase (LIPG), lipoprotein lipase (LPL), and the methylmalonic aciduria cblB type (MMAB)/mevalonate kinase (MVK) loci were genotyped . They are thus correlated values, so linear regression analyses will identify similar associations. Medication use was also not associated with either TC or LDL-C. Levels of HDL-C appear to be under strong genetic control, yet despite such high heritability  lipid levels through medication use may be expected to disproportionately occur in subjects with dyslipidemia due to a genetic predisposition, thus decreasing the ability to identify lipid-genotype associations. To address this issue, we performed three complementary analyses, including removing all subjects on lipid-lowering medications, the strategy employed by large meta-GWAS  consortium, which studied anthropometric traits BMI and waist circumference. A total of 18,211 SNPs from 24 loci (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, In summary, we conducted a GWAS of major lipid traits using EHR derived data to analyze SNPs that had previously been associated with lipid phenotypes, as well as other SNPs residing on the Metabochip, in an extremely obese cohort. Although several lipid loci replicated, other previously identified lipid and body weight loci did not. Possible differences may be due to the use of EHR data for phenotyping, characteristics of the cohort, and/or decreased statistical power. Nevertheless, the availability of extant EHR phenotype data and the relatively low cost of the specialized Metabochip can be effectively used to conduct a GWAS.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


MicroRNAs (miRNAs) regulate messenger RNAs (mRNAs) and as such have been implicated in a variety of diseases, including cancer. MiRNAs regulate mRNAs through binding of the miRNA 5’ seed sequence (~7–8 nucleotides) to the mRNA 3’ UTRs; polymorphisms in these regions have the potential to alter miRNA-mRNA target associations. SNPs in miRNA genes as well as miRNA-target genes have been proposed to influence cancer risk through altered miRNA expression levels.MiRNA-SNPs and miRNA-target gene-SNPs were identified through the literature. We used SNPs from Genome-Wide Association Study (GWAS) data that were matched to individuals with miRNA expression data generated from an Agilent platform for colon tumor and non-tumor paired tissues. These samples were used to evaluate 327 miRNA-SNP pairs for associations between SNPs and miRNA expression levels as well as for SNP associations with colon cancer.BRCA1), ORAA 1.31 95% CI 1.01, 1.78, and rs8905 (PRKAR1A), ORGG 2.31 95% CI 1.11, 4.77.Twenty-two miRNAs expressed in non-tumor tissue were significantly different by genotype and 21 SNPs were associated with altered tumor/non-tumor differential miRNA expression across genotypes. Two miRNAs were associated with SNP genotype for both non-tumor and tumor/non-tumor differential expression. Of the 41 miRNAs significantly associated with SNPs all but seven were significantly differentially expressed in colon tumor tissue. Two of the 41 SNPs significantly associated with miRNA expression levels were associated with colon cancer risk: rs8176318 (Of the 327 SNPs identified in the literature as being important because of their potential regulation of miRNA expression levels, 12.5% had statistically significantly associations with miRNA expression. However, only two of these SNPs were significantly associated with colon cancer. To test the hypothesis that SNPs alter miRNA expression levels, we use non-tumor tissue and evaluate differences in expression across genotype. However, since a SNP could alter miRNA expression levels equally in both tumor and non-tumor tissue, such an association would not necessarily contribute to cancer risk. To determine if SNPs are associated with the carcinogenic process through miRNA regulation, we also evaluate if miRNA expression is different across genotypes between tumor and non-tumor tissues. Additionally, we assess if miRNAs that are associated with SNPs are differentially expressed in colon tumors. Finally, we evaluate the association between SNPs associated with miRNA expression and risk of colon cancer.The study population consisted of individuals previously enrolled in a study of Diet, Lifestyle, and Colon cancer at the University of Utah and the Kaiser Permanente Medical Research Program (KPMRP)  for whomhttp://genespring-support.com/files/gs_12_6/GeneSpring-manual.pdf) is the median of the 75th percentiles of all the samples divided by the individual 75th percentile of each sample.RNA (miRNA) was extracted from formalin-fixed paraffin embedded tissues. We assessed slides and tumor blocks that were prepared over the duration of the study prior to the time of miRNA isolation to determine their suitability. The study pathologist reviewed slides to delineate tumor and non-tumor tissue. Cells were dissected from 1–4 sequential sections on aniline blue stained slides using an H&E slide for reference. Total RNA containing miRNA was extracted, isolated, and purified using the RecoverAll Total Nucleic Acid isolation kit (Ambion); RNA yields were determined using a NanoDrop spectrophotometer. 100 ng total RNA was labeled with Cy3 and hybridized to Agilent Human miRNA Microarray V19.0 and were scanned on an Agilent SureScan microarray scanner model G2600D. The Agilent Human microarray was generated using known miRNA sequence information compiled in the Sanger miRBase database v19.0. The microarray contains probes for 2006 unique human miRNAs, with one to four unique probes for each of the known miRNAs. The miRNA array contains 60,000 unique human sequences and averages 30 replicates per probe sequence. Data were extracted from the scanned image using Agilent Feature Extract software v.11.5.1.1. Data were required to pass stringent QC parameters established by Agilent that included tests for excessive background fluorescence, excessive variation among probe sequence replicates on the array, and measures of the total gene signal on the array to assess low signal. If samples failed to meet quality standards for any of these parameters, the sample was re-labeled, hybridized to arrays, and scanned. If a sample failed QC assessment a second time the sample was deemed to be of poor quality and the individual was excluded from down-stream analysis. To minimize differences that could be attributed to the array, amount of RNA, location on array, or other factors that could erroneously influence expression, total gene signal is normalized by multiplying each sample by a scaling factor stratified by tumor site. Within each tumor site, the scaling factor   that had be scanned over the course of the study, and found repeatability correlation coefficient of 0.98 ; previouhttp://www.ncbi.nlm.nih.gov/gap) by the Fred Hutchinson’s Cancer Research Center.Blood was drawn for participants who provided informed consent; these participants included those from the aforementioned study at the University of Utah, KPMRP, and in the Twin Cities metropolitan area in Minnesota . GWAS da4).A literature search was conducted to identify all miRNA-related SNPs shown to be associated with susceptibility to any type of cancer and more specifically to colorectal cancer ,19–51. WThe study data flow is shown in http://www.ncbi.nlm.nih.gov/projects/SNP/) was utilized to identify SNP coordinates: all SNP chromosomal coordinates are from the assembly GRCh37 (GRCh37.p13). Ensembl’s Variant Effect Predictor (VEP) tool was utilized through the Ensembl GRCh37 site (http://grch37.ensembl.org/info/docs/tools/vep/index.html) to yield variant location and effect. VEP was utilized using all default settings. All SNPs were found in VEP. MiRNASNP v2.0, based on miRBase build 19 and dbSNP version 137 (http://bioinfo.life.hust.edu.cn/miRNASNP2/index.php) [We utilized various bioinformatics tools. DbSNP (dex.php)  was utilWe evaluated miRNA expression in both non-tumor colonic tissue and expression differences between tumor and non-tumor tissue to obtain a better understanding of how the SNPs relate to miRNA expression. Looking at non-tumor tissue allowed us to evaluate the effect of the SNP on miRNA expression. A SNP associated with miRNA expression across genotypes in non-tumor tissue could influence the baseline expression level of the miRNA but not influence cancer risk if it equally altered miRNA expression in tumors. Thus, changes in expression between tumor and non-tumor tissue were evaluated because of their potential importance for the carcinogenic process.0: β = 0 vs. H1: β≠0 using R 3.1.2 (cran.r-project.org). All statistical analysis was performed using miRNA expression data that was both normalized and log2 transformed. The mean expressions reported in Tables Statistical analysis was performed in three stages. First, we evaluated the miRNA expression for linear trend across genotypes adjusting for age, study center and sex using a linear regression model. P-values were generated from the bootstrap method  by creatPrior to adjustment for multiple comparisons, six SNPs within miRNA genes and 16 SNPs within miRNA-target genes were associated with differentially expressed miRNAs in non-tumor colonic tissue by genotype . Twelve Six SNPs within miRNA genes and 15 SNPs within miRNA-targets genes were identified as being associated with differential miRNA levels between tumor and non-tumor tissue ; 12 of tFurther evaluation of miRNAs that were significantly influenced by SNPs prior to adjustment for multiple comparison in either non-tumor tissue or when comparing differences between tumor/non-tumor . A third SNP, rs276466, was associated with increased risk of colon cancer with the heterozygote genotype  only and not the homozygote rare genotype and therefore may be a spurious association.Evaluation of associations between colon cancer and SNPs that were significantly associated with miRNA expression levels showed two SNPs that were also significantly associated with increased risk of colon cancer . Within It has been suggested that SNPs associated with risk of colon cancer could be functioning through their impact on miRNA regulation . In thisBRCA1 and predicted to be a binding site for hsa-miR-525-5p when the G allele (or C in our data) is present [AA 1.34 95% CI 1.01, 1.78). This variant has been reported as being associated with decreased BRCA1 expression, increased breast cancer risk, and greater likelihood of having stage IV breast cancer [Two SNPs in miRNA-target genes were identified as associated with an increased risk of colon cancer; these SNPs also were associated with statistically significant mean differential miRNA expression across genotypes. Of these, rs8176318, located in the 3’ UTR of  present , was asst cancer . ExpressPRKAR1A, that was significantly associated with decreased expression in tumors relative to non-tumor tissue of the miRNA that targets PRKAR1A, hsa-miR-214-3p, in subjects of the homozygote common (TT) genotype as compared to the heterozygote and homozygote rare  genotypes. Additionally, a much higher percentage of non-tumor tissue did not express hsa-miR-214-3p in the heterozygote genotype as compared to the TT (common) genotype, and even less expression was observed for the homozygote rare genotype. Hsa-miR-214-3p was statistically significantly upregulated in tumor versus non-tumor tissues, and the SNP rs8905 was seen to significantly increase the risk of colon cancer . In this instance, it is likely that the alteration of the miRNA expression is caused by the SNP and this directly contributes to colon tumor risk.We also identified another SNP, rs8905, in the 3’ UTR of Our data did support some of the literature in terms of SNP and miRNA associations. In a recent study, two SNPs within the promoter region of hsa-miR-143/145, rs353292 and rs353293, were significantly associated with an increased risk of colorectal cancer (CRC) in a predominately Chinese population [Dikaiakos et al.  reportedAFF1 rs17703261 and KIAA0423 (or FAM179B) rs1053667, were significantly associated with non-specified cancer risk. In that work, AFF1 rs17703261 was inversely associated with cancer risk  and KIAA0423 rs1053667 was directly associated with cancer risk  [AFF1 are hsa-miRs-19a, -19b, -585, and -648. In our study, we identified a significant decrease in expression of hsa-miR-648 in the homozygote rare (TT) genotype in non-tumor tissue. Additionally, we found that expression of this miRNA is significantly downregulated in tumor tissue compared to non-tumor tissues. However, we did not observe an association between AFF1 rs17703261 with the risk of developing colon cancer. The miRNAs that were identified as targeting KIAA0423 in Ryan et al. were hsa-miRs-19a and -19b. We identified significantly lower expression of hsa-miR-19b-3p in the heterozygote genotype as compared to the homozygote common genotype in non-tumor colonic tissues. We also found expression of this miRNA to be upregulated in tumor versus non-tumor tissues. However, rs1053667 was not associated with risk of colon cancer.In a review by Ryan et al. , AFF1 rsCD80), rs1305 (VTCN1), and rs44044254 and rs1559931 (ICOS). In their study, they found an increased risk of CRC with the homozygote rare genotype of rs1305 and a decreased risk of CRC with the codominant and dominant model for rs4404254 and rs1559931. We saw slightly reduced, non-significant risk for all of these SNPs with colon cancer.Wu et al.  investigAFF1, rs17703261 which is predicted to cause a loss of targeting by hsa-miR-648. This miRNA is slightly downregulated in tumor as compared to non-tumor tissues in our data. The homozygous rare genotype has significantly less expression of hsa-miR-648 than the other genotypes. Other examples are SLC10A7 rs105760 and KIAA0423 rs1053667, which are predicted to cause loss of targeting by hsa-miR-25-3p and hsa-miR-19b-3p, respectively. Rs1053667 and rs105760 were associated with reduced expression in tumor as compared to non-tumor tissues of the predicted lost miRNAs with the variant allele. A further example, rs9874 (SELS) is predicted to cause a gained targeting by hsa-miR-181a-5p, and we see an increase in mean expression between tumor and non-tumor tissue with the variant allele. Additionally, BRCA1 rs8176318, is predicted to have a gain of function for hsa-miR-20a-3p. We evaluated this miRNA/SNP pair and did not see an association between the predicted gained miRNA and this SNP. However, as mentioned previously, BRCA1 rs8176318 was associated with the G allele specific (C in our tables) miRNA hsa-miR-525-5p and we did see a reduction in expression of hsa-miR-525-5p in non-tumor tissues with the variant allele as well as a lowered level of mean miRNA expression in tumor tissue as compared to non-tumor tissue. These results would support the theory that a loss of the presence of the target (as a result of the SNP) causes a reduction in the level of miRNA expression.It has been suggested that miRNA expression levels are associated with expression of their corresponding target genes, and that the presence of the target genes prevents miRNA degradation by nucleases . To inveSLC10A7, is associated with MCM7, MIR106B, MIR25, MIR93 and AP4M1 and several SNPs, rs105756, rs999885, and rs1527423. This can make the interpretation of results difficult. While there are study limitations, a major strength of this study is the ability to evaluate hypothesized SNP/miRNA associations and to evaluate associated SNPs and miRNAs with colon cancer.There are several considerations when evaluating our results. First, our study is comprised of colon cancer cases while many studies included both colon and rectal cancer cases. Differences in associations with cancer could differ based on the differences in cases definition. Our findings elucidate the complexity of miRNA regulation, especially the role of SNPs in the carcinogenic process that involves miRNA. MiRNAs are involved in the regulation of multiple genes and, even though SNPs were associated with miRNAs, the influence of miRNAs on other genes may determine the association with cancer. For example, hsa-miRNA-25-3p, along with its regulation of Out of the 327 unique SNP-miRNA pairs evaluated only 41 were associated with miRNA expression levels. Of these, only two SNPs were associated with colon cancer risk. While it has been hypothesized that SNPs in miRNA regions can influence cancer risk through miRNA regulation, our data suggest that such associations are relatively rare when evaluating colon cancer.


We report (1) the quantitative investigation of text reading in posterior cortical atrophy (PCA), and (2) the effects of 2 novel software-based reading aids that result in dramatic improvements in the reading ability of patients with PCA.Reading performance, eye movements, and fixations were assessed in patients with PCA and typical Alzheimer disease and in healthy controls (experiment 1). Two reading aids (single- and double-word) were evaluated based on the notion that reducing the spatial and oculomotor demands of text reading might support reading in PCA (experiment 2).Mean reading accuracy in patients with PCA was significantly worse (57%) compared with both patients with typical Alzheimer disease (98%) and healthy controls (99%); spatial aspects of passages were the primary determinants of text reading ability in PCA. Both aids led to considerable gains in reading accuracy  and self-rated measures of reading. Data suggest a greater efficiency of fixations and eye movements under the single-word reading aid in patients with PCA.These findings demonstrate how neurologic characterization of a neurodegenerative syndrome (PCA) and detailed cognitive analysis of an important everyday skill (reading) can combine to yield aids capable of supporting important everyday functional abilities.This study provides Class III evidence that for patients with PCA, 2 software-based reading aids (single-word and double-word) improve reading accuracy. In this study, we set out to characterize text reading in PCA (experiment 1) to inform the design of a reading aid for this patient group (experiment 2).Posterior cortical atrophy (PCA) is a progressive syndrome most frequently caused by Alzheimer disease (AD), characterized by posterior atrophy and prominent impairment in visuospatial and visuoperceptual functionWe developed 2 reading aids (single- and double-word) intended to support reading in PCA by minimizing the spatial and oculomotor demands of text reading. Both aids moved words successively into a fixation box; we hypothesized that such presentation would assist in localizing words within sentences and identification of the onset of subsequent lines of text by reducing the susceptibility of text reading to visual disorientation, excessive crowding, and fixation instability.The current study compared the reading performance of individuals with PCA, those with typical AD (tAD), and healthy controls. Experiment 1 examined the hypothesis that spatial factors are the primary determinants of PCA text reading accuracy. Experiment 2 tested the hypothesis that reducing the spatial and oculomotor demands of text reading would significantly improve reading ability in PCA.Neurology® Web site at Neurology.org). Based on clinical and neuroimaging data, the patients with PCA all fulfilled clinical criteria for a diagnosis of PCA14 and research criteria for probable AD.15 The patients with tAD fulfilled research criteria for a diagnosis of typical amnestic AD.15 Demographic information did not significantly differ among PCA, tAD, and control groups (18F amyloid imaging performed as part of another investigation or CSF) was available for 5 of 15 patients with PCA and 4 of 6 patients with tAD. All results were consistent with AD pathology , with PCA and tAD groups fulfilling criteria for atypical and tAD, respectively.16Fifteen patients with PCA, 6 patients with tAD, and 6 healthy controls participated in both experiment 1 and 2. Numbers of patients with PCA were limited because of the low prevalence of PCA; small numbers of patients with tAD and healthy control participants reflected expectations of near-ceiling performance while fulfilling counterbalancing requirements for experiment 2  in a standard presentation block-of-text format , with each passage split into 3 paragraphs. Passages were selected from the BBC news archive to reduce priming from current events. Words were in black Arial Unicode MS font size 16, with a visual angle of letter height subtending 0.45° when viewed from a distance of 50 cm, presented on a gray background.Participants were given a maximum of 300 seconds to read each passage. For each word, participants who took more than 10 seconds to respond were prompted to move onto the next word. Participants were not discouraged from using their finger to maintain their place when reading. Passages were administered through a repeated-measures design that included presentation conditions from experiment 2 (see below). Latencies were defined as the time taken to read each passage and were manually determined from when passages were first presented. Words read correctly were marked as accurate, regardless of word order. An Eyelink II  recorded gaze location at 250 Hz.Between-group differences in reading accuracy, reading speed, and performance on neuropsychological measures were calculated using Wilcoxon rank sum tests. Three separate models analyzed spatial influences on reading accuracy .Between-group differences in fixation number/duration and saccade number/amplitude were assessed using Wilcoxon rank sum tests.z = −3.43, p < 0.001) and controls ; there was a trend toward tAD patients reading less accurately than controls . Overall accuracy would have been lower if word order had been considered, particularly in the PCA group, because words were marked correct regardless of when they were read in each passage  and control group , with the tAD group also slower than controls .A heatmap showing the effect of word location on PCA reading accuracy for an example passage is shown in  passage . Mean paPatients with PCA were more accurate reading words further from the center of the page or paragraph, words on paragraph perimeters, on lines at the beginning of paragraphs, and in earlier paragraphs .There were no significant effects of any of the spatial variables on reading accuracy of patients with tAD. The control group did not make enough errors to allow for an accuracy analysis.p > 0.6) or accuracy (p > 0.3) from the remainder of the PCA group ; a modified t test17 found that the patient with tAD who used their finger was slower  but not less accurate (p > 0.4) than the remainder of the tAD group .In total, 4 patients adopted a strategy to maintain their place when reading by using their finger: 3 patients with PCA  and one patient with tAD . The patients with PCA who used their finger did not significantly differ in reading speed , 2 reading aids were designed to provide the optimal conditions for reading in PCA by minimizing the spatial, perceptual, and oculomotor demands of reading: (1) single-word: passages presented one word at a time in a central fixation box; and (2) double-word: identical to the single-word condition except that each target word was accompanied by the subsequent word, displayed parafoveally to the right of the fixation box .19 This motion was intended to act as a cue to assist disorientated readers, following reports of patients with PCA being able to better localize moving stimuli.21 The double-word condition in addition presented the subsequent word in each passage to the right of the fixation box in order to assess whether participants' reading would benefit from the presence of words to the right of fixation.23 Words remained stationary within the fixation box until read; subsequently, consecutive words were moved into the box by the experimenter , single-word, and double-word. Each passage was read in every condition by each participant (in the same order) in a repeated-measures design to control for lexical and syntactic differences between passages. All 3 presentation conditions were arranged in 1 of 6 variants of a Latin Square design within 3 blocks each composed of 6 passages, with presentation condition always differing between each passage; this was done to avoid confounding differences between presentation conditions and practice effects. The order of these blocks varied across participants to control for passage effects (table e-1). Because of time constraints, one patient with PCA read passages under baseline and single-word, but not double-word, conditions. Controls completed a third of the trials, with no passage repeats and varying presentation order. After each passage, patients with PCA rated their reading ease, comprehension, and pleasantness on a 4-point auditory-verbal scale . For the first 3 passages, PCA and tAD groups were also asked a global comprehension question (“Can you tell me the gist of that article?”) to ensure that participants were extracting semantic information from each passage. Eye movements were recorded as in experiment 1.Regression models of accuracy and eye movement analyses were identical to those in experiment 1 except spatial variables were replaced with presentation condition. Regression models were used to test for an interaction between patient group and presentation condition. Global comprehension question responses were assigned by blinded raters (n = 14) to the appropriate corresponding paragraph. Differences in global comprehension and self-rated ease, comprehension, and pleasantness measures were compared within- and between-group using Wilcoxon signed rank and rank sum tests.This study provides Class III evidence on the primary research question of whether 2 reading aids, single- and double-word, improve reading accuracy in patients with PCA.z = 3.62, p < 0.001) and double-word  relative to the baseline condition. There was no significant interaction between group (PCA vs controls) and condition because of near-ceiling performance by controls .Percentage error rates and reading latency data for each presentation condition are shown in z = 38.17, p < 0.001) and double-word  conditions. These improvements were evident in every individual patient with PCA . Accuracy was lower for words read later in each passage  and words of higher frequency . There were no effects of repeats (p > 0.6) or word length (p > 0.2). There was no significant difference in reading latency between the baseline condition and single-word (p > 0.3) or double-word (p > 0.7) conditions.Relative to baseline, PCA reading accuracy was significantly higher in both single-word  and double-word  conditions. Only 2 of 6 and 1 of 6 patients with tAD improved significantly with the single-word and double-word condition, respectively; the greatest increase in accuracy for a patient with tAD was from 93% to 99%. The tAD group performed more accurately in the single-word than double-word condition . There were no effects of repeated passages (p > 0.1), word length (p > 0.3), frequency (p > 0.3), or word order (p > 0.4). Reading speed was fastest in the baseline relative to both the single- and double-word conditions , and faster in the double-word than single-word condition .Relative to baseline, patients with tAD showed modest increments in accuracy with the single-word , and faster in the double-word than single-word condition .Reading accuracy was near-ceiling in all 3 conditions. As with patients who had tAD, reading speed was faster in the baseline than single-word or double-word condition , more pleasant , and more readily understood  than in the baseline condition. Patients with PCA also rated single-word reading as significantly easier  and more pleasant  but not better understood (p > 0.2) than double-word reading.See figure e-1 for self-reported measures of reading experience in patients with PCA, who rated single-word and double-word reading as significantly easier  but not baseline (p > 0.2) or double-word (p > 0.5) condition.Neither patients with PCA nor patients with tAD showed within-group differences in global comprehension across baseline, single-word, and double-word conditions . However, patients with PCA showed a trend toward better global comprehension than patients with tAD in the single-word condition . Single-word reading also led to decreased saccade amplitude relative to the baseline condition .Saccade and fixation data for each condition are shown in table e-2. As with the baseline condition (experiment 1), patients with PCA made significantly more saccades and fixations than patients with tAD or controls in both single-word and double-word conditions. However, the single-word condition was the only condition in which PCA fixation durations did not differ significantly from patients with tAD or controls, representing an increase in fixation duration relative to the baseline condition , single-word (96.2%), and double-word (88.3%) conditions suggests that this lack of a significant improvement might be attributed to ceiling effects. We propose that the efficacy of any home-based reading intervention modeled on the current aids rests not solely on objective measures of reading, but is particularly contingent on its perceived utility and user-friendliness. Consequently, we believe this absence of a significant improvement is offset by other reliable improvements in self-rated measures of reading ability and comprehension. A related potential concern, that global aspects of passage processing are lost under reading aid conditions, is not substantiated when considering both objective and subjective comprehension measures. A second potential issue is that near-ceiling accuracy in the tAD group prevented the identification of factors that reduced reading ability in patients with tAD relative to control participants. Third, despite improvements in reading accuracy, neither reading aid resulted in increases in reading speed. Potential reading applications based on the current aids might allow more efficient rates of presentation maintained by users rather than the experimenter. Because apraxia is a common symptom of PCA,28 we regard the current interventions as reading aids rather than reading rehabilitation: an aid does not influence the underlying impairment , while rehabilitation does. We plan to develop these aids into assistive technology to support reading ability in patients with PCA and other individuals with dementia-related visual dysfunction.The current investigation demonstrates how the neurologic characterization of a neurodegenerative syndrome (PCA) and a detailed cognitive analysis of an important everyday task (reading) can be combined to yield an aid capable of supporting continued functional ability in patients living with that condition. Both reading aids resulted in robust increases in reading ability and subjective increases in reading ease, comprehension, and pleasantness. Eyetracking data suggested that, in particular, the single-word reading aid promotes a greater efficiency of eye movements. Although some eye movement–based reading therapies result in improvements in reading ability that persist across time and generalize to material encountered outside of the training program,