N = 38 human participants), while experiment 2 assessed behavioral facilitation effects (N = 24 human participants). Across all stimulus conditions, MEG demonstrated context-based facilitation across multiple time windows starting at 100 ms, in occipital brain areas. This finding indicates context-based facilitation at an early visual processing level. In both experiments, we furthermore found an interaction of context and lexical familiarity, such that stimuli with associated meaning showed the strongest context-dependent facilitation in brain activation and behavior. Using MEG, this facilitation effect could be localized to the left anterior temporal lobe at around 400 ms, indicating within-level  facilitation but no top-down effects on earlier processing stages. Increased pre-lexical familiarity (in PWs familiarized utilizing training) did not enhance or reduce context effects significantly. We conclude that context-based facilitation is achieved within visual and lexical processing levels. Finally, by testing alternative hypotheses derived from mechanistic accounts of repetition suppression, we suggest that the facilitatory context effects found here are implemented using a predictive coding mechanism.Word familiarity and predictive context facilitate visual word processing, leading to faster recognition times and reduced neuronal responses. Previously, models with and without top-down connections, including lexical-semantic, pre-lexical , and visual processing levels were successful in accounting for these facilitation effects. Here we systematically assessed context-based facilitation with a repetition priming task and explicitly dissociated pre-lexical and lexical processing levels using a pseudoword (PW) familiarization procedure. Experiment 1 investigated the temporal dynamics of neuronal facilitation effects with magnetoencephalography (MEG;  The goal of reading is to derive meaning from script. This highly automatized process benefits from facilitation depending on word familiarity and text context. Facilitation might occur exclusively within each level of word processing  but could alternatively also propagate in a top-down manner from higher to lower levels. To test the relevance of these two alternative accounts at each processing level, we combined a pseudoword (PW) learning approach controlling for letter string familiarity with repetition priming. We found enhanced context-based facilitation at the lexical-semantic but not pre-lexical processing stage, and no evidence of top-down facilitation from lexical-semantic to earlier word recognition processes. We also identified predictive coding as the most likely mechanism underlying within-level context-based facilitation.Efficient reading relies on automatized visual word recognition , which iComputationally, Separation of processing levels in visual word recognition research remains challenging. Experimental priming paradigms ensure a high degree of control over context factors, but require the matching of large numbers of psycho-linguistic parameters, which is difficult . AlternaUsing this strategy, we here dissociate between facilitation at pre-lexical and lexical levels of word processing. First, we matched pre-lexical characteristics  across words and PWs, ensuring comparable levels of pre-lexical processing difficulty between conditions cf. . Second,In the first experiment, we investigated pre-lexical versus lexical-semantic contributions to context-based facilitation in visual word recognition at a neuronal level, using MEG. Pre-lexical properties , insufficient performance during PW familiarization , self-reported developmental speech disorder (N = 1), technical artifacts during the MEG measurement (N = 4), insufficient number of trials after artifact rejection , contraindication to MEG measurement , or drop out by choice of participants . All participants gave written informed consent according to procedures approved by the local ethics committees  and received 10 € per hour or course credit as compensation.A total of 38 healthy native speakers of German  recruited from university campuses participated in familiarization procedures and MEG recordings and were included in the final sensor level analyses. All participants were right-handed as assessed by the Edinburgh Handedness Inventory , had norWuggy software  to account for potential confounds from the parameters . Participants were familiarized with 60 PWs before the actual repetition priming task was conducted in the MEG (see section “PW familiarization” below for details). The second group of PWs was never seen by the participants before the MEG experiment. In addition, four further lists of 120 PWs each were generated as fillers for the familiarization procedure (one list per session).Sixty German nouns  and 120 pronounceable PWs were presented twice during MEG acquisition. In addition, 80 catch trials were presented (see section “Repetition priming” below). PWs were divided into two sets of 60 items, such that both PW lists and the set of words were matched on orthographic similarity  and number of syllables . Words and PWs were presented in black bold Courier New font (14 pt.) in front of a white background. In the behavioral sessions, stimuli were presented on an LCD monitor with a refresh rate of 60 Hz, while during the MEG session, stimuli were projected with a refresh rate of 60 Hz onto a translucent screen.Participants visited the lab on the two days before the MEG experiment, and during each visit completed two familiarization sessions of ∼20 min in length. The two previous days were chosen to take advantage of sleep consolidation effects . Each falme4 package  as fixed effect and participant and item as random effects on the intercept were performed with the  package  in R, ve package . All eff10.1523/ENEURO.0321-18.2019.f3-1Extended Data Figure 3-1Figure 3-1, DOCX file.Results from the LMM analyses of d’ sensitivity indices from the PW familiarization sessions of both experiments 1 and 2, including pairwise comparisons from session to session. Download The repetition priming task during MEG recording was conducted on day 3 and included words, familiarized PWs, and novel PWs. At the start of each trial, participants had to fixate between two vertical black bars presented above and below the center of the screen  were each presented in two trials, once during each half of the experiment. As a consequence, we presented 120 trials per stimulus condition adding up to 360 trials; 75%  of these trials were repetition trials, allowing the investigation of familiarity effects in a highly predictive context. The remaining 25%  trials were non-repetition trials, in which each possible combination of words, familiarized, and novel PWs appeared equally often, i.e., 10 times. Also, we presented 80 catch trials resulting in a total of 440 trials. The repetition priming task lasted ∼40 min, divided into three blocks separated by breaks of ∼5 min.MEG datasets were acquired in accordance with guidelines for MEG recordings , using ahttp://www.fil.ion.ucl.ac.uk/spm/software/spm12/).Structural MR images were acquired for 34 participants with a 1.5 T Siemens magnetom Allegra scanner  using a standard T1 sequence . To enable co-registration of MR images with MEG data, vitamin E capsules were placed at the positions of two of the MEG head localization coils ; the nasion could be identified anatomically in structural MR images. Fiducial coordinates were identified in SPM12  interaction obtained with separate or common baselines for prime and target. Download th order median filter was applied to the data, while for muscle artifact detection, an 8th order Butterworth IIR filter (110–140 Hz) was applied. The filtered data were z-transformed and averaged across sensors. Trials were rejected if for any time point the z value exceeded a threshold of z = 20 for jump artifacts and z = 6 for muscle artifacts, following standards established for the local measurement characteristics. Trials contaminated with eye blink, eye movement, or heartbeat artifacts were cleaned using independent component analysis  per condition could be retained. Non-repetition trials were averaged across conditions for analysis, with on average 52.6 trials per participant available (range: 29–80).Individually for each participant, trials were selected for analysis in which the head position fell within a range of 5 mm  relative to the majority of other trials. Trials contaminated with sensor jump and muscle artifacts were rejected automatically, using the FieldTrip routine for automatic artifact detection. For jump artifact detection, a 9sis ICA; . Componehttps://github.com/sashel/permANOVA/). Clusters were defined as spatially and temporally adjacent samples with F values exceeding an uncorrected α-level of 0.001  and prime/target effect . As the low number of non-repetition trials did not allow separate analyses of these effects for the different conditions, data were pooled across familiarity conditions . Within each familiarity condition, the number of repetition trials was randomly stratified to match the number of non-repetition trials. In the second analysis, we examined in repetition trials how familiarity  and context (prime vs target) interact. This analysis served to examine the effects of different familiarity types on the neuronal repetition effect.post hoc LMM analyses for pairwise differences between relevant conditions. All post hoc tests were based on participant-specific and condition-specific ERF values averaged across sensors and time points from the respective significant cluster, and included participant and item as random effects on the intercept. Since not all trials entered the analyses due to exclusion of artefactual trials, which might have affected the matching across letter string conditions, OLD20 and number of syllables, both z-transformed and centered, were entered as additional fixed effects.To determine the nature of significant interaction and main effects, we performed To rule out the possibility that our baseline correction approach, i.e., using separate baselines for ERFs elicited by prime and target stimulus in a trial, has created artificial effects due to the presentation of hash marks only before the target, we performed the analyses of repetition congruency by prime/target and familiarity by prime/target a second time, using the period before the prime as a common baseline for correction of ERFs to both stimuli. Of in total 24 significant clusters from the analyses after separate baselining, 17 were also found significant in the analysis after common baselining. Therefore, in the results and discussion sections, we will focus on those clusters replicated with the common baseline approach. Clusters with durations < 30 ms were not interpreted  and negative (in case of left sensors) peaks of the ERFs were identified per participant, condition, and sensor . In case of central sensors close to the midline , we separately decided whether to select the positive or negative peak, depending on which of the two peaks was absolutely higher in the across-participant ERFs. We decided against taking this approach in the majority of sensors because the ERFs typically declined during later time windows, in many cases reaching a value higher than the actual peak in absolute terms. Therefore, selecting the positive peak in the case of right sensors, and the negative peak in the case of left sensors, was the best compromise between automatic peak determination and avoidance of misplacing the actual peak value with a value that falls within the time range of decline of the ERF. We then subtracted the preceding peak value of respective other polarity (between stimulus onset and detected peak) from the already defined peak value. Statistical analyses were then performed on the absolute peak difference, using the cluster-based permutation procedure as described above, defining clusters solely based on spatial adjacency between sensors due to the lack of the temporal dimension. Given its independence from the pre-stimulus baseline, hash mark strings presented before the target cannot influence this analysis. However, a limitation of this analysis is that it cannot detect significant differences occurring at time ranges before and after the peak. Therefore, the results of this analysis did not influence whether a specific cluster was interpreted or not.http://www.fil.ion.ucl.ac.uk/spm). A regular 3D dipole grid (10-mm resolution) based on the T1 template was then warped with the inverse of the resulting transformation matrix. This procedure resulted in individual dipole grids for each participant, in which each grid point was located at the same brain area across participants. For each grid point and participant, lead fields were computed with a single shell forward model of the inner surface of the skull . For analyses on separate conditions, the sign of half of the trials was randomly flipped. For analyses on condition differences, condition labels were randomly exchanged across trials. The square of the dipole’s norm averaged across all permutations was taken as noise estimate. This noise estimate was subtracted from the square of the true data, and the data were divided by the noise estimate. Negative values were set to zero, and the square root was taken. Finally, the signal of each source location was normalized by its variance to counter the depth bias. For visualization, source locations thresholded at 50% of the maximum source activation were plotted on cortical surfaces using the  package  in Pytho package .https://osf.io/fc69p/.The raw data, stimulus lists, and analysis code of both experiments described in the article are freely available online at During the MEG measurement, participants correctly identified 94% of catch trials, indicating that they were attending to the presented letter strings.post hoc LMM: estimate = 2.22e−14, SE = 0.19e−14, t = 11.61; post hoc LMM: estimate = –0.58e−14, SE = 0.20e−14, t = 2.94; As manipulation check of context effects, we investigated the interaction between prime/target and repetition congruency  effects, combined over all familiarity conditions. Repetition trials A but not10.1523/ENEURO.0321-18.2019.f5-2Extended Data Figure 5-2A) the familiarity cluster F1 contrasting familiar PWs > words and (B) the interaction cluster CxF contrasting prime versus target by words versus familiar PWs. Download Figure 5-2, TIF file.Source locations for , ERF time course (B), and boxplot (C), averaged across prime and target. Download Figure 5-3, TIF file.Main effect of lexical familiarity. Topographical map  the interaction of context (prime vs target) by lexical familiarity, (B) main effects of pre-lexical familiarity, (C) main effects of lexical familiarity, and (D) main effect of context (prime vs target). Topographical maps represent F values of significant sensors; note the different scales. Non-significant sensors are set to zero. Peak latencies averaged across significant sensors and all conditions are depicted above the topographical maps. Download Figure 5-5, TIF file.Significant clusters obtained in the peak-to-peak analysis for  familiarity but higher lexical familiarity  than novel PWs. In contrast, as a result of the familiarization training, familiarized PWs should have higher levels of familiarity than novel PWs specifically at the level of pre-lexical processing. Thus, we had assumed that effects of pre-lexical familiarity should be reflected in ERF differences between familiar PWs and both novel PWs and words, while effects of lexical familiarity should be reflected in ERF differences between words and both novel and familiar PWs  from sensor and time point of the strongest effect, separately for prime and target, for pre-lexical (F1) and lexical (F2) familiarity clusters represented in Table 4-1, DOCX file.Results from post hoc statistic controlling for OLD20 and number of syllables). Post hoc LMMs revealed that lexical but not pre-lexical familiarity reliably modulated the repetition effect: While during prime presentation the negative-going ERF amplitude was largest for words , it was smallest for words during target presentation  from sensor and time point of the strongest effect, separately for prime and target, for the prime/target × lexical familiarity interaction cluster represented in Table 5-1, DOCX file.Results from To assess potential influences from low-pass filtering, we performed an additional control analyses with a 40-Hz low-pass filter. Results did not differ qualitatively from the results described in the previous sections obtained with a 20-Hz low-pass filter . Significant results from the peak-to-peak analysis strongly support the interaction between prime/target and familiarity effects at left frontal sensors, the main effects of familiarity at left posterior and left frontal sensors, as well as main effects of prime versus target at bilateral frontal sensors, resembling the effects of clusters CxF, F1, F2, and C3 in The main finding from experiment 1 (MEG study) was that only lexical familiarity interacted with context  to facilitate visual word recognition at the N400 window only. Please note that in the following, for the sake of brevity, we will subsume the processing of words and PWs under the term visual word recognition, as we assume similar pre-lexical processing for words and novel PWs reflecting the orthographic familiarity (OLD20) match. The finding of stronger repetition suppression for words was consistent with previous studies  and idenThe interaction of lexical familiarity and context at the N400 indicated within-level context-based facilitation at the lexical level. We related this interaction to lexical level processing since words, i.e., meaningful stimuli, differentiated from PWs, i.e., meaningless stimuli. This is in line with previous work  that would allow differentiating between fatigue and predictive coding, since only the latter would predict a systematic influence of repetition probability across trials. Finally, in experiment 1, we were surprised that no evidence for an influence of pre-lexical familiarity on context-based facilitation was found. To replicate the MEG pattern in behavior and systematically examine the role of word status and implement a repetition probability manipulation, we ran a second, behavioral, repetition priming experiment.In experiment 2, we implemented the explicit investigation of word status by adding a third group of PWs. With a paired association task, we associated semantic content to these non-words. Similar as in experiment 1, we also included familiar PWs without meaning. Note, PWs with and without semantic associations were visually/perceptually familiarized to the same degree. Therefore, the two groups of PWs only varied regarding their associated semantic meaning. Including this additional lexical familiarity condition allowed us to examine potentially different roles of word status and the presence of semantic associations.We measured behavioral response times in a repetition priming paradigm. Participants had to indicate whether or not a letter string had a semantic association. A yes response would be valid for words and familiarized PWs with semantic associations, but not for novel and only perceptually familiarized PWs.As stated in the discussion of experiment 1, we also implemented a repetition probability manipulation . Repetition probabilities varied across three blocks, to investigate whether the priming effect  increases when the local task context allows predicting that the prime is highly likely identical to the target. In previous studies with different visual stimuli higher repetition probability enhanced priming effects, mainly supporting predictive coding .N = 4), insufficient performance during PW familiarization , or failure to complete the experimental protocol (N = 2). Four participants were excluded after data analysis due to insufficient performance (<25% correct for non-repeated words). All participants gave written informed consent according to procedures approved by the local ethics committee and received 10 € per hour or course credit as compensation.A total of 24 healthy native speakers of German recruited from university campuses  were included in the final data analysis. All participants had normal or corrected-to-normal vision, and normal reading abilities as assessed with the adult version of the Salzburg Reading Screening  and 180 pronounceable PWs with characteristics similar to experiment 1 were presented in a repetition priming task. PWs were divided into three sets, each of which was matched to the word set on orthographic similarity OLD20, . ParticiSix variants of the familiarization task were prepared, across which the assignment of the three PW sets to the familiarized, i.e., familiar versus semantic, as well as to the novel condition was varied . In addiParticipants performed five PW familiarization sessions in the course of three consecutive days, i.e., two sessions each on day 1 and 2, and one session on day 3 (before the repetition priming task). Each session lasted about 1 h, and participants could take a short break after the first half, as well as a mandatory 1-h break before the next session. Each session consisted of reading aloud each PW (mean error rate across sessions: 1.4%), a computer-based paired-association task with congruent versus incongruent parings of PWs and object images, and a naming task. While one set of PWs was familiarized pre-lexically as in experiment 1, i.e., merely through repeated exposure (“familiar PWs”), one set was additionally associated with semantic information (“semantic PWs”). The paired-association procedure was adapted from previous studies , howeverFamiliar and semantic PWs were presented in random order for 800 ms, followed by an object image  for 1500 ms or until response C. DuringParticipants were asked to learn a meaning for the presented PWs based on the frequency with which the PWs were paired with certain object images. They were explicitly informed about the inconsistent pairings for half of the PWs. Participants were instructed to silently read the presented PWs and to respond as accurately and quickly as possible, whether a presented object image matched the preceding PW or not. In addition, they were encouraged to guess if insecure. Participants responded by pressing one of two buttons on a keyboard with either the left or right index finger. To prevent potential response biases, the assignment of response hand and response varied from trial to trial (by presenting a red bar indicating non-match on one side and a green bar indicating match on the other side of the object image). In the first familiarization session, participants completed a short practice block of ten trials before the start of the actual paired-association task.In the naming task D, each Pt = 17.11; post hoc analyses for pairwise sessions). This indicates that participants improved in identifying matching and non-matching PW-object combinations. In the final familiarization session, participants reached high mean accuracies of 93.17% (range: 74.72–99.72) for the identification of matching objects for semantic PWs, and 89.65% (range: 60.47–99.38) for the identification of non-matching objects for PWs familiarized without semantics  revealed that d’ for the paired-association task significantly increased across sessions from 0.41 in session 1 to 2.06 in session 5 . In the final session, participants named the correct object for between 51.67% to100% of semantic PWs  revealed that d’ significantly increased from 0.23 in session 1 to 2.43 in session 5 . This task was chosen to elicit the same response for semantic PWs as for words. Each letter string  was presented once per block, either in the repetition or in the non-repetition condition. In total, 240 trials (60 per condition) were presented in each block. Letter strings were used at maximum twice for non-repetition trials; in this case, they were combined with two different letter strings. Before the task, eight practice trials were completed. The total duration of the priming task was around 45 min.Analogous to the analysis of the PW familiarization procedure, behavioral data of the repetition priming task were analyzed using LMMs allowing random effects of both participant and items (prime and target stimulus) on the intercept, as well as analysis of imbalanced data . We mainWe first performed an analysis with factors repetition congruency , reflecting the main manipulation of context effects in experiment 2, and repetition probability . To assess pre-lexical and semantic contributions to behavioral context and familiarity effects, we investigated the four-way interaction between repetition congruency, repetition probability, pre-lexical, and lexical familiarity. The latter two were manipulated orthogonally, such that familiarity was entered as two factors coding pre-lexical  and lexical familiarity . Since context provided by the prime stimulus might override familiarity effects , we addipost hoc LMMs including only the relevant conditions. Behavioral data and analysis scripts are published under https://osf.io/fc69p/.All  LMMs included the interactions of all fixed effects described so far. Since not all trials entered the analyses , which might have affected the match across letter string conditions, OLD20 and number of syllables were included as additional fixed effects. All fixed effects were centered and z-transformed. For each significant interaction, pairwise differences between conditions were investigated using In the semantic association judgments of the repetition priming experiment, average accuracies for repetition trials were high, albeit not at ceiling, across all repetition probabilities  which was stronger for repetition  compared to non-repetition trials ; i.e., the priming effect  was smaller for a repetition probability of 25% vs 50%  and smaller for 50% vs 75%  and familiar PWs .To investigate the influence of pre-lexical and lexical familiarity in the absence of valid contextual information, we focused on non-repetition trials. We observed a significant interaction between pre-lexical and lexical familiarity . This ints < 1, including the three-way interaction; see t = 11.13; post hoc contrasts: semantic vs novel PWs: estimate = –0.048, SE = 0.0059, t = 8.11; semantic vs familiar PWs: estimate = –0.051, SE = 0.0060, t = 8.52; Repetition probability did not interact with pre-lexical or lexical familiarity  and non-repetition trials (right) averaged across familiarity conditions. B, Familiarity influence on context effects, i.e., repeated (left) versus non-repeated targets (right). Effects are separated for familiarity conditions, with an additional separation for letter strings with and without semantic associations, averaged across repetition probabilities. Colored dots and lines represent individual participants. Download Figure 6-1, TIF file.Accuracies in experiment 2 (semantic association judgment task). Extended Data Table 10-1Table 10-1, DOCX file.Results from the LMM analyses investigating repetition congruency (repetition vs non-repetition), probability, familiarity, and semantics in accuracies during repetition priming (experiment 2). Download Extended Data Table 10-2Table 10-2, DOCX file.Results from the LMM analyses on accuracies during repetition priming (experiment 2), separately for repetition and non-repetition trials. Download In general, the behavioral results replicated the main MEG findings. Context-based facilitation, here implemented as repetition congruency, on response times was stronger for words and PWs with semantic associations in contrast to PWs without meaning. The interaction of lexical familiarity and context replicated the modulation of lexical information on context-based facilitation found in the N400. We also observed that recently increased pre-lexical familiarity, in familiarized PWs without meaning, resulted in faster response times compared to novel PWs in non-repetition trials, i.e., in the absence of valid contextual information. This finding is compatible with the increased activation to familiar PWs within the left angular/supramarginal gyrus shown in the MEG. Finally, we found strong general priming effects that replicate the strong context effects demonstrated in the MEG results. Once more, we found no evidence for an interaction of pre-lexical familiarity and context-based facilitation.A word status effect, i.e., words versus PWs with associated meaning, was also found in response times, but the difference in response times was much smaller when the contextual information was valid. This pattern indicates that even recently learned letter strings use semantic meaning to facilitate word recognition on a lexical level in a predictable context cf. . Also, wIn the two experiments of the present study, we found evidence for context-based facilitation of visual word recognition within the lexical-semantic processing level based on a predictive coding mechanism. Most prevalent was the increased facilitation, reflected in reduced brain activation at the left anterior temporal cortex around 400 ms and faster behavioral responses, when semantic information was present . We founOne of the main goals of this study was to investigate whether context-based facilitation of visual word recognition is implemented via top-down feedback from higher to lower processing levels, or restricted to within each processing level; i.e., assessing the architecture of context-based facilitation. The two alternative architectures were formalized in previous neuro-cognitive models of visual word recognition. Despite not finding evidence for pre-lexical influences on context effects in the present study, we could identify an activation cluster in the left angular/supramarginal cortex, showing a pre-lexical familiarity effect. At the sensor level, the activation in response to familiarized PWs differed from novel PWs and words without an interaction with context. In behavior, we also observed facilitated recognition of pre-lexically familiarized in contrast to novel PWs when no valid contextual information was available. These findings reflect that pre-lexical familiarity has a central role in visual word recognition , but no One could argue that the learning paradigm did not build up a sufficiently strong pre-lexical representation to influence context-based facilitation. In our opinion, this is less likely for two reasons. In both experiments, we could find pre-lexical facilitation when no valid context-based expectations could be formed. This finding is a manipulation check showing that PW learning was successful. The second reason is that in the behavioral experiment, the learned lexical-semantic information was successfully used to increase context-based facilitation , which is also associated with semantic word characteristics  and valid versus invalid context  at the N400 also provides evidence against fatigue. A fatigue mechanism cannot explain the increased activation for unexpected targets in non-repetition trials compared to primes. At the same time, this increase fits well with predictive coding. In experiment 1, the repetition probability was 75%. As a consequence, a repetition was likely expected in every trial. Irrespective of repetition or non-repetition trials, this expectation is transformed in a prediction and, in case of a non-repetition trial, the prediction is not met resulting in a prediction error. The increase in the N400 amplitude for non-repeated targets versus primes might indicate a higher prediction error for mispredicted versus unpredicted stimuli , 2018. TThe current interpretations concerning the architecture and mechanistic implementation of context-based facilitation are not necessarily compatible. First, our favored architecture  implemenStill, another incompatibility is prevalent. We could not find evidence for the assumptions concerning the processing levels involved in context-based facilitation and the architecture proposed by the predictive coding theory . PredictFinally, one can speculate that specific lexical and pre-lexical information is transformed after completion of lexical access . The retrieved pre-lexical and lexical-semantic information might be used to predict the future stimuli already at the sensory level . Note, pIn sum, our investigation of context-based and familiarity-based facilitation of visual word recognition indicated within-level facilitation at visual and lexical processing levels. We found no support for hierarchical, top-down facilitation from a predictive (higher-level) context  to lower levels of processing . At a mechanistic level, we could identify predictive coding as the most likely candidate for the implementation of facilitation processes (as compared to fatigue and sharpening). A novel approach of our study was the explicit manipulation of pre-lexical  familiarity, via a PW familiarization training procedure. We could not find support for context-based facilitation at the pre-lexical level but could identify a context-independent pre-lexical familiarity effect in the left angular/supramarginal gyrus. Thus, we conclude that context-based facilitation relies on information about visual and lexical-semantic features of upcoming words. Interestingly, in natural reading, visual information is typically available through para-foveal pre-processing , while l


There has been a growing interest in the relationship between sedative-hypnotics use and the risk of Alzheimer’s dementia (AD) risk. This study aimed to evaluate the risk of AD associated with the use of sedative-hypnotics. A retrospective cohort study was conducted with randomly selected 5% samples from ≥50 years old beneficiaries of National Health Insurance Service (NHIS) of Korea from January 2002 to December 2015. The exposure to sedative-hypnotics was defined when prescribed over 30 defined daily dose (DDD) after January 2004 and it was categorized by prescribed dosage, types and half-lives of benzodiazepines. Time-dependent Cox regression model with a lag period of 5-years was used to evaluate the association between use of sedative-hypnotics and the risk of subsequent AD. Sensitivity analysis was performed for restricting sedative-hypnotics only when prescribed with insomnia. A total of 268,170 subjects were identified and subjects exposed to sedative-hypnotics showed a higher risk of AD  than those who were not. There was an increased risk of AD among subjects exposed to benzodiazepines or zolpidem  and antidepressants or low-dose antipsychotics . The risk of AD was increased regardless of dose of sedative-hypnotics and half-life among benzodiazepines, especially in exposure to more than 360 DDD of sedative-hypnotics  and the long-acting benzodiazepine . Hypnotics are widely prescribed for controlling insomnia. There has been an emerging issue about the health outcomes of hypnotics use because of the high prescription rate not only in Korea but also worldwide, especially among elderly people –3. AmongDementia is becoming an issue for public health because the number of dementia patients is growing rapidly worldwide in ageing societies , 11. TheThere have been observational studies reporting the association between hypnotics use and the risk of dementia –26. AlthKorea has the National Health Insurance Service (NHIS), which is a single medical insurance claim system. NHIS, which covers over 97% of the Korean population, collects individuals’ demographic factors as well as all medical claim data such as disease diagnosis and drug prescriptions from every resident in Korea.In this study, we hypothesized that brain hypoactivity or cognitive impairment caused by sedative effect of hypnotics could precipitate the development of dementia. However, pathophysiology of dementia differed by type and vascular or anatomical effect of sedative hypnotics on brain was less likely, so we would focus on the risk of Alzheimer’s dementia. Therefore, we investigated the association between sedative-hypnotic use and the risk of Alzheimer’s dementia using the NHIS database representative of the Korean population.th Revision (ICD-10), which included Alzheimer’s dementia , vascular dementia [F01], and other types of dementia .This study was approved by the Institutional Review Board of Seoul National University Hospital (H-1508-031-694). We designed a retrospective cohort study with the NHIS data from January 2002 to December 2015, which comprised a randomly selected sample of 5% of NHIS beneficiaries over 50 years old. People who died, were lost to follow-up, diagnosed with any type of dementia, or had prescribed any sedative-hypnotics before January 2004 were excluded. The patients excluded by diagnosis of dementia were defined using the International Classification of Disease 10The sedative-hypnotics used in this study included BZDs and zolpidem. In addition, antidepressants and low-dose formulation antipsychotics as off-label prescribed hypnotic drugs in Korea were also included. These drugs have sedative potent and widely prescribed for insomnia in Korea. These study drugs are listed on We tracked the prescription of these sedative-hypnotics from January 2004 and determined the accumulated dosage. The dosage of sedative-hypnotics was standardized by defined daily dose (DDD), which is a statistical measure of drug consumption suggested by the World Health Organization (WHO) . We clasA) receptor agonists (BZDs and zolpidem) and other drugs (sedative antidepressants and sedative antipsychotics). We calculated the accumulated dosage of each class of sedative-hypnotics separately and considered subjects to be exposed when each prescribed dosage exceeded 30 DDD. If subjects were exposed to both GABAA receptor agonists and other drugs, the subjects were categorized as being exposed to both classes of sedative-hypnotics. Classification by half-life was considered only among BZD drugs. We classified BZDs into short-acting BZDs (<3 hours), intermediate-acting BZDs (3–20 hours), and long-acting BZDs (>20 hours) based on their half-lives. If a patient was exposed more than two BZDs with different half-lives, he or she was considered to be exposed to longer-acting BZDs. When analysing by BZDs’ half-life, patients who were exposed to zolpidem, antidepressants, or low-dose antipsychotics were treated as censored after the date of exposure.We also classified the exposures by prescribed dosage, types, and half-lives among BZDs. We categorized the prescribed dosage of sedative-hypnotics into three groups, which were 30 to 179 DDD, 180 to 359 DDD, and over 360 DDD. In addition, we classified sedative-hypnotics into two classes based on the mechanism—gamma-aminobutyric acid A  and 95% confidence interval (CI) –39. BecaWe restricted the sedative-hypnotics only when prescribed with the diagnostic code of insomnia . We also included the exposure to sedative-hypnotics without the diagnostic code of insomnia into the model as a separate category. To compare the risk of Alzheimer’s dementia between never users who prescribed none of any sedative-hypnotics and users who prescribed at least one sedative-hypnotics, we categorized the prescribed dosage of sedative-hypnotics into four groups, which were none, 1 to 29 DDD, 30 to 179 DDD, 180 to 359 DDD, and over 360 DDD.Insomnia could be a presenile appearance of Alzheimer’s dementia. Thus, we additionally analyzed the association between sedative-hypnotics use and Alzheimer’s dementia among subjects who had insomnia.In these sensitivity analysis, insomnia was not adjusted in the Cox model.We identified 486,622 subjects, who were randomly selected 5% of a sample of Korean NHIS beneficiaries aged 50 years and over, between January 2002 and December 2015. Of these, subjects who died or lost follow-up, had diagnosed with any type of dementia, and had used of any sedative-hypnotics between January 2002 and December 2003 were excluded. In addition, subjects who had invalid data were excluded. Finally, a total of 268,170 subjects remained for the analyses. Of these, the mean follow-up time was 10.97 years, and 27,925 patients developed Alzheimer’s dementia during the study period .Characteristics of the study population between non-exposed and ever-exposed to sedative-hypnotics are shown in A receptor agonist exposure was related to a higher risk of Alzheimer’s dementia  than exposure to other types including antidepressants or antipsychotics , but exposure to both classes showed the highest risk  compared to non-exposure. When classifying by BZD half-life, we found that BZD exposure was significantly associated with Alzheimer’s dementia regardless of half-life. The HR of short-acting BZDs was 1.53 (95% CI: 1.35–1.73), intermediate-acting BZDs was 1.62 (95% CI: 1.49–1.76), and long-acting BZDs was 1.77 (95% CI: 1.65–1.89), after adjustment.A receptor agonist exposure  and exposure to both classes , but not in other classes of exposure . Subjects who were exposed to sedative-hypnotics with diagnostic code of insomnia for over 360 DDD had the highest risk of Alzheimer’s dementia , which was similar to the main analysis. Among BZD exposures, intermediate-acting BZDs showed the highest risk of Alzheimer’s dementia .In sensitivity analysis , the HRsAmong subjects who had insomnia diagnosis , the association between use of sedative-hypnotics and Alzheimer’s dementia was similar to that of the main analysis . ExposurIn our retrospective cohort study from the National Health Insurance Database of Korea with a mean follow-up period of 10.97 years, the risk of Alzheimer’s dementia was significantly associated with sedative-hypnotics use regardless of prescribed dosage, drug type, or half-life of benzodiazepine.We excluded subjects who were prescribed any sedative-hypnotics before 2004, which led to approximately 55% of the total subjects remaining. This may also provide evidence that the prevalence of prescription of sedative-hypnotics was high at approximately 45% for the Korean population over 50 years old who were prescribed at least one sedative-hypnotic.A receptor agonists) and the risk of dementia has been reported, and our findings support these results [In previous studies, the association between benzodiazepines or Z-drugs Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


Does one-on-one delivery or group-based delivery of the Promoting Resilience in Stress Management for Parents (PRISM-P) intervention improve psychosocial outcomes, such as resilience and benefit finding, when compared with usual care among parents of children who receive a new diagnosis of cancer?This randomized clinical trial of 94 parents of children newly receiving a diagnosis of cancer found that compared with usual care, one-on-one delivery of the intervention was significantly associated with improved parent-reported resilience and benefit finding. These improvements were not observed with group delivery of the intervention.This intervention may help parents cope and find meaning after their child has received a diagnosis of a serious illness. Parents of children with serious illness, such as cancer, experience high stress and distress. Few parent-specific psychosocial interventions have been evaluated in randomized trials.To determine if individual- or group-based delivery of a novel intervention called Promoting Resilience in Stress Management for Parents (PRISM-P) improves parent-reported resilience compared with usual care.This parallel, phase 2 randomized clinical trial with enrollment from December 2016 through December 2018 and 3-month follow-up was conducted at Seattle Children’s Hospital. English-speaking parents or guardians of children who were 2 to 24 years old, who had received a diagnosis of a new malignant neoplasm 1 to 10 weeks prior to enrollment, and who were receiving cancer-directed therapy at Seattle Children’s Hospital were included. Parents were randomized 1:1:1 to the one-on-one or group PRISM-P intervention or to usual care. Data were analyzed in 2019 .The PRISM-P is a manualized, brief intervention targeting 4 skills: stress management, goal setting, cognitive reframing, and meaning making. For one-on-one delivery, skills were taught privately and in person for 30 to 60 minutes approximately every other week. For group delivery, the same skills were taught in a single session with at least 2 parents present.Participants completed patient-reported outcome surveys at enrollment and at 3 months. Linear regression modeling evaluated associations in the intention-to-treat population between each delivery format and the primary outcome  and secondary outcomes  at 3 months.P = .04) and for benefit finding . No significant associations were detected between either platform and other parent-reported outcomes.In total, 94 parents enrolled, were randomized to 1 of the 3 groups, and completed baseline surveys . Their median (interquartile range) ages were 35 to 38 (31-44) years across the 3 groups, and they were predominantly white, college-educated mothers. Their children had median (interquartile range) ages of 5 to 8 (3-14) years; slightly more than half of the children were boys, and the most common cancer type was leukemia or lymphoma. One-on-one PRISM-P delivery was significantly associated with improvement compared with usual care in parent-reported outcomes for resilience  with the effects of usual care on improved self-reported resilience among parents of children receiving a new diagnosis of cancer. Hence, a PRISM for parents (PRISM-P) was adapted and pilot tested.11Members of our group have previously developed a novel resilience intervention called Promoting Resilience in Stress Management (PRISM) for Adolescents and Young Adults (AYAs) with cancer.The objective of the present phase 2 randomized clinical trial was to determine the efficacy of 2 PRISM-P formats (group or one-on-one delivery) compared with usual psychosocial care among parents of children with cancer. Our primary aim was to determine if either intervention delivery format was associated with improved parent-reported resilience compared with UC 3 months following enrollment. We hypothesized that PRISM-P, with either format, would be associated with higher parent-reported resilience than UC. Our secondary objectives included explorations of the effect of each format on parent-reported benefit finding, hope, social support, health-related quality of life, stress, and psychological distress.CONSORT) reporting guideline for the trial conduct and results reporting.22 The Seattle Children’s Hospital Institutional Review Board approved this study. Eligible participants were English-speaking parents or legal guardians  of children who were 2 to 24 years old, received a diagnosis of a new malignant neoplasm 1 to 10 weeks prior to enrollment, were receiving cancer-directed therapy at Seattle Children’s Hospital, and had provided written informed consent (children aged ≥18 years), written assent (children aged 13-17 years), or verbal assent (children aged 7-12 years). Children younger than 7 years did not provide assent. All parent participants provided written informed consent. To avoid intrafamily correlation or data contamination, only 1 parent per family was eligible. If multiple caregivers in a single family were interested in participating, we asked them to identify the primary patient caregiver or the person who would most commonly be present at the ill child’s bedside. Each parent received a $25 gift card following each survey completion, for a total of $50 across the study.We conducted this phase 2, parallel, 1:1:1 randomized clinical trial at Seattle Children’s Hospital in Seattle, Washington, between December 2016 and December 2018  reviewed clinic rosters weekly to identify eligible families. Consecutive, eligible parents and their children were approached in outpatient clinics or inpatient wards. Following discussion of the study, parents and children provided consent or assent as described above.23 having 22 participants with complete data in each arm provided 80% power with a 2-sided α of .05 to detect the minimal clinically important difference in parent-reported resilience.We continued enrollment until at least 22 parents in each arm completed the study . This stParents were randomized 1:1:1 to UC alone, UC plus individual PRISM-P (one-on-one), or UC plus group PRISM-P (group). The randomization algorithm was constructed using permuted blocks with varying sizes. Owing to the nature of the intervention, we were unable to blind participants to randomization status.All participants received UC. At our center, this includes an assigned social worker who conducts a comprehensive assessment at the time of diagnosis and provides additional, ad hoc supportive care thereafter. Common assistance includes financial, housing, and other concrete resources. Although visits may provide a layer of professional psychosocial support, formal mental health support for parents (rather than for the child with cancer) is not routine. Parents judged by the clinical team to need professional counseling are referred to clinicians outside the hospital.19 For the initial AYA-directed version, we modified cognitive behavioral therapy methods to create a preventative, brief, skills-based training program targeting 4 key resilience resources .19For the parent-directed version (PRISM-P), we iteratively adapted the AYA program with semistructured parent interviews and pilot studies to test the PRISMA-P feasibility and acceptability.11 All 18 parent recipients (100%) endorsed PRISM-P and recommended it for other parents. Second, we held a half-day symposium in which 72 parents learned PRISM skills in small groups. Again, feedback from all participants (100%) suggested the program was valuable.We conducted 2 preliminary projects to explore delivery options of PRISM-P. First, we confirmed the feasibility and acceptability of one-on-one PRISM-P delivery.In the one-on-one arm of the present study, 4 separate sessions (1 session for each resource) were scheduled approximately every other week in conjunction with planned hospital admissions or outpatient clinic visits or by telephone, based on parent preference. Each session lasted no more than 60 minutes. Boosters were delivered in person or by phone.In the group arm, all 4 sessions were conducted on the same day. We scheduled groups on Saturdays, approximately once every other month and endeavored to include 2 to 5 parents in each group. For instances in which a parent canceled or was unable to attend, they were invited to subsequent groups until they attended one or until 6 months after enrollment, whichever came first. Following the group session, participants were invited to sign up for an email list-serve with other members. Boosters were delivered via group email, and parents were invited to communicate electronically ad lib among themselves.24All PRISM-P sessions (one-on-one and group) were delivered by the same psychologist (C.C.J.). Per our manual, she received at least 8 hours of standardized training in PRISM-P scripts, including mock one-on-one sessions and group sessions, both with role playing. All sessions (one-on-one and group) were audio recorded. One of 5 randomly selected one-on-one sessions and all group sessions were scored for fidelity using a standardized tool.32We requested demographic data in surveys and extracted child medical characteristics from the medical record. We asked all parents to complete a comprehensive survey composed of validated instruments with strong psychometric properties and demonstrated responsiveness at the time of enrollment , and 3 months later. Surveys were offered by paper or online and delivered per parent preference. The domains evaluated by the parents and the study instruments used for those evaluations are given in the Box. Resilience. The 10-item Connor-Davidson Resilience Scale assesses self-perceived resilience by querying an individual’s typical responses to adversity.25 Items are scored on a 5-point Likert scale; total scores range from 0 to 40, with higher scores reflecting greater resilience. Published mean (SD) scores are 31.8 (5.5) among healthy US adults and 30.0 (6.0) among parents of children with cancer.25Benefit finding. The 14-item Benefit Finding Scale queries domains of personal growth, such as personal priorities, daily activities, and family.26 Total score is the mean of item scores, which range from 1 to 5, with higher scores suggesting higher benefit finding.Hope. The 12-item Hope Scale measures the overall perception that one’s goals can be met.27 Total scores range from 8 to 64, and higher scores suggest greater hope.Social support. The 19-item Medical Outcomes Study social support survey addresses emotional, informational, tangible, affectionate, and positive social interactions.28 Total score is the mean of item scores , with higher scores suggesting better perceptions of social support.Health-related quality of life. The Medical Outcomes Study 36-item short-form health survey evaluates physical functioning, body pain, physical and role limitations due to physical and emotional health problems, as well as emotional well-being, social function, fatigue, and general heath perceptions.29 Domain scores are computed algebraically and transformed to a scale of 0 to 100, with higher scores suggesting better health-related quality of life.Perceived stress. The 10-item Perceived Stress Scale measures the degree to which life situations are appraised as stressful.30 Items are scored on a 5-point Likert scale; total scores range from 0 to 40, with higher scores reflecting higher stress.Psychological distress. The 6-item Kessler Psychological Distress Scale screens for global psychological distress.32 Scores range from 0 to 24 points; higher scores reflect greater distress, with scores higher than 6 and higher than 12 suggesting moderate and high distress, respectively.Following randomization, staff contacted each parent to share their assignment, schedule completion of the baseline survey, and, as applicable, PRISM-P sessions. When surveys were not returned within 1 week of their due date, staff contacted families by phone once weekly for 3 weeks. Those surveys not received within 12 weeks were considered missing.The primary outcome was the change in parent-reported resilience at 3 months relative to that at baseline. Secondary outcomes included changes in all other assessed instrument scores at 3 months.34 We generated 20 imputed data sets and reported the final pooled results across them. We defined minimal clinically important differences for linear instruments as half the SD of the mean pooled baseline scores.23 Per our a priori statistical plan, all testing was 2-sided and conducted at a statistical significance level of P < .05 without correction for multiple comparisons. We performed all statistical analyses, including multiple imputations, using Stata, version 15 (StataCorp). Data were analyzed in 2019 .In this intention-to-treat analysis, we analyzed and reported data as planned. Parents who were randomized and completed baseline surveys were included in all analyses regardless of whether they completed their assigned PRISM-P sessions or their follow-up surveys. Our primary aim was to examine associations between PRISM-P and changes in instrument scores between baseline and 3 months. We focused on changes because they are more clinically meaningful. However, given that all instruments had restricted ranges such that direction and magnitude of changes could be influenced by baseline values, score changes were regressed on study arms with baseline instrument values controlled for as covariates. We handled missing data with multiple imputation with chained equations in which missing variables were iteratively imputed fully conditional on other instruments at baseline and 3 months, and baseline characteristics.Of 152 eligible parents, 107 (70%) enrolled and were randomized to one-on-one (n = 36), group (n = 35), or UC (n = 36), and 94 participants  completed baseline surveys . ParticiAmong the randomized parents, 31 parents in one-on-one (86% randomized and 97% with baseline surveys), 28 parents in group , and 30 parents in UC  received their intervention as assigned. In total, 26 parents in one-on-one , 22 parents in group , and 29 parents in UC  completed 3-month surveys. There were no demographic differences between parents who received their assigned intervention vs those who did not. However, participants who may have had fewer immediate social and economic resources  were overrepresented in the group who did not complete the 3-month surveys, and parents whose children had brain tumors did not complete 3-month surveys as often as other parents  time from enrollment to the first session was 18 (13-27) days, between sessions was 17 (14-27) days, and from enrollment to PRISM-P completion was 63 (57-77) days. Among parents in the group PRISM-P, median (IQR) time from enrollment to PRISM-P was 23 (12-47) days. The median (IQR) number of group participants was 2 (2-3). The median (IQR) time from enrollment to 3-month survey completion was similar across all groups: for parents in the one-on-one arm, it was 115 (98-125) days; in the group arm, it was 103 (97-109) days; and in the UC arm, it was 98 (93-108) days.Raw survey scores for participants in each group at each time point are given in P = .04) and benefit finding   . No otheThere were no differences between parents who received UC and those who received the group PRISM-P .6 Recommendations for standard psychosocial care include early access to interventions to support parent coping.6 In this phase 2 randomized clinical trial, we compared 2 delivery formats of PRISM-P, a novel psychosocial intervention designed to build parental resilience, to usual psychosocial care. Our goal was to determine if 1 or both PRISM-P delivery formats helped parents of children with newly diagnosed cancer feel more resilient. We found that the one-on-one delivery was associated with improved parent-reported resilience (our primary outcome) and benefit finding (a secondary outcome). We identified no differences in other secondary outcomes, such as social support and health-related quality of life.Serious pediatric illness such as cancer is highly stressful to parents and caregivers. This stress may impair support for the ill child and well siblings and negatively affect the family unit.38 Furthermore, PRISM-P targets resilience resources known to protect parents from stressors of cancer.44 Building new or strengthening existing resources may help them navigate the inevitable life changes accompanying serious pediatric illness. That one-on-one PRISM-P recipients felt more resilient and identified more benefit during their early cancer experience suggests that they may be buffered against the cumulative burdens of caregiving.We chose self-perceived resilience as our primary outcome because it is strongly associated with individual well-being.We did not observe the same improvement in resilience in the PRISM-P group delivery. There are several potential reasons for this finding, including that a gathering of parents who do not know one another may contribute to, rather than alleviate, stress, especially if they feel pressure to share personal experiences. Indeed, the 4 parents who declined to join our study because they did not want the randomization explicitly said that they did not want to be assigned to a group.An additional limitation of the group was its intermittent scheduling. We were deliberately flexible to facilitate participation. Regardless, attrition was greatest in this randomization arm, perhaps because parents who were delayed in scheduling lost interest or found it difficult to attend. Although we had hoped to have at least 4 parents in each group, the median group size was only 2. Such a small number may have felt discouraging to those expecting more people or created additional pressures for parents to share their thoughts. We cannot determine if larger group sessions would have had similar or different results. Finally, the single delivery day may have undermined skill learning. In summary, a 1-day session with more than 1 parent present was not only less feasible, it also appeared less effective.47 Parent distress typically spikes at the time of diagnosis and then stabilizes at a new normal 3 to 6 months later.49 Positive or negative psychosocial functioning in this later time frame predicts longer-term outcomes.50 Hence, we believe interventions with the potential to positively shape these trajectories are critical. Future iterations of PRISM-P will need to explore whether and how to directly focus on alleviating distress.Neither PRISM-P delivery format was significantly associated with social support, health-related quality of life, stress, or distress. This finding may be because we were underpowered for these secondary outcomes. Although PRISM-P does not directly target social support and quality of life, we thought we would see more of an effect on stress and distress. Parent distress during pediatric cancer is important because it is associated with poor quality of life, physical comorbidities, and marital function.52 Clinical psychosocial professional staffing is often limited, and available personnel are necessarily focused on pediatric patients rather than on parents.53 Parents express concern about leaving their child’s bedside to focus on their own well-being, and many cannot engage in ongoing therapy.54 It is primarily for those reasons that early intervention delivery has been unsuccessful.8Providing psychosocial services to parents is difficult under the auspice of research or clinical service. To date, few interventions have been designed for parents, and fewer still have been successfully delivered early in the cancer experience.21 Hence, it spared professional psychosocial staff for families with higher needs. In the present study, we limited potential variability in interventionist skill by having a single doctoral-level psychologist (C.C.J.) deliver all PRISM-P sessions (one-on-one and group). Although this strengthens the internal validity of our findings, it also limits them: whether we would see similar effects from lesser trained interventionists is unclear.We attempted to overcome these barriers by keeping PRISM-P brief . In our other studies, PRISM was delivered successfully by trained, nonclinical professionals, such as college graduates.This study had several important limitations. First, we had a small sample size, which raises concerns about power stability of statistical modeling. Missing data compounded this problem both at baseline and at follow-up. Although our statistical methods were able to address the missing data for the 3-month outcome, we could not fully explore differences between parents who did and those who did not complete baseline survey data. That parents who were unmarried or had lower incomes at baseline were less likely to complete 3-month surveys. That they had lower baseline scores suggests that parents who may be in the most need of help were the least likely to remain in the study—an important limitation to the program—and that our efficacy results may be biased toward the null by these missing data because these are the parents who could reasonably be expected to improve the most from psychosocial interventions.Second, similar to most parent intervention research, our sample was mostly white, English-speaking mothers at a large, well-resourced hospital. We enrolled only 1 parent per family and did not evaluate dyadic or intrafamily resilience. This limits generalizability, in particular to populations at higher risk for poor outcomes due to existing racial, ethnic, socioeconomic, or other health inequities. In addition, we lacked power and sample diversity to conduct relevant subgroup analyses.Third, whereas the association between parent and child well-being is well established, we did not collect data regarding child health or the parent-child relationship. Thus, we could not determine whether or how PRISM-P delivery affected the children with cancer.Fourth, how to optimize and operationalize PRISM-P remains unclear. We did not design this study to compare the efficacy of the 2 formats against each other; thus, we could not identify a clear winner. Our results suggested barriers and opportunities for both. Ideal formats may include options for parents, depending on whether they prefer group formats, and provision of additional resources to make the program feasible for parents who are single or economically disadvantaged.In summary, the PRISM-P intervention showed a positive effect on parent-reported resilience and benefit finding when delivered individually to parents of children with cancer. These findings underscore a critical goal in caregiver support: PRISM-P may help parents feel more resilient, which in turn may facilitate their continued ability to care for their child.


Direct antiviral agents (DAA) has dramatically improved the therapy outcome of hepatitis C-virus (HCV) infection, both on the waiting-list and post liver transplantation (LT). DAA are generally well-tolerated in patients with mild to moderate liver and kidney failure, but some DAAs are contraindicated in patients with severe dysfunction of these organs. Today there are few studies of peri-LT DAA use and treatment is commonly discontinued at the time of LT. We report here our experience of DAA therapy given continuously in the perioperative LT period in a real-life setting in Sweden.In total 10 patients with HCV-cirrhosis, with or without hepatocellular carcinoma, and a median age of 60.5 years  were treated with DAAs on the waiting list for LT, and continued in the early postoperative period without any interruption, on the basis of not having reached a full treatment course at the time of LT. Sofosbuvir and a NS5A inhibitor with or without ribavirin, or sofosbuvir and ribavirin only, were given. The distribution of genotypes was genotype 1 and 3, in 4 and 6 patients, respectively. Six of the 10 patients had previously been treated with IFN-based therapy.There were no adverse events leading to premature DAA discontinuation. All recipients achieved a sustained viral response 12 weeks after end-of-treatment (SVR12). At the time of LT the median MELD-score was 16.5 (range 7–21), CTP-score 9.0 (range 5–10), creatinine 82.5 μmol/L , bilirubin 33 μmol/L  and PK-INR 1.5 (range 1.1–1.8). The median duration of DAA therapy was 60 days (range 18–132) pre-LT, 54 days post-LT (range 8–111 days) and in total 15.5 weeks (range 12–30 weeks).Interferon-free DAA therapy of HCV-infection given in the immediate pre- and post-operative LT period is safe, well-tolerated and yields high SVR rates. Chronic hepatitis C virus (HCV) infection affects an estimated 71 million people in the world with fatal consequences in approximately 400,000 persons per year , 3, 4. TTolerance of the previous standard-of-care (SOC) treatment, pegylated-interferon (peg-IFN) and ribavirin (RBV), in cirrhotic patients as well as LT recipients was suboptimal due to severe side-effects such as infections and increased risk of rejection, leading to frequent cessation of therapy . FurtherHowever, some patients on the waiting list will undergo LT before receiving a full DAA treatment course, and therapy is commonly stopped at the time of LT because of fear of unrecognized DAA-associated complications in the immediate postoperative days, as this time period rarely has been included in larger therapeutical trials.Thus, the aim of the current study was to evaluate the safety and efficacy of DAA therapy given without interruption in the peri-LT period in a real-world setting. Our findings confirm a high tolerability and efficacy of DAA treatment in this vulnerable situation with fragile patients undergoing LT.All liver transplanted patients >18 years of age with chronic hepatitis C infection (HCV) who received DAA therapy continuously in the pre- and post-LT period, between April 2013 to December 2016, at the Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden, were included in this retrospective study. All patients were transplanted due to end-stage liver disease and/or hepatocellular carcinoma (HCC). The retrospectively collected data were not considered by the ethical committee (diary number 340–16), the Swedish Medical Products Agency, or any other institutions to violate personal integrity, and accordingly the ethical committee did not require any written or oral consent. No special recording concerning patient consent was performed for this retrospective study as it was not required by the Gothenburg Ethical Committee . This study is conformed according to the ethical guidelines of the 1975 Declaration of Helsinki.Patients received IFN-free sofosbuvir-based therapy, in combination with daclatasvir, daclatasvir and RBV, ledipasvir and RBV or RBV only, respectively. The DAA-regimens were chosen based on two different situations. In the very early study period, around 2013, the only DAA available was sofosbuvir and this was the only drug of choice. Sofosbuvir was combined with ribavirin in these cases. In later time periods when NS5A-inhibitors had become available, we chose to use NS5A-inhibitors in combination with sofosbuvir ± ribavirin. This choice was based on the potential interactions between HCV protease inhibitors and calcineurin inhibitors, especially ciclosporin, making this alternative less attractive. Thus, HCV protease inhibitors were avoided if possible.The DAA treatment was initiated when patients were on the waiting list for LT and continued at the day of surgery as well as directly post-LT. The baseline immunosuppression given post-LT was a combination of tacrolimus (TAC) and mycophenolate mofetil (MMF).All liver transplant candidates and all liver transplant patients are very rigorously followed according to our liver transplantation protocol, which includes daily monitoring of various blood parameters, control of immunosuppressive levels, in addition to thorough clinical assessments.Genotype analysis was performed prior to DAA-therapy . HCV RNAth week until LT. At baseline, every 4th week until LT as well as preoperatively at the day of LT, MELD- (Model for End-stage Liver Disease) and CTP (Child-Turcotte-Pugh)-scores were calculated  patients composing our study cohort, initiated DAA when on the waiting list and continued therapy, without interruption, on the day of LT and early post-operative. The 10 study patients received sofosbuvir-based treatment, 4 in combination with daclatasvir, 3 together with RBV only, 2 with daclatasvir and RBV and 1 patient with ledipasvir and RBV. In all, 6 of 10 patients received RBV. The DAA therapy duration on the waiting list was in median 60 days (range 18–132) and continued in median for 54 days post-LT (range 8–111) . The totPatient demographics preoperatively at the LT-day are reported in All patients had an on treatment virological response (OTVR) and undetectable HCV RNA in serum at the time of LT. HCV-RNA levels for each patient both before and after liver transplantation are illustrated in The adverse events reported during the day of LT as well as during the first postoperative month, divided into two time periods, are summarized in 9) post-LT related to hypersplenism and MMF therapy. Two patients had severe thrombocytopenia (<50x109 cells/L) related to hypersplenism while on the waiting list, before DAA initiation, with low levels also at the LT-day aggravated further during the first postoperative week. Two patients had bilirubin >2.5xULN at the LT-day judged to be caused by chronic liver disease and RBV therapy. These two patients plus another two had hyperbilirubinemia during the first post-LT week assessed related to abdominal bleeding (2pts), RBV treatment and delayed graft function (1pts), respectively. The two patients with abdominal bleeding had to be re-operated within 2 days post-LT.Preoperatively at the LT-day one patient had hemoglobine <90g/dL deemed related to severe liver disease, neoadjuvant therapy with sorafenib for HCC and RBV therapy. During the first and second postoperative period, 3 and 5 patients, respectively, were anemic (<90g/dL) related to surgical bleeding (2 pts), RBV and immunosuppressive therapy. One patient developed neutropenia  and protease inhibitors . In thisIn the current study none of the patients had a rejection during the post-LT study period . This loBoth our female study patients developed seizures approximately one month post-LT. One of them was intermittently confused during the first 3 postoperative weeks. She had delayed liver graft function, mild hypertension, renal failure and 4 weeks post-LT at the day of scheduled DAA stop, an isolated seizure. The cerebral symptoms may have been caused by a posterior reversible encephalopathy syndrome (PRES) , which iThe other female patient also had a seizure at 1 month post-LT judged by neurologists and the transplant team to be caused by cerebral bleeding and vasculitis, complicated a few weeks later by PRES. We therefore chose to change the CNI immunosuppression also in this patient with subsequent favorable results regarding the PRES symptoms. Any relation between PRES and DAA therapy seems unlikely since the DAAs were stopped 3 weeks before the first cerebral symptoms.In our study 7 of 10 patients had hepatocellular carcinoma (HCC) as one of the indications for LT. None of them had recurrence of their HCC during DAA treatment or during the study follow-up period. There have been many contradictive reports on whether DAA-therapy increases the incidence of HCC-recurrence  as well In one of our earlier studies of DAA therapy in a post-LT cohort, the SVR12 rate was 97.8% . This goSome reports suggest that all patients, irrespective of their HCV genotype, should be treated immediately after LT to prevent recurrent hepatitis C and fibrosis progression in the graft , 20. OurA future shorter treatment alternative, especially in those with burnt-out cirrhosis or cirrhosis in combination with HCC and no chance for curative pre-LT DAA therapy, may be to initiate DAA therapy when the patient is transferred to the transplant center for the LT-operation, and to continue DAA therapy directly post-LT, without interruption, for a short period of time, e.g. 4–8 weeks. This strategy may be sufficient to eradicate the HCV-infection when combined with explanting the cirrhotic HCV-infected liver, and is strenghtened by our study, but warrants further investigation.Although our data points towards excellent outcome following DAA therapy in the immediate peri-LT setting, it is important to highlight the limitations of the study, e.g., the small sample-size, few HCV genotypes represented , and no use of protease inhibitors. Further studies are necessary to confirm that DAAs given in the immediate peri-LT period are safe, well-tolerated and effective in this vulnerable patient category. If our results are confirmed expensive re-treatments after LT, due to premature discontinuation of DAA therapy at time of operation, may be avoided. Furthermore, the challenging task to differentiate between rejection and active HCV-infection in posttransplant liver biopsies will be an eliminated problem.In conclusion, there is no need to discontinue DAA therapy at the time of LT in patients given DAA while on the waiting list. Antiviral therapy can, if carefully selected, safely be continued without interruption in the immediate perioperative period. This strategy may be a well-tolerated, shorter and less expensive HCV treatment option yet leading to high SVR-rates.S1 Dataset(XLSX)Click here for additional data file.


The new HIV treatment guidelines in China recommend antiretroviral therapy (ART) for all people living with HIV, but significant gaps in implementation still exist. Pre-exposure prophylaxis (PrEP) can effectively reduce the risk of HIV transmission among men who have sex with men (MSM). This study assessed the epidemiological impact and cost effectiveness of PrEP, enhanced biomedical interventions and their combination among MSM in China.A deterministic mathematical model was developed and projected over 20 years to assess the impact of the PrEP, biomedical interventions and their combinations. Incidence and prevalence of HIV were measured, and cost-effectiveness was assessed using incremental cost  per quality-adjusted life year (QALY) gained.A total of 0.78 million new HIV infections were estimated to occur over the next 20 years if no additional interventions are implemented among MSM. The PrEP-only strategy covering 25–75% of HIV-negative high-risk MSM can prevent 0.09–0.20 million (12.1–25.7%) new infections, at a cost of 17,277–18,452 Int.$/QALY. The optimal cost-effectiveness path is from test-and-treat to the combination strategy of test-and-treat and PrEP. Some strategies could almost eliminate new HIV infections over the next 20 years.PrEP, test-and-treat, and their combinations among MSM are effective and cost-effective relative to current policy. PrEP is an important and cost-effective addition to current policy in China.The online version of this article (10.1186/s12879-018-3516-8) contains supplementary material, which is available to authorized users. HIV/AIDS continues to be a serious public health problem in China, especially among key risk populations. It is estimated that 780,000 people were living with HIV (PLWH) in China in 2011, of whom 32.5% were men who have sex with men (MSM)  and MSM The Chinese government has increased policy attention and scaled up responses to the HIV/AIDS epidemic , includiIt is important to assess the potential impact of PrEP strategies and their combination with other biomedical interventions in the Chinese context. In this study, we used mathematical modeling to investigate the epidemiological impact and cost-effectiveness of various biomedical interventions and their combinations on HIV transmission over the next 20 years in China. This study assesses the benefits both of full implementation of current policies and the timely introduction of novel policies, and makes recommendations for future HIV policy responses in China.We developed a deterministic compartmental mathematical model that divides the population at risk into five groups based on HIV serostatus, disease stage and CD4 count, and further divides the population into three groups based on serostatus and treatment state. This model builds on previous models in China , the USAThe compartment structure shown in Fig. The system of ODEs developed to describe Fig. Scenario 1: Test-and-treat strategy that is fully compliant with the WHO 90–90-90 recommendations, effectively representing the current HIV treatment guidelines implemented at much greater effectiveness than the current standard. This scenario assumed annual testing rates of 90% for all MSM, with an ART utilization rate of 90% for all diagnosed PLWH, and 90% of all PLWH receiving ART achieving viral suppression .Scenario 2–4: PrEP for high-risk MSM with coverage of 25, 50% or 75% of the entire population of identified HIV-negative high-risk MSM.Scenario 5–7: PrEP for high-risk MSM (with the same three levels of PrEP coverage) combined with expanded annual VCT of 90% MSM.Scenario 8–10: PrEP for high-risk MSM (with the same three levels of PrEP coverage) combined with the test-and-treat strategy.We projected a base-case model that assumed current Chinese HIV treatment guidelines were followed for the next 20 years with no change in testing uptake and treatment entry rates. Against this base case we modeled several alternative scenarios and all of their combinations:PrEP was modeled separately with and without widespread VCT because current levels of HIV testing amongst MSM are low, and PrEP implemented against this low backdrop of VCT may have limited effectiveness. Test-and-treat to the 90–90-90 standard was modeled as a separate policy scenario to the base case to reflect low current testing and treatment entry rates, especially in rural areas with limited ability to finance the required interventions . We defiWe estimated the cost of all policy scenarios and conducted a full health economic analysis. Policy scenario costs were estimated on the basis of known costs of testing, ART treatment and average cost of treating AIDS and associated opportunistic infections. PrEP costs were assumed on the basis of the domestic price of Truvada. Costs were only estimated for that proportion of the population assumed to be covered by a given intervention. We compared the estimated cost of each policy with the HIV/AIDS-related healthcare costs averted by reduced infections or slowed disease progression, relative to the base case only. Cost-effectiveness analysis was conducted following standard protocols , calculaWe conducted two scenario-based sensitivity analyses. We tested the impact of the PrEP and combined scenarios when PrEP adherence was 30, 60% or 90%, to explore the possible effectiveness with various adherence rates. Secondly, we tested the impact of the PrEP and combined scenarios after adjusting for 100% risk compensation, in which all high-risk MSM in the PrEP program completely ceased all forms of safer sex behavior, to test the potential impact on a PrEP program of risk compensation. Full details and results of these sensitivity analyses are given in Additional file The model estimates of the HIV prevalence and incidence rate among Chinese MSM in the past eleven years showed good fit with the national estimates and surveillance data  Fig. 2)2), and aThe costs and health benefits (QALYs) for all intervention scenarios are shown in Table With PrEP effectiveness of 60%, the PrEP-only strategies for high-risk MSM (scenario 2–4) can prevent 0.09–0.20 million infections, 12.1–25.7% of the total new infections, yielding an average CER of 17,277–18,452 Int.$/QALY.Compared to the base-case scenario, the combination strategies of PrEP and expanded VCT (scenario 5–7) could prevent 0.24–0.36 million new infections, 30.8–47.0% of the total new infections, at a cost of 13,835–18,110 Int.$ per QALY gained. With a combination of test-and-treat and PrEP for 75% of high-risk MSM (scenario 10), 0.58 million new infections  could be prevented, at a cost of 12,218 Int.$ per QALY gained. When resources are available, the optimal cost-effectiveness path is from test-and-treat to the combination strategy of test-and-treat and PrEP (25% of high-risk MSM), with an ICER of 72,545 Int.$/QALY; followed by the same combination strategy of test-and-treat and PrEP, but with higher PrEP coverage, costing 65,428–73,500 Int.$ per QALY gained depending on coverage level.Table The sensitivity ranges of the epidemiological impact and cost-effectiveness are also shown in Table We also tested the robustness of our findings to changes in the assumption about PrEP effectiveness, which depends on PrEP adherence ), suggesting that risk compensation could be a significant hindrance to the impact of this strategy in situations where PrEP effectiveness is not ideal.Finally, we modeled the impact of all interventions over a 30-year time horizon, shown in section 3.2 of the supplementary materials.This study used a compartmental mathematical model to estimate the future trends of the HIV epidemic among MSM in China and to evaluate the cost-effectiveness of individual and combined biomedical interventions. The base case scenario estimated that without scale-up of current treatment strategies and implementation of new interventions the HIV epidemic will not be well controlled in MSM. The provision of PrEP to 25% of high-risk MSM in combination with a fully implemented test-and-treat strategy could prevent more than 0.5 million new HIV infections by 2037. With the combined strategy of test-and-treat and PrEP among high-risk MSM it is possible to achieve HIV elimination by 2033. All individual and combined biomedical interventions were shown to be cost-effective, and two strategies were also shown to be cost-saving.UNAIDS proposed the ambitious 90–90-90 targets to end the HIV epidemic by 2030. However, in this study, we found that the 90–90-90 strategy alone may not be sufficient to eliminate HIV transmission. Under this strategy, HIV incidence at 2037 is estimated to be 2.4 per 1000 person-years, which is much higher than the incidence threshold for HIV elimination. This result confirms findings from other studies , 27, 28 This study also confirms other findings about the effectiveness and cost-effectiveness of PrEP strategies among MSM , 29–31, Previously published clinical trials , 33 haveAnother concern about PrEP is risk compensation. A recent meta-analysis found evidence of an increase in condomless sex and STI prevalence among PrEP users . One stuOur study has several limitations. First, heterosexual transmission was not discussed in our model, although 17–35% of Chinese MSM are married . Second,Our findings suggest that both test-and-treat and PrEP can be effective tools for HIV prevention among MSM, and are predicted to be cost-effective even with poor PrEP effectiveness. HIV elimination is achievable in the next 20 years with a combination of these biomedical interventions. PrEP for HIV prevention should be considered for implementation among high-risk MSM in China.Additional file 1:Supplementary Appendix. A complete description of the mathematical methods used in development of the model. (DOCX 5387 kb)


Associations of low-to-moderate consumption of red and processed meat with mortality would add to the evidence of possible adverse effects of these common foods. This study aims to investigate the association of red and processed meat intake with mortality. The Adventist Health Study-2 (AHS-2) is a prospective cohort study of ~96,000 Seventh-day Adventist men and women recruited in the US and Canada between 2002 and 2007. The final analytic sample after exclusions was 72,149. Cox proportional hazards regression was used and hazard ratios (HR) and confidence intervals (CI) were obtained. Diet was assessed by a validated quantitative food frequency questionnaire (FFQ), calibrated using six 24-h dietary recalls. Mortality outcome data were obtained from the National Death Index. During a mean follow-up of 11.8 years, there were 7961 total deaths, of which 2598 were Cardiovascular diseases (CVD) deaths and 1873 were cancer deaths. Unprocessed red meat was associated with risk of all-cause mortality  and CVD mortality . Processed meat alone was not significantly associated with risk of mortality. The combined intake of red and processed meat was associated with all-cause mortality  and CVD mortality . These findings suggest moderately higher risks of all-cause and CVD mortality associated with red and processed meat in a low meat intake population. Over the last fifty years, global meat consumption has increased in both developing and developed countries . In the Several studies have found positive associations between intake of red and/or processed meat and total, cardiovascular disease (CVD), or cancer mortality ,8,9. TheThe Adventist Health Study-2 (AHS-2) has been previously described in detail . It is an = 267); bad or inadequate data  (n = 507); missing more than 69 responses in the dietary section (2172); Canadian residents (n = 4393); extreme values of total energy  (n = 2044); missing age, sex, or race (n = 538); age younger than 25 years at baseline (n = 8); and prevalent diseases related to mortality outcomes  or prevalent CVD defined as previous coronary bypass, angioplasty/stent, carotid artery surgery, myocardial infarction, stroke, or transient ischemic attack (TIA); or angina pectoris or congestive heart failure treated in the past 12 months) . The analytic sample remaining was 72,149.For this analysis, exclusions were applied: missing dietary variables (AHS-2 participants were requested at enrolment to complete a quantitative food frequency questionnaire (FFQ) consisting of more than 200 food items. Unprocessed red meat intake was reported as two items in the FFQ: “hamburger, ground beef ” and “beef or lamb as a main dish ”. Processed meat was reported as: “processed beef, lamb ” and “processed chicken or turkey ”. Pork was classified as processed meat because most of the pork products listed in the single pork question in the FFQ were processed ”). The frequency of intake ranged from “never or rarely” to “2+ per day”, and serving sizes consisted of three levels , and one-and-a-half servings). The assigned weights for frequency and serving size in the FFQ used in AHS-2 have been previously described . The intThe FFQ has been validated using six 24-h dietary recalls from a representative subset of the original AHS-2 cohort . The deaMortality outcome data were obtained from the National Death Index and were available through December 2015. International Statistical Classification of Diseases, 10th Revision (ICD-10) codes were used to determine the underlying cause of death. Individuals who died due to unnatural causes such as motor vehicle accidents and homicides  were censored at their time of death . ICD-10 codes for CVD mortality ranged from I00 to I78; cancer mortality ranged from C00 to C97.Covariates were self-reported by questionnaire at enrolment, including information on demographics, medical history , family medical history, socioeconomic factors, lifestyle factors, and diet. Covariates were selected a priori as possible confounders (see Tables footnotes for covariates details).R = 0.56), we combined both variables by summing the daily intakes from unprocessed red meat and processed meat together to create one single variable. Regression calibration of the exposures was used, where reported, to minimize the possible bias in the association estimates due to measurement error [Time-dependent Cox-proportional hazards regression with attained age as the time variable and left truncation by age at study entry, controlling for potential confounding covariates, was used to assess the association between the consumption of red and processed meat and all-cause, CVD, and cancer mortality. We used multiple imputation, guided where possible, for missing data ,15, in wnt error ,18. Onlynt error . Six 24-nt error .We tested for interaction of the exposures of interest with age, sex, and race. Other covariates were also tested for possible interactions with the exposures, and for possible interactions with each other where suspected. We separately conducted subgroup analyses by sex and race, in which we used sex- and race-specific ranges and values of intakes for the exposures. Further, we conducted separate analyses on those who reported they never smoked in order to address the effect of residual confounding by smoking in the original models. The proportional hazards assumption of the model was assessed using log(−log) plots, Schoenfeld residuals, and attained-age interaction terms; there was no violation. We also calculated population attributable risk comparing the 90th percentile of the combined intake of red and processed meat (~49 g/day) with zero-intake  . SAS . The associations were attenuated yet remained significant for total and CVD mortality, but not cancer mortality in the multivariable models without adjustment for other meats (model 2). In the multivariable model with mutual adjustment for other meats (model 3), participants in the 90th percentile intake of unprocessed red meat (compared with zero-intake) had a higher risk of all-cause mortality  and CVD mortality . Processed meat alone was not significantly associated with risk of mortality when adjusted for other meats. Red and processed meat (combined) were associated with higher risk of all-cause mortality  and CVD mortality   .Results from subgroups are presented as forest plots, where 90th percentiles versus zero-intake contrasts were used . UnproceWe also evaluated the linear relationships of these exposures with all-cause, CVD, and cancer mortality using 4-knot restricted cubic splines . UnproceTo explore the effects of residual confounding by smoking, we conducted separate analyses among participants who had never smoked . We repoWe calculated population attributable risk, in which we compared the 90th percentile of the combined intake of red and processed meat (~49 g/day) with zero-intake. If the relationships were causal, approximately 6.3% and 9% of total and CVD deaths, respectively, could have been prevented if those in the 90th percentile of combined intake of red and processed meat had abstained.In the Adventist Health Study-2 (AHS-2), we found relatively low levels of consumption of red and processed meat to be positively associated with all-cause and CVD mortality in multivariable-adjusted models, compared to zero-intake. The associations appeared to be linear  and of moderate strength. Stronger associations—though less precise—were observed when the exposures were calibrated suggesting that measurement error biased the uncalibrated results towards the null.Other studies from the U.S. and Europe have found positive associations between red or processed meat consumption and all-cause and CVD mortality ,26,27,28Regarding cancer mortality, the three cohorts in the US have found significant associations, in contrast to our null findings. This could be due to insufficient dietary adjustments in those studies  ,35,36; lPreviously in AHS–2, Orlich et al. found that vegetarians had a 12% reduced risk of all-cause mortality as compared to nonvegetarians ; this coSome possible causal mechanisms have been proposed for the link between red and processed meat consumption and mortality. Red meat is rich in saturated fatty acids, which have been associated with dyslipidemia, particularly elevated low-density lipoprotein (LDL) . High LDThis study fills an important gap in the literature, in that we were able to evaluate the association of red and processed meat at low consumption levels compared to zero-intake subjects, whereas other studies have only compared risk at higher intake levels. For example, the 90th percentile of unprocessed red meat intake in our population was 46.5 g/day, which is approximately equivalent to a half serving per day—meat serving size ranges from 3 to 4 ounces 85–113 g)—in the FFQ of AHS-2. However, in HPFS and NHS, men who consumed 1.46 serving/day were compared with those who consumed 0.17 serving/day, and women who consumed 1.64 serving/day were compared with those who consumed 0.37 serving/day 5–113 g—i. BesidesAn inherent limitation in this type of study is measurement error in dietary assessment. In particular, processed meat measurement by FFQ showed low validity compared to multiple recalls. This low validity correlation for processed meat may be due to the infrequent consumption of processed meat; infrequently consumed foods may be missed by dietary recalls. However, validity for unprocessed red meat was relatively high. Another limitation is the single dietary assessment, whereas dietary habits may have changed. However, a majority of subjects in the AHS-2, especially middle-aged and elderly, tend to have fairly stable dietary intakes over time . FinallyIn conclusion, we found higher all-cause and CVD mortality to be associated with relatively low intake of red and processed meat (and of unprocessed red meat in particular), compared to zero intake. While caution is appropriate in inferring causation from observational data, these results suggest possible adverse effects of red and processed meat, even with low to moderate levels of intake.