Binaural processing, particularly the processing of interaural phase differences, is important for sound localization and speech understanding in background noise. Age has been shown to impact the neural encoding and perception of these binaural temporal cues even in individuals with clinically normal hearing sensitivity. This work used a new electrophysiological response, called the interaural phase modulation-following response (IPM-FR), to examine the effects of age on the neural encoding of interaural phase difference cues. Relationships between neural recordings and performance on several behavioral measures of binaural processing were used to determine whether the IPM-FR is predictive of interaural phase difference sensitivity and functional speech understanding deficits. Behavioral binaural frequency modulation detection thresholds were measured to assess sensitivity to interaural phase differences while spatial release-from-masking thresholds were used to assess speech understanding abilities in spatialized noise. Thirty adults between the ages of 35 to 74 years with normal low-frequency hearing thresholds were used in this study. Data showed that older participants had weaker neural responses to the interaural phase difference cue and were less able to take advantage of binaural cues for speech understanding compared to younger participants. Results also showed that the IPM-FR was predictive of performance on the binaural frequency modulation detection task, but not on the spatial release-from-masking task after accounting the effects of age. These results confirm previous work that showed that the IPM-FR reflects age-related declines in binaural temporal processing and provide further evidence that this response may represent a useful objective tool for assessing binaural function. However, further research is needed to understand how the IPM-FR is related to speech understanding abilities. Accurate processing of binaural information is key to sound source localization and the detection of target signals in background noise. One cue used for binaural processing results from differences in the time of arrival of an auditory signal at the two ears. The interaural phase differences (IPDs) between the signal at each ear are detected at the level of the brainstem. The ability to use these binaural IPD cues is dependent on accurate neural firing to the rapid fluctuations in signal amplitude over time, termed temporal fine structure, and the accurate comparison of these temporal cues between the ears. Recent research has shown that aging can impact the ability to process binaural temporal fine structure information independent of hearing loss, resulting in reduced IPD sensitivity  and defiRecent reports have focused on the use of non-invasive electrophysiological measures to assess the effects of age on the neural encoding of binaural temporal cues . For exaRecently, there has been growing interest in the use of a new electrophysiological measure called the interaural phase modulation-following response (IPM-FR), which has been developed as a more efficient method to assess the neural encoding of IPDs . SimilarTo date, only one study has examined whether the IPM-FR is sensitive to the effects of age on binaural temporal processing . SimilarIn addition, examining relationships between electrophysiological responses and measures of speech understanding in noise can provide information about neural processes that underlie speech perception deficits. For example, Therefore, while the current study was designed to confirm the effects of age on the IPM-FR, it primarily aimed to evaluate relationships between the IPM-FR and several new behavioral measures of binaural temporal processing to (1) confirm that the IPM-FR is reflective of IPD sensitivity and (2) determine whether variability in the IPM-FR is related to speech understanding in noise abilities. Many common behavioral tests of binaural temporal processing tend to require extensive training periods on the part of the examiner and the listener as well as a high number of stimulus repetitions to obtain reliable estimates of binaural sensitivity . These iAn additional practical aim of the current study was to explore potential differences in IPM-FRs recorded using different stimulus parameters. Since the stimulus used to elicit the IPM-FR is amplitude modulated, a steady-state response that follows the AM rate occurs in addition to the steady-state neural response to the phase reversal rate. This envelope following response, commonly known as the auditory steady-state response (ASSR), provides a measure of neural phase locking at the place of stimulation equal to the carrier frequency. The ability to concurrently elicit the ASSR along with the IPM-FR is an additional advantage of this electrophysiological measure, as the ASSR may serve as an estimate of hearing sensitivity , temporaThis work aimed to (1) confirm previous findings that the IPM-FR, measures of binaural FM detection, and measures of spatial release from masking are sensitive to the effects of age on binaural temporal processing; (2) evaluate associations between the IPM-FR and performance on behavioral measures of IPD sensitivity and speech perception; and (3) explore differences in IPM-FRs elicited using different AM rates. It was predicted that, consistent with previous work e.g., , age wouParticipants included 30 adults  who ranged in age from 35 to 74 years (mean age: 62.3 years). All participants were right-handed and were native speakers of American English. No participants reported taking medications that impacted sleep or had mood-altering affects. Pure-tone hearing thresholds for each participant as well as mean pure-tone thresholds averaged across participants are depicted for the right and left ears in Interaural phase modulation-following responses were elicited with a 500-Hz tone that was 100% sinusoidally amplitude modulated (AM) at either 40.8 or 81.6 Hz. The modulation envelope of the stimulus remained diotic, but the phase of the carrier frequency was square-wave modulated at a rate of 6.8 Hz such that when the instantaneous phase at one ear was +45°, the phase in the other ear was −45°, creating an IPM depth of ±90°. The 6.8-Hz IPM rate was chosen based on the results of Stimuli were presented bilaterally at 80 dB SPL through Etymotic ER2 insert earphones using Neuroscan software  in an acoustically treated and electrically shielded booth. IPM-FRs were recorded from a 64-channel tin-electrode cap  with the ground electrode on the forehead and the reference electrode at Cz. Responses were analog low-pass filtered on-line at 200 Hz and were converted using an analog-to-digital sampling rate of 1,000 Hz. Application and preparation of the electrode cap, along with IPM-FR recording, lasted approximately 2 h. During recording, participants were seated in a comfortable chair, asked to relax, minimize eye and muscle movements, and watch a movie of their choice with subtitles.The electrophysiological data was processed in Neuroscan Edit . Eye-blink artifacts were corrected offline using eye movement information collected from the horizontal and vertical planes from electrodes located inferior to and at the outer canthi of both eyes. A spatial, singular value decomposition was used to calculate the amount of covariation between a vertical eye channel and each electrode. This vertical eye blink activity was then removed from each electrode on a point-by-point basis. The remaining ongoing response recorded in each condition was then high-pass filtered at 2 Hz and epoched from 0 to 5000 ms relative to stimulus onset. Epochs exceeding ±100 μV were rejected from analysis. The spectrum of each five second epoch was computed using a 10,000 point Fast Fourier Transform (FFT) which provided a resolution of 0.2 Hz. Mean response magnitudes were calculated by vector averaging these FFT values across all epochs in each condition. IPM-FRs were obtained as the spectral magnitude in the 6.8-Hz bin while ASSRs were obtained as the spectral magnitude in the 40.8- or 81.6-Hz bins for each participant from the electrode at the right mastoid (M2). This electrode site was chosen for analysis based on a previous report that IPM-FR and ASSR magnitudes tended to be largest across participants at the right mastoid , which iThe measured IPM-FR is thought to consist of energy related to the steady-state response to the IPM rate as well as neural activity that is thought to randomly vary in phase and amplitude over time. Therefore, both the magnitude of the response at 6.8 Hz and this SNR metric were used as measures of the IPM-FR in an attempt to better characterize response strength.The behavioral binaural FM detection tasks and spatial release-from-masking tasks were completed using test batteries included in PART  on an iPDiotic and dichotic FM detection thresholds were measured using a four-interval, two-cue, two-alternative forced choice procedure . Each stSpatial release from masking was measured using sentences from three male speakers from the Coordinate Response Measure . The tarnlme package (Separate linear regression models were created in R (R Core Team) using the  package  to assest-tests, with α = 0.05, were used to assess potential effects of AM rate on the IPM-FR magnitude and SNR. Similarly, paired t-tests were used to assess the effects of stimulus condition (diotic vs. dichotic) on ASSR magnitude. Since the AM remained diotic in each stimulus condition, a comparison of ASSR magnitude to the dichotic test stimulus which contained IPDs and the diotic test stimulus which did not contain IPDs would assess the degree to which the recording and response quality remained comparable across alternating stimulus repetitions.Similar linear regression models were created to assess relationships between the neural measures and performance on the binaural FM and spatial release-from-masking measures. In these models, either IPM-FR magnitude or SNR from each AM rate condition was added as a fixed effect to predict each behavioral outcome measure. Paired F = 2.79, p = 0.11, R2 = 0.09] or as measured by 500-Hz thresholds averaged across ears .Participant age was not significantly associated with hearing sensitivity as measured by an average of pure-tone thresholds across frequency and ears  and significant effects of age on both IPM-FR magnitude  and SNR  in the 81.6 Hz-AM rate condition. For these measures, older individuals tended to have weaker IPM-FRs compared to younger individuals  = 10.85, p = 0.003, R2 = 0.28] and diotic  test conditions, such that older individuals had smaller ASSR magnitudes compared to younger participants. These age-related changes in ASSR magnitudes were not present in either the dichotic or diotic test conditions when the higher 81.6-Hz AM stimulus was used.Additional analyses were completed to assess the potential effect of age on the ASSR in each test condition. For the 40.8-Hz AM rate condition, age had a significant effect on ASSR magnitude in both the dichotic  such that older individuals had higher FM detection thresholds, and therefore poorer performance on this task compared to younger individuals. However, results did not indicate that age had a significant effect on performance in the dichotic FM condition or on the FM difference score. Both age and hearing sensitivity had significant effects on target-to-masker ratio thresholds in the separated listening condition of the spatial release-from-masking task . Neither age nor hearing sensitivity had a significant impact on performance in the more difficult colocated condition of this task where the distractor speakers were located at the same azimuth as the target speaker. When performance on these two listening conditions were compared, analyses revealed a significant impact of both age and hearing sensitivity on spatial release-from-masking thresholds . For these measures, participants who were older or who had poorer average across-frequency hearing thresholds required more favorable target-to-masker ratios to obtain 50% performance  = 16.55, p < 0.001, R2 = 0.37] and the FM difference score . Relationships between the IPM-FR SNR and these binaural FM measures are depicted in F = 4.34, p = 0.046, R2 = 0.13]. However, further analyses revealed that this relationship was primarily mediated by the effect of age. When the effects of age were accounted for in the model, the relationship between the IPM-FR SNR and diotic FM thresholds was no longer significant . IPM-FR magnitudes in either AM rate condition and IPM-FR SNRs in the 40.8-Hz AM condition were not related to performance on any binaural FM measure.Analysis showed that the IPM-FR SNR in the 81.6-Hz AM condition was significantly predictive of dichotic FM detection thresholds  and spatial release-from-masking thresholds . The combination of average hearing threshold and IPM-FR magnitude as fixed effects in the model accounted for even more variability in target-to-masker ratio thresholds in the separated listening condition  than IPM-FR magnitude alone  = 4.79, p = 0.02, adjusted R2 = 0.21]. In other words, the significant relationships between IPM-FR magnitude and performance on these spatial release-from-masking tasks may be primarily mediated by the effects of age. No other IPM-FR measures were significantly associated with performance on the spatial release-from-masking tasks.Linear regression analyses revealed that IPM-FR magnitude in the 81.6-Hz AM condition was significantly predictive of target-to-masker ratio thresholds in the separated listening condition . However, there was no significant difference in SNRs between the two stimulus conditions . In addition, there was no significant difference between neural responses in the diotic control condition at 6.8 Hz across the two AM rates .Mean neural response magnitudes and standard deviations for each electrophysiological measure are plotted in t-tests were also completed to determine whether ASSR magnitudes were significantly different across dichotic and diotic recording conditions. This analysis revealed that there was a significant effect of test condition (diotic vs. dichotic) on the 40.8-Hz ASSR such that ASSR magnitude was significantly higher in the dichotic condition compared to the diotic control condition . In contrast, the magnitude of the 81.6-Hz ASSR was not significantly impacted by test condition .Paired The current study aimed to confirm the effects of age on the electrophysiological IPM-FR and behavioral measures of binaural temporal processing . In addition, this work was designed to determine whether age-related variability in the neural encoding of IPD cues, as measured by the IPM-FR, is related to performance on each behavioral task. Finally, the current study also aimed to explore potential differences in IPM-FRs measured using stimuli with different AM rates.This study showed that age had a significant effect on IPM-FR magnitude and SNR. These findings are consistent with previous work  and provInterestingly, while age did have a significant impact on diotic FM detection thresholds, it did not have a significant effect on dichotic FM detection thresholds or FM difference scores, which are thought to reflect IPD processing abilities. This is inconsistent with findings from Participants in the current study were required to have hearing thresholds within normal limits  at 500 Hz. Variations in hearing sensitivity at higher frequencies were not expected to have any impact on the binaural FM measures or the IPM-FR, as a 500 Hz carrier tone was used as a stimulus for each of these measures. However, variability in higher frequency hearing thresholds may indicate differences in the overall health of the auditory system that could impact auditory processing, including the encoding and detection of low-frequency IPD cues. In order to account for this possibility, hearing sensitivity was characterized as the average of hearing thresholds from 250 to 8000 Hz across ears. This metric accounts for variability in low-frequency hearing thresholds as well as variability in high-frequency hearing thresholds across participants. The current results did not show any effect of hearing sensitivity on the IPM-FR or the binaural FM detection measures. Previous studies have not shown significant effects of high-frequency hearing sensitivity on low-frequency IPD discrimination using a variety of behavioral measures , which iEven though variability in high-frequency hearing thresholds was not expected to impact low-frequency IPD sensitivity, results showed that hearing sensitivity did have a significant effect on spatial release-from-masking thresholds and performance in the spatially separated speech-on-speech listening condition. It is likely that poorer high-frequency hearing sensitivity impacted the audibility of certain speech cues necessary for this behavioral task. Results showed that age also had a significant effect on these measures and had a stronger relationship with speech understanding than average hearing sensitivity. This is consistent with previous findings that have shown that both age and hearing sensitivity can independently impact performance on these spatial release-from-masking measures .Since the ASSR reflects phase locking to the temporal envelope of the amplitude modulated stimulus, this electrophysiological measure can represent an index of temporal processing abilities. The current study showed that age had a significant impact on the 40.8 Hz ASSR recorded in each test condition, but did not significantly impact the 81.6 Hz ASSR. This finding suggests that in addition to impacting binaural temporal fine structure processing, age may also affect temporal envelope processing abilities. This finding is consistent with results from Relationships between binaural FM thresholds and the IPM-FR were examined in order to better understand whether this electrophysiological measure is reflective of neural processes underlying behavioral measures of IPD sensitivity. Results showed that the IPM-FR SNR in the 81.6-Hz AM condition was associated with dichotic FM detection thresholds as well as the FM difference score that estimated benefit received from the addition of binaural information in the dichotic FM compared to the diotic FM task. The IPM-FR was able to account for 37% and 40% of the variability in these binaural FM detection measures, respectively. Unlike the IPM-FR, these FM detection tasks were not sensitive to the effects of age in the current study. However, the relationship between the IPM-FR and these binaural FM measures suggests that age-related variability the neural encoding of IPDs may be reflected by performance on these behavioral tasks. Previous studies that established links between the IPM-FR and behavioral IPD sensitivity used stimuli analogous to those used to the elicit the IPM-FR . This woSpeech understanding abilities were assessed using measures of spatial release from masking. The current results showed that IPM-FR magnitude in response to the higher AM stimulus was significantly associated with target-to-masker ratio thresholds in the spatially separated speech-on-speech masking task. Linear regression model predictions of individual performance in this condition were further improved by including average hearing threshold estimates as an additional predictor in the model, such that the model was able to account for approximately 25% of the variance in performance on this task. However, this was not the case when participant age was added as an additional predictor in the model. Similarly, analyses revealed that the relationship between IPM-FR magnitude and spatial release-from-masking thresholds were also likely mediated by the effects of age. In other words, while the variability in the neural encoding of IPD cues was associated with performance on these behavioral speech perception measures, it was not able to account for a substantial amount of variability in performance over what was already accounted for by participant age.These results are inconsistent with those from The current results suggest that changes in stimulus AM rates can impact the IPM-FR. These findings have implications for how stimulus parameters may be optimized to improve IPM-FR measurement reliability as well as to increase sensitivity to participant factors that may contribute to hearing difficulties. The lower AM rate used in the current study is similar to that used in initial studies on the IPM-FR , and theAuditory steady-state responses were compared to assess recording quality between the dichotic test condition and the diotic control condition that alternated within each recording block. This data quality check is important for the current study because neural responses to the diotic control stimulus were used to calculate IPM-FR SNRs, and any systematic contamination of responses to a particular stimulus would compromise SNR estimations. Results from the current work showed that the 40.8-Hz ASSR was larger in the dichotic test condition compared to the diotic control condition. This was an unexpected finding, given that the only difference between the two stimuli was the addition of periodic IPMs in the temporal fine structure of the ongoing AM stimulus in the dichotic test condition. One possibility is that the higher 40.8-Hz ASSR magnitude observed in the dichotic condition is reflecting the presence of harmonics in the neural response to the IPMs in the stimulus, and do not reflect actual changes in the ASSR. As can be seen in The current work confirmed that the IPM-FR is sensitive to the effects of age on the neural encoding of IPD cues. In addition, this study verified that the IPM-FR is reflective of neural processes underlying behavioral IPD discrimination using tests of binaural FM sensitivity. Therefore, these results confirm that the IPM-FR represents a robust tool for the objective assessment of IPD sensitivity. However, further work is required to better understand links between the neural encoding of IPD cues as measured by the IPM-FR and behavioral measures of binaural temporal processing, especially those that assess speech understanding abilities. In addition, future research should continue to investigate the effects of different stimulus parameters on neural and behavioral measures of IPD sensitivity to better understand the effects of age on these responses. The continued development of measures that are sensitive to participant factors that are thought to impact binaural temporal processing and that are also reflective of functional auditory abilities will be integral to the clinical identification and management of auditory difficulties, especially in patients with normal hearing sensitivity.The data supporting the conclusions of this article may be made available by the authors upon request.The studies involving human participants were reviewed and approved by the joint institutional review board of the Department of Veterans Affairs Portland Health Care System and Oregon Health & Science University. The participants provided their written informed consent to participate in this study.CB and FG conceived the study. CB, FG, TK, and RM designed the experiments. TK and RM collected and analyzed the data. CB, FG, TK, and RM interpreted the results. TK drafted the manuscript and revisions. CB, FG, and RM provided critical reviews of the manuscript and approved the final version. All authors contributed to the article and approved the submitted version.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.


Only 5% of Australian children and adults eat enough fruit and vegetables. Two common barriers are high cost and limited access. Food co-operatives (‘co-ops’) may have the potential to reduce these barriers. We conducted a scoping analysis of food co-ops in the Sydney region to describe their characteristics and objectives. We also conducted a survey of members and non-members of co-ops to assess their fruit and vegetable intake using validated questions. Fifteen food co-ops were identified in the Sydney region and the most common objective was to provide cheap affordable produce. Most co-ops (61%) were in areas of high socio-economic status (SES). Members of food co-ops had a higher vegetable intake than non-members  and were also more likely to meet the recommendations for fruit and vegetable intake [odds ratio (OR) = 4.77 ]. Implications of this study are that if food co-ops can be implemented on a wider scale, they hold potential for improving fruit and vegetable intakes. Diets low in fruit and vegetables are risk factors for cardiovascular disease, obesity, cancer and mortality . The AusTwo commonly reported barriers to fruit and vegetable consumption are high cost and limited access . People Recognition of the wider range of influences on food preferences ,13 meansOur research aims to explore the feasibility of establishing food co-ops in Australia with a view to improving fruit and vegetable intake. Firstly, we performed a scoping analysis to identify food co-ops in the Sydney metropolitan region with the aim of describing their characteristics, functions and objectives. Secondly, we undertook an online survey to examine whether adults (>18 years) participating in food co-ops in the Sydney metropolitan region differ in their fruit and vegetable intake compared to adults who do not participate in co-ops. We hypothesized that co-op members have a higher intake of fruit and vegetables than adults who do not participate in co-ops.A scoping analysis (or review of the current situation) of food co-ops was conducted from October 2017 to June 2019 to identify those operating in the Sydney metropolitan area specified by the Australian Electoral Commission . FormallCurrent food co-ops were identified, and their websites were explored. Co-ops were excluded if they did not sell fruits and vegetables, were located outside of the Sydney metropolitan area defined by the NSW Government ,24, or iWe conducted an online survey using admin-approved advertisements in Facebook parent groups located in Sydney with at least 500 members. A convenience sample of adults who resided in the greater Sydney area, were aged >18 years old, and did not have any major health conditions were recruited to participate in an online survey using Research Electronic Data Capture (REDCap) tools hosted at the University of Sydney. REDCap is a secure web application for building and managing online surveys and databases. They were asked to read the Participant Information Statement online and written consent was obtained via a check box on the questionnaire before proceeding. The questionnaire collected demographic data  and used validated short questions about daily fruit and vegetable consumption  and percentages (%) where categorical, and mean and standard deviation (SD) when continuous. To examine differences between groups, we used Pearson’s Chi-Square test for categorical variables and independent samples t-test for continuous variables. Three logistic regression models were created to examine the relationship between study factor and three binary outcomes . First, we conducted univariate logistic analysis for each explanatory variable; then, we fitted the baseline multiple logistic models including all covariates; next, we excluded each variable, except for the study factor, one by one from the highest p-value to the lowest p-value to determine the best fit of the model, after adjusting for context-specific variables (age and education), statistically significant variables and other potential confounders. Each model was presented separately based on the Hosmer–Lemeshow Goodness of Fit and Omnibus Tests of Model Coefficients. p-values of less than 0.05 were considered to be statistically significant. All statistical analysis was conducted by using IBM SPSS Statistics for Windows version 24.0 .Demographic variables are presented as frequencies .A total of 21 food co-ops were identified within the Sydney metropolitan area. One co-op (Bondi Food Collective) is no longer in operation, two co-ops were duplicates , and three co-ops  did not include fruit and vegetables. These six co-ops were excluded, leaving 15 food co-ops for analysis . Three oSeven co-ops (47%) supplied fruits and vegetables only and eight included other foods as well. Prices for boxes of food supplied ranged from $AUD12 for a small box to $AUD55 for a large box. Thirteen co-ops (87%) were not for profit and depended on volunteers. Five (33%) operated within schools and involved the school community. Only two co-ops relied on donated food from non-government organisations (NGOs) such as Foodbank . A totalThere was a diverse range of objectives for setting up food co-ops. The most common objective was to supply affordable or cheap produce (80% of food co-ops). Ecological commitment  was listed as a main purpose by 40% of the identified co-ops and another 40% mentioned quality/fresh produce and organic/pesticide-free or non-genetically modified food as a main purpose. Other objectives were to support local farmers (27%) and for good health (20%). Many of the school-based co-operatives included learning activities for children and they were involved in sorting the produce. The Staples Bag was specifically aimed at low-income populations. Rhubarb Food Co. was running educational workshops with a diverse range of topics . Ignite Just Society was a church-based co-op and one of the main purposes was to support disadvantaged populations and activities included fundraising. The Inner City Family Food Co-op aimed to support families with access issues, in that many of the people that participated did not have a car. Green Gradz was set up to provide school children the opportunity and experience to run a business, and also as a social enterprise to support a school teacher for an orphanage in Thailand .A total of 402 eligible adults started the online survey, with 317 (79%) completing the survey and included in the analysis. Out of 317 study participants, 305 (96%) reported whether or not they have participated in a food co-op, and 12 (4%) participants did not provide an answer to this question. A total of 51 out of 305 (17%) of participants reported being part of a food co-op. Demographic variables are shown in There were some differences between the co-op members and non-members with respect to employment status. Members of food co-ops had a lower prevalence of being in full-time, part-time or in casual employment (75%) compared to the non-members (81%). Additionally, there were differences in the family size between groups, with the adults in food co-ops having more children (mean ± SD: 2.1 ± 0.83) than non-members (1.8 ± 0.90).Fifty-one (17%) of survey respondents were members of a food co-op compared to 254 (83%) who were not. There were 41 of 51 members who reported that they knew the number of members in the food co-op (10 missing observations) with an average of 14 people (SD: 8) in each food co-op. Almost all (98%) food co-op members purchased fruit and vegetables, while less than half (47%) bought other food items. The majority (69%) of the members of a food co-op collected a box once per fortnight spending an average AU$28 per box (SD: 10.7).p = 0.007). The mean difference was 0.54 serves daily, with a 95% CI of 0.15 to 0.93 serves daily.More than half (55%) of the survey respondents consumed two or three serves of vegetables daily but only 8% met the vegetable recommendation (five or more serves of vegetables daily) . The meap = 0.801). The mean difference was 0.041 serves daily, with a 95% CI of −0.275 to 0.356 serves daily.Most participants (62%) consumed one or two serves of fruit daily and just over half of participants met the fruit recommendation (two or more serves of fruit daily). The mean fruit intake among the members of food co-ops (1.71 serves daily) was slightly higher compared to that among people who did not participate in food co-ops (1.67 serves daily). However, this was not statistically significantly different  of participants thought that they had ‘too little’ vegetables and 42% considered that they had enough serves of vegetables daily . In contN = 24) of participants met the Australian guidelines for five or more serves of vegetables daily but a much higher proportion (53% N = 160) of people met the Australian guidelines for two or more serve of fruits each day (Only 8% (each day . Combinip = 0.032). The adjusted odds ratio for whether members met the fruit and vegetable recommendation was 4.77 , indicating members of food co-ops have more than 4-fold the odds of meeting the Australian guideline for both fruit and vegetables daily than non-members.In terms of meeting both fruit and vegetable guidelines, there was a small percentage in both groups, with 4 (8%) out of 51 participants of food co-ops meeting the fruit and vegetable recommendation in daily intake compared to 7 (3%) in 254 participants who did not participate in food co-ops (Our study has provided a snapshot of the numbers and characteristics of current food co-ops operating in the Sydney metropolitan region. There were a diverse range of aims given for establishing food co-ops and the most common reason was to increase affordability. Interestingly, most food co-ops were located in high SES areas and there were less options in disadvantaged areas. Our study also demonstrated that members of co-ops had significantly higher intakes of fresh vegetables than non-members and there was also evidence that food co-op members were more likely to meet the Australian guidelines for combined fruit and vegetable intake than non-members. This finding may mean that establishing food co-ops on a wider scale may be an effective community-based strategy for improving consumption of fruit and vegetables.Our study findings are similar to a study from Canada, which showed that fruit and vegetable consumption and overall diet quality was significantly improved for those who frequently shopped from food co-ops compared with people who purchased from other stores such as supermarkets ,30. In oWhen considering how best to implement food coops on a wider scale, and in which regions, an important finding from our scoping analysis was that many co-ops operating in Sydney are based in areas of high SES. We recommend a targeted approach, establishing co-ops in areas of low SES, where people have a greater likelihood of having lower intakes of fruit and vegetables. It was also clear from our research that co-ops located in areas of disadvantage had a focus on affordability, a very important barrier to fruit and vegetable intake . This woAnother notable finding was that many of the food co-ops have been set up through schools; this may be an important leverage point to develop community-based activities around nutrition and healthy eating. In the USA, a school-based project ‘Brighter Bites’, which involved weekly distribution of fresh, donated produce from local food banks, resulted in significant improvements in fruit and vegetable intake over two months ,22. The One of the strengths of the cross-sectional survey is that we used validated questions from the Australian Health Survey  which haLimitations to the study include the cross-sectional survey design, which prevents drawing causal inferences between co-op membership and dietary intake, and this could be tested using an experimental study design. Other limitations include potential recall and measurement biases arising from self-reported consumption of dietary intake and potential confounders such as income were not measured. Our analysis was somewhat limited by the lower proportion of survey respondents who were part of a food co-op. However, this was expected because of the generally low number of co-ops operating in Sydney. In addition, convenience sampling from Facebook groups may limit generalizability, as some food co-ops may not have an online website or online presence.Innovative solutions to increase fruit and vegetable consumption on a population level are urgently needed. Increasing fruit and vegetable intake can reduce the risk of cardiovascular disease, stroke and some cancers. Our research suggests that people participating in food co-ops tend to have a higher intake of fresh vegetables than non-members of food co-ops and are more likely to meet Australian guidelines for daily fruit and vegetable intake than non-members. This is important, as wide-scale implementation of fruit and vegetable co-ops could be an effective way of increasing fruit and vegetable intake in the community. We also found that food co-ops are acceptable, as there were diverse food co-ops already operating in the Sydney metropolitan region, with most in higher SES areas. Enabling communities to establish co-ops in areas of lower SES, for example by providing advice and resources, may facilitate implementation. Harnessing this community-based method may also result in wider benefits such as improving the food and social environment, creating new social networks, facilitating social engagement and enabling access to transport and fresh food markets.


Virtual reality (VR) neuropsychological tests have emerged as a method to explore drug effects in real-life contexts in attention deficit hyperactivity disorder (ADHD) children. Functional near-infrared spectroscopy (fNIRS) is a useful tool to measure brain activity during VR tasks in ADHD children with motor restlessness. The present study aimed to explore the acute effects of methylphenidate (MPH) on behavioral performance and brain activity during a VR-based working memory task simulating real-life classroom settings in ADHD children. In total, 23 children with ADHD performed a VR n-back task before and 2 h after MPH administration concurrent with measurements of oxygenated hemoglobin signal changes with fNIRS. Altogether, 12 healthy control (HC) subjects participated in the same task but did not receive MPH treatment. Reaction time (RT) was shortened after MPH treatment in the 1-back condition, but changes in brain activation were not observed. In the 2-back condition, activation of the left dorsolateral prefrontal cortex (DLPFC) and bilateral medial prefrontal cortex (mPFC) was decreased alongside behavioral changes such as shorter RT, lower RT variability, and higher accuracy after MPH administration. Bilateral mPFC activation in the 2-back condition inversely correlated with task accuracy in the pre-MPH condition; this inverse correlation was not observed after MPH administration. In ADHD children, deactivation of the default mode network mediated by mPFC reduced during high working memory load, which was restored through MPH treatment. Our results suggest that the combination of VR classroom tasks and fNIRS examination makes it easy to assess drug effects on brain activity in ADHD children in settings simulating real-life. Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children. ADHD is defined by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity. Patients with ADHD exhibit complex multisystem impairments in fronto-cingulo-striato-thalamic and fronto-parieto-cerebellar networks that mediate attention, inhibition, working memory, and timing . In addiTo date, administration of psychostimulant drugs, especially methylphenidate (MPH), has been a treatment of choice for ADHD children . HoweverTo overcome these limitations, the utility of virtual reality (VR) has been recognized in terms of diagnosis and treatment of ADHD. VR facilitates the creation of dynamic, immersive environments with three-dimensional stimuli in which attention can be tested in an environment comparable to that experienced in the real world, improving ecological validity . In the However, few studies have evaluated brain activity during VR tasks in ADHD patients. One of the reasons for the paucity of research on brain activity during VR tasks is due to difficulties in examination. It is physically challenging to perform functional magnetic resonance imaging (fMRI) or single-photon emission computed tomography (SPECT) scanning while using VR devices, especially for young ADHD patients with motor restlessness. Moreover, research on drug effects requires repeated pre- and post-administration imaging, which necessitates employment of a simple and easy tool to measure brain function. In this context, research using functional near-infrared spectroscopy (fNIRS) has been growing. fNIRS is a non-invasive imaging technique that uses near-infrared light to measure functional brain activity through changes in concentration of oxygenated hemoglobin (HbO) and deoxygenated hemoglobin (Hb). The main advantage of fNIRS over other functional neuroimaging modalities such as fMRI, SPECT, or magnetoencephalography (MEG) is its portability . The fMRNevertheless, over the last few years, fNIRS has been used extensively to investigate cortical alterations in patients with various psychiatric disorders, such as schizophrenia; mood, anxiety, and eating disorders; and substance use disorder . For exaVarious studies using fNIRS have been conducted in ADHD patients. In most studies using tasks for evaluating attention or inhibition, ADHD patients exhibited lower prefrontal activity than that of healthy control (HC) subjects during the task –20 althoHowever, there has been limited research investigating the effects of medication on brain activity using fNIRS in VR tasks which simulates real-life classroom settings. As cognitive skills are ultimately applied in the classroom setting, especially in school aged children, attention and executive function can be better encapsulated in the virtual classroom environment than using traditional computerized neuropsychological tests. Furthermore, previous studies used the Go/No-go and oddball tasks mainly to explore inhibitory function. However, inhibition alone is insufficient to explain the pathophysiological mechanisms of ADHD. Working memory (WM) impairment is considered a core deficit of ADHD associated with prefrontal dysfunction.WM is defined as the ability to maintain information in an easily accessible state for a short period of time. According to the state-based model, the working memory contents are determined by perceptual & long-term memory representations being in a particular state of accessibility, maintained by neural activities controlled by the attentional processes  25). In. In25). The N-back task is a well-known working memory paradigm which has been used extensively in functional neuroimaging studies on ADHD . A few sBased on these findings, we aimed to investigate the acute effects of MPH on behavioral performance and brain activity of children with ADHD during a VR n-back task in a virtual classroom setting. To the best of our knowledge, this is the first study using a VR-based working memory task and fNIRS to explore the effects of MPH in ADHD children.Altogether, 23 right-handed Korean children with ADHD  and 12 healthy control (HC) children  participated in this study. The number of participants required for adequate statistical power was based on previous studies that investigated drug effects in ADHD patients through fNIRS –42 and aSeveral measurements were conducted to assess the psychological state of participants. The ADHD Rating Scales (ADHD-RS), an 18-question parent rating scale, was used to identify the presence of ADHD in children. Behavioral problems were assessed with the Korean version of the Child Behavior Checklist (CBCL), an 118-item parent-rated scale which queries behavioral problems in the past 6 months ; ChildreThe protocol used for this study was approved by the Institutional Review Board of Yonsei University College of Medicine Gangnam Severance Hospital. Written informed consent and assent were obtained from all participants and one of their parents.We investigated the effects of ADHD medication in a controlled pre- and post-MPH study design, whereby participants performed n-back tasks with the 1-back and 2-back conditions. The experimental protocol is summarized in The background of this VR task was a virtual classroom. The participants began by finding themselves in a typical classroom in a Korean school with desks facing ahead and blackboards in front of them. The participants' point of view was of the first person, facing the teacher, with other avatar classmates seated nearby . The mesThe n-back task consisted of three block sets. Each block set contained alternating 1-back (low WM load) and 2-back (high WM), and in-between 0-back (control) conditions . Each stimulus was presented for 500 ms with an interstimulus interval of 1.5 s. Overall block-set time was 160 s, and total session time was 8 min. The total number of trials in experimental conditions was 120. Subjects were instructed to press the button with their right index finger as quickly as possible, when the current stimulus was the same as the previously shown letter (1-back), or with the letter shown two screens back (2-back). Since it is extremely difficult for young ADHD patients to remain still when not performing a task, our baseline (control) task required participants to respond to each stimulus with a button press to rule out motion artifacts and equalize the motion load with the experimental task. To diminish habituation or practice effects in the post-MPH session, two task versions with different stimuli were employed. These two versions were randomly assigned to each subject.The software was written in Visual Studio 2017(C#) and designed on Unity 2018.2. The avatars and structures comprising the virtual environment were built using a 3Ds Max 2014. We used the 3D development platform  to develop the virtual classroom environment. Our VR classroom was implemented in the VR theater which provides a semi-immersive environment with a 2.18-m radius curved screen, providing 150° field-of-view . The averaged oxy-Hb concentration changes (avgΔHbO2) during the task period baselined from 5 s before task initiation was calculated in each channel after block averaging of multiple trials. Finally, the regional representative value of avgΔHbO2 was extracted by averaging categorized channels based on the specified region of interest (ROI). The selection of the brain ROI was completed before data analysis. The 48 channels were categorized as right and left dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC), which constituted eight ROIs. The channels corresponding to each region are shown in 2 per channel of each group according to 1-back and 2-back tasks.We used a multichannel high density fNIRS device , which consisted of 24 laser diodes emitting two wavelengths (780/850 nm) and 32 photodetectors separated by a 1.5 cm unit distance. The laser and detector pairs were separated at a 3 cm distance. Sampling rate was 8.138 Hz. The alignment of 48 channels is shown in For n-back task results, the total reaction time (RT), RT variability, and accuracy were used as dependent variables for analysis. RT variability was calculated by dividing the standard deviation of the individual RT by the mean value, as reported previously . We compt-test for numerical variables or Chi square (χ2) test for categorical variables. The means and standard deviations of avgΔHbO2 were calculated for each ROI and in each group to compare group differences and verify the effects of pre- and post-MPH effects on fNIRS results. For comparison of behavioral performance and fNIRS data between pre- and post-treatment conditions in ADHD participants, we used a two-tailed paired t-test. An independent two-sample two-tailed t-test was used for comparing variables between ADHD and HC groups. The normality of the data was evaluated by visual inspection of quantile-quantile plots and the Shapiro-Wilk test. To examine the association between behavioral performance and fNIRS data, we conducted correlation analysis using the Pearson's method. The statistical threshold was set at p < 0.05. All statistical analyses were completed with IBM SPSS version 25 .Group differences in clinical characteristics between ADHD and HC groups were compared using an independent sample t = −4.64, p < 0.001), ADHD-RS-inattention and hyperactive-impulsive subscales scores , CBCL total and attention problem subscale scores . The mean ADHD_RS score of the ADHD patients was 20.96, which indicates relatively mild level of ADHD severity. The SSQ score was low in both groups  with few symptoms. The typical mean MPH dose of ADHD subjects was 29.35 mg .Baseline characteristics of the study participants are presented in The average accuracy rates and RTs in each n-back task for HC and ADHD participants are summarized in 2 measured using fNIRS are presented in 2 changes were observed in any area when comparing pre- and post-MPH conditions  and mPFC activation. There was a negative correlation between accuracy and avgΔHbOThe present study aimed to investigate the feasibility of using fNIRS to investigate the neural substrates of single-dose MPH effects in children with ADHD during a VR working memory task. The combination of VR and fNIRS in this study revealed that this model was able to easily measure the effects of various drugs and interventions on children with ADHD in an environment simulating a real-world setting. Furthermore, it enables a setting that explores changes in brain activity during a neuro-rehabilitation program using VR environments. To our knowledge, this is the first study using a VR environment to measure the impact of MPH on working memory with fNIRS in ADHD subjects.In the current study, task performance improved after MPH treatment; this was verified by shorter RT in the 1-back condition and shorter RT, lower RT variability, and higher accuracy in the 2-back condition compared to that in pre-medicated ADHD subjects. This result is generally consistent with previous studies reporting performance enhancing effects of MPH in ADHD patients –55. ConvWe observed increased activation in the left DLPFC and bilateral mPFC in pre-medicated ADHD subjects during the VR 2-back task, which decreased after MPH administration. However, there were no significant differences between HC and ADHD children. In most NIRS studies comparing children with ADHD to HCs in different executive functioning tasks, altered prefrontal activity was reported: some studies reported reduced activity in ADHD –19, wherIncreased activation in bilateral mPFC was negatively correlated with accuracy of the 2-back task in pre-medicated ADHD subjects, whereas this association disappeared after MPH treatment. This result implies that mPFC was abnormally hyper-activated in ADHD subjects during the 2-back task, which was accompanied by low performance. The mPFC is a brain region that constitutes the default mode network (DMN) along with the medial and lateral parietal and temporal cortices . The DMNBy contrast, in the 1-back condition, we found no difference in brain activation between pre- and post-MPH conditions. Given that only RT was shorter after MPH treatment for behavioral performance, and there was no significant difference in accuracy or RT variability, it can be assumed that the difference before and after drug was minimal due to the low level of 1-back difficulty, reflected by a ceiling effect from the pre-test. The only study that explored the effect of MPH during the n-back task in ADHD children reported no differences in brain function in the 1-back condition between pre- and post-drug administration, which is concordant with our study . In addiIn the present study, the VR classroom environment provided a more ecologically valid and motivating task than that of traditional computerized cognitive tasks, suggested by the improved task performance of ADHD children. We propose several advantages of using a VR task over traditional computerized WM tasks. Previous studies have indicated that ADHD children find digital technology environments more enjoyable and are more immersed in the task , 68. NonOur study has several limitations which we hope to address in future studies. First, the study design was not optimized for neuropharmacological analysis. A double-blind placebo-controlled or a cross-over design with drug-naive ADHD children should be conducted. Since we did not include a placebo group, the superior task performance in post-MPH ADHD subjects could be due to a repeat effect. In addition, unlike the ADHD patients, the HC did not repeat the tests, making it difficult to compare the HC group with the post-MPH group or to eliminate the time effect. Therefore, it is not entirely clear whether the changes in brain activation in the ADHD group were truly induced by the treatment or were simply a function of time. However, considering the NIRS imaging results, the improved behavioral performance was accompanied by changes in brain activity such as reduced hyperactivity of bilateral mPFC in post-MPH ADHD subjects, making it difficult to fully explain solely based on repeat effects. Further, WM tasks are generally considered to have strong test-retest reliability and to be relatively unaffected by practice effects . In addiTo our knowledge, this is the first study to explore the effects of MPH on brain activity during a VR-based WM task reproducing real-classroom settings in ADHD children. We observed that activation of bilateral mPFC decreased after MPH treatment in a high-load WM task. Further, bilateral mPFC activation was negatively correlated with task accuracy in pre-MPH condition; this correlation disappeared after MPH administration. These findings suggest that mPFC-mediated inappropriately excessive mind-wandering during a high-load WM task in ADHD children may have disappeared after MPH administration. Taken together, these results suggest that the combination of VR tasks and fNIRS examination is a technique that enables examination of the effects of interventions within a real-life setting in ADHD children and adolescents.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Institutional Review Board of Yonsei University College of Medicine Gangnam Severance Hospital. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.EK and NL devised the project, the main conceptual ideas, and proof of the outline. EK, NL, and JY designed the detailed study design. JY, NH, JK, and JH examined participants, performed the experiments, and acquired and organized the data. SJ and JC conducted analyses of the experimental data, drafted the manuscript, and designed the figures with supervision from EK. JO and J-jK contributed to interpreting the results and worked on the manuscript. All authors discussed the results and commented on the manuscript. EK supervised the project. All authors contributed to the article and approved the submitted version.JC was employed by OBELAB Inc. The remaining 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.


The aim of this review was to investigate whether e-cigarette use compared with non-use in young non-smokers is associated with subsequent cigarette smoking.PubMed, Embase, Web of Science, Wiley Cochrane Library databases, and the 2018 Society for Research on Nicotine and Tobacco and Society for Behavioural Medicine conference abstracts.All studies of young people (up to age 30 years) with a measure of e-cigarette use prior to smoking and an outcome measure of smoking where an OR could be calculated were included .Independent extraction was completed by multiple authors using a preprepared extraction form.2I=88%).Of 9199 results, 17 studies were included in the meta-analysis. There was strong evidence for an association between e-cigarette use among non-smokers and later smoking  when the results were meta-analysed in a random-effects model. However, there was high heterogeneity (Although the association between e-cigarette use among non-smokers and subsequent smoking appears strong, the available evidence is limited by the reliance on self-report measures of smoking history without biochemical verification. None of the studies included negative controls which would provide stronger evidence for whether the association may be causal. Much of the evidence also failed to consider the nicotine content of e-liquids used by non-smokers meaning it is difficult to make conclusions about whether nicotine is the mechanism driving this association. Existing evidence suggests that electronic cigarette (e-cigarette) use is less harmful than smokingOne systematic review and meta-analysis of the association between baseline e-cigarette use and later smoking concluded that e-cigarette use was associated with an increased likelihood of smoking at the follow-up.In this systematic review and meta-analysis, we updated and extended previous reviews in which e-cigarette use and later smoking have been explored while looking at a broad range of evidence. Our aim was to investigate whether e-cigarette use, compared with non-use, in young non-smokers is associated with subsequent cigarette use by combining evidence from studies investigating e-cigarette use and subsequent smoking where an OR could be calculated. Additionally, we aimed to use stratification to explore sources of heterogeneity and biases in conclusions regarding the gateway hypothesis. From our knowledge of the evidence base and considering this is a fast-moving area of research, we expected to identify a substantial number of studies that have been published since the review by Soneji and colleagues.https://osf.io/3gc2y/). Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) and MOOSE guidelines were followed (where applicable).The protocol for this systematic review and meta-analysis was published online prior to initiating the search and can be found on the Open Science Framework  were included. Studies had to have a baseline or retrospective measure of e-cigarette use  prior to initiating smoking and a measure of cigarette smoking  as an outcome. Studies had to include a comparison group , which could include young people who were never, trial or not recent e-cigarette users or smokers, dependent on the study. Review articles and animal studies were excluded.Our search strategy was a replication and extension of a strategy used in a similar review.Studies were initially selected for screening using the following search terms within the titles, abstracts or keywords: Cigar* OR Tobacco OR Smok* AND Electronic Cigarette* OR E-Cig* OR Electronic Nicotine Delivery System* OR Vape OR Vaping OR Alternative Nicotine Delivery System*. Boolean operators and truncations differed depending on the database. Relevant MeSH terms were included when searching the PubMed database. An example search can be found in the 10.1136/tobaccocontrol-2019-055433.supp1Supplementary datawww.covidence.org), an online systematic review tool that is in partnership with Cochrane, was used to streamline and document this process.Study selection and data extraction took place over three stages. Stage 1 consisted of title and abstract screening; stage 2 consisted of a full-text screening; stage 3 consisted of data extraction from selected studies. A full list of extracted data is included in the When insufficient information was available to determine eligibility, we contacted study authors. Where insufficient information was provided or obtained, the text was excluded from the review.The risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). The selection, comparability and outcome domains of the tool were used to assess the risk of bias in all full texts included in the review. The studies were rated as good, fair or poor quality based on the star system of the tool . ORs of the association between e-cigarette use and later cigarette use were combined using a random-effects model. All unadjusted ORs were calculated using observed data points that were obtained from the original study or directly from the author if insufficient information was provided in the original study. Calculated effect sizes were double checked by the review team.Adjusted ORs were reported as they were in the original study and adjusted risk ratios were converted to ORs using a modified version of a formula published in the Cochrane Handbook (Section 12.5.4.4)In a random-effects model, we calculated the pooled ORs from unadjusted and adjusted ORs for ever cigarette use at follow-up among never smokers at baseline, in ever compared with never e-cigarette users at baseline. Where multiple exposure or outcome measures were included in the original study, this estimate was used in the main analysis. If ever use of e-cigarettes was not reported, then the main effect reported in the study was included in our main analyses.Where possible , we also analysed the results in a series of subgroups—we pooled odds for: (i) ever versus never e-cigarette use at baseline and ever versus never smoking at follow-up; (ii) ever versus never e-cigarette use at baseline and current (past 30 days) versus non-current use of cigarettes at follow-up, and (iii) current versus non-current e-cigarette use at baseline and ever versus never smoking at follow-up. In retrospective studies, measures of e-cigarette use prior to smoking were treated as baseline and smoking status at the time of the study was treated as the follow-up. We aimed to pool the results of regular (at least monthly for >6 months) cigarette use at follow-up among never smokers at baseline, in regular compared with non-regular e-cigarette users at baseline; however, insufficient data were available to do so.2I statistic. Sources of heterogeneity were explored through subgroup analysis. All analyses were conducted using Stata SE V.15.1 and Review Manager V.5.Heterogeneity of study effect estimates can be indicated by an This research was done without public involvement. The public was not invited to partake in the conception or design of the study, or the interpretation of the results. The public was not invited to contribute to the writing or editing of this document for readability or accuracy. The results of this meta-analysis will be disseminated to the public as widely as possible.Details of the study characteristics are shown in the In terms of observed exposures, most studies explored ever e-cigarette use with never e-cigarette users as a comparator. Two studies looked at current users with not current users as the comparatorMost of the included studies used ever smoking as an outcome. One study explored experimentation with smoking, as well as frequent and infrequent smoking,Covariates included in the analyses varied greatly between studies. One study only adjusted for four covariates,The quality of studies  was good in most cases when rated using the NOS . One stuThe results of individual studies included in the main meta-analysis can be found in I²=88%) and adjusted (I²=85%) analyses.When pooled in a random-effects meta-analysis, e-cigarette use in non-smoking young people was associated with a four-and-a-half-fold increase in the odds of subsequent smoking . Pooling the adjusted estimates, the association was still strong but somewhat weaker . Heterogeneity statistics indicated there was high heterogeneity in both the unadjusted . The results of the pooled adjusted analysis were similar with slightly lower odds . Heterogeneity between included studies was still high in the adjusted analysis (I²=84%).Pooled analyses of studies exploring ever vaping among never smokers and subsequent ever smoking resulted in a pooled unadjusted OR of 4.17 (95% CI: 3.53 to 6.29). Heterogeneity between included studies in this analysis was high (I²=41%). Adjusted analyses showed similar but weakened results when pooled . Heterogeneity was indicated as low in the adjusted pooled analyses (I²=5%).Among never smokers, pooled unadjusted analyses indicated ever e-cigarette users had increased odds of subsequently becoming a current smoker  compared with never e-cigarette users. Heterogeneity estimates indicated low heterogeneity (I²=49%). The pooled adjusted analysis also indicated increased odds of ever subsequently smoking . Heterogeneity estimates also indicated low heterogeneity when the adjusted results were pooled (I²=5%).Past 30-day use of e-cigarettes among never smokers was associated with increased odds of ever subsequently smoking  in pooled unadjusted analysis. Heterogeneity estimates indicated low heterogeneity (I²=32%) but high heterogeneity between studies including those under the age of 18 years (I²=88%). Adjusted pooled analyses are reported in the When the unadjusted main analyses were stratified by age (including versus excluding under the age of 18 years) the pooled OR among studies including those under the age of 18 years was slightly higher  than the pooled OR of studies excluding those under the age of 18 years . Heterogeneity estimates indicated that there was low heterogeneity between studies excluding those under the age of 18 years . Adjusted pooled analyses are shown in the Due to limited variation in quality rating of studies using the NOS, fair and poor quality studies were pooled and compared with good quality studies. The pooled unadjusted OR for studies rated as good quality  was lower than the pooled odds ratios for fair/poor quality studies . Heterogeneity measures indicated that high-quality studies were less heterogeneous than fair/poor quality studies  and moderate in the UK (I²=52%). The other studies were located in the Netherlands, Germany, Canada and Mexico. Pooling these results, the odds of subsequent smoking was 4.75 (95% CI: 2.54 to 8.89) with high heterogeneity between studies (I²=96%). Adjusted pooled analyses are shown in the There were only two countries in which more than one included study was conducted; 10 studies took place in the USA and 3 took place in the UK. The pooled estimate for unadjusted odds of studies conducted in the USA was 3.95 (95% CI: 3.17 to 4.92) and in the UK was 5.55 (95% CI: 3.94 to 7.82). Heterogeneity for studies conducted was high in the USA (2I statistics) or selection bias across the included studies.The risk of bias across studies is shown in a funnel plot in Our results indicated that self-reported non-smokers who have used e-cigarettes have four-and-a-half-fold higher odds of subsequently reporting being smokers than those who have not. The pooled adjusted estimate indicated a weaker, although still strong, association with nearly three-fold increased odds of later smoking. Subgrouping and stratification revealed some differences between groups, but all findings indicated a strong positive association. The main findings were consistent with the findings of Soneji and colleagues,Three of the four preselected Bradford-Hill criteria  were commonly rated as having been met in the included studies. Despite the high heterogeneity statistics, the included study estimates are consistently in the same direction and there are plausible causal pathways . This suggests that the results provide some support for a causal relationship between e-cigarette use and later smoking. This is in line with the theory that e-cigarettes act as a gateway to smoking.The majority of studies included in the meta-analysis satisfied the temporality criterion. All studies except one were longitudinal and measured exposure prior to smoking and smoking at follow-up; therefore, the observed association between earlier e-cigarette use and later smoking is unlikely to be due to reverse causality . However, smoking status is sometimes misreported by young people,It is also worth noting that our measure of specificity was relatively liberal. We rated studies as specific if they adjusted for more than basic demographic factors. In a recent cross-sectional study, accounting for shared risk factors fully explained the relationship between e-cigarette use and current smoking, demonstrating the importance of adjusting for potential confounders such as alcohol and drug use, peer smoking and risk-taking behaviour.To meet the final pre-selected Bradford-Hill criterion, dose–response, increased e-cigarette use should lead to greater risk of later smoking. Despite the most likely causal pathway from e-cigarette use to later smoking being via nicotine addiction,IOur heterogeneity statistics of 88%  and 85%  indicate that our effect estimates should be interpreted with caution. Although there is no commonly agreed on strict threshold for heterogeneity, as a rough guide, the Cochrane Handbook suggests that In conclusion, there is a strong consistent association in observational studies between e-cigarette use among non-smokers and later smoking. However, findings from published studies do not provide clear evidence that this is explained by a gateway effect rather than shared common causes of both e-cigarette use and smoking. This emphasises the need for a scientific forum to discuss the evidence to date and directions for future research. Future research should consider including relevant potential confounders, such as better measures of impulsivity and other measures of propensity to risk taking, and objective measures of smoking status in order to better explore the potential role of e-cigarettes as a gateway to smoking. Studies that explore the genetic underpinnings of these behaviours and use negative control outcomes may also help improve our understanding of the association between e-cigarette use and later smoking. A scoping review, including qualitative evidence, could provide a clearer understanding of the why e-cigarette use is associated with later smoking. Importantly, any recommendations regarding e-cigarette regulations to limit the burden of future smoking must consider the potential beneficial impact of e-cigarette use on smoking cessation.There are concerns that e-cigarettes may cause youth and young adults who have never smoked before to start smoking.A previous meta-analysis of nine studies has shown that there is a positive association between e-cigarette use and later smoking (sometimes referred to as the gateway hypothesis).Our meta-analysis of 17 studies indicates e-cigarette use among non-smokers is associated with later smoking.However, the results do not provide strong evidence of a gateway effect.


The data presented in this article relate to the research article entitled “assessing psychological adaptation during polar winter-overs: The isolated and confined environments questionnaire (ICE-Q)” [1]. These data were acquired in order to develop a standardized instrument – the ICE-Q – designed to assess psychological adaptation within isolated, confined, and extreme environments. A total of 140 winterers from several sub-Antarctic  and Antarctic  stations voluntarily participated. Data were collected by multiple self-report questionnaires including a wide variety of well-known and validated questionnaires to record the winterers’ responses to polar stations. Data were gathered across two or three winter seasons within each of the 5 polar stations to ensure sufficiently large sample. From four to seven measurement time along a one-year period were proposed to the participants, resulting in 479 momentary assessments. Results of exploratory factor analyses, confirmatory factor analyses, exploratory structural equation modelling, reliability analyses, and test-retest provided strong evidence for the construct validity of the ICE-Q (19–item 4-factor questionnaire). The four factors were social, emotional, occupational and physical. Future studies would examine the dynamic of psychological adaptation in isolated, confined and/or extreme environments during polar missions. Participants were members of 14 distinct polar missions from several sub-Antarctic  and Antarctic  stations. Data were gathered during several winter seasons and in several polar stations to ensure sufficiently large sample (no winterer participated in more than one winter season). The data presented in this article is complementary to the research article entitled “assessing psychological adaptation during polar winter-overs: The isolated and confined environments questionnaire (ICE-Q)” . A totalrtest-retest over a 5-month period = .65), emotional , occupational  and physical .Results of exploratory factor analysis with varimax rotation including all the items of the preliminary version of the ICE-Q are presented in 2Participants were winterers from several sub-Antarctic and Antarctic stations. The study protocol was carried out in accordance with the Declaration of Helsinki and was approved by the European space agency, the Paul Emile Victor institute and the local institutional review board. After comprehensive verbal and written explanations of the study, all the subjects gave their written informed consent to participate. Participants were asked to return the completed questionnaires directly to the researchers within two days after receiving the battery in their personal email account. The questionnaires were sent and returned the first days that the respondents were on site and at 3, 5, 6, 8, 10, and/or 12 months into the mission.A battery of well-known and validated questionnaires was used to record the winterers' responses to polar stations. Because of the high workloads and psychological challenges of isolated, confined and extreme environments, shortened versions of the original scales were sometimes used. Participants completed the group environment scale (GES)  measurin


Infrared light radiates from almost all the matter on earth and its strategic use will be an important issue for the enhancement of human life and the sustainable development of modern industry. Since it has frequency in the same region as phonons or molecular vibrations of materials, measuring its emission or absorption spectra helps us in characterizing and identifying the materials in a non-destructive manner. Meanwhile, if we can spectroscopically design the infrared emission by tuning the chemical composition or artificially controlling the nano- to mesoscale structures, it will have a great impact on industrial applications, such as in thermophotovoltaics, energy-saving drying furnaces, spectroscopic infrared light sources, and various types of infrared sensors.In this Special Issue, recent studies by researchers who are working on MEMS-based infrared detectors, nanomaterial-based infrared detectors, thermal emitters, or fiber optics, have been contributed. Important topics of growing interests are the wavelength-selective infrared emitters and detectors where we can see rapid development in the field of nano-plasmonics and metamaterials, and we also collected contributions from narrow-band gap semiconductors.This Special Issue collected 13 research papers, including one featured article. These are categorized as follows.(1)Infrared nano/micro devices based on lithographic techniques and MEMS structures.2O3–Al bilayer, exhibiting great possibilities for miniature multi-wavelength spectroscopic devices. Yoshino et al. developed, a simple process to mechanically fabricate ordered Au nanodot arrays that respond to nearinfrared light, and also reported the feasibility of its application to plasmonic sensors [2-based metal insulator metal-structured metasurface for the thermal emitter of the thermophotovoltaic system [Dao et al. have demonstrated a compact design for membrane-supported, wavelength-selective infrared (IR) bolometers . The fab sensors . The devc system . The pro(2)Materials for infrared thermal emitters/absorbers and detectors based on compound semiconductors and their variants.2 layer under the ITO disk arrays. Chiu et al. examined the optical properties of alloys with noble metals (Au and Pt). The six different metals  which possess good properties for heat resistance, stability, and magnetism were mixed with noble metals to improve the properties [Ngo et al. reported the synthesis and demonstration of niobium-doped titanium dioxide for the application in plasmonic antenna and surface-enhanced infrared absorption . The nanoperties . The optoperties . The vol(3)Infrared-sensing applications using fiber and laser technology, and hyperspectral camera.2H2 [Inada et al. evaluated the performance of a fluorescent detection system in an extirpated pig stomach and a freshly resected human stomach and were able to successfully detect NIR fluorescence emitted from the clip in the stomach through the stomach wall by the irradiation of excitation light (λ: 808 nm) . The pro2H2 . The dat2H2 . They prWe would like to thank all authors for submitting their papers; most of them kindly contributed to this Special Issue in response to our invitation. We would also like to acknowledge all the reviewers for dedicating their time and timely reviews to improve the quality of this Special Issue.


The continued explosive spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) despite aggressive public health measures has triggered an unprecedented international vaccine effort. However, correlates of protection, which can help guide intelligent vaccine design, are not known for SARS-CoV-2. Research on influenza immunity and vaccine development may provide valuable lessons for coronavirus efforts, especially considering similarities in rapid evolutionary potential. The apparent inevitability of future novel coronavirus outbreaks must prompt work on a universal coronavirus vaccine. The case fatality ratio (CFR) varies widely by country and while population characteristics and access to healthcare are critically important factors, differences in the extent of testing of mild cases are likely responsible for some of the observed variation in the CFR through effects on the denominator. Interestingly, in the hardest hit areas, only a small fraction of the population has been reported to be infected. It is unclear how much of this is due to asymptomatic clinical presentations, testing availability, viral transmission dynamics, changes in individual behavior, and aggressive isolation and quarantine actions. Some experts suspect a significant number of mild or asymptomatic infections go undiagnosed, leading to a falsely elevated CFR and making the pandemic much more difficult to control in the setting of asymptomatic transmission2. Public health measures helped to extinguish the SARS outbreak 17 years ago, but so far, they have only been able to slow down the coronavirus disease 2019 (Covid-19) pandemic3.The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread throughout the world with explosive outbreaks underway throughout much of Europe and the United States. Even though the pandemic has slowed down in some countries, other nations are still experiencing a rapid rise in cases and their healthcare systems are pushed to the limits4. The focus of the response is haste, understandably so, leading to use of novel technologies, including DNA plasmids, viral vectors, virus-like particles, Baculovirus/mammalian expression systems, and mRNA vaccines among others. Many of these utilize sequencing information that was made available quickly after the onset of the outbreak and can be developed more rapidly than classical vaccine preparation strategies utilizing live virus as substrate, which necessitate the use of cumbersome biosafety protection measures5. The purpose of most early candidate vaccines is development of antibodies against the Spike glycoprotein (S protein), which have been implicated in protection against SARS-CoV in animal models and have been found in SARS-COV and SARS-CoV-2 convalescent patient sera8. However, we do not yet have evidence to show that anti-S protein antibodies are protective in humans against SARS-CoV-2, and if they are, how much protection is afforded. Recent data have shown 94% of patients who recover from mild Covid-19 have neutralizing antibodies 2 weeks after symptom onset, but neutralizing antibody titers correlate only moderately with measured anti-S protein antibody9. Careful study of potential patients with SARS-CoV-2 reinfection may help shed light on this question, but cases have not been documented in the literature. Reports may be confounded by prolonged RNA shedding, which can persist over 30 days in almost 10% of patients, regardless of resolution of symptoms10. The viability of virus associated with prolonged shedding and consequently the infectivity of these patients is also unknown, considering that in a separate study of nine patients, live SARS-CoV-2 was isolated only up to day 7 despite ongoing high viral loads by reverse transcription polymerase chain reaction11. The distinction between viable virus and RNA shedding may have ramifications on study of immune correlates of viral clearance.In order to combat the disease, governments, international organizations, private companies, and academic institutions across the planet have launched a multifaceted vaccine development response with unprecedented rapidity. At least 110 vaccine candidates are in preclinical testing and at least 5 vaccines have already begun early clinical testing13. Only in the past few years, a century after the advent of the 1918 influenza pandemic that was one of the most catastrophic events in human history responsible for 50–100 million deaths, a concerted effort was initiated to accelerate the development of a universal influenza vaccine14. Many unknowns exist with respect to SARS-CoV-2, but research into influenza immunity and vaccine development may provide valuable lessons for Covid-19 and may help guide vaccination strategies. We have known for decades that antibodies against hemagglutinin (the dominant surface protein of the influenza particle) at a titer of 1:40 or greater are associated with >50% reduction in disease, but more recent data have suggested antibody against influenza neuraminidase, another viral surface protein, may be a superior predictor of clinical outcomes16. We have no such knowledge of correlates of protection against coronaviruses, and specifically against SARS-CoV-2, thereby making the process of developing an effective vaccine that much more difficult. Interestingly, the importance of anti-neuraminidase immunity in protection against influenza was recognized during the H3N2 pandemic. Through serendipitous ongoing trials, researchers were able to seize an opportunity to obtain preinfection and postinfection sera demonstrating the ability of anti-neuraminidase antibodies to reduce infection rates17. We need to obtain similar information for SARS-CoV-2 to help guide and refine vaccine development.Vaccine development against respiratory viruses is a challenging task. Currently, the only approved vaccines against respiratory viruses are those against influenza. Despite decades of research, modern vaccines have had limited effectiveness against seasonal influenza and are unlikely to provide broad protection against novel influenza strains capable of causing pandemics19. Influenza surface proteins have non-conserved regions which can accommodate mutations that limit the effect of antibodies without impairing enzyme activity (antigenic drift), potentially leading to loss of immunity in infected or vaccinated individuals from one season to the next20. Genetic drift of spike protein has been demonstrated in endemic human coronavirus OC43, suggesting mutations can be accumulated in non-conserved regions over time21. Furthermore, an escape mutation conferring resistance to neutralizing antibody was found in vitro after applying immune pressure to 2002/2003 SARS-CoV. Interestingly, this mutation was also found to have occurred naturally in 2003/2004 SARS-CoV strains raising the possibility that SARS-CoV-2 has the potential to evolve resistance against antibodies induced by some vaccine strategies currently under development18. Genetic differences within the receptor-binding domain (RBD) discriminating two major types of circulating SARS-CoV-2 indicate that the virus is already adapting22. Targeting of conserved epitopes has been proposed as a strategy to combat influenza’s adaptive capabilities and may be a potential strategy against SARS-CoV-2 as well. Amino acid sequence similarity between SARS-CoV S protein and SARS-CoV-2 S protein has been estimated only at 77% with significant changes present in the RBD23. In this context, many antibodies against SARS-CoV S protein have not shown promising SARS-CoV-2 binding and neutralizing capacity26. Similarly, antibodies against SARS-CoV-2 RBD have not shown cross-reactivity to SARS-CoV RBD or Middle East respiratory syndrome-CoV RBD24. Recent work has clarified that, despite only 46.7% protein sequence similarity between the SARS-CoV S1B receptor-binding subdomain and the SARS-CoV-2 S1B receptor-binding subdomain, the S1B RBD core domain is highly conserved27. Antibodies have been identified targeting epitopes in S1B RBD core domain, which show cross-reactive potential against both SARS-CoV and SARS-CoV-227. These findings may help guide development of vaccines with broader coverage, though the protective effects of such antibodies have yet to be demonstrated in animal models or human studies.Both influenza and coronaviruses have an inherent capacity for rapid mutation due to the low fidelity of RNA polymerase and a capability to form novel viruses through reassortment with a vast reservoir of zoonotic viruses28. Similarly, antibodies against S protein diminished over time in SARS survivors29. We are then faced with a critically important but unanswered question: For how long will SARS-CoV-2 circulate? Whereas the SARS outbreak was extinguished, all five characterized pandemic influenza viruses established endemicity, facilitated, at least in part, by antigenic drift and waning antibody titers. Though impossible to predict with certainty, the prospect of SARS-CoV-2 also establishing endemicity is one the medical community needs to be prepared for, including the potential for accumulation of mutations in the face of increasing immune pressure. Considering that three coronavirus outbreaks have occurred in the past two decades, even if SARS-CoV-2 disappears in a similar fashion to SARS-CoV, it seems inevitable that another novel coronavirus outbreak will occur in the future. Acknowledging the limitations in cross-protection of most SARS-CoV-induced antibodies against SARS-CoV-2, it is quite likely that vaccines tailored to SARS-CoV-2 would not offer protection against novel coronaviruses26. Even with advances in the rapidity of vaccine development technology, the delay between epidemic onset and implementation of a novel vaccine candidate in the community is responsible for immense societal costs.An additional problem is the waning of antibody titers over time after vaccination or recovery from live infection. Consequently, individuals are left vulnerable to reinfection, as demonstrated in influenza, even with an identical strain during the next seasonAfter the SARS outbreak, we lost interest and failed to complete development of a vaccine for use in case of a recurrent outbreak. We must not make the same mistake again. Instead we must go further. We must work toward a universal coronavirus vaccine with broad protection against a diverse number of coronaviruses. We need to understand the correlates of protection against coronaviruses and improve our understanding of their pathogenesis, transmission, and viral evolution. These studies will be absolutely necessary for us to intelligently design efficacious vaccines not just against SARS-CoV-2 but also against other coronaviruses that are likely to emerge in the future. If work on influenza can serve as a lesson, a universal coronavirus vaccine will not be easy to develop, but if we do not start work on one now, we will find ourselves in a similar situation during the next outbreak.


The severity of the COVID-19 pandemic has led to an unprecedented effort to develop vaccines against SARS-CoV-2 infection since this seems to be the most effective strategy to counter the pandemic. In the past weeks, the administration of vaccines has started in different parts of the world sustaining the hype of significantly containing the impact of SARS-CoV-2 infection. However, the rapid time lapse from vaccine development to distribution has raised several concerns on its safety and efficacy. This topic is particularly felt by patients with chronic conditions and immumodulating therapies that could compromise their immune system such as inflammatory bowel disease (IBD). Here, we explore the potential future implications of the SARS-CoV-2 vaccines introduction in the IBD field, touching upon the clinical experience coming from available data on vaccinations against other infections. We also dissect the factors associated with the acceptability of SARS-CoV-2 vaccination, describing the possible strategies that gastroenterologist should adopt to reach the highest rate of vaccinations in IBD patients. The COVID-19 pandemic has caused more than 108 million cases and 2 million deaths worldwide ,4. OtherHere, we explore the potential future implications of the SARS-CoV-2 vaccines introduction in the IBD field, touching upon the clinical experience coming from available data on vaccinations against other viral infections. We will also dissect the factors that will be eventually associated with the acceptability of SARS-CoV-2 vaccination in IBD patients.During the course of disease, the majority of IBD patients need long-term immuno-modulatory therapy and thus are at increased risk for infectious diseases. Many of these diseases are easily preventable by vaccination. A detailed summary of the main vaccines recommended in IBD patients according to international guidelines is reported in Indeed, to maximize their efficacy, vaccination should be preferentially dispensed during disease remission, at least 4 weeks before starting the immunosuppressive therapy or at its lowest possible dose. Moreover, the immune response to a booster vaccine administered during immunosuppressive therapy is less disturbed than that to a primary vaccine administration. Conjugate vaccines may be favorably given rather than polysaccharide vaccines since they are able to promote higher affinity antibody production with longer lasting immune and memory responses. Finally, when available, immunosuppressed patients may be usefully verify their immunization through specific serology tests after the completion of a primary vaccination . We beliIn this scenario, the vaccination status and dedicated serological tests should be assessed as soon as the disease is diagnosed and missing vaccinations should be prescribed, preferably before the immunosuppressive regimen is started. Despite these recommendations, several studies have reported low administration rates of advised vaccinations in IBD cohorts ,10,11. MSo far, several reports have shown that the incidence of COVID-19 in IBD patients is not different from that found in the general population . FurtherTherefore, the advent of SARS-CoV-2 vaccinations should represent an opportunity to catch with enthusiasm and confidence with the end goal of quickly promoting health and safety, and restoring the best possible treatments for IBD patients.More than 100 candidate SARS-CoV-2 vaccines are actually under development. Most of them are targeting the surface membrane S-protein that is involved in receptor binding, membrane fusion and entry into host cells . Among tBeside these, viral vector-based SARS-CoV-2 vaccines have been also developed. They are able to promote robust immune responses and can induce both humoral and cellular immunity . In partIn this scenario, the intrinsic immune-mediated nature and the need for immunomodulating or biological therapies in IBD patients have led to several questions on the safety and the efficacy of the SARS-CoV-2 vaccines . First, As stated above, more than one SARS-CoV-2 vaccine will be available from the end of 2020 and the beginning of 2021. Therefore, the primary goal of the World Health Organization (WHO) and local health systems will be to vaccinate the largest proportion of the population to achieve herd immunity and ultimately prevent wider SARS-CoV-2 spread . HoweverConsequently, a difficult future task to face for gastroenterologists will be to get the highest acceptance rate of SARS-CoV-2 vaccination in their IBD patients. Recently, factors associated with the likelihood of accepting SARS-CoV-2 vaccination have been extensively studied in large population cohorts in order to drive public health information campaigns and to address vaccine hesitancy ,33. In tHowever, as part of an exhaustive information, gastroenterologists will have to alert patients that the vaccine does not give 100% protection against COVID-19 and that, at the moment, we are not sure that it prevents the transmission of SARS-CoV-2 infection . TherefoSARS-CoV-2 vaccination represents a key milestone on the steep path toward the ultimate challenge: defeating the SARS-CoV-2 pandemic and come back to a “normal” life. To this end, it is essential that the majority of the population will get vaccinated. IBD patients, as those affected by other immune-mediated inflammatory diseases, will have an early access to the vaccine. Consequently, gastroenterologists must make every effort for obtaining the highest consent to SARS-CoV-2 vaccination. A detailed description of its favorable risk-benefit ratio based on transparent efficacy data together with the reassurance of vaccine safety will be a crucial task to be implemented. Obviously, a vigilant surveillance on vaccine efficacy and safety, especially in the long term, is necessary, taking also into account that data in subgroups of patients with chronic diseases or during immunosuppressant therapies are still largely lacking . Finally