Recent work suggests that hair cells are not the most vulnerable elements in the inner ear; rather, it is the synapses between hair cells and cochlear nerve terminals that degenerate first in the aging or noise-exposed ear. This primary neural degeneration does not affect hearing thresholds, but likely contributes to problems understanding speech in difficult listening environments, and may be important in the generation of tinnitus and/or hyperacusis. To look for signs of cochlear synaptopathy in humans, we recruited college students and divided them into low-risk and high-risk groups based on self-report of noise exposure and use of hearing protection. Cochlear function was assessed by otoacoustic emissions and click-evoked electrocochleography; hearing was assessed by behavioral audiometry and word recognition with or without noise or time compression and reverberation. Both groups had normal thresholds at standard audiometric frequencies, however, the high-risk group showed significant threshold elevation at high frequencies (10–16 kHz), consistent with early stages of noise damage. Electrocochleography showed a significant difference in the ratio between the waveform peaks generated by hair cells  vs. cochlear neurons , i.e. the SP/AP ratio, consistent with selective neural loss. The high-risk group also showed significantly poorer performance on word recognition in noise or with time compression and reverberation, and reported heightened reactions to sound consistent with hyperacusis. These results suggest that the SP/AP ratio may be useful in the diagnosis of “hidden hearing loss” and that, as suggested by animal models, the noise-induced loss of cochlear nerve synapses leads to deficits in hearing abilities in difficult listening situations, despite the presence of normal thresholds at standard audiometric frequencies. Most hearing impairment in adults is sensorineural in origin. It is caused by damage to the inner ear, where the cochlear hair cells normally convert mechanical vibrations into electrical signals that are transmitted via glutamatergic synapses to the sensory fibers of the cochlear nerve. Each human cochlea contains only ~15,000 hair cells and ~40,000 nerve fibers. Once destroyed, neither cell type regenerates in any mammalian ear ).Recent animal studies showing that noise exposure can lead to cochlear neuronal degeneration, even when hair cells recover and thresholds return to normal  have chaPart of the reason for the relative insensitivity of threshold measures to cochlear synaptopathy is that, near threshold, a small increase in sound level can compensate for a large loss of neurons, by increasing discharge rates in remaining fibers and by spreading activity to additional fibers along the cochlear spiral . AnotherCochlear synaptopathy may also be key to the genesis of other perceptual anomalies associated with noise damage, including hyperacusis and tinnitus –23, whicBased on the animal work, we hypothesized that cochlear synaptopathy is widespread among young people who regularly abuse their ears, despite the presence of a normal audiogram. For the present study, we recruited young adult subjects and divided them according to noise-exposure history into high-risk and low-risk groups. We found significant deficits in difficult word-recognition tasks in the high-risk group that were associated with significant elevation of pure-tone thresholds at frequencies higher than those normally tested and with changes in auditory evoked potentials consistent with the presence of cochlear synaptopathy, also known as hidden hearing loss.Young adults were recruited from local colleges and universities. Subjects were between 18 and 41 yrs of age, in good health, with no history of ear or hearing problems, and no history of neurologic disorders. They were all native speakers of English with unremarkable otoscopic examinations. To be eligible, participants had to have normal audiometric thresholds from 0.25–8 kHz in both ears. There were no other inclusion criteria beyond the ability to give voluntary informed written consent prior to participation. This research study was reviewed and approved by the Institutional Review Board of Northeastern University.systematically used hearing protection devices when exposed to loud sounds. Based on their responses, each subject was assigned to a group, low-risk or high-risk for ear damage. Most high-risk subjects were studying music performance in local music colleges and conservatories. Most low-risk subjects were students in communication science and disorders.All subjects completed a series of questionnaires see  that incTo these generic medico-legal, noise and ear health questions, were added 5 items relating to the subject’s self assessment of their hearing abilities in different listening environments  and 3 items relating to their ability to localize a sound source. Subjects were asked to answer the question “can you follow the conversation?” by rating their ability on a scale from 0  to 10 (perfectly). Participants were then asked to rate separately the loudness and annoyance of 12 everyday sounds  on a scale from 0  to 100 (unbearably loud / extremely annoying). Finally, participants were asked to rate on a scale from 0  to 100 (completely agree) with 10 statements related to hyperacusis .All the following tests were administered in a sound-treated booth at the Northeastern University Speech-Language and Hearing Center.® Astera2 audiometer. Pure-tone air-conduction thresholds were measured from 250 Hz to 16,000 Hz at octave intervals and also at 9, 10, 11.2, 12.5 and 14 kHz. At 8 kHz and below TDH-39P headphones were used; above 8 kHz, we used a circumaural HDA200 high-frequency headset. Bone-conduction thresholds were acquired from 250 Hz to 4,000 Hz by placing a Radioear B-71 vibrator over the mastoid process of the temporal bone. Word recognition performance was assessed monaurally at 35 dB HL using the Northwestern University Auditory Test Number 6 (NU-6) list consisting of 50 phonemically balanced words. Word recognition scores were assessed in 5 conditions using different word lists for each condition: in quiet or in the presence of ipsilateral noise at a signal-to-noise ratio of 5 dB or 0 dB (3 conditions) or after digital time compression to 45% or 65% of original duration, both with a 0.3 sec reverberation added  [Audiometric thresholds were obtained using an Otometrics Madsenditions) . In orde™ Distortion Product Otoacoustic Emission (DPOAE) system and software . DPOAEs were measured as amplitude vs. frequency sweeps—or DPgrams—with two primary tones f1 and f2 (f2/f1 = 1.22), at f1 = 65 dB SPL and f2 = 55 dB SPL. Primary frequencies were swept from f2 = 500 Hz to 12 kHz, with 4 logarithmically spaced steps per octave. The DPOAE at 2f1-f2 was extracted from the ear canal sound pressure after both waveform and spectral averaging, without corrections for standing wave artifacts.Stimulus generation and data acquisition were handled by a GSI Audera™ AEP/CAEP computer system and software . Subjects’ ear canals were prepped by scrubbing with a cotton swab coated in Nuprep®. Electrode gel was applied on the clean portion of the canal and over the gold-foil of each tiptrode before insertion. A horizontal montage was used with a ground on the forehead at midline, one tiptrode as the inverting electrode and the other tiptrode as the non-inverting electrode in the opposite ear. Impedance between pairs of electrodes were <2 kΩ. Acoustic stimuli were delivered via silicone tubing connected to the ER-3A earphones. Stimuli were 100 μs-clicks delivered at 94.5 dB nHL in alternating polarity at a rate of 9.1 Hz or 40.1 Hz. Ipsilateral clicks were presented with a 55 dB nHL contralateral broadband masker to eliminate contamination of the ABR responses with contributions from the contralateral ear. Electrical responses were amplified 100,000X with a 10–3,000 Hz passband filter. Up to 2,000 sweeps were averaged, with artifact rejection enabled in the software.Stimulus generation and data acquisition were handled by a GSI AuderaThe summating potential (SP) and action potential (AP) peaks were defined by visual inspection by two observers : SP placements were identical in 98% of cases; AP placements were identical in all cases. The SP peak was defined as the highest inflection point within the first msec post-stimulus onset, i.e. where the slope either approached or reached zero. The AP peak was placed at the maximum value between 1 and 2 msec post onset: in all but two cases (both from the high-risk group) the AP peak was between 1 and 1.5 msec. SP and AP amplitudes were defined as the difference between peak and baseline (lowest amplitude within the first msec).2)) with degrees of freedom equal to n-2.Two-tailed heteroscedastic t-tests were used to test the statistical significance of the mean differences observed between our two groups. Two-way ANOVAs were used to compare the mean differences between groups when there were two independent variables. To test for the significance of the correlation coefficient, we computed the t value as follow: t = r √ ((n-2)/ were studying music performance in local colleges and conservatories. Most low-risk subjects  were studying communication sciences and disorders and were knowledgable about the damaging effects of noise/music overexposure on the inner ear. None of these subjects was familiar with the content of the NU-6 word list.All subjects had normal audiometric thresholds (< 20 dB HL) across the standard audiometric frequencies (0.25–8 kHz), and mean hearing thresholds were closely matched between groups . HoweverOuter hair cell (OHC) function was evaluated by recording distortion product otoacoustic emissions (DPOAEs), which are created and amplified in the healthy inner ear, and propagated back to the ear canal, where they can be measured in the sound pressure recorded in response to two continuous tones in the appropriate frequency and level ratios . DPOAEs According to the questionnaires, no participants felt they had hearing difficulties in a quiet environment. All subjects rated their performance as close to “perfect” with average scores > 95% in both groups . AlthougWhen asked to rate the loudness and annoyance of 12 everyday sounds, subjects in the high-risk group tended to give higher values. However, only differences in annoyance ratings reached statistical significance ; p<0.01.To assess cochlear neural function, we measured click-evoked auditory brainstem responses from “tiptrode” electrodes in the ear canal . Animal Individual SP/AP ratios were computed and averaged across groups. The high-risk group had a mean SP/AP ratio nearly twice that of the low-risk group , p<0.001Of the many speech-in-noise tests used in clinical studies , we chosTo gain insight into whether the performance decrements were due to synaptopathy or the high-frequency threshold shifts, we compared the correlations between individual speech scores and the SP/AP ratio  to the cRecent animal studies of the noise-exposed or aging ears have shown that synaptic connections between hair cells and cochlear neurons can degenerate well before the loss of sensory cells themselves. This cochlear synaptopathy has been called “hidden hearing loss”, in part, because it can hide behind a normal audiogram . Animal This study aimed to test the hypothesis that “hidden hearing loss” is widespread among young adults with normal audiometric thresholds, especially those who abuse their ears regularly. We identified and recruited college students and divided them into high-risk and low-risk groups based on self-report of exposure to loud sounds and use of hearing protection devices. Both subject groups had normal audiometric thresholds up to 8 kHz, as this was one of the entry criteria. Standard audiometric testing does not assess thresholds above 8 kHz, although younger people can easily hear tone frequencies at least an octave higher (16 kHz). We chose to measure high-frequency thresholds (from 8–16 kHz), because animal studies show that, regardless of the frequency spectrum of the traumatic sound, the first signs of noise-induced hair cell damage and threshold elevation are at the extreme cochlear base, i.e. in cochlear regions tuned to the very highest frequencies for that species , 36, 37.Indeed, our high-risk subjects showed significant threshold elevations at all test frequencies > 8 kHz, reaching ~20 dB HL on average at 16 kHz . This hiIn animals, cochlear synaptopathy can be diagnosed via the suprathreshold amplitudes of ABR wave 1, when the interpretation is not complicated by hair cell damage and the threshold shift that it causes , 39. In per se, in the high-risk group, which clearly contributed to the intergroup differences in SP/AP ratio. These results are strikingly similar to those in a prior study comparing SP and AP amplitudes before and immediately after exposure to music traumatic enough to cause a temporary threshold shift of 10–15 dB [Indeed, although intergroup differences in AP amplitudes were not significant in the present study , the SP/10–15 dB . In thatInterpretation of the electric response in and around the SP peak is complicated, because it could have contributions from two types of potentials: 1) non-linear components in the receptor potentials from inner and/or outer hair cells which are not cancelled by stimulus reversal, and 2) excitatory post-synaptic potentials (EPSPs) from cochlear nerve terminals under inner hair cells . Both these contributions can have negative or positive components. Thus, for example, enhancement of the SP could arise from loss of a negative EPSP rather than from the enhancement of a positive hair cell non-linearity. It is also possible that the putative synaptopathy in the high-risk group has attenuated the middle-ear muscle reflex, as observed in synaptopathic mice . This reAlthough an increased SP/AP ratio in the high-risk group is consistent with cochlear synaptopathy, possible contribution of the basal-turn hair cell damage inferred from the high-frequency threshold elevations  must alsPrior human work has suggested that the SP/AP ratio might be diagnostic for Ménière’s disease , an inneIt is well know that two people with the same audiogram, whether normal or abnormal, can have different speech discrimination abilities, especially in a noisy environment , 49, andHere, we show that our high-risk subjects report increased difficulty in noisy environments  and haveRecent human studies suggest beneficial effects of musical training on speech-in-noise abilities , 51. ThuSensorineural hearing loss, especially in aging ears, is often accompanied by tinnitus and hyperacusis. It has been suggested that loss of sensory outflow from the auditory periphery causes a compensatory increase in “central gain” that underlies these perceptual anomalies , 52. IndPresent data suggest that a combination of ear-canal electrocochleography, high-frequency audiometry and word recognition tasks can possibly identify the earliest signs of noise damage to hair cells and neurons, neither of which is detected by standard audiometry. In animal studies of noise-induced damage, mid-cochlear synaptopathy is seen at exposure levels lower than those that damage the basalmost hair cells and elevate high-frequency thresholds . Thus, iNoise damage early in life likely accelerates the age-related further loss of hair cells and cochlear neurons, even in the absence of further ear abuse , 39. ClaAlthough the noise-induced loss of cochlear synaptic connections can happen within hours post-exposure , the degS1 Appendix(DOC)Click here for additional data file.S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.


N = 15) with a comparison group of hearing adults (N = 15) matched on age and education level. The adults with CI showed significantly better scores on the speechreading task than the hearing comparison group. Furthermore, within the group of adults with CI, there was a significant positive correlation between age at implantation and speechreading performance; earlier implantation was associated with lower speechreading scores. These results are both consistent with the hypothesis of perceptual compensation in the domain of speech perception, indicating that more prolonged dependence on visual speech information in speech perception may lead to improvements in the perception of visual speech. In addition our study provides metrics of the ‘speechreadability’ of 123 words produced in British English: one derived from hearing adults (N = 61) and one from deaf adults with CI (N = 15). Evidence for the validity of these ‘speechreadability’ metrics come from correlations with visual lexical competition data.Previous research has provided evidence for a speechreading advantage in congenitally deaf adults compared to hearing adults. A ‘perceptual compensation’ account of this finding proposes that prolonged early onset deafness leads to a greater reliance on visual, as opposed to auditory, information when perceiving speech which in turn results in superior visual speech perception skills in deaf adults. In the current study we tested whether previous demonstrations of a speechreading advantage for profoundly congenitally deaf adults with hearing aids, or no amplificiation, were also apparent in adults with the same deafness profile but who have experienced greater access to the auditory elements of speech via a cochlear implant (CI). We also tested the prediction that, in line with the perceptual compensation account, receiving a CI at a later age is associated with superior speechreading skills due to later implanted individuals having experienced greater dependence on visual speech information. We designed a speechreading task in which participants viewed silent videos of 123 single words spoken by a model and were required to indicate which word they thought had been said via a free text response. We compared congenitally deaf adults who had received CIs in childhood or adolescence ( The perceptual compensation hypothesis refers to the idea that sensory deprivation within one sensory modality will stimulate compensatory perceptual improvement in another sensory modality . IndividA body of work by N = 96) and with severe to profound early onset (94% experienced onset ≤ 4 years) deafness (N = 72) to speechread consonant-vowel nonsense syllables, words and sentences. The adults with early onset deafness showed enhanced speechreading ability relative to the hearing adults on all three types of speechreading stimuli, indicative of superior visual phonetic perception in the deaf adults. N = 112) of adults with early deafness (onset < 4 years) with that of a group of hearing adults (N = 220) on a sentence-level speechreading task. They found significant advantages for the deaf adults who identified 43.55% of the target words correctly compared to only 18.57% for the hearing group. They concluded that “the need to rely on visual speech throughout life and particularly for the acquisition of spoken language by individuals with early onset hearing loss, can lead to enhanced speechreading ability.” Similar results were reported by In contrast with the findings on adults with acquired hearing loss, studies with groups of adults who have congenital or early onset deafness have been more consistent in demonstrating significant speechreading advantages compared to hearing adults. A range of skills are likely to underpin this speechreading advantage in those born deaf. In particular it is clear that individual differences in cognitive skills play an important role in speechreading skill ; devices which convert acoustic stimuli into electrical signals and directly stimulate the auditory nerve to provide deaf individuals with access to sound . For indHowever, it is important to recognize that a CI uses a maximum of 22 electrodes to replace the function of around 16,000 hair cells and as a consequence conveys highly impoverished information about speech sounds compared to a normally functioning human cochlea . The redN = 97) showed significantly higher speechreading performance than a comparison group of hearing adults (N = 163) when they were assessed prior to cochlear implantation. This advantage maintained in the months and years following cochlear implantation despite these deaf adults substantially increasing their auditory-only word recognition abilities. Additionally, N = 8) of participants who had experienced sudden onset deafness less than a year before they received a CI and who still showed significantly superior speechreading performance compared to the hearing participants prior to, and following, cochlear implantation. They argued on the basis of this that “a high level of speechreading ability can be acquired rapidly during a period of auditory deprivation,” a position in stark contrast to that of The study by N = 28) with CIs, the majority of whom received their CI in adulthood (>19 years), and a sample of hearing adults (N = 43). As was the case in the original As part of a study looking at audiovisual spoken word training, N = 31; M age = 10 years, SD = 0.47) with that of hearing children  on a task that required them to identify vowel-consonant-vowel nonsense syllables. They reported no significant differences between the groups in terms of their identification performance when the syllables were presented in a visual-only format, indicating no speechreading advantage for these deaf children with CIs over their hearing peers. This finding is consistent with the results from a study by In this study we therefore focused on deaf adults and aimed to test whether the group-level speechreading advantage demonstrated by As mentioned above, auditory speech perception outcomes following implantation are highly variable and are impacted by a number of different variables. For post-lingually deafened adults, factors identified as predictors of auditory speech perception following implantation include duration of pre-implant deafness and residual hearing pre-implant . For preIn the present study we focus on one variable that has been consistently associated with variability in auditory speech perception outcomes following CI; age at implantation. Age at implantation effects on speech perception outcomes have been discussed in the context of sensitive periods for the development of the central auditory system. One study has addressed this question of whether there is evidence of a relationship between age at implantation and speechreading ability and has done so in children with CIs: To summarize, in the present study we tested the following hypotheses:(1)Profoundly, congenitally deaf adults with CIs would show a significant advantage in their single word speechreading skills compared to a matched group of hearing adults.(1)Within the group of adults with CIs, age at implantation would relate to speechreading skill, with earlier implanted adults showing less good speechreading skills.Sixty one native English-speaking hearing participants provided data for this study. All reported normal hearing and normal or corrected-to-normal vision. The participants were either undergraduate students participating for course credit or volunteers from the wider community who had responded to adverts to take part in the study. All provided informed consent prior to participation in the study. An additional 13 participants consented to participate in the study but were excluded from the current dataset as a result of not completing all items in the task.M = 8.27, SD = 5.05). All reported normal or corrected-to-normal vision and profound deafness.Fifteen congenitally deaf participants with CIs participated in this study. Age at implantation ranged from 2 to 19 years (N = 61) on the basis of age and education level, with these 15 matched hearing participants forming the hearing comparison group (HCG). There were no significant differences in the distribution of ages between the CI  and HCG  groups . The groups also did not differ significantly in terms of the distribution of highest education level achieved .To faciliate comparisons between the speechreading performance of CI and hearing participants, each of the 15 CI participants was individually matched to a hearing participant from the larger hearing sample (Supplementary Table S1 for full list). All words were either concrete nouns or colors. Information on the visual speech lexical competition experienced by the speechread target words was sourced from the Phi-Lex database .A video of each word being spoken by a female model was made using a Sony Handycam (HDR-CX115). The word was spoken aloud at a normal conversational volume during the recording and the videos were subsequently edited to mute the volume such that the participants saw a natural production of the word but without any sound. The same model produced each word. The model maintained a neutral facial expression in the production of every word and the camera distance, lighting and background conditions were consistent for each word . This meant they could score a maximum of 123 on the task.Prior to completing the speechreading task the participants provided demographic information via the web-based tool. Additional audiological information was collected from the participants with a CI via a paper-based response form prior to their completion of the speechreading task.SD = 9.94; range = 2–48) out of 123. This was equivalent to a mean proportion correct of 0.18 . The mean number of words identified correctly by the hearing participants was significantly above the floor of 0  and significantly below the ceiling of 123 .The mean number of words identified correctly by the 61 hearing participants was 22.38  and by the matched HCG was 24.20  . This was equivalent to a mean proportion correct of 0.33 (SD = 0.14) for the CI group and 0.20 (SD = 0.08) for the HCG. Levene’s test indicated unequal variances between the two groups. Therefore the unequal variance Welch t-test was used. This showed that deaf CI users scored significantly higher than the hearing control group on the speechreading task, t(23.35) = 3.25, p = 0.003, d = 1.19. The mean number of items correct for the matched HCG used for this group comparison  did not differ significantly from that of the remaining hearing participants , , suggesting that the level of performance of these matched hearing participants was representative of the performance level of the wider hearing sample.The mean number of words identified correctly by the CI participants was 40.80 , with those participants who received their CIs at a later age showing higher speechreading scores than the earlier implanted participants . A regression analysis predicting speechreading task score with age and education level entered at Step 1 and age at implantation at Step 2 indicated that age at implantation accounted for significant unique variance in speechreading performance, accounting for 30% of the variance over and above the 11% accounted for by age and education level (Table 1).Within the CI group there was a significant positive correlation between age at implantation and score on the speechreading task . These data provide a metric of ‘speechreadability’ of the 123 words when produced in British English.For the 61 hearing participants, the proportion correct for individual items ranged from 0.77 (for ‘rabbit’) to 0.00 . r(121) = 0.79, p < 0.001, BCA bootstrapped 95% CI = 0.70–0.85]. For the 15 deaf participants with CIs, proportion correct for individual items ranged from 0.87  through to 0.00 . Supplementary Table S2 presents data on the proportion correct responses to each of the 123 items for the participants with CIs.There was a high degree of concordance between the hearing participants and the deaf participants in terms of the relative success rates on the individual items  and the CI participants  indicating that words that had fewer visual (visemic) lexical competitors were more successfully identified by both groups of participants.Relationships between the proportion of correct responses to an item (PropCorr) and word properties of that item were examined for the 86 words that had continuous visual lexical competition data (ConV) available for them. The distribution of the PropCorr and ConV variables showed deviations from normality so bias corrected and accelerated bootstrapped 95% confidence intervals (1000 bootstrap samples) are presented for the correlation coefficients. The number of correct responses for the items showed a significant negative correlation with ConV for both the hearing participants [The first aim of this study was to compare the single word speechreading ability of hearing adults and deaf adults with CIs in order to test the hypothesis that prelingually deaf adults who received an implant in childhood or adolescence would show a speechreading advantage. We found that the mean score on the speechreading task was significantly higher for the adults with CIs than for the matched comparison group of hearing adults. The performance of the matched HCG did not differ significantly from that shown by the larger sample of hearing participants who were not selected for the HCG, suggesting HCG performance was representative of the broader hearing sample. This finding of a speechreading advantage for the deaf adults with CIs in this study is consistent with the findings of In terms of the locus of this compensation, the finding in this study of an advantage for the adults with CIs on a single word speechreading task in which there was no sentential context suggests that the deaf speechreading advantage is not exclusively driven by an enhanced ability to use sentence-level contextual information to facilitate identification of individual words. This is not to say that the use of top down sentence-level processing to aid speechreading is not something that deaf adults develop the capacity to use to effectively support speechreading in real word contexts, but rather that they also have enhanced skills in domains that support the type of context-free lipreading performance assessed in this task. This suggests that they may be better at visually perceiving individual phonemes. Alternatively, they may be better either at perceiving rapid sequences of phonemes or at using coarticulatory information in phoneme sequences to disambiguate visual phonetic information  Future studies should aim to test this by comparing the performance of hearing adults and deaf adults on a speechreading task in which they have to speechread both individual phonemes  and also non-words which use the phonotactics of the ambient spoken language .The second aim of this study was to test the hypothesis that, within the CI group, later implantation would be associated with superior speechreading skills. We found a significant positive correlation between age at implantation and speechreading performance, indicating a speechreading advantage for those implanted at later ages. This result is consistent with the hypothesis that a greater duration or degree of dependence on visual information for speech perception leads to improved visual speech perception skills and therefore with the idea of perceptual compensation in the domain of speech perception. The finding of superior visual speech perception skills in later implanted adults is also consistent with the findings of It was also the case that we did not have extensive information regarding the language skills of the CI participants. It is possible that variability in underlying spoken language knowledge within the CI group may have influenced their performance on the speechreading task and hence the relationship between age at implantation and speechreading score. However, this would be dependent on the later implanted participants showing superior spoken language skills to the earlier implanted participants, a situation which is the reverse of that typically observed. Additionally, the language demands in this speechreading task were relatively low. Participants identified single words, all of which were early acquired concrete nouns, meaning that the contributions of existing language knowledge to task performance are likely to have been minimized.The speechreading task used in this study was completed remotely via the internet. Unfortunately this meant that we were unable to collect measures of participant’s other cognitive skills known to be important to individual differences in speechreading skill, such as phonological skills and working memory capacity see , 2013. FThe results of this small scale study provided two strands of evidence that are consistent with perceptual compensation in the domain of speech perception. First, prelingually deaf adults with CIs showed a significant advantage in terms of their performance on a visual-only speechreading task compared to a comparison group of hearing adults matched on age and education. Second, age at implantation within the CI group showed a significant positive relationship with performance on the speechreading task; participants who received their implants later in life showed superior visual-only speech perception skills. We argued that in both cases these patterns of findings resulted from increased dependence on visual speech information leading to compensatory improvements in perception of speech via the visual modality.This research was approved by the University College London Research Ethics Committee. Online informed consent was obtained from each participant.HP and MM designed the study. AR-L collected the data. HP analysed the data. HP and MM wrote the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Leishmania major rodent reservoir and the development of these rodents is known to have a significant dependence on environmental and climate factors. ZCL in Tunisia is one of the most common forms of leishmaniasis. The aim of this paper was to build a regression model of ZCL cases to identify the relationship between ZCL occurrence and possible risk factors, and to develop a predicting model for ZCL's control and prevention purposes. Monthly reported ZCL cases, environmental and bioclimatic data were collected over 6 years (2009–2015). Three rural areas in the governorate of Sidi Bouzid were selected as the study area. Cross-correlation analysis was used to identify the relevant lagged effects of possible risk factors, associated with ZCL cases. Non-parametric modeling techniques known as generalized additive model (GAM) and generalized additive mixed models (GAMM) were applied in this work. These techniques have the ability to approximate the relationship between the predictors (inputs) and the response variable (output), and express the relationship mathematically. The goodness-of-fit of the constructed model was determined by Generalized cross-validation (GCV) score and residual test. There were a total of 1019 notified ZCL cases from July 2009 to June 2015. The results showed seasonal distribution of reported ZCL cases from August to January. The model highlighted that rodent density, average temperature, cumulative rainfall and average relative humidity, with different time lags, all play role in sustaining and increasing the ZCL incidence. The GAMM model could be applied to predict the occurrence of ZCL in central Tunisia and could help for the establishment of an early warning system to control and prevent ZCL in central Tunisia.Transmission of zoonotic cutaneous leishmaniasis (ZCL) depends on the presence, density and distribution of  Leishmania major and is well spread in rural areas where human resources in public health and infrastructure are limited. The cycle of transmission of the disease is complex because of the impact of climate change. In this study we evaluated the impact of bioclimatic factors on the transmission of the disease in three districts of Sidi Bouzid, central Tunisia. We found that the occurrence of zoonotic cutaneous leishmaniasis is mainly related to average temperature with 4 months lags, rodents' density lagged 2 months, relative humidity with 4 months lags and cumulative rainfall lagged 1 month. We also confirmed that our best-fit model predict well the occurrence of the disease.Zoonotic cutaneous leishmaniasis is a human vector-borne disease caused by the parasite  Cutaneous leishmaniasis (CL) is a neglected tropical disease widespread in the Middle East, the Mediterranean basin and North Africa ,2. Most In Tunisia, the incidence of cutaneous leishmaniasis climbed from only one endemic governorate in 1983 to 15 endemic governorates in 2014 [Leishmania infantum MON-24. In central Tunisia, ZCL caused by Leishmania major MON-25 is considered dominant and distributed across arid zones [Leishmania killicki MON-8, was detected in the South-East of Tunisia [Three clinical-epidemiological forms of cutaneous leishmaniasis identified in Tunisia, vary across regions . In the id zones . The thi Tunisia . Accordi Tunisia , the oriZCL remains primarily a disease responsible for considerable morbidity and disfigurement . The disHowever, the association between climate factors and ZCL incidence was not clearly elucidated. The way climate factors influence transmission of the disease became the main research concern. In fact, recent studies mainly used time series analysis to assess the relationship between climatic  factors and daily (or monthly) records of the disease. Diverse models were used, and the choice of a model may have large influence on quantifying climate effects. The most used model of time series analysis in the field of epidemiology, is the Autoregressive Integrated Moving Average (ARIMA) analysis ,18. ThisAlthough ARIMA process can be a robust technique for improving the quality of prediction, it assesses linearly the relation between the response variable and the predictor covariates. However, recent studies have identified non-linear relations of climate factors on ZCL incidence. Failure to model relations correctly can lead to model misspecification that can affect the error structure of the model. Studying non-linear time series analysis is still limited compared to linear series.Generalized additive models (GAM)  have beeIn this paper, we first aimed to model the relationship between the incidence of ZCL with the underlying predictor factors using the generalized additive models and its extension, the generalized additive mixed models considering the autocorrelation; and second, to predict the occurrence of the disease based on the best-fit model.The whole project was approved by the ethical committee of Pasteur Institute in Tunis, Tunisia. But in this paper we presented the results of an ecological study with monthly number of ZCL cases and climate variables.Our study area covers three districts of Bir Badr, Hichria and Zefzef. These districts are selected all around the salt pan "Garaat Njila" located in the governorate of Sidi Bouzid, central Tunisia . Such arIn our work monthly ZCL records were used, from July 2009 to June 2015. Data were obtained from an active system of epidemiologic surveillance, implemented in Sidi Bouzid, central Tunisia. All new cases of people seeking treatment at primary health care facilities and other cases notified among patients' neighbors and families by the active research of the nursing stuff were included in this surveillance. Also, all schools in this area have been asked to check and notify all ZCL cases among students. Moreover, members of the research team performed a community-based active ZCL surveillance, and notified cases in schools with a clinical suggestive form of cutaneous leishmaniasis were diagnosed by physicians and nurses from the health care facilities. Parasitologic diagnosis of ZCL lesions was carried out only for a group of patients using direct examination, skin culture, PCR TagMan and PCR high-resolution melting. No laboratory exam was undertaken by dint of the good knowledge of the disease by the medical staff, the population in this region, the high sensitivity and specificity of clinical diagnosis.The number of monthly ZCL notifications was accounted according to the date of the lesion onset for the period between July 2009 and June 2015 after being reported on a standardized sheet. Data were anonymized and for this study, we only count the number of cases monthly. There is no information about patients.The whole project was approved by the ethical committee of Pasteur Institute in Tunis, Tunisia, but in this paper we presented the results of an ecological study with monthly number of ZCL cases and climate variables.We used 2009–2014 counts for the development of the predictive models and set aside 2014–2015 counts for independent validation of the prediction.The bioclimatic variables used for this study were monthly data between July 2009 and June 2015, recorded from a private station implemented in the study area. The variables collected were: average minimal temperature, average maximal temperature, average of averages temperatures, cumulative precipitation, average relative humidity, average wind speed, maximum wind speed, and average rodent density estimated according to their activity.Our study used real data of ZCL notifications, environmental and bioclimatic variables from July 2009 to June 2015. We used a generalized additive model (GAM) and a generalized additive mixed model (GAMM) with natural cubic splines. These models were used to assess the relation between ZCL incidence and climate factors . These covariates were included into the model as fixed effects. However, autoregressive terms were considered as random effects.The first stage of the analysis was to determine the optimal lags of explanatory covariates to be used in the models. Therefore, we used cross-correlation function (CCF). The latter allowed us to determine the significant delayed dependencies, among various lags, in the association between explanatory variables and ZCL cases .The cross-correlation terms are retained in the model if the absolute value of cross-correlation coefficient is two times larger than the standard error .The different patterns of associations between environmental and bioclimatic variables defined by temperature, rainfall, relative humidity, wind speed and rodents' density, with ZCL cases were assessed using Quasi-Poisson generalized additive model (GAM) –31, usinjXj is replaced by a sum of smooth functions of the covariates ∑fj(Xj) [μt is the expectation of the response variable, yt, θ is the corresponding parameter vector and f(.) are smoothing functions of predictor variables, xt, estimated according to data. These smooth functions make the residual sum of squares (RSS) small and smooth to avoid the problem of overfitting the data. Thus, the function f minimizes:λ is a non-negative tuning parameter. The term f to fit the data well, and the term λ ∫ f"(t)2dt is a penalty term that adjust too "wiggliness" in the smoothing function, to avoid overfitting curves to the data. It encourages f to be smooth. The larger the value of λ, the smoother f will be. The tuning parameter λ controls the roughness of the smoothing functions. This parameter is determined in such a way that the generalized cross-validation is as small as possible [A GAM is a semi-parametric extension of the generalized linear model (GLM) where the linear predictor ∑β ∑fj(Xj) . Both GL ∑fj(Xj) ,34. Unli ∑fj(Xj) . The genpossible .Several GAMs were employed and generated to best fit the data. We started by performing a complete model, including all independent variables and then we proceeded to variable selection based on a stepwise backward process, using the Generalized Cross-Validation (GCV) score  as selecyi, and p covariates, xi = T, associated with fixed effects and a q × 1 vector of covariates zi associated with random effects. Given a q × 1 vector b of random effects, the observations yi are assumed to be conditionally independent with means υ(.) is a specified variance function, mi is a prior weight and ϕ is a scale parameter, and follow a generalized additive mixed model [g(.) is a link function, fj(.) are smooth functions, the random effect b is assumed to be distributed as θ is a vector of variance components.GAMM is the extension of GAM, which is proposed to overcome overdispersion and autocorrelation in observations. Compared to GAM, this class of models allows flexible dependence of a response variable on independent variables, using nonparametric regression. Also, it includes correlation between observations in the model by using random effects . Supposeed model  written The main property of the GAMM model is that independent factors are used in additive nonparametric functions in the fixed effect, and correlation between observations are considered in the random effect.Independent validation of the best-fit models was performed using data from July 2014 to June 2015. Agreement between model predictions of ZCL cases using the best-fit model, and the actually reported ZCL cases during 2014–2015, was evaluated through confidence interval analyses.There were 861 notified ZCL cases over the study period, from July 2009 to June 2014 in the three districts of Sidi Bouzid, central Tunisia. The peak of ZCL mainly occurred from August to December during the same epidemiological year . Also, tCross-correlation analysis  showed tThe probability distribution of the ZCL incidence required for GAM model is slightly over-dispersed . A Quasi-Poisson distribution fitted adequately the data.ZCLi is the ZCL cases in the ith observation. The terms f1 to f5 are the smoothing functions, and β0 is the intercept  score to compare the statistical performances of different models. The lowest GCV value yields to the best fit model. Results from the best-fit GAM model with a Quasi-Poisson distribution showed a significant associations between ZCL incidence and accumulated rainfall lagged 1 month, average temperature lagged 4 months, relative humidity with 4 months lag and rodent's density lagged 2 months  . So, thentercept .The estimated effects of environmental and climate variables on ZCL incidence are shown in From From the GAM model, the pattern of the relation between bioclimatic factors and ZCL incidence was assessed. However, the correlation between the observations of the response variable was not evaluated. So, the autocorrelation function of ZCL cases was checked , and revAt this stage, we retained the significant variables from the best fit GAM model, and used its extension, GAMM, to consider the autocorrelation of observations and whiten the errors. So, we included Autoregressive Moving Average (ARMA) processes in the error structure. According to the autocorrelation function and the partial autocorrelation function plots of the dependent variable, the error structure might be an AR(1) or ARMA. The results of the prediction analysis, using the GAMM model and carried out using data from July 2014 to June 2015, were drawn with the original values . ResultsL. major is considered as one of the most important diseases in Tunisia, few studies have been conducted studying the complicated relationships between the transmission of the disease and climatic and environmental variables. Previous studies conducted in Tunisia in 2000 and 2009 [Although cutaneous leishmaniasis caused by and 2009 ,39 reveaand 2009 . In 2012and 2009  used theand 2009 .In our study, we focused on the ZCL cases from July 2009 to June 2015 and we estimated lagged effects of diverse bioclimatic and environmental variables, including minimum temperature, maximum temperature, average temperature, cumulative rainfall, relative humidity, average wind speed, maximum wind speed, and rodent's density, on the incidence of ZCL using monthly data. We estimated significant effects of monthly average temperature, cumulative rainfall, relative humidity and rodent's density on ZCL incidence after accounting for distributed lag effects.We found that cross-correlation between ZCL incidence and independent variables was not very high, although some were statistically significant. But, we retained the significant lagged variables in association with the incidence. In fact, the cycle of transmission of the disease is considered complex since the existence of three seasonality patterns: the first one stressed the importance of climate changes in the study region caused by the construction of dams and irrigation projects. Second, the climate variability may affect the density of rodents' reservoirs which is highly affected by the availability of chenopods, a plant exclusive food source of rodents, in the region . So, traThen, we identified the relationship between ZCL and the selected environmental and bioclimatic factors in Sidi Bouzid, central Tunisia. To explain this association, a Quasi-Poisson GAM regression was chosen to be the model adopted that integrates parametric and non-parametric terms. GAM is specifically designed to analyze data when the impact of the predictors on the outcome is not necessarily linear. The results of our research stated the robustness and flexibility of GAM to reveal meaningful curvatures in exploratory analyses and the good quality of fitting.We found that the outbreak of ZCL was associated more with local environmental diversity than with climate factors. In fact, our results showed that rodent's density and weather variables could be used to predict ZCL transmission. To our best knowledge this is the first study incorporating rodent's density in the model, together with climate variables.Our GAM model showed that the significant effect of ZCL incidence was associated with monthly cumulative rainfall lagged 1 month. In fact, rainfall would increase the density of the halophytic plant, chenopods, that constitute the food of rodent's reservoirs ,7. ConsePhlebotomus papatasi increases as the relative humidity rises. The optimum relative humidity is 75% for saving eggs. When the humidity is too low, laying eggs will be affected, and adult mosquito mortality will increase. Increasing humidity will also facilitate feeding for the adult sandfly, enhancing its survival.We also found that ZCL was associated with rodent density with 2 months lagged effect jointly with relative humidity lagged 4 months. Relative humidity has an influence on the survival of sandfly eggs and adults, the biting behavior of female adult sandfly, and laying of eggs. At the same temperature, egg hatchability of The results of our GAM model showed that average temperature lagged 4 months has significant effect on ZCL occurrence. According to some studies ,45, tempDespite the flexibility of our model that provided a better assumption of the nature of relationships between each bioclimatic factors and the number of ZCL cases, one limitation has to be pointed out. The short-term time series used in this work may not validate our predictive model. However, we need to extend the number of observations up to 10 years to validate a robust predictive model. Such recommendations are essential to improve the model and may help governors to detect earlier an outbreak occurrence and reduce, as well as possible, number of ZCL cases.A predictive model using spatiotemporal data needs to be the next goal to be accomplished in further studies towards the construction of an early warning system (EWS) of ZCL in Sidi Bouzid, central Tunisia. To this end a sustained surveillance and monitoring efforts of ZCL and climate factors are needed to provide time series sufficiently long for developing and evaluating forecasting models.To conclude, a complex relationship between environmental, bioclimatic factors and ZCL occurrence was found in central Tunisia. Additive models offer flexible modeling tools for regression problems. Understanding the role of the environmental and bioclimatic factors in ZCL occurrence can help to guide government policy-makers towards the creation and implementation of more effective policies to tackle the disease, and has important implications for prevention measures.S1 Dataset(XLSX)Click here for additional data file.


Consumption of red meat and alcohol are known risk factors for colorectal cancer, but associations for dietary fat remain unclear. We investigated the associations of dietary fat, protein, and energy intake with prevalence of colorectal adenoma.We performed a prospective cross-sectional study on asymptomatic persons who underwent a screening colonoscopy at a single center during a routine health check-up from May to December 2011. Dietary data were obtained via a validated Food Frequency Questionnaire (FFQ), assisted by a registered dietician. We also obtained information on alcohol consumption and smoking status, and measured metabolic syndrome markers including abdominal circumference, blood pressure, fasting glucose, serum triglyceride and high-density lipoprotein cholesterol. We calculated odds ratio (OR) and 95% confidence interval (CI) to evaluate the associations using the polytomous logistic regression models. As a secondary analysis, we also conducted a matched analysis, matched by age and sex (557 cases and 557 non-cases).P for trend = 0.07) after adjustment for total energy intake. However, after controlling for metabolic syndrome markers, body mass index, smoking status, alcohol consumption, and family history of colorectal adenoma, which were all significantly high in the colorectal adenoma patients group, the association became attenuated .The study sample included 557 cases  with histopathologically confirmed colorectal adenoma, and 1157 controls . The proportion of advanced adenoma was 28.1% of men and 18.5% of female, respectively. Although vegetable protein intake was inversely associated with the prevalence of colorectal adenoma, further adjustment for potential confounding factors attenuated the association, resulting in no significant associations. There were no significant associations between dietary fat intake and colorectal adenoma in energy-adjusted models. For vegetable protein in women, the OR for the comparison of those in the highest tertile with those in the lowest tertile was 0.47 (95% CI 0.25–0.91, In conclusion, we did not observe the significant associations for intakes of total energy, total, animal and vegetable fats, and total, animal and vegetable proteins in relation to colorectal adenoma prevalence. In general, physical activity, low total energy intake, low red and processed meat consumption, and limited alcohol drinking were known to give beneficial effect for cancer prevention. Diet has long been regarded as the most important lifestyle risk factor for colorectal cancer. However, role of many dietary factors in colon carcinogenesis remains unresolved.Colorectal cancer has been 1 of the most common cancers in Western countries, and the incidence rate has recently been increasing in Asian countries. In Korea, the incidence rates of colorectal cancer have continued to increase in both sexes, resulting in becoming the second most common cancer in males and the third most common cancer in females.–5 On the contrary, another study showed that curcumin, the active ingredient of the Indian spice turmeric, had chemopreventive effect on high protein diet-associated colorectal cancer in rat.In animal and in vitro studies which investigated the effect of dietary proteins on colorectal cancer, high protein diet led to DNA damage of colonocytes, decreasing colonic mucosal thickness, and reduction of the height of colonocyte brush-border membrane.,8 whereas meat consumption was significantly associated with an increased risk of colorectal cancer. In animal studies, dietary fat induced the secretion of bile acids, which result in injury and regression of colonic mucosal epithelium, finally increasing the risk of colorectal cancer.,11 However, the effect of dietary fat on colorectal cancer has been inconsistent in epidemiological studies.,13 A recent meta-analysis suggested that dietary fat may not be associated with the increased risk of colorectal cancer. But, most of the included studies were performed in Europe and America, so the results are difficult to extrapolate to the Asian population. Furthermore, there were only a few prospective studies to examine the association of dietary intake and colorectal cancer.Inverse association between the intake of vegetables, fruits, or fish oil and risk of colorectal cancer has been suggested in several meta-analyses, The identification of modifiable risk factors for colorectal adenoma contributes to prevent colorectal cancer from progressing. Studies that examined dietary risk factors for colorectal adenoma reported that fat and red meat intake increased the risk for colorectal adenoma, whereas fiber, fruit, and vegetable intake decreased the risk.,17 However, findings with regard to dietary risk factors are still controversial. According to 1 study, whereas the intake of fresh vegetables or fiber of the colorectal adenoma group was not particularly higher than that of the control group, it still significantly decreased the risk of progression of advanced adenoma in colorectal cancer in the carcinoma-adenoma sequence. Meanwhile, a recent meta-analysis reported that vegetable intake was not associated with the incidence of colorectal adenoma, whereas fruit intake was found to have protective effects against colorectal adenoma. As such, various research findings regarding dietary risk factors of colorectal adenoma have been reported. In addition, although high-fat and high-protein diets are known as dietary risk factors of colorectal adenoma, clinical studies have failed to provide sufficient evidence supporting this. Moreover, as in the case of colorectal cancer, Western research findings on the dietary risk factors of colorectal adenoma in Asians whose lifestyle and diet differ from those of Westerners are difficult to apply. Furthermore, as with colorectal cancer, it would be incorrect to simply apply Western research data on risk factors of colorectal adenoma.Colorectal adenomas are considered precursors to colorectal cancer through adenoma-carcinoma sequence.In this regard, this study aimed to examine the associations between the intakes of dietary protein and fat and prevalence of colorectal adenoma in Koreans by comparing the macronutrient intakes of Korean patients with colorectal adenoma and advanced adenoma with those of a normal control group.22.1We performed a prospective cross-sectional study on asymptomatic persons, who underwent a colonoscopy at Seoul National University Hospital Healthcare System Gangnam Center during a routine health check-up from May to December 2011. Colonoscopy was conducted after nutritional surveys on the same day. And thereafter, colorectal adenoma patients and adenoma-free control group was setup after colonoscopy.We included a total of 557 patients and 1157 controls, aged 30 to 76 years. Participants were asked about socio-demographic status, alcohol consumption, smoking status, and family history of colorectal cancer. We also measured metabolic syndrome marker including abdominal circumference, blood pressure (BP), fasting glucose, serum triglyceride and high-density lipoprotein (HDL) cholesterol. Polyps were verified as adenomatous, hyperplastic, or inflammatory through pathological examination by colonoscopies. If participants had a diagnosis of colorectal adenoma, we included as cases.Patients were excluded as follows: incomplete study due to poor bowel preparation and cecal intubation failure, and past history of colorectal adenoma, colorectal cancer, inflammatory bowel disease, intestinal tuberculosis, and bowel resection. We also excluded the patients with diagnosis of colorectal cancer (n = 7) or unreasonable energy intake (beyond mean of logarithm of energy ± SDs) (n = 6).The study protocol was approved by the Institutional Review Board of Seoul National University Hospital, and written informed consents were obtained from all participants.2.2 assisted by a registered dietician. Participants were asked to estimate their usual frequency of consumption of various foods and typical portion sizes for the year preceding the interview date. Each food item had 9 options for frequency (ranging from “never or less than once per month” to “3 times per day”) and 3 options for portion size. For these analyses, we examined total energy intake and the following macronutrients: total protein; animal protein; vegetable protein; total fat; animal fat; and vegetable fat.Dietary intake was assessed before colonoscopy at the same day using a validated Food Frequency Questionnaire (FFQ),2.3: central obesity (waist circumference >90 cm [men] or >80 cm [women]); a triglyceride level ≥150 mg/dL; HDL cholesterol<40 mg/dL (men) or <50 mg/dL (women); fasting plasma glucose ≥100 mg/dL or treatment for diabetes; systolic BP ≥130 mm Hg or diastolic BP ≥85 mm Hg or treatment for hypertension.Metabolic syndrome was diagnosed when 3 or more of the following 5 criteria were present according to the modified Adult Treatment Panel III (ATP III), as adopted by the updating guidelines of the National Cholesterol Education Program (NCEP-ATP III)With regard to smoking, current smokers were defined as those who had been smoking at least 1 cigarette per day during the previous 12 months.An advanced adenoma was specified a presence of adenoma with villous component (at least 25% villous structure), with high-grade dysplasia, ≥10 mm in estimated diameter and/or presence of 3 or more synchronous adenomas.2.4t test for continuous variables. For categorical variables, we calculated the proportion of characteristics and conducted a chi-square test. Animal fat, vegetable fat, animal protein, and vegetable protein intake was adjusted for energy by residual methods. We calculated odds ratio (OR) and 95% confidence interval (CI) to evaluate the associations using the polytomous logistic regression models. As a secondary analysis, we also conducted a matched analysis, matched by age and sex (557 cases and 557 non-cases). For test for trends, the median value of each tertile in control group was included in the models as a continuous variable. We adjusted for age , sex (men or women), total energy intake , waist circumstance , smoking status , alcohol intake , body mass index , HDL cholesterol , fasting glucose , and family history of colorectal cancer (yes or no). All analyses were performed using SAS 9.3 . All statistical tests were 2-sided, and P values <0.05 were considered statistically significant.We calculated the means and SDs, and compare baseline characteristics between cases and non-cases using a 33.1Demographic and clinical characteristics of the study participants, stratified by sex and case-control status, are shown in Table 3.2Although vegetable protein intake was inversely associated with the prevalence of colorectal adenoma, further adjustment for potential confounding factors attenuated the association, resulting in no significant associations Table . There wWhen we examined the effect of replacing carbohydrate with animal and vegetable protein, and observed an inverse, but not statistically significant, association between vegetable protein intake and advanced adenoma in men after adjusting for age, total energy intake, waist circumference, BMI, HDL cholesterol, fasting glucose, alcohol intake, and smoking status Table . For wom3.3P for trend = 0.07) after adjustment for total energy intake (Table P for trend = 0.13). There were no significant associations between dietary fat intake and colorectal adenoma in this model . For vegetable protein in women, the OR for the comparison of those in the highest tertile with those in the lowest tertile was 0.47  cholesterol by 12.9%, and triglycerides by 10.5%, and to increase HDL cholesterol by 2.4%.This study had some limitations. First, our study was a cross-sectional design; therefore a causal inference may not be clear. However, participants provided dietary information before colonoscopy; thus recall bias may not be likely. Second, although the subjects of the research were healthy people who underwent health examinations, they were people who chose a single health promotion center. Therefore, they cannot be assumed to represent the nutrition intake of all Koreans, which indicates a sample selection bias. In addition, as they are people who undergo health examinations regularly, they tend to be more interested in their health care than the average population and are well-educated about health care, leading to further differences in diet and exercise with an average Korean. Third, a survey on physical exercise, which is known as a strong confounding factor when evaluating nutritional risk factors, could not be properly adjusted in this study. Generally, people who are physically more active tend to eat healthier and be more interested in health; therefore, correcting for physical exercise level is important when analyzing correlations between diet and risk of disease. However, adjustment for other healthy lifestyle factors attenuated the associations toward no association. Further adjustment for physical activity would have showed still no association.The incidence of colorectal adenoma—a precancerous lesion of colon cancer—is increasing in Korea and other Asian countries. Western studies have reported the association between dietary factors and the disease. However, it seems likely that risk factors of the incidence of colorectal adenoma will differ between various ethnic groups. Despite the aforementioned limitations, this study is important as a prospective case-control study conducted with Korean subjects to evaluate macronutrient risk factors of colorectal adenoma and advanced adenomas.In conclusion, this study showed no clear relationship between the incidence of colorectal adenoma/advanced adenoma and protein/fat intake. In the female patients, vegetable protein intake and the incidence of the disease showed an inverse association in the age-adjusted models, but became statistically not significant in the full-adjusted models.


The diagnosis and treatment of the possible visual sequelae in those with traumatic brain injury (TBI) represents an important area of health care in this special population. One of their most prevalent yet elusive visual symptoms is visual motion sensitivity (VMS). In this review, we present the basic VMS phenomenon and its related symptoms, clinical studies in the area, clinical research investigations using the visual-evoked potential (VEP) as a cortical probe, and possible mechanisms and related neurophysiology that may underlie VMS. Lastly, therapeutic interventions are briefly described, as well as future directions for clinical research and patient care in those with VMS and TBI. The use of binasal occluders (BNO) and bitemporal occluders (BTO) in medicine, in particular ophthalmology, has a long and interesting history for the treatment of strabismus . Mention of such occlusion dates back to at least 600 AD or so  for a re. Thus, sHowever, approximately 30 years ago, the employment of BNO in optometry took a new direction. It began to be used for the treatment of visual motion sensitivity (VMS) in brain-injured patients, typically those with mild traumatic brain injury (mTBI). VMS is a relatively common symptom in these patients, likely occurring in approximately 40% of the patients  Figure , sittingIn this review, we will cover both the clinical and laboratory-based studies involving BNO and VMS, with an emphasis on the objective, visually-evoked potential (VEP) findings. Both the clinical utility, as well as the possible underlying perceptual and neurological mechanisms, will be addressed. Future directions for research will also be considered.The following resources were used for the present review. They included computer searches using PubMed, Yahoo, Google, and Google Scholar. Search terms included “visual motion sensitivity”, “VMS”, “visual motion perception”, “binasal occlusion”, “BNO”, “vision in mTBI/TBI”, “brain injury”, “VEP”, and “magnocellular pathway”. In addition, relevant books, book chapters, and published papers in the area were used other than those found in our formal computer searches. Surprisingly, given the high prevalence and bothersome nature of VMS, there is a relative paucity of clinical studies and case reports in this area of mTBI/TBI, as well as in other forms of acquired brain injury (ABI) and neurological disorders  ,8. UnforOne of the earliest case reports in this area was that of Proctor 2009) in a 46-year-old male patient  in a 46-,4,6. He first patient was a 67-year-old male who was involved in an MVA. His initial visual symptoms included diplopia, pain in his right eye with ocular movement, and balance problems. An ophthalmological vision examination shortly after the MVA revealed diplopia for which base-out prisms were prescribed, but without any relief. Months later, he was examined by his optometrist of many years, and thus all of the MVA-related visual symptoms could be compared against those pre-injury. The patient reported the same visual symptoms as he did earlier to the ophthalmologist, but he now exhibited several new visual signs: reduced distance visual acuity, reduced stereoacuity at near, vertical phoria at near, and large exophoria at near. None of these symptoms and signs were present prior to the MVA. Due to his visual symptoms, especially related to balance, it was decided to try BNO on the patient. Immediately, his symptoms were markedly reduced, especially during ambulation. The BNO, along with the oculomotor-based vision therapy, were prescribed with continued success. The second patient was a young, female administrator who had sustained an mTBI one year earlier. She had hit the top of her head and was temporarily “stunned”. Her symptoms included reading difficulties, light sensitivity, discomfort on the computer, variable ocular focusing, spatial disorientation, and balance problems. All busy environments, including her office, triggered her balance and disorientation problems. The patient’s comprehensive optometric vision examination was unremarkable, and visual acuity was 20/20. However, she was nauseous for several hours after each section of the basic vision test battery, which is not uncommon in these patients. Thus, she elected not to perform any further vision testing and to forgo the tentatively suggested vision therapy. About two years later, the patient returned to the same optometric clinic with the same persistent visual problems. In the interim, she was being treated for anxiety, with some degree of intermittent relief of her visual symptoms. There were now fewer symptoms during the subsequent vision examination, and all testing could be completed. She was recommended a course of vision therapy. In addition, BNO was attempted. The effect of the added BNO was immediate, with about 80% reduction in her symptoms as she ambulated about the doctor’s office. The markedly reduced symptoms of VMS in busy environments, such as the street and her workplace, continued. The combination of the BNO and the vision therapy has allowed her to remain much less symptomatic under all naturalistic conditions over the several months of follow-up.More recently, Gallop (2014) presented two cases of mTBI in which BNO was found to be helpful . The firBased on the above clinical studies, what might be the prevailing mechanism? A most intriguing suggestion was proposed by Gallop 1998) [ [8]. He Once again, and surprisingly, there have been a paucity of studies in clinical laboratories assessing the efficacy of BNO in mTBI/TBI. The first investigation was published nearly 20 years prior to the more recent studies. All three investigations included the VEP as the primary outcome measure.The first investigation of BNO in mTBI/TBI was by Padula et al. (1994) . This hoFollowing a comprehensive optometric vision examination, the VEP  testing commenced. Important details of the methodology are as follows. A central/near retinal periphery field, checkerboard pattern was used as the test stimulus. It had high-contrast with a check size of 30 minutes of arc and a stimulus pattern reversal rate of 1.9 reversals/s. An ABA experimental design was used: A = habitual distance refraction, B = habitual distance refraction plus the vertically-oriented, translucent tape BNO and 2 BI prisms before each eye, and then condition A again to assess for and assure a stable baseline. The primary VEP metric was its peak-to-peak amplitude (N1-P1), a standard VEP parameter. The VEP was completed in all ten normal controls and in nine of the ten individuals with TBI.t-test, p < 0.01). Some patients reported a reduction of symptoms  with the BNO/prism combination incorporated into their distance spectacle prescription. No other related testing was performed, such as formally assessing visuomotor ability or general ambulation with and without the BNO/prism combination. The VEP findings were as follows. In the normals, the VEP amplitude with the combined BNO/prisms increased in 6/10, decreased in 2/10, and remained the same in 2/10, with a range of −14% to +11%, and a mean decrease in amplitude of −0.41 microvolts, as compared to the baseline values. These small, mixed findings suggested a ‘noise’ phenomenon; that is, a lack of any consistent cortically-based physiological effect, as one might predict in this control population. In contrast, in the TBI group, the amplitude increased in 8/9 and decreased in 1/9, with a range of −5% to +54% . There was a statistically significant effect of the BNO/prism combination in the TBI group versus the control group  [ [8], PadThe next and most recent experiments in this area were performed in the Ciuffreda laboratory about 20 years later ,12. Thesfirst investigation by Ciuffreda et al. (2013) [In the . (2013) , the queThe VEP  stimulus and test conditions were as follows. The test target consisted of a 17 H by 15 V degree, alternating , black-and-white, checkerboard pattern  placed one meter away along the subject’s midline. Luminance was 64 cd/m-squared with a contrast of 85%. The test duration was 20 s. Two trials per test condition  were averaged in each subject, and then averaged across each group, for the parameters of amplitude and latency. A schematic representation of a subject with the BNOs in place is presented in decrease with BNO was found in all 10 subjects, which was statistically significantly  . These findings were repeatable 2–7 days later in a subset of subjects in each diagnostic group.The mean amplitude (microvolts) findings are presented in  < 0.01) . In the subjects , which wLatency was also assessed. It was within normal limits, and was not statistically different under any of the test conditions and diagnostic groups.p < 0.01). They reported reduced symptoms . Furthermore, they reported more accurate and comfortable ambulation, fixating of objects in the field, and grasping of objects. They also indicated that the VEP stimulus appeared clearer, brighter, and flickered less. In the other two mTBI/VMS subjects, they disliked the blocked field of the BNO, despite their objective cortical and subjective improvements with the BNO.Lastly, the subjective impressions of both groups were queried. All VN subjects disliked the BNO. The blocked field was annoying and produced a sense of visual discomfort. In contrast, eight of the ten mTBI subjects with VMS liked the BNO (second investigation by Yadav and Ciuffreda (2014) [and/or base-in prisms on adults with chronic mTBI and symptomatic VMS?” There were 15 patients with medically-diagnosed mTBI (mean age 35.2 years) with the symptom of VMS, and there were 20 matched, visually-normal (VN) controls (mean age 25.5 years) without the symptom of VMS, with both groups having 20/20 or better visual acuity in each eye. None had a history of seizures, strabismus, amblyopia, or any ocular, systemic, or degenerative neurological disease. All underwent a comprehensive optometric vision examination prior to laboratory testing.In the a (2014) , the quep < 0.05).The same VEP apparatus as described in detail in their earlier experiment above was used . HoweverVN  : Firstly, the baseline (20.8) and the prism only (20.6) conditions were not significantly different, which suggested that the prisms did not affect the VEP amplitude. Secondly, the BNO only condition (17.1) was significantly less than found in either the baseline (20.8) or the prism only (20.6) conditions. Thirdly, the BNO (17.1) and the BNO plus prism (18.1) conditions were not significantly different. Together, these findings suggested that the BNO condition alone was sufficient to have a significant effect on the VEP amplitude; the incorporation of the base-in prisms had no cortical advantage.mTBI  : Firstly, the baseline (20.9) and the prism only (21.0) conditions were not significantly different. Secondly, the BNO only (23.2) condition was significantly greater than either the baseline (20.9) or prism only (21.0) conditions. Thirdly, the BNO only (23.2) and the BNO plus prism (22.0) conditions were not significantly different. These findings suggested that the BNO condition alone was sufficient to have a significant effect on the VEP amplitude; the incorporation of the base-in prisms had no cortical advantage. mTBI  : For both diagnostic groups, the mean latency was significantly increased for the BNO and/or prism conditions as compared to the baseline by a few milliseconds. This suggests small but significant increases in visual processing time for these optical conditions. However, all were within their laboratory and literature normative values.p < 0.05) showed an increase in amplitude with the BNO only (range −9.7 to +40.6), there was a mixed result (7/15 increased) with the combined BNO plus prism (range −19.4 to +92.3), and again a mixed result (8/15 increased) with the prism only (range −18.8 to +22.7). Again, the mTBI findings revealed the uniqueness and consistent advantage of the BNO alone on cortical activity.The individual amplitude findings  are presented in The VEP findings were repeated three weeks later in two subjects from each diagnostic group. The coefficient of variation (COV) statistic was used to assess this aspect. Values can range from 0.00 to 1.00, with smaller values indicating less variability, and hence better repeatability. Values ranged from 0.00 to 0.07, thus indicating an extremely good repeatability in these subjects.p < 0.05) reported the tasks to be best with the BNO, thus consistent with and confirming the objective VEP findings. Some of their comments are worth noting: most felt more stable, comfortable, and confident ambulating with the BNO; some commented on perceiving less “visual noise” especially in the periphery; and others indicated a sense of reduced sensory overload. Thus, there was a manifold of subjectively-based changes and improvements with the BNO present. Further research in this important area is warranted.Lastly, subjective testing was performed and compared under three visual and/or visuomotor conditions in those with mTBI: (1) viewing of either a blank wall, a stationary checkerboard pattern, or a flickering checkerboard pattern; (2) near grasping of objects; or (3) walking down a long corridor. For all conditions, most subjects . Fourth, testing should be extended to the moderate and severe TBI populations using the VEP and simpler vision and visuomotor testing/tasks. Fifth, in all types of TBI, the impact on quality of life (QOL) needs to be assessed to determine the positive effects on specific visual demands and tasks, both vocational and avocational. Sixth, and lastly, brain imaging should be performed to determine the site(s) of activity unique to the application of BNO in all categories of TBI.BNO is a non-invasive method and is easy to apply in patients with mTBI and VMS.BNO seems to be an effective treatment method in patients with mTBI in reducing the symptoms caused by increased VMS.BNO provides immediate and sustainable effects in patients with mTBI and VMS.BNO seems to have a positive visuo-cortical effect in patients with mTBI and VMS.Using this simple clinical technique would be beneficial in treating these patients and helping them in performing their activities of daily living (ADL).The use of BNO in patients with mTBI should be fruitful in future investigations. The clinical and laboratory data thus far show promise in the mTBI population with symptomatic VMS. While the possible mechanisms remain somewhat unclear and elusive, this should not prevent the clinician from attempting this approach, and related ones, in these patients. The clinician’s goal should be to provide symptom reduction and a better quality of life, which frequently will occur with the prescription of BNO.


Testicular cancer has become the paradigm of adult-onset cancer survivorship, due to the young age at diagnosis and 10-year relative survival of 95%. This clinical review presents the current status of various treatment-related complications experienced by long-term testicular cancer survivors (TCS) free of disease for 5 or more years after primary treatment. Cardiovascular disease and second malignant neoplasms represent the most common potentially life-threatening late effects. Other long-term adverse outcomes include neuro- and ototoxicity, pulmonary complications, nephrotoxicity, hypogonadism, infertility, and avascular necrosis. Future research efforts should focus on delineation of the genetic underpinning of these long-term toxicities to understand their biologic basis and etiopathogenetic pathways, with the goal of developing targeted prevention and intervention strategies to optimize risk-based care and minimize chronic morbidities. In the interim, health care providers should advise TCS to adhere to national guidelines for the management of cardiovascular disease risk factors, as well as to adopt behaviors consistent with a healthy lifestyle, including smoking cessation, a balanced diet, and a moderate to vigorous intensity exercise program. TCS should also follow national guidelines for cancer screening as currently applied to the general population. Testicular cancer (TC) is the most common cancer, affecting young men aged 18–39 years , TC is hA few hypotheses have been proposed to explain the pathophysiology of CVD in TC survivors (TCS), including the direct vascular damage hypothesis, the indirect hypothesis, and more recently the multiple-hit hypothesis , 10. TheA prior investigation  showed tRaynaud phenomenon is another clinical manifestation of vascular damage and is estimated to be present in approximately 25% to 61% of TCS –30. The The indirect hypothesis postulates that cisplatin-based chemotherapy increases the prevalence of CVD risk factors in TCS, resulting in increased CVD events . MultiplA multiple-hit hypothesis that encompasses both the direct and indirect hypotheses has recently been proposed to explain the elevated risk of CVD among TCS , 45. ThiThe relative risk of CVD among TCS treated with chemotherapy is 1.4- to 7.1-fold significantly higher compared to the general population or to those managed with surveillance only , 46, 47.To determine CVD risk after modern-era cisplatin-based chemotherapy in TC patients, Haugnes et al.  evaluateUsing age-adjusted Cox regression analyses, increased risks of atherosclerotic disease were reported after radiation only , chemotherapy only , and combined radiation/chemotherapy  compared with surgery only (P-trend = 0.02) . In partP < 0.05) and older age at diagnosis (P < 0.01) were independent risk factors [Several studies –50 have Currently, there are no established evidence-based CVD screening recommendations developed specifically for TCS. In November 2013, the American College of Cardiology and the American Heart Association released guidelines for the assessment of cardiovascular disease risk, the management of elevated cholesterol and increased body weight, and lifestyle modifications to reduce CVD risk in adults in the general population . Health Syndromic, cancer treatment, and shared etiologic exposures are the major causative factors of SMN .  FigureP < 0.05), which remained elevated for more than 35 years. In another study [P trend < 0.001), and risks remained elevated for ≥20 years after exposure (P < 0.01) [After receiving radiotherapy for TC treatment, TCS have significantly increased risks of leukemia  and solier study , infradier study  and a 2.er study . The riser study  and pancer study , respect < 0.01) , 59. Sev < 0.01) , 60, 61 P trend = 0.001) [2 and 2.0% after a cumulative etoposide dose of ≥2000 mg/m2 [Cisplatin and etoposide are integral chemotherapeutic agents used in standard chemotherapy regimens to treat TC . Both ci= 0.001) . The 5-y00 mg/m2 .Most prior studies of second solid cancer focused on TCS treated before modern cisplatin-based chemotherapy became widely adopted prior to early 1980s  10, 13,, 23. WheTCS should follow national guidelines for cancer screening as applied to the general population, given their increased risks of SMN . EarlierApproximately 20 to 40% of long-term TCS experience symptoms of peripheral neuropathy after cisplatin-based chemotherapy , 29, 69.GST) P1, M1, and T1 on self-reported paresthesia among long-term TCS. The GSTP1-GG genotype conferred a significantly lower risk of developing paresthesia in the fingers  and toes  than the GSTP1-AA and GSTP1-AG genotypes. Recently, a genome-wide analysis of cisplatin-induced peripheral neuropathy in survivors of adult-onset cancer reported that genetically determined expression level of RPRD1B was associated with cisplatin-induced peripheral neuropathy [RPRD1B expression or knockdown cause a deficiency in DNA repair mechanisms known to be critical in repairing cisplatin-induced lesions [Oldenburg et al.  investiguropathy . Defects lesions  and resu lesions .No therapeutic agents are currently recommended for the prevention of peripheral neuropathy due to the paucity of high-quality, consistent evidence. For management of drug-induced peripheral neuropathy, the ASCO Clinical Practice Guideline  recommen2 of cumulative cisplatin dose, 50% self-reported tinnitus and hearing loss compared to 20% of those treated with ≤400 mg/m2 [P < 0.001). The same study [P trend for each <0.05). For each 100 mg/m [P < 0.001) resulted. However, cisplatin dose did not affect noise-induced hearing damage (10% patients) (P=0.59) [Cisplatin selectively damages the outer hair cells of the cochlea , causing00 mg/m2 . Older a00 mg/m2 –80. A re00 mg/m2  reportedme study  also fou(P=0.59) .GSTP1 [GSTM3 [COMT [TPMT [WFS1 [105Val-GSTP1 protected against cisplatin-induced ototoxicity in cisplatin-treated TCS, whereas GSTM1 positivity was detrimental for hearing ability [S-transferases (GSTs) genes likely cause differential expression of the cisplatin-detoxifying enzymes, consequently rendering TCS suspcetible to varying degrees of cisplatin-induced hearing impairment. A recent genome-wide association study [WFS1 (wolframin ER transmembrane glycoprotein) was significantly associated with cisplatin-associated ototoxicity (P=1.4 × 10−8), with higher cisplatin doses exacerbating hearing loss in TC patients with the risk allele. In the general population, WSF1 mutations causes the Mendelian disorders DFNA6  and the recessive Wolfram syndrome (with hearing loss) [A few reports have identified significant associations of germline genetic polymorphisms of various genes with platinum-related ototoxicity, including megalin , GSTP1 [GSTP1 , 82, GST1 [GSTM3 , 82, COMM3 [COMT , TPMT [8MT [TPMT , and WFSMT [WFS1 . Both alon study  of 511 Tng loss) , 87.There are no effective pharmacologic agents available to prevent or treat cisplatin-induced ototoxicity. TCS should use ear protection to minimize noise exposure and additional hearing loss. Since the peak concentration of cisplatin may be directly associated with the severity of ototoxicity , 88, wheThe incidence of fatal bleomycin-induced pulmonary toxicity is approximately 1–3% , 90. CorBLMH gene, which inactivates bleomycin [Bleomycin hydrolase is an enzyme encoded by the leomycin . A Dutchleomycin .P=0.007) and older age (P=0.008) were both significantly related to restrictive lung disease [A large Norwegian study  of 1049  disease . Compare disease . A populP < 0.05). A Danish investigation [2) reported that the glomerular filtration rate (GFR) decreased by a median of 18% during treatment. At a median follow-up of 65 months , 38% of survivors had persistent renal dysfunction. Research in the general population has demonstrated a relationship between decreased GFR and the presence of microalbuminuria, leading to increased risks of CVD and all-cause mortality [Cisplatin damages the proximal and distal renal tubular epithelium and the renal collecting duct system, as well as the glomeruli at higher doses , 99. Twotigation  of 34 TCortality , 103. Amortality , 47. To ortality  and avoiP < 0.05). Health care providers should regularly assess TCS for symptoms of hypogonadism and check hormonal status as clinically indicated. Clinical symptoms of hypogonadism should guide treatment decisions with testosterone replacement therapy [Orchiectomy, testicular dysgenesis syndrome, postorchiectomy chemotherapy or radiotherapy, and aging are the predominant causes of hypogonadism and premature hormonal aging in long-term TCS . A Norwe therapy . ReferraThe association of infertility and TC is well established. Approximately 50% of patients with newly diagnosed TC have decreased sperm counts (<20 million/mL), low sperm motility indices (<40), and a high percentage of abnormal sperm cells (>80%) prior to initiation of any radiation or chemotherapy . In a muRadiotherapy can adversely affect reproductive function of TCS in the short-term , 125, siP=0.022). However, sperm counts were not significantly related to number of cycles of chemotherapy in a limited cohort of patients for whom the results of semen analysis were available (N = 71) [P < 0.001). Similarly, a recent investigation [In a retrospective study  of 178 T(N = 71) . After a(N = 71)  showed ttigation  reportedAmong patients with stage II or III nonseminomatous germ cell tumor who have had a serologic complete response but have persistent enlarged retroperitoneal lymph nodes after cisplatin-based chemotherapy, RPLND is a standard treatment. To potentially avoid toxicities associated with cisplatin-based chemotherapy, RPLND is another treatment option for low-volume stage II nonseminomatous germ cell tumor with normal β-hCG and AFP levels after orchiectomy . Injury Health care providers should address the possibility of infertility and discuss fertility preservation options with TC patients as detailed by the American Society of Clinical Oncology Clinical Practice Guideline for fertility preservation for patients with cancer . If clinAvascular necrosis commonly affects the femoral head, often bilaterally , with anP < 0.01) [N = 70–112; median follow-up: 1–3 years) reported no significant differences in performance on cognitive tests between TC treatment groups , two investigations [N = 55) or no additional treatment (N = 14) reported that chemotherapy was significantly associated with cognitive decline with a dose-response relationship observed at 12 months . Although the extent to which cisplatin-based chemotherapy may have negative effects on long-term cognitive function in TCS is unclear, cognitive complaints among long-term survivors are common and independent of treatment modality [The underlying mechanisms of chemotherapy-related cognitive impairment have not been elucidated. Several neuroimaging studies of breast cancer survivors have reported that white matter activation patterns involved in cognitive functioning are altered after chemotherapy –144, lik < 0.01) , 147. A  < 0.01)  of 666 p < 0.01) –150 of Tigations , 152 repigations  reportedmodality , 148–151P < 0.001). Young age, peripheral neuropathy, economic difficulties, excess alcohol use, sexual concerns, and prior treatment for mental illness were significantly associated with HADS-defined anxiety disorder [A Norwegian study  reporteddisorder . A recendisorder  showed tdisorder –156 repodisorder , and havdisorder  were repP < 0.001). Several factors were significantly associated with chronic fatigue in this study: [Chronic fatigue, defined as symptoms with a duration of ≥6 months, is a common and distressing cancer-related adverse effect . The pres study:  high levs study:  reportedP < 0.01), peripheral neuropathy , and obesity . The type and prevalence of AHOs after BEPX4 were largely similar to EPX4 and BEPX3. Increasing age at clinical evaluation, current tobacco use, and nonmarried status were associated with increased numbers of AHOs, whereas weekly vigorous physical activity was protective (P < 0.05). Self-reported health was excellent/very good in approximately 60% of TCS, but this proportion decreased as number of AHOs increased (P < 0.001)  is critical. A recent multi-institutional investigation  of 952 N< 0.001) .Due to their young age at diagnosis, long-term survival, and current use of largely homogeneous therapies, TCS comprise an ideal cohort for adult-onset cancer survivorship research . Moreove