Birth size has been positively associated with age at menarche and height in adolescence and adulthood, but the relevant biological mechanisms remain unclear. Among 262 Norwegian term-born singleton girls, birth size measures  were analysed in relation to adolescent hormone levels , age at menarche and adolescent (ages 12.7–15.5 years) and body size  using survival analysis and general linear modelling. The results were adjusted for gestational age at birth, age and menarcheal status at measurement in adolescence and maternal age at menarche. Birth weight, birth length and head circumference were positively associated with adolescent weight and height, and small birth size was associated with earlier age at menarche. Subscapular skin-fold thickness at birth was not associated with adolescent body size, but low fold-thickness was associated with earlier age at menarche. Measures of birth size were inversely related to circulating levels of dehydroepiandrosterone sulphate in adolescence, but there was no clear association with other hormones. These results suggest that physical and sexual development in puberty and adolescence is influenced by prenatal factors, and in combination, these factors may influence health and disease later in life. Studiesin utero . Birth sin utero . The facWe have examined the relation between birth size characteristics and potential BC risk factors , and spen=561) of all women; the other group of women with one or more of the following risk factors for giving birth to a small birth size for gestational age child : a previous low-birth-weight child or perinatal death, cigarette smoking at conception, pre-pregnancy weight below 50 kg, chronic renal disorder or hypertension (n=1384).The study is based on the Norwegian part of an international study among pregnant women in 1985–1986, described in detail elsewhere (n=5), were reluctant to participate (n=8) or gave practical reasons (n=26). Of the remaining 338 invited girls, 262 attended the follow-up examination (77.6%). Mean age at examination in adolescence was 14.0 years (range 12.7–15.5 years). The examination included anthropometric measurements, serum samples and a questionnaire related to health and life style factors, pubertal development and menstrual status. The study was approved by the Regional Committee for Medical Research Ethics and by the Norwegian Data Inspectorate.In 2001–2002, girls born in the original study were invited to a follow-up examination in adolescence. Among a total of 523 invited girls, 146 were excluded because they were not born at term (before week 37 or after week 42) or because exact gestational age was missing. In addition, 39 girls were excluded either because they had died , head circumference (in mm) and subscapular skin-fold thickness . Each measure was categorised into three groups of similar size (tertiles). Information on maternal age at menarche (years) and gestational age at delivery (days) was collected at birth.Birth size measurements included length , weight (in g), ponderal index  and waist-to-hip ratio) age at menarche and to adolescent levels of oestradiol, prolactin, dehydroepiandrosterone sulphate (DHEAS), androstenedione and also free testosterone index (FTI), calculated as  × 100. Analyses of DHEAS and prolactin were carried out in all girls, regardless of menstrual status, but for oestradiol, androstenedione and FTI were restricted to those in the follicular phase of their menstrual cycle at examination . We excluded six girls who had blood levels of LH higher than 10.0 U lμmol l−1 for DHEAS, 0.7 and 11.0 nmol l−1 for androstenedione, 0.1 and 2.9 nmol l−1 for testosterone and 1.5 and 12.8 nmol l−1 for 17-OH-progesterone. The lower detection limits were 0.6 nmol l−1 for progesterone, 0.8 μmol l−1 for DHEAS and 0.1 nmol l−1 for testosterone. The lower and upper detection limits were 0.07 and 7.34 nmol l−1 for oestradiol, 3 and 180 nmol l−1 for SHBG, 0.05 and 200.00 mIU l−1 for LH and 11 and 3180 mIU l−1 for prolactin. For each hormone, analyses were performed in a single kit on the same day. For girls with levels of progesterone, oestradiol or DHEAS below the detection limit, levels were set to 0.1 nmol l−1, 0.01 nmol l−1 and 0.1 μmol l−1, respectively.Testosterone and androstenedione levels were measured by a double antibody technique on an Elecsys 2010 analyser . Levels of oestradiol, progesterone and DHEAS were measured using a competitive immunoassay on an Immulite 2000 analyser . Levels of SHBG, LH and prolactin were measured by an immunometric assay on an Immulite 2000 analyser. Reagents and calibrators supplied by the manufacturers were used. 17-OH-Progesterone levels were measured using radioimmunoassay technique with reagents and calibrators supplied by Orion Diagnostica . The lower and upper reference values for women were 0.9 and 11.7 Median age at menarche for each birth size group was estimated by Kaplan–Meier survival analysis and multivariable analysis was performed using Cox regression. Differences in adolescent body size and hormone levels between groups according to birth size, and linear trends across birth size categories, were evaluated using general linear modelling. Mean values with 95% confidence intervals (CI) within each birth size category are reported. In the hormone analyses, we used logarithmic transformation, as these variables were not normally distributed, and geometric means are therefore reported.n=195) and the random sample (n=67) for all variables included using general linear modelling. We also conducted stratified analyses of these groups for birth size related to age at menarche, adolescent body size and levels of prolactin and DHEAS. All statistical analyses were conducted using the statistical software SPSS for Windows, Release 13.0, Copyright© SPSS Inc., 1989–2004 .We evaluated potential confounding by BMI and age in adolescence, maternal age at menarche and residential area (Trondheim or Bergen). All analyses of body size and hormone levels in adolescence were adjusted for residential region and age in adolescence. In addition, we adjusted for menarcheal status (pre or post) in the analyses of adolescent body size and levels of prolactin and DHEAS. In other hormone analyses, we adjusted for time as menarche and day of menstrual cycle. All analyses were adjusted for gestational age. To minimise confounding by the relatively high prevalence of risk factors for SGA births, we compared the high-risk group (At examination during adolescence (mean age 14.0 years), 199 out of 262 girls (76.0%) had reached menarche . For allvs ⩽49 cm), the longest were on average 6.2 cm taller (164.6 vs 158.4 cm) and 4.2 kg heavier (55.0 vs 50.8 kg) in adolescence. Girls in the heaviest birth category (⩾3700 g) were 4.4 cm taller and 4.7 kg heavier in adolescence than those with birth weight below 3200 g. For ponderal index, there was a negative association with adolescent height; girls who were thin at birth were on average taller in adolescence, but the association was attenuated after adjustment for age, menarcheal status and residential region. Girls in the highest category of birth weight and head circumference had higher BMI in adolescence compared with girls of average birth size . None of the birth size variables were related to waist/hip ratio in adolescence, and skin-fold thickness at birth showed no association with any of the anthropometric variables in adolescence (data not shown). Adjustment for gestational age had no influence on the observed associations (results not shown).We found that birth length, weight and head circumference were positively associated with adolescent height and weight . The assP-trend=0.03) was attenuated after adjustment for age at puberty, menarcheal status and residential region (P-trend=0.12)  compared with 2.28 μmol l−1  for the lowest category of birth weight.A negative association between head circumference at birth and circulating level of prolactin in adolescence (nd=0.12) . For othFor girls who were in the follicular phase of the menstrual cycle , we founP-values >0.1, results not shown). Stratified analyses of these groups showed similar results as the overall analyses.Comparing girls from the random sample with those whose mothers had higher risk of delivering an SGA child, we found no difference for any of the variables , with age at menarche  through puberty and reaching a peak in early adult life, followed by a continuous decline with age . DehydroOur findings could be interpreted both as further indications of the earlier maturation previously reported in children of small birth size and as a potentially lifelong influence of developmental plasticity on adrenal androgen production. The increase in concentration of DHEAS parallels the increase in skeletal age through puberty (Oestrogens are believed to be involved in BC development, both prenatally  and lateLongitudinal growth in childhood may be positively associated with subsequent BC risk (There are only weak indications that the inverse relation of birth size with adrenal androgen production in childhood and adolescence continues into adulthood , as a smIn conclusion, relatively low birth size was associated with earlier age at menarche and larger body size in adolescence, but negatively related to adolescent DHEAS level. The results demonstrate a link between prenatal factors and subsequent growth and development.


Information integration across the senses is fundamental for effective interactions with our environment. The extent to which signals from different senses can interact in the absence of awareness is controversial. Combining the spatial ventriloquist illusion and dynamic continuous flash suppression (dCFS), we investigated in a series of two experiments whether visual signals that observers do not consciously perceive can influence spatial perception of sounds. Importantly, dCFS obliterated visual awareness only on a fraction of trials allowing us to compare spatial ventriloquism for physically identical flashes that were judged as visible or invisible. Our results show a stronger ventriloquist effect for visible than invisible flashes. Critically, a robust ventriloquist effect emerged also for invisible flashes even when participants were at chance when locating the flash. Collectively, our findings demonstrate that signals that we are not aware of in one sensory modality can alter spatial perception of signals in another sensory modality. According to the global neuronal workspace (GNW) model, consciousness relies on information being broadcast via long-range connectivity in a frontoparietal system5. As a result, signals that we are aware of in one sensory modality should be able to influence processing in brain areas dedicated to processing signals from another sensory modality. By contrast, processing of signals that we are not aware of should be largely confined to their own sensory system and have only little effect on perception of signals in another sensory modality.Information integration across the senses is critical for effective interactions with our natural environment. The extent to which multisensory integration depends on perceptual awareness is controversial17. With respect to the spatial ventriloquist illusion, we have recently demonstrated that a sound that we are aware of can boost a flash under dynamic flash suppression into perceptual awareness depending on audiovisual spatial congruency18.Indeed, in line with the first prediction, a vast body of research has demonstrated that aware signals from one sensory modality thrust unaware signals in another sensory modality into perceptual awareness according to the classical multisensory principles of temporal coincidence, spatial concordance and semantic and phonological congruency19 or in bistable perception20.By contrast, little evidence has been provided for modulatory effects of unaware signals in one sensory modality on aware signals from another sensory modality. Most notably, the McGurk illusion has been shown to be abolished when visual facial movements are obliterated from awareness under flash suppression3. Yet, while these results suggest that the brain can compare auditory and visual letters/phonemes in the absence of awareness, congruency priming does not necessarily imply genuine multisensory interactions. Further, the effects were only observed in terms of response times rather than perceptual representations or choices.Surprisingly, a recent study demonstrated that participants were faster at responding to supraliminal audiovisually congruent (resp. incongruent) stimuli when those supraliminal stimuli were preceded by subliminal congruent (resp. incongruent) primes21. These results, however, need to be interpreted with caution, as the ventriloquist effect was reported as significant for visual signals only in patients’ neglected, but not in their intact hemifield. Furthermore, this study characterized the ventriloquist effect only for unaware but not for aware visual signals in patients’ neglected hemifield.To our knowledge, only one previous study provided tentative evidence that unaware visual signals in patients with hemi-neglect induce a ventriloquist effect and bias patients’ perceived sound location27 one may argue that potentially low-level spatiotemporal information rather than phonological information as in the McGurk illusion may be integrated in the absence of awareness.In the light of these controversial findings it remains unknown whether unaware signals in one sensory modality can influence conscious perception of signals in another sensory modality. Given accumulating evidence that multisensory interactions emerge already at the primary cortical level29 and continuous dynamic flash suppression (dCFS)30 we investigated in two psychophysics experiments whether visual signals that observers did not consciously perceive can influence spatial perception of sounds. Critically, we adjusted the saliency of the visual flash, such that the dynamic continuous flash suppression obliterated visual awareness only in a fraction of trials. This allowed us to compare spatial ventriloquism for physically identical flashes that do or do not enter participant’s awareness.Combining the spatial ventriloquist illusionAfter giving informed consent, 41 healthy young adults  participated in experiment 1, 28 subjects  in experiment 2. The study was performed in accordance with the principles outlined in the Declaration of Helsinki and was approved by the local ethics review board of the University of Birmingham.For the first experiment we hypothesized medium effect size (Cohen’s d = 0.5) for the ventriloquist effect in the invisible condition. Hence, we computed sample size (n) for one sided t-test and desired statistical power equal to 0.9, n = 35. To determine sample size for experiment 2 we used effect size based on the sample from the first study (Cohen’s d ≈ 0.7); for the same statistical power (0.9) we obtained n = 18. We continued with data acquisition until the number of included data sets was equal to required sample size .2. On the ‘flash present’ trials, one eye viewed the target stimulus (i.e. the flash), which was a grey disc (Ø 0.3°) presented for 50 ms in the upper left, lower left, upper right or lower right quadrant, i.e. at ±3° visual angle along the azimuth and ±1.2° elevation from a grey central fixation dot. The elevation of ±1.2° was selected to enable effective multisensory interactions between flash and sound irrespective of flash elevation. The luminance of the flash was adjusted individually via adaptive staircases to obtain 60% invisible trials. To suppress the flash’s perceptual visibility, four dynamic Mondrians  were shown to the other eye30. In dynamic CSF original static rectangles31 are replaced with dynamically moving gratings30. The Mondrians were centred on the four potential locations of the target stimuli. Each Mondrian consisted of sinusoidal square gratings (d = 0.6°) which changed their colour and position randomly at a frequency of 20 Hz. Each grating’s texture was shifted every 16.6 ms (i.e. each frame of the monitor with 60 Hz refresh rate) to generate apparent motion. Visual stimuli were presented at four possible locations that were equidistant from a central fixation spot. They were framed by a grey aperture  of 8.97° × 14.15° in diameter to aid binocular fusion. Mask and target screen allocation  alternated between eyes across trials, to enhance suppression.Participants sat in a dimly lit room in front of a computer monitor at a viewing distance of 95 cm. They viewed one half of the monitor with each eye using a custom-built mirror stereoscope. Visual stimuli were composed of targets and masks that were presented on a grey, uniform background with a mean luminance of 15.6 cd/mAuditory stimuli were 50 ms bursts of white noise. They were presented via six external speakers, placed above and below the monitor at 64 dB sound pressure level. Upper and lower speakers were aligned vertically and located centrally, 3° to the left and 3° to the right of the monitor’s centre .32 running on MATLAB R2014a . Staircase procedures were implemented using Palamedes toolbox33.Psychophysical stimuli were generated and presented on a PC running Windows XP using the Psychtoolbox version 3.0.11Visual stimuli were presented dichoptically using a gamma-corrected 30″ LCD monitor with a resolution of 2560 × 1600 pixels at a frame rate of 60 Hz (NVIDIA Quadro 600 graphics card). Auditory stimuli were digitized at a sampling rate of 44.8 kHz via an M-Audio Delta 1010LT sound card. Exact audiovisual onset timing was confirmed by recording visual and auditory signals concurrently with a photo-diode and a microphone.30. Hence, the 3 × 3 factorial design manipulated (1) ‘flash’  and (2) ‘sound location’  .In a spatial ventriloquist paradigm, participants were presented with an auditory burst of white noise emanating from one of three potential locations: left, centre or right. In synchrony with the sound, one eye was presented with (i) no flash or a brief flash in participants’ (ii) left or (iii) right hemifield under dynamic continuous flash suppression to the other eyend) Fig. . In ordeEach trial started with the presentation of the fixation dot for duration of 1200 ms Fig. . Next, p36 (PAS) via a four choice key press. This Perceptual Awareness Scale encouraged participants to categorize trials as invisible, only if they were ‘completely invisible’. Third, they reported the location of the flash (upper or lower hemifield) via a two choice key press. Critically, we designed orthogonal auditory and visual tasks to minimize decisional biases between visual and auditory localization responses. In order to minimize response interference between responding to the set of three questions, we ensured that the responses mapped to distinct sets of buttons . The button/hand assignment and order of questions was counterbalanced across participants  via a three choice key press. Second, they rated the visibility of the flash  according to a previously published Perceptual Awareness Scale37). Further, we could assess the information that is available for visual spatial localization during invisible trials and select participants that were not better than chance when locating flashes that they judged as invisible . The latter allowed us to investigate the influence of flashes on sound localization, when they were invisible and unaware in a so-called objective sense (i.e. objective awareness criterion37).This visibility judgment provided a subjective awareness criterion. Critically, prior to the main experiment we adjusted the flash’s luminance in adaptive staircases individually for each participant, such that the flash was visible only on 40% of the trials. This allowed us to quantify multisensory interactions as indexed by spatial ventriloquism  for flashes that were visible  or invisible , such that the flash was visible on 40% of the trials. The adaptive staircases were applied using a slightly modified experimental paradigm where the sound was presented always from the middle, the flash in one of the four quadrants and participants reported only flash visibility  and location . After an initial long staircase , we performed four times two interleaved adaptive staircases .Prior to the main experiment, participants were familiarized with stimuli and task. In particular, we adjusted the flash luminance in adaptive staircases (step size up: 8.8 cd/m2) and only after 4 consecutive ‘not seen’ responses or after 3 consecutive ‘seen’  responses.During the main experiment participants completed a total of 8 experimental sessions, resulting in a total of 432 trials . To maintain the targeted proportion of invisible trials , a staircase procedure was also used throughout the main experiment. To minimize the variability of the flash luminance during the main experiment we adjusted brightness of the flash in smaller step sizes (3.3 cd/m36). This approach is ideal to ensure an approximate visibility level of 40% across all participants. However, it raises the possibility that the ventriloquist effect may be driven by flash stimuli with higher luminance values.In the first study flash luminance was adjusted throughout the experiment to maintain a visibility level of approximately 40% . Yet, we note that the results were basically equivalent if all participants were included.The second study was identical to the first except that the flash luminance was adjusted only prior to the main experiment for each participant, but kept constant throughout the main experiment.For data analysis, we reduced the four visibility levels to two visibility levels: 1. Visible = clear image + almost clear image + weak glimpse and 2. Invisible = not seen. Further, we pooled over flashes in upper and lower fields given their negligible elevation . Unless otherwise stated, statistical analysis was identical for the two experiments.perceived sound location for each of the 2  × 3  conditions by averaging the localization responses across trials. Next, we averaged the perceived sound locations separately for trials where the flash was presented on the left and right and computed the difference in average perceived sound location for ‘visual right’ minus ‘visual left’ trials as the index for the spatial ventriloquist effect  with exception of unidirectional Bayes factors, which were computed using JASPFor the reported results, we limited the analysis to subjects based on the following two exclusion criteria: First, we included only subjects that provided reliable visibility judgments as indicated by ‘better than chance localization accuracy’  for visible flashes (i.e. exclusion of six subjects from experiment 1 and three subjects from experiment 2). Second, to ensure reliable parameter estimation, we included only those participants who had at least 10 trials in each of the 2 (flash location: left vs. right) × 3  conditions, for both visible and invisible categories respectively (i.e. exclusion of three subjects from experiment 1 and six subjects from experiment 2). For individual distribution of PAS ratings see Fig. Further, we would like to emphasize that the results were basically equivalent when including all participants . In other words, significant results were again significant, non-significant results again non-significant, when no participants were excluded.We investigated whether the audiovisual spatial bias (i.e. ventriloquist effect) was significantly different for visible  and invisible trials using paired t-tests.37). Further, we investigated whether participants at the group level were at chance when locating a flash they judged invisible by comparing their accuracy scores against 50% chance performance in a right tailed one-sample t-test. For p values greater than 0.05 we computed Bayes factors to provide further evidence for the null hypothesis (i.e. 50% chance performance).We investigated whether the ventriloquist effect was present independently for both invisible and visible flashes. Hence, we computed the ventriloquist effect separately for trials where visual signals were judged visible or invisible and tested whether the ventriloquist effect was significantly greater than zero in right-tailed one sample t-tests independently for visible and invisible trials. Demonstrating a ventriloquist effect for invisible trials suggests that flashes can influence perceived sound location, when participants are subjectively not aware of them (i.e. subjective awareness criterion37). Using directionally informed tests in i. classical statistics and ii. Bayesian inference we identified chance performers based on a binomial test on their flash localization performance on trials in which the flash was judged as invisible. First, to link with previous reports in the literature we defined chance performers individually based on a ‘null-result’ using a directional binomial test (i.e. ‘not significantly better than chance’) in classical statistics39. Second, as a ‘null-result’ in classical statistics is not decisive, we also used Bayesian statistics that allows one to quantify and compare the evidence for the null model that embodies the null-hypothesis in relation to an alternative model. Hence, using Bayes factors we compared a binomial distribution model that a priori fixes the probability to 0.5 (i.e. null model of chance performance) with one that includes the probability parameter p as a free parameter constrained by a positive prior distribution . Please note that imposing a positive prior distribution makes the Bayesian test a more stringent for defining chance performers.We asked whether invisible flashes are able to influence the perceived sound location, even in participants that are not better than chance when locating flashes they judged as invisible . As has been explained in detail in Shanks43, the flash localization accuracy may be lower in chance than non-chance performers in this experimental session because of performance noise and hence if measured again may increase, a statistical phenomenon referred to as ‘regression towards the mean’. Conversely, participants’ sound localization performance may be affected by -partly - independent noise. As a result, we may underestimate and falsely define observers as chance performers and conversely overestimate the ‘unaware’ ventriloquist effect.Nevertheless, because both selection criteria were applied in a non-crossvalidated fashion as is currently common in the fieldAs described earlier we counterbalanced the task order (either: flash location – visibility – sound location or: sound location – visibility – flash location) across participants, because the task order can affect our analysis results in three important ways:First, the presentation order of the questions can influence observer’s performance accuracy on the different tasks. For instance, as a result of memory noise, observers’ flash localization accuracy may be reduced when the flash localization task was presented last with additional consequences on the size of the ventriloquist effect. We therefore compared flash localization accuracy and the size of spatial ventriloquism for first vs. last task in a two-sample t-test.Second, as a result of the reduced flash localization accuracy, we may have classified participants as chance performers mainly when the flash localization task was presented last. To assess the effect of task order on the classification as chance performers we compared the number of chance performers across the groups where the flash localization task was presented first vs. last in a Chi-square test.Third, to assess the effect of task order on the exclusion of participants we compared the number of excluded participants across the groups where the flash localization task was presented first vs. last in a Chi-square test.A paired t-test comparing the ventriloquist effect for invisible and visible trials demonstrated a significantly greater ventriloquist effect for visible than invisible flashes  = 7.99, p < 0.001 chance performers: 0.47 ± 0.05, t(27) = 8.57, p < 0.001 experiment 2: all participants: 0.46 ± 0.07, t(17) = 6.45, p < 0.001; chance performers: 0.46 ± 0.07, t(12) = 6.34, p < 0.001).To investigate whether the ventriloquist effect emerged for visible and invisible flashes we performed one sample t-tests independently for each of these two visibility levels.29  = 8.62, p < 0.001; Cohen’s d ± 95% Confidence Interval: 1.5 ± 0.55; experiment 2: 0.51 ± 0.06, t(17) = 9.14, p < 0.001; Cohen’s d: 2.15 ± 0.82).For visible trials, we observed a significant ventriloquist effect  as expected based on numerous previous studies01 = 1.72; experiment 2: 53.6 ± 2%, t(17) = 0.91, p = 0.047; BF01 = 1.69), therefore the results reported so far only provide evidence that flashes that participants consider invisible (i.e. subjective awareness criterion) are still able to elicit a robust ventriloquist effect.Crucially, we also observed a significant ventriloquist effect for flash stimuli that participants judged as invisible  = 3.86, p < 0.001; Cohen’s d: 0.67 ± 0.5; experiment 2: 0.09 ± 0.03, t(17) = 3.22, p = 0.003; Cohen’s d: 0.76 ± 0.68). Participants’ flash localization accuracy was slightly above chance  = 1.88, p = 0.034; corresponding BFTo ensure that the ventriloquist effect for invisible trials was not driven by participants that had residual visual information for visual flash localization, we repeated this analysis using the more stringent so-called objective criterion for perceptual awareness. Hence, we included only those subjects that were individually not better than chance when locating an invisible flash based on binomial testing (i.e. objective awareness criterion). The constraint of individual chance performance reduced the number of subjects that could be included in the analysis .Nevertheless, despite the reduced number of subjects, we still observed a highly significant ventriloquist effect for invisible trials  = 3.22, p = 0.002; Cohen’s d: 0.61 ± 0.54; experiment 2: 0.08 ± 0.03, t(12) = 2.84, p = 0.007; Cohen’s d: 0.79 ± 0.8)  = −0.5, p = 0.687; BF01 = 4.97)  at the group level was not significantly better than chance but nearly equal to 50%  = 0.41, p = 0.341; BF97) Fig. . Hence, As classical statistics does not allow the acceptance of the null-hypothesis, we also used unidirectional Bayesian tests that can formally provide positive evidence for the null-hypothesis of chance performance individually for each participant. Specifically, we computed Bayes factors comparing the evidence for the null-model of chance performance with the evidence for alternative model of better than chance performance and selected only subjects as chance performers with Bayes factors >3 (i.e. positive evidence for the null-model). This reduced the number of included chance performers in both experiments .Nevertheless, despite this more stringent objective awareness criterion we again observed significant ventriloquist effect for invisible trials  = 2.61, p = 0.008; Cohen’s d: 0.53 ± 0.58; experiment 2: 0.09 ± 0.03, t(11) = 3.09, p = 0.005; Cohen’s d: 0.89 ± 0.84).A two sample t-test did not reveal a significant effect of question order on flash localization accuracy  or the size of ventriloquist effect .2 = 0.50, p = 0.478; experiment 2: χ2 = 1.68, p = 0.196) or Bayesian statistics . Further, question order did not significantly affect the exclusion of participants .Likewise, a Chi-square test did not reveal a significant effect of question order on the number of subjects classified as chance performer using criteria based on binomial testing .Moreover, across both experiments the ventriloquist effect persisted even for invisible flashes when participants showed chance performance on flash localization (i.e. objective awareness criterion).Collectively, our two experiments show that invisible flashes, that human observers are not aware of, can influence where they report sounds, that they are aware of.45 that has previously been implicated in mediating activations along the dorsal stream into the intraparietal sulcus under CFS46, but see49. Because participants were engaged in a spatial localization task and the ventriloquist effect relies on integration of spatial representations from vision and audition, the dorsal stream may be critical in our paradigm51. Second, it may modulate sound processing via sparse direct connectivity between primary auditory and visual areas52. Third, some flash-induced neural activity may evade flash suppression and propagate across the cortical hierarchy into higher order association areas such as intraparietal sulcus or even prefrontal cortices56. While this activation may not be sufficient to allow better than chance flash location, it enables to bias participants’ sound localization.Invisible flashes may influence sound localization during continuous flash suppression via at least three distinct neural circuitries. First, an invisible flash may interact with auditory signals via subcortical mechanisms such as the colliculo-pulvinar pathway57. The level of neural activity then concurrently determines (i) whether the flash is able to enter perceptual awareness and (ii) the precision of the spatial representation and thereby the strength of the ventriloquist effect59. Thus, visible flashes would induce a ventriloquist effect via the same neural circuitries as invisible flashes and induce a greater ventriloquist effect, as they induce higher neural activity and thus more precise spatial representations in visual cortices.The ventriloquist effect may be smaller for invisible than visible flashes, because invisible flashes may evoke weaker or less reliable activations than visible flashes already at the primary cortical level as a result of state-dependent effects or various sources of internal neural noise55. Moreover, it is well established that multisensory integration progressively increases along the cortical hierarchy with only about 15% neurons showing multisensory properties in primary sensory areas22 and more than 50% in classical association areas such as intraparietal or superior temporal sulci53.Alternatively, visible flashes may induce a stronger ventriloquist effect by employing additional neural circuitries (e.g. via higher order association areas) that are not engaged by weaker invisible flashes. In this account the spatial representations elicited by a flash at the primary cortical level may be preserved, yet be less effective in influencing the sound processing system. This latter account dovetails nicely with current perspectives on the neural organization of multisensory integration. Specifically, auditory and visual information are thought to be integrated via multiple circuitries including subcortical mechanisms, direct connectivity between primary sensory areas and convergence in higher order association areasThus, when a visual flash escapes the continuous flash suppression and enters participants’ awareness, a strong ventriloquist effect emerges most likely via integration in association areas such as intraparietal sulci (IPS) that contain exuberant multisensory neurons and may potentially amplify multisensory integration via feed-back loops with lower level sensory areas. By contrast, when continuous flash suppression blocks neural activity at least to some extent from propagating into higher order association areas, audio-visual interactions are greatly attenuated or even abolished leading to a smaller ventriloquist effect. Under this ‘multiple neural circuitries’ account, auditory and visual signals interact most likely at both pre- and post-aware processing stages by placing different demands on distinct neural circuitries (e.g. direct connectivity vs. higher order association cortices).61 may enable us to better dissociate between these different mechanisms. For instance, while flash suppression is thought to affect processing in primary visual areas alike contrast modulation59, attentional blink may alter processing mainly at higher attentional levels. In fact, we suspect that our current paradigm potentially combines both mechanisms by placing attentional demands at four locations.The combination of different psychophysical blinding methods that affect visual processing at variable depthsIn conclusion, to our knowledge our findings provide the first demonstration that invisible flashes can alter and bias where we perceive sounds. These results suggest that low level sensory information can interact across sensory modalities at least to some extent prior to perceptual awareness. Nevertheless, audiovisual interactions as indexed by spatial ventriloquism were stronger for visible relative to invisible flashes that participants were not able to locate better than chance. This raises the possibility that aware visual signals may also engage multisensory mechanisms in higher order association areas or other neural circuitries that are less engaged in the absence of perceptual awareness. Future studies using EEG and fMRI are needed to identify the neural systems that enable audio-visual interactions in the presence and absence of subjective and objective awareness.Supplementary Material


Coix lachryma‐jobi L. (coix) under low‐temperature stress, growth and physiological parameters were investigated in seedlings. Meanwhile, transcriptome profile in coix seedlings was characterized as well. The results showed an increase of 11.90%, 13.59%, and 10.98% in stem diameter, the aboveground and belowground biomass in 5 mg/L uniconazole application group (U3), compared with control check low‐temperature group (CKL). Some anti‐oxidase activities also show significant difference between CKL and U3 (p < .05). Transcriptome results showed that 3,901 and 1,040 genes had different expression level at control check (CK) and CKL, CKL and U3. A considerable number of different expressing genes (DEGs) related to the plant hormone signal transduction, photosynthesis, reactive oxygen species (ROS)‐related genes, and secondary metabolism in response to uniconazole application were identified in this study. The transcriptomic gene expression profiles present a valuable genomic tool to improve studying the molecular mechanisms underlying low‐temperature tolerance in coix. At the same time, it would provide a certain basis for the application of UNZ in the production of coix resistance under low temperature.Uniconazole (UNZ) can alleviate a variety of abiotic stresses such as low temperature. With application of UNZ on  Coix lachryma‐jobi L (coix) under low‐temperature stress, growth and physiological parameters were investigated in seedlings. Meanwhile, using Illumina sequencing technology, transcriptome profile in coix seedlings was characterized as well.With application of S3307 on  The nutrient solution was renewed every other day, and the pH was maintained at 5.8. When two leaves of plant were fully expanded, seedlings were subjected to treatments  and were centrifuged at 15,000 2.3Mixed samples of five leaves in the treatment of CK, CKL, and U3 were used for RNA extraction (Invitrogen Trizol Reagent of RNA extraction kit 15596018). A cDNA library was constructed using a NEB kit for library preparation and sequenced using an Illumina HiSeq2500 (Beijing Biomarker Technologies Co.)2.4High‐quality sequencing reads data were first broken into short fragments (K‐mer) using Trinity software, and then, the short fragments were extended to longer fragments (Contig)  to obtain annotation information for unigenes. Based on BLAST parameters, those unigenes with an E‐value less than 10–5 were selected. Sequences of selected unigenes were aligned within databases .Unigene sequences were compared in the following databases using BLAST software  . Primers were designed using Gene Runner software . The sequences and the annealing temperature of each primer are shown in the Table PtACTIN calculated by the 2−ΔΔCt method . The data were subjected to statistical analysis by SPSS 20.0 for testing the significance of differences.All the data presented in the tables and figures were the mean values of three replicates at least, in which results were expressed as mean ± standard deviation . After uniconazole, the activities of CAT, SOD, and POD of leaves in U3 increased by 13.22%, 13.19%, 68.41%, and 21.71% comparing to CKL (p < .05). The SOD, POD, and CAT activities of the roots increased by 16.19%, 5.79%, 83.83%, and 16.34% comparing to CKL, respectively (p < .05), from Figure Low‐temperature stress decreased POD, CAT, APX, and SOD activities significantly (p < .05). The chlorophyll a content of the U3 group increased significantly compared with CKL (p < .05), while was not significant compared with CK (p > .05). The chlorophyll b and total content of the U3 group increased significantly compared with CKL and CK (p < .05). The chlorophyll b and total content of the U3 group was 6.10% and 5.01% higher than that of the CKL group separately.Chlorophyll a, chlorophyll b, and total chlorophyll decreased significantly after low‐temperature stress from Figure 3.2To comprehensively investigate the transcriptome and gene expression profiles of coix seedlings under normal condition, low‐temperature stress, and UNZ treatment, three cDNA samples from coix leaves were prepared and sequenced using Illumina HiSeq x‐ten platform. An overview of the RNA‐Seq reads derived from the three libraries was presented in Table With the Trinity program , followed by Zea mays  and Setaria italica   unigenes were successfully matched to homologous sequences in at least one of databases. Among them, 8,268 (10.04%), 24,986 (30.36%), 10,459 (12.71%), 16,078 (19.54%), 22,047 (26.80%), 19,975 (24.28%), 31,467 (38.24%), and 34,496 (41.93%) unigenes were found in COG, GO, KEGG, KOG, Pfam, Swiss‐Prot, eggNOG, and Nr databases, respectively. The Nr database produced the largest number of annotations. Compared with other species, coix showed the most matches to ) Figure .GO assignments system was used to classify the possible functions of coix genes. A total of 24,986 unigenes were successfully annotated and classified into 50 functional groups of three major GO categories  Figure . The topTo further analyze the unigenes, we searched the annotated sequences for the genes involving in COGs classifications. All unigenes were aligned to COG database to predict and classify possible functions, and COG function classification of consensus sequences was showed in Figure 3.4Wilcoxon signed‐rank test (FDR < 0.01 and fold change ≥ 2) showed 3,901 and 1,040 genes had different expression level at CK_VS_CKL and CKL_VS_U3, respectively , 4 AUX/IAA family (AUX/IAA), 3 auxin response factor (auxin), 1 jasmonic acid‐amido synthetase JAR2 (JAR2), 1 ethylene receptor 3 isoform X3 (Ethylene), putative GID1‐like gibberellin receptor (Gibberellin), and BR‐signaling kinase 2 (BR), were found between CK and CKL. Among these genes, up‐regulated genes were more than down‐regulated genes. There were 7 annotated DEGs in plant hormone signal transduction pathways between CKL and U3. Among them, AUX/IAA and auxin were significantly up‐regulated. These results suggested that the expression level change in many genes should be directly associated with the dynamic characteristics of UNZ regulating the plant hormone signal transduction of coix responding to low temperature , photosystem II reaction center PSB28 protein (PSB28), photosystem I subunit O (PSAO), photosynthetic NDH subunit of lumenal (NDH), photosystem I reaction center subunit psaK (psaK), photosystem II core complex proteins psbY (psbY), photosystem I psaG/psaK (psaG/psaK), photosystem I reaction center subunit N (PsaD), chloroplastic, chloroplastic, peroxisomal (S)‐2‐hydroxy‐acid oxidase, and peroxisomal (S)‐2‐hydroxy‐acid oxidase. Among these DEGs, most genes were down‐regulated genes. Low temperatures could decrease level of Ros in study, in which results were inconsistent with Sharma ‐2‐hydroxy‐acid oxidase GLO3, peroxidase 52, peroxidase 21, and peroxidase 54 were significantly up‐regulated. These results suggested that the expression level change in many genes would be directly associated with the dynamic characteristics of UNZ regulating photosynthesis and Ros pathways of coix responding to low temperature  was observed between the RNA‐Seq and qRT‐PCR (Figure To confirm the accuracy of the Illumina RNA‐Seq results, 9 of the transcripts related photosynthesis, sugar, and secondary metabolism were selected for qRT‐PCR Table . The expR Figure . The qRT4In this work, we explored physiochemical and transcriptomic changes of coix in response to UNZ under low‐temperature stress. Our physiochemical data clearly demonstrated that the coix seedlings experienced complex changes in growth parameters, anti‐oxidant enzymes, and chlorophyll contents Figures ; Table 1In this study, the major pathways involved in the cold response were photosynthesis, flavonoid biosynthesis, phenylpropanoid biosynthesis, plant hormone signal transduction, and carbon fixation in photosynthetic organisms, as well as starch and sucrose metabolism under low temperature. The pathways were closely associated with low‐temperature stress (Chen, Tian, et al., Plant hormones played essential roles in response to abiotic stress through their involvement in signaling networks and physiological processes (Colebrook, Thomas, Phillips, & Hedden, 5Our dataset included comprehensive analysis in sequence and DEGs profiling data that provide a dynamic perspective on transcriptomic variations in coix seedlings responding to UNZ under low temperature. Many DEGs were simultaneously found in CK‐VS‐CKL and CKL‐VS‐U3 libraries in different functional pathways, such as plant hormone signaling, photosynthesis, and Ros, as well as secondary metabolism. These results provided novel insights into the mechanism of UNZ enhancing the tolerance of coix seedlings to low‐temperature stress with respective of physiology and transcriptome. At the same time, it provided some references for the coix cultivation in Heilongjiang and other cold regions.The authors declare that they do not have any conflict of interest.This study does not involve any human or animal testing.FigS1Click here for additional data file.FigS2Click here for additional data file.FigS3Click here for additional data file.FigS4Click here for additional data file.TableS1‐S5Click here for additional data file.


T1‐weighted dynamic contrast‐enhanced (DCE) perfusion magnetic resonance imaging (MRI) has been broadly utilized in the evaluation of brain tumors. We aimed at assessing the diagnostic accuracy of DCE‐MRI in discriminating between low‐grade gliomas (LGGs) and high‐grade gliomas (HGGs), between tumor recurrence and treatment‐related changes, and between primary central nervous system lymphomas (PCNSLs) and HGGs.We performed this study based on the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis of Diagnostic Test Accuracy Studies criteria. We systematically surveyed studies evaluating the diagnostic accuracy of DCE‐MRI for the aforementioned entities. Meta‐analysis was conducted with the use of a random effects model.Twenty‐seven studies were included after screening of 2945 possible entries. We categorized the eligible studies into three groups: those utilizing DCE‐MRI to differentiate between HGGs and LGGs , between recurrence and treatment‐related changes  and between PCNSLs and HGGs . The pooled sensitivity, specificity, and area under the curve for differentiating HGGs from LGGs were 0.93, 0.90, and 0.96, for differentiating tumor relapse from treatment‐related changes were 0.88, 0.86, and 0.89, and for differentiating PCNSLs from HGGs were 0.78, 0.81, and 0.86, respectively.Dynamic contrast‐enhanced‐Magnetic resonance imaging is a promising noninvasive imaging method that has moderate or high accuracy in stratifying gliomas. DCE‐MRI shows high diagnostic accuracy in discriminating between HGGs and their low‐grade counterparts, and moderate diagnostic accuracy in discriminating recurrent lesions and treatment‐related changes as well as PCNSLs and HGGs. Dynamic contrast‐enhanced‐Magnetic resonance imaging has high diagnostic accuracy in grading gliomas and moderate accuracy in surveillance of high‐grade gliomas and differentiation from primary central nervous system lymphomas. DCE‐MRI is a promising noninvasive imaging technique in diagnosing different types of brain tumors. The present standard therapy of HGGs is surgical resection and concomitant chemoradiation.Although magnetic resonance imaging (MRI) is routinely applied to classify brain tumors, conventional MRI has shortcomings.Perfusion‐weighted imaging is commonly used for the assessment and classification of intracranial tumors, and may be performed as dynamic susceptibility contrast‐enhanced (DSC) MRI, T1‐based dynamic contrast‐enhanced (DCE) MRI, and arterial spin labeling (ASL).A number of single‐center studies in mainly small cohorts have shown the potential of DCE‐MRI.2This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis of Diagnostic Test Accuracy Studies criteria.2.1The search was systematically conducted on June 8, 2017 using PubMed, Ovid Embase, and the Cochrane Library. The detail of the search strategy is presented in the Supplementary Material 2.2The abstracts of all articles retrieved in the initial search were screened by board‐certified neuroradiologists and in‐training neuroradiologists with research experience in perfusion imaging in neuro‐oncology. Selected full text manuscripts were reviewed to determine their relevance in detail. Both processes were executed by independent reviewers according to the following criteria. The inclusion criteria were: (a) DCE performed on brain tumor patients prior or during treatment; (b) study assessed diagnostic or prognostic value of DCE parameters. The exclusion criteria were: (a) no DCE (T1‐weighted perfusion) was performed; (b) no brain tumor patients were examined; (c) the study was conducted in pediatric population (<18 years old); (d) animal/laboratory study; (e) review articles, case reports, letters, commentaries, or conference proceedings; (f) brain tumor histology was not confirmed; (g) non‐English articles. In cases of discrepancies between two reviewers, a third one resolved the case.For the meta‐analysis, selected full manuscripts were reviewed by two independent reviewers and in cases of discrepancies between two reviewers, all discrepancies were resolved by consensus. The inclusion criteria were: (a) the studies assessed the diagnostic accuracy of DCE‐MRI for discriminating between HGGs and LGGs, between recurrence and treatment‐related changes, and between PCNSLs and HGGs. The exclusion criteria were: (a) patient population clearly overlapped with other studies cohorts; (b) the information for extracting or calculating true‐negative (TN), false‐negative (FN), true‐positive (TP), and false‐positive (FP) values was not listed. Studies assessing the prognostic value of DCE‐MRI were excluded due to their small number. If overlapping studies showed no distinct information, the study with more patients was chosen.2.3Data were extracted from the included studies. Data included sensitivity and specificity to calculate subsequently the TN, FN, TP, and FP for each of the diagnostic task under investigation, number of patients, age of patients, study design, tumor histology, MRI field strength, whether DCE‐MRI was followed with DSC‐MRI or not, methods of a region of interest (ROI) analysis, deconvolution with arterial input function, and DCE model. The same two reviewers, who performed full‐text screening, independently conducted data extraction, and all inconsistencies were resolved by consensus.2.4We assessed the study quality based on the Quality Assessment of Diagnostic Accuracy Studies QUADAS‐2) instrument , negative likelihood ratios (NLRs), diagnostic odds ratios (DORs), and their 95% CIs were calculated for each comparison. The values of DCE parameters with the highest diagnostic accuracy were used. Random effects models were applied to address the expected heterogeneity. The accuracy was determined using a summary receiver operating characteristic curve (SROC) plot. To quantify error and accuracy, the area under the curve (AUC) was calculated. AUC values of more than 0.9 represented high accuracy and 0.7 ≤ AUC ≤ 0.9 reflected moderate accuracy.Ktrans, ve, and vp), applied pharmacokinetic model (model‐independent and two‐compartment model approaches), and methods of ROI analysis .The pooled sensitivity and specificity were calculated in subgroups (studies number ≥4) created based on DCE perfusion imaging derived parameters , specificity was also heterogeneous (I2 = 41.57%). The funnel plot revealed publication bias (P = 0.010).The pooled sensitivity was 0.93 and the pooled specificity was 0.90. Table3.3.2Ktrans. Heterogeneity was lower for the studies that used ve. The model‐independent parameters were not entitled for subgroup meta‐analysis due to the small number of studies.The results of the subgroup analyses are shown in Table 3.43.4.1shows PLR, NLR, and DOR. Figure I2 = 72.77%) and the specificity analysis presented low heterogeneity (I2 = 0.00%).The pooled sensitivity was 0.88 and the pooled specificity was 0.86. Table 3.4.2Ktrans estimation had no obvious heterogeneity. Articles with ve, vp calculation, and “hot‐spot” ROI placement were not eligible for further subgroup meta‐analysis.Table 3.53.5.1shows PLR, NLR, DOR, and AUC. Figure I2 = 51.10% and 69.63%, respectively).The pooled sensitivity and specificity were 0.78 and 0.81, respectively. Table 3.5.2The results of the subgroup analyses are detailed in Table 4Our results suggest that DCE‐MRI can stage gliomas into HGGs and LGGs with high diagnostic performance, whereas the accuracy in discriminating between tumor recurrence and unspecific treatment‐induced changes, and between PCNSLs and mimicking HGGs is slightly lower. The overall diagnostic performance results indicate that DCE‐MRI can be successfully utilized in the current neuro‐oncological clinical practice.Our work adds to the existing literature and a previous systematic review and meta‐analysis, which had compared the diagnostic value of selected advanced MRI techniques, including DCE‐MRI, in brain tumors.Among the applied ROI methods for stratifying gliomas, “hot‐spot” measurement had higher accuracy than whole volume ROI, in line with the report by Santarosa et alTo differentiate between recurrence and treatment‐related changes, the model‐independent showed clearly higher sensitivity and AUC than for the 2‐compartment model‐derived perfusion biomarkers, as reported by Hamilton et alThere are some limitations in our study. First, the analysis of studies aiming at grading gliomas revealed publication bias and the composition of the two groups was imbalanced. Most analyses indicated substantial heterogeneity in terms of MR field strength, different types of MR coils, pulse sequence parameters, volume of contrast agent, injection time, which all could affect the outcomes. Some studies performed DCE using only half of contrast agent for DCE‐MRI, followed with DSC‐MRI.In conclusion, our results suggest that DCE‐MRI is a promising noninvasive imaging method that has good accuracy in diagnosing different types of brain tumors. Specifically, DCE‐MRI has high diagnostic performance in stratifying gliomas in high‐ or low‐grade, and moderate diagnostic accuracy in differentiating recurrence from treatment‐related changes, and PCNSLs from HGGs. Significant efforts for the standardization of the acquisition parameters and the postprocessing should be, however, intensely made.None declared.SO, AU, JU, ST, and SB were involved in conception and design. SO, AU, IL, JU, ML, SMH, ES, ST, and SB were involved in acquisition of data (screening and data extraction). SO, ARG, JPG, XG, and SB were involved in statistical analysis and interpretation of data. All authors were involved in drafting, editing and critical revision for important intellectual content. All authors gave final approval of the version to be published. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.


To determine whether lumbar anatomy parameters are in dynamic change and related factors.This is a retrospective study. Participants who did lumbar computed tomography (CT) scanning in Shandong University Qilu Hospital from October 2017 to March 2019 were selected. The 476 participants were randomly selected as male or female, with the age ranging from 17 to 87 years . All the measurements were taken based on the CT scanning image and the measurement of lumbar morphology was conducted using picture archiving and communication systems (PACS). The angle between the horizontal alignment and pedicle center on median sagittal view, the angle between upper endplate and lower endplate on median sagittal view as well as transverse section angle (TSA) using Magerl point in the axial view was determined by reconstructive CT analysis.P = 0.002), 5.60° ± 2.89° to −4.14° ± 5.90° (P = 0.030), and 4.75° ± 2.95° to −2.87° ± 4.68° (P < 0.001), respectively. Additionally, the angle between the horizontal alignment and pedicle center on median sagittal view in male participants of lumbar two was dramatically decreased, from 4.83° ± 2.79° to −4.45° ± 5.97° (P = 0.30). And that of lumbar three in female participants was significantly decreased, from 4.56° ± 2.52° to −2.88° ± 5.03° (P = 0.029). Furthermore, of the overall participants, the angle between upper endplate and lower endplate on median sagittal view of lumbar one to four was associated with aging . The angle of lumbar one, two and four in male participants and lumbar one to four in female participants were all significantly related to aging . Moreover, in the participants overall, the TSA of lumbar one to three was significantly associated with aging . In addition, this angle in lumbar one to lumbar four in male participants were all negatively associated with aging .In the overall participants, the angle between the horizontal alignment and pedicle center on median sagittal view of lumbar one to three was significantly decreased with aging, from 3.90° ± 2.81° to −4.18° ± 6.86° (Lumbar anatomy parameters are in dynamic change in an age and gender dependent manner. During spine surgery in elderly patients, more attention should be paid to these anatomic changes. The bones in the living body are dynamically changingBased on previous findings, our group established the “non‐union settlement theory,” which was firstly applied in knee osteoarthritisDenis established “spinal three column theory” in 1983Indeed, in clinic, we found that with aging the incidence of degenerative kyphosis increasesTaking osteoarthritis and kyphosis into account, we found some similarity of these two diseases. Firstly, both diseases are accompanied by loading force change. In kyphosis, the sagittal balance is disturbed, leading to changed loading force line. Secondly, they are both degenerative diseases, which have similar pathological processes. It is reported that osteoarthritis and kyphosis are related to osteoporosis; in addition, different levels of osteoporosis lead to non‐union settlement phenomena, causing unbalanced force. Last but not the least, these two diseases may be cured by restoring the balance of the force line. The novelty of this present study is to determine the dynamic change of lumbar parameters from adulthood to older age, which is not focused previously. Additionally, this finding may provide another treatment method for spine degenerative diseases.Considering the fact that the nature of some bones are still changing, and given the importance of lumbar structure in degenerative kyphosis, herein we determined: (i) whether lumbar anatomy parameters are changing with aging; and (ii) whether the change in lumbar anatomy parameters is associated with gender.Each patient provided informed consent for participation in the study. This retrospective study was conducted in accordance with the Declaration of Helsinki  and was approved by the Regional Ethics Board of Hebei Medical University (T2016‐001‐1).This study was designed as a retrospective study and aimed to explore the influences of demographic and physical properties on lumbar morphology. A total of 476 patients  underwent CT scanning from October 2017 to March 2019. The age of participants ranged from 17 to 87 years, with a mean of 55.19 ± 14.28 years. Three observers examined the lumbar anatomy parameters and recorded them independently. The measurement of lumbar morphology was conducted using picture archiving and communication systems (PACS). Two investigators collected and analyzed data independently.Inclusion criteria for the study were as follows: (i) ethnic Han patients; (ii) eligible imaging data for measurement; (iii) clear record of age and gender; and (iv) a retrospective study.Exclusion criteria for the study were as follows: (i) participants with endocrine system diseases ; (ii) spinal trauma diseases ; (iii) congenital and developmental anomalies ; (iv) tumor ; (v) infections ; (vi) immune system diseases ; and /or (vii) clear history of hormone use.Qualified participants underwent CT scanning in Qilu Hospital of Shandong University. Reconstructed sagittal and axial view of the CT scan was established in workstation. Three observers did the measurement without detailed information of participants. These observers recorded data independently and directly transferred these data to persons who performed statistical analysis. Statistical analysts collected detailed information and performed data analysis.Definition: in one vertebra body, the angle between the lowest upper endplate and the highest lower endplate. Measurement method: on median sagittal view, we determined the angle between upper endplate and lower endplate of the same vertebra. Clinical significance: this parameter is an indicator of spine sagittal balance. The bigger this angle, the more sever the kyphosis. The present study determined the AULE from lumbar one to lumbar four Fig. A.SSA was defined as the angle between the horizontal alignment and pedicle center, when the pedicle screw was inserted. Measurement method: SSA was examined as previously reported. Briefly, on median sagittal reconstructive view, the angle between the horizontal alignment and pedicle center was recorded as SSA. The angle was recorded as “+” when the pedicle center line is above the horizontal alignment. In turn, we record the angle as “‐” when the pedicle center line is below the horizontal alignment. Clinical significance: this is an important parameter for surgeons to install pedicle screw. In the present study, we examined SSA from lumbar one to lumbar four Fig. B.Definition: we positioned the Magerl point, which was defined as the cross point of the tangent to the outer edge of the superior articular process and the medial transverse process. Line “a” was defined as the line that crosses the pedicle center and the Magerl point; and line “b” was defined as the median sagittal view. TSA is the angle between line a and line b. Measurement method: TSA was measured as previously reportedt test or Wilcoxon rank sum test as appropriateH testr) was calculated and scatter plots were shown. Univariable linear regression was used to calculate regression coefficients (β) and R2. A P value less than 0.05 was judged to be statistically significant. In this study, gender was analyzed as a qualitative variable and other parameters were analyzed as quantitative variables. All analyses were done using R . Pearson correlation coefficient analysis was used to analyze potential association. Correlation results were interpreted as none or very week (−0.1 to 0.1), weak (−0.3 to −0.1 or 0.1 to 0.3), moderate (−0.5 to −0.3 or 0.3 to 0.5), and strong (−1.0 to −0.5 or 1.0 to 0.5). Multiple linear regression was conducted to assess the independent association. P < 0.05 (two‐tailed) was considered statistically significant. A highly significant difference was defined as P < 0.01 (two‐tailed).We computed the baseline characteristics  for each genderP = 0.032). Additionally, SSA of lumbar one , lumbar two  and lumbar three  in different age stages also showed a remarkable difference.To investigate whether lumbar anatomy parameters are changing throughout life, we analyzed participants from 17 years to 87 years of age. As demonstrated in Table P = 0.030). As shown in Table P = 0.029).To further determine whether this difference is gender‐affected, we analyzed each parameter separately. As illustrated in Table P < 0.001, P < 0.001, P = 0.015, P < 0.001, respectively). Respectively, AULE of lumbar one to lumbar three was decreased as age increased. However, AULE of lumbar four was increased as age increased. SSA of lumbar one to lumbar three showed significant difference in different age stages , indicating SSA of lumbar one to lumbar three was negatively associated with age. Additionally, TSA of lumbar one to lumbar three illustrated negative relation to age .We further determined the correlation between aging and lumbar parameters despite other factors. As indicated in Table Given the importance that men and women have different hormone changes which may affect bone change, we further investigated whether the dynamic change in lumbar is gender‐dependent. To address this issue, these data of two genders was analyzed respectively.P < 0.001), lumbar two (P < 0.001) and lumbar four (P = 0.020) was correlated to age. In detail, male AULE in lumbar one (r = −0.3510) and lumbar two (r = −0.2728) was decreased with aging, while male AULE in lumbar four (r = 0.1663) was increased with aging.As indicated in Table P < 0.001, P < 0.001, P < 0.001, respectively). This association was negatively related .Additionally, as indicated in Table P = 0.017, P = 0.001, P = 0.005, P = 0.036, respectively).Furthermore, as indicated in Table P = 0.003, P < 0.001, P = 0.041, P < 0.001, respectively). Respectively, female AULE in lumbar one to lumbar three was decreased with aging , while female AULE in lumbar four was increased with aging (r = 0.2752).As indicated in Table P < 0.001, respectively).Moreover, as shown in Table P = 0.264, P = 0.655, P = 0.693, P = 0.800, respectively).However, as shown in Table Collectively, the change of lumbar anatomy parameters was associated with age and this association was gender‐dependent.Previous study found some bones were not unchanged with agingIn the present study, we found that all of the lumbar anatomy parameters were correlated to age. In addition, this correlation was age‐dependent and gender‐dependent. Importantly, male and female participants did not show the exact same change. In detail, in both genders, AULE in lumbar one and lumbar two was decreased with aging, while AULE in lumbar four was increased with aging. In addition, in both genders, SSA in lumbar one to lumbar three was negatively associated with age. However, male AULE in lumbar three showed no significant difference while female AULE in lumbar three showed significant difference. Moreover, male TSA in lumbar one to lumbar four was negatively associated with age, while female TSA in lumbar one to lumbar four demonstrated no significant difference. Collectively, these data indicated that, with increased age, body structure also changed in accordance to required force balance, and that structural change may be affected by gender.Our group established the non‐uniform settlement theory by researching anatomy, radiology, biomechanics, and clinicIn the musculoskeletal system, bone plays an important role in maintaining position by its supporting functionDegenerative kyphosis is partially caused by osteoporosisNon‐uniform settlement theory was firstly applied in osteoarthritis, and the present study found degenerative kyphosis also had the non‐uniform settlement phenomenon. Firstly, decreased AULE indicated that anterior vertebral body lost more height than posterior vertebral body. Secondly, the compacted vertebral body had the ability to afford body loading. Furthermore, the lumbar anatomy parameters, including anterior, medial, and posterior, all changed with aging. Importantly, this pathological process is chronic, finally leading to degenerative diseases. Notably, restoring body biomechanics may be a potential treatment for these mentioned diseases.Our group previously established “non‐uniform settlement phenomenon” in osteoarthritis and “dynamic change” in the hip. These two findings are correlated and in consequence. Since bone suffers from different loading and osteoporosis occurs differently, the shape, bone mineral density, and strength of the bone all change to adapt to its nature. In this process, the bone is in dynamic change, and finally we found this non‐uniform settlement phenomenon. In the present study, we found lumbar anatomy parameters were in dynamic change, however, whether this change was induced by osteoporosis needs to be further discussed.The present study also had some limitations. First of all, this is retrospective study, and more information should be discussed in the follow‐up prospective study in order to exclude the effect of other factors. Secondly, the mechanism and initiation factor of kyphosis were not investigated in the present study.Collectively, the height of anterior column of lumbar one was decreased with aging which is associated with kyphosis, and the TSA in lumbar one, lumbar two and lumbar three was negatively associated with age. In turn, this association is gender‐dependent. Spinal surgeons should pay attention to these changes when performing the related operation.


Thymic carcinomas (TCs) are rare aggressive tumors with no standard first‐line treatment. This study was conducted to determine the optimal chemotherapy regimen for advanced TC.This retrospective study included 67 patients treated for stage IV TC in 2006–2015. The primary endpoints were the objective response rate (ORR) and progression‐free survival (PFS) with different chemotherapy regimens. Multivariate Cox regression analysis was used to identify factors associated with PFS, including metastatic status, radiotherapy post‐chemotherapy, primary lesion resection before chemotherapy, and chemotherapy regimen.P = 0.890). Median PFS, one‐year PFS rate, and two‐year PFS rate were 7.0 months, 26%, and 6% with paclitaxel‐platinum treatment and 12 months, 48%, and 24% with gemcitabine‐platinum treatment (log‐rank P = 0.030). Median PFS, one‐year PFS rate, and two‐year PFS rate were 18.0 months, 57%, and 33% with surgical resection and 7.3 months, 31%, and 7% without resection (log‐rank P = 0.030). Median PFS, one‐year PFS rate, and two‐year PFS rate were 13.0 months, 52%, and 20% with radiotherapy and 4.3 months, 22%, and 7% without radiotherapy (log‐rank P = 0.001). In multivariate analysis, metastatic status , surgical resection , and radiotherapy  were associated with superior PFS.A total of 36 patients received a paclitaxel‐platinum regimen, 31 received a gemcitabine‐platinum regimen, 14 underwent primary lesion resection, and 33 underwent radiotherapy. ORR was 31% (11/36) and 29% (9/31) in the paclitaxel‐platinum and gemcitabine‐platinum groups, respectively (Both gemcitabine‐platinum and paclitaxel‐platinum regimens were efficacious for advanced TC. Primary lesion resection and radiotherapy may also benefit selected patients. Although thymic tumors are the most common primary tumors in the anterior mediastinum, overall they are rare. They occur at a rate of only 1.5 cases for every million people each year in the US.The purpose of this study was to evaluate the optimal first‐line chemotherapy regimen in patients with advanced TC.A total of 67 patients with stage IV (including IVa and IVb) TC admitted to Beijing Cancer Hospital between January 2006 and December 2015 were recruited. The study was approved by the Hospital's Institutional Review Board. All patients provided written informed consent before collection and use of their clinical information.The enrollment criteria were as follows: (i) diagnosis of TC based on the 2004 World Health Organization criteria, which was established by experienced pathologists; (ii) clinical stages IVa or IVb, according to Masaoka‐Koga staging systemThe Response Evaluation Criteria in Solid Tumors (RECIST 1.1) system was used to evaluate tumor response. Objective response rate (ORR) was defined as the sum of the complete response (CR) and partial response (PR). Progression‐free survival (PFS) was defined as the length of time from the first cycle of chemotherapy to the time of documented tumor progression or death.P < 0.05) in the univariate analysis were included in the multivariate Cox proportional hazards model. All P‐values were two‐sided, and P < 0.05 was considered significant. All statistical analyses were performed using SAS .The primary endpoints of the study were the ORR and PFS of different chemotherapy regimens. Baseline clinical characteristics and ORRs of the two regimens were compared using Pearson's chi‐square test or Fisher's exact test. The following factors were analyzed to determine their effects on PFS: age, sex, metastatic status, radiotherapy after chemotherapy, resection of primary lesion before chemotherapy, type of chemotherapy regimen, and number of cycles of chemotherapy. The Kaplan‐Meier method was used to estimate median PFS, PFS rates at one year, and two years. Univariate analysis was conducted using the log‐rank test to identify prognostic factors for PFS. Significant factors (n = 32) or more than one organ (n = 10). The extra‐lymphatic sites of metastasis included bone (19 patients), lungs (16 patients), liver (14 patients), and adrenal glands (three patients). Twenty‐seven patients had both lymph node and distant metastases. All patients received four to six cycles of chemotherapy.A total of 67 patients with Masaoka‐Koga stage IV TC were enrolled in this study. Their clinical characteristics are summarized in Table Patients were followed until 30 July 2018, with a median follow‐up period of 27.8 months . By the time of last follow‐up, 58 patients had experienced progressive disease (PD) and 29 patients had died. The mortality rate was 43.2% (29/67).n = 36; 53.7%) or a gemcitabine‐platinum regimen  as their first‐line chemotherapy regimen. The paclitaxel‐based group patients received paclitaxel (175 mg/m2) plus cisplatin , carboplatin , or nedaplatin  every three weeks for a maximum of six cycles. The gemcitabine‐based group patients were treated with gemcitabine  plus cisplatin , carboplatin , or nedaplatin  every three weeks for a maximum of six cycles. The distribution, PR, PD/SD (stable disease), and ORR of each regimen are shown in Table P = 0.890).All patients received either a paclitaxel‐platinum regimen (P = 0.030).Figure P = 0.030).Only 14 patients 20.9%) underwent surgical resection before chemotherapy because resection was difficult to achieve. In four of these patients, the tumor was completely resected; in the other 10 patients, only palliative surgery was performed. Figure 0.9% undeP = 0.001).A total of 33 patients (49.3%) received radiotherapy after chemotherapy. Figure P = 0.080).Figure P = 0.003).Figure P = 0.005), radiotherapy after chemotherapy , and metastatic status  were independent prognostic factors for PFS (Table P = 0.225). Age, sex, and number of cycles of chemotherapy were also not significantly associated with PFS.In stepwise multivariate Cox regression analysis, surgical resection  of R0 resection for stage IV thymomas and TCs.Many studies have confirmed surgical resection as the most important factor in the treatment of TC. Kondo and Monden reported five‐year survival rates of 67%, 30%, and 24% for total resection, subtotal resection, and inoperable treatment, respectively.It has been previously reported that patients with advanced TC may benefit from radiotherapy.There is currently no standard first‐line chemotherapy regimen for advanced TC. Cisplatin‐ and adriamycin‐based regimens have been recommended by some authors, with response rates ranging from 42% to 50% and median PFS durations ranging from six to eight months.The literature is unclear regarding the efficacy of gemcitabine‐platinum regimens in TC. Only one study demonstrated that the regimen was effective in advanced TC, producing an ORR of 61.5% and a median PFS of 14.5 months.The current study is limited by its retrospective nature and small sample size. However, because of the low incidence of TC, it is difficult to develop a large, prospective clinical study.In conclusion, both gemcitabine‐platinum and paclitaxel‐platinum regimens demonstrated promising efficacy in advanced TC. Resection of the primary lesion before chemotherapy and radiotherapy after chemotherapy may be beneficial options for selected patients.No authors report any conflict of interest.Figure S1. Kaplan‐Meier curves comparing progression‐free survival of patients with stage IVa or stage IVb tumors.Table S1. Distribution and response rates of the two chemotherapy regimens.Click here for additional data file.