Gay social networking apps have grown in popularity among men who have sex with men offering opportunities for rapid and confidential collection of vital data as well as social connection. The goal of our study was to explore factors associated with utilization of pre‐exposure prophylaxis (PrEP) and antiretroviral treatment (ART), and self‐reported undetectable viral load (UVL) using data collected by the gay social networking app Hornet.In 2016, the Global Forum on MSM & HIV (MSMGF) partnered with Hornet, to support an educational initiative called Blue‐Ribbon Boys. One aspect of the initiative prompts Hornet users to answer a short series of yes‐no questions about their sexual health. Using survey responses, we evaluated factors associated with PrEP and ART use as well as self‐reported UVL by fitting separate multivariable generalized estimating equation models.In total, 16,008 unique Hornet users started the survey, of which 12,126 (76%) provided sufficient data for analyses. Of the 10,774 HIV‐negative men, 13% reported PrEP use in the past year. PrEP use was associated with a recent sexually transmitted infection (STI) test or treatment ; and taking steps to protect oneself from HIV . Among HIV‐positive Hornet users (n = 1243), ART use was associated with older age , a recent STI test or treatment ; and awareness of unlikely HIV transmission with UVL . UVL was associated with older age , a recent STI test or treatment , and awareness of unlikely HIV transmission with UVL .Study findings underscore the importance of STI testing and treatment as well as information about HIV transmissibility for encouraging PrEP and ART use. Our findings also reveal age disparities, which can undermine incidence reduction among gay men. Gay social networking apps can be effectively used for rapid data collection and sexual health promotion with men who have sex with men. STI testing and treatment programmes offer important opportunities for encouraging PrEP and ART use. Information about HIV transmissibility with consistent ART use should be incorporated into prevention messaging tailored to various age groups. The internet provides benefits to gay and bisexual men who are marginalized or otherwise excluded from mainstream society by providing a safe space and by alleviating social isolation that may result from societal homophobia In 2016, the Global Forum on MSM & HIV (MSMGF) entered into an innovative public‐private partnership with the geospatial gay social networking application Hornet, to create and launch Blue‐Ribbon Boys. Blue‐Ribbon Boys is a global initiative to educate, empower, and mobilize gay and bisexual men around sexual health. The initiative makes information about HIV pre‐exposure prophylaxis (PrEP), testing, and treatment easily available to both HIV‐negative and HIV‐positive Hornet users in select markets. With 9 million users worldwide at the time it launched Blue‐Ribbon Boys, Hornet was the leading gay social networking app in Brazil, Egypt, Mexico, the Philippines, Russia, Taiwan, Thailand and Turkey. At present, Hornet has 25 million users. The overall goal of Blue‐Ribbon Boys was to create robust demand for unobstructed access to quality sexual health services.The goal of our study was to explore factors associated with uptake of HIV services among men who have sex with men using data collected through Hornet's Blue‐Ribbon Boys initiative. Specifically, the study aimed to: (1) describe utilization of anti‐retroviral medications  in a global sample of Hornet users; and (2) examine factors associated with self‐reported PrEP and treatment use and viral suppression in multivariate analyses. Study findings draw attention to the important and unique role gay social apps play in collecting data, promoting sexual health and addressing barriers to HIV service utilization among men who have sex with men that could lead to improvements along the HIV services cascade. In this paper, we use the terms gay and bisexual men, and men who have sex with men interchangeably, with the understanding that sexual orientation and same‐sex sexual behaviour are intricately and specifically influenced by context, culture, community affiliation, identity, gender expression and emotional connection.22.1This study is based on a secondary data analysis using responses from a brief online survey that was part of the Blue‐Ribbon Boys initiative, implemented by the gay social networking app, Hornet. Hornet Data collection occurred from November 2015 to April 2016, during which time Hornet users were invited to participate in a brief questionnaire regarding their sexual health. Hornet users were eligible to participate in the study if they self‐identified as male, were age 18 and over, and gave their consent. All participants received a blue ribbon icon on their profile photo signifying their participation in the initiative.This project followed a two‐step consent procedure. First, Hornet users were provided the app's privacy policy as part of Hornet's terms of service. Second, Hornet users were informed that participation in the survey portion of the Blue‐Ribbon Boys initiative would be voluntary and that responses would be linked with anonymized personal information contained in their user's account online profiles using a unique participant user ID. Survey takers were able to opt‐out of the survey at any time, with no interruption to their app services and at no consequence to their Hornet membership. Users must have read and endorsed the privacy policy before being able to use the app and receive an invitation to participate in the survey. After endorsement of the privacy policy, Hornet users could choose to make their demographic information publicly available to other users via app filters. The privacy policy explicitly restricts use of personal demographic information provided by Hornet users for the purposes of administering app updates, providing customer services, and making available other initiatives, like surveys. In addition, Hornet users are informed that anonymized personal information could be shared in aggregate.At the completion of the study, sexual health data collected were merged with an anonymized dataset containing study participant personal demographic and behavioural characteristics  using a unique participant user ID. Study procedures were reviewed by the University of California, San Francisco's Institutional Review Board , which determined that the protocol was exempt under Category 4.2.2Do you know your HIV status? HIV‐negative participants were then asked: Are you taking PrEP? Have you asked your healthcare provider if PrEP is right for you? Are you taking steps to protect yourself from HIV? In the past year, have you had an test and/or received treatment for a sexually transmitted infection (STI)? HIV‐positive respondents were asked: Are you taking anti‐retroviral treatment daily? Have you achieved or maintained an undetectable viral load? Are you aware that if you are undetectable it's virtually impossible to transmit HIV? In the past year, have you had an STI test and/or treatment? Men who indicated they did not know their HIV status were asked: In the past year, have you had an STI test and/or received treatment? Are you taking steps to protect yourself from HIV? Do you plan to get an HIV test in the next three months? Have you researched resources for getting an HIV test? Blue‐Ribbon Boys was offered as an initiative (including its survey) in 71 countries and in languages spoken by most Hornet users across participants’ country of residence, including English, Portuguese, French, Spanish, Thai and Vietnamese. Hornet's market expansion into Latin America, Southeast Asia and Western Europe influenced language offerings.Blue‐Ribbon Boys utilised a short, yes‐no survey, which began with the question: 2.3Our primary outcomes of interest were: (1) PrEP use among HIV‐negative participants; (2) antiretroviral treatment (ART) use among HIV‐positive participants; and (3) undetectable viral load (UVL) among HIV‐positive participants. All outcomes of interest were dichotomized to no and yes. We evaluated demographic and behavioural factors associated with of PrEP use, ART use and UVL by fitting separate multivariable generalized estimating equations (GEE) models with a logit link function for our dichotomous outcomes that used an exchangeable correlation matrix with robust standard errors, accounting for clustering by country (n = 71) using all complete data available. Analyses were limited to observations with available data on the outcomes of interest. For model building, the demographic and behavioural characteristics were informed by hypothesized predictors of our outcomes a priori. Associations were considered statistically significant using an α cut‐off of 0.05. All statistical analyses were conducted using STATA version 13.1 .33.1In total, 16,008 unique Hornet users started the survey, of which 12,126 (76%) provided sufficient data for analyses. The median age of participants was 25 (IQR = 21 to 30). The study sample was comprised of individuals who identify as Asian (29%), White (20%), Latino/Hispanic (7%) and Black (5%). Thirty‐four percent of participants did not report their race/ethnicity and 2% indicated “other.” More than half of study participants (56%) indicated they were not in a relationship and another 34% did not answer this question. The most frequent languages used by the participants in their profiles were English (38%), Thai (24%), Portuguese (12%) and Spanish (10%). Other languages comprised 17% of the sample. Regionally, most participants were from Asia (50%), North America (17%), Europe (16%), or South America (14%). Most participants reported being HIV negative , or unsure of their HIV status , while ten percent (n = 1243) of participants reported being HIV positive  and viral load (n = 1145), 79% reported ART (n = 924) use and 79% (n = 900) reported having UVL. Of the HIV‐positive survey participants who responded to the ART awareness question (n = 1118), 81% reported being aware that an UVL made it virtually impossible to transmit HIV ; and taking steps to protect oneself from HIV . PrEP use was also less likely to be reported by respondents who had their language application set as Spanish  and Thai  when compared to English speakers. PrEP use was not associated with sexual position or role preferences.versus English. ART use was not associated with sexual position or role preferences and relationship status.ART use was positively associated with older age , having recently received an STI test or STI treatment ; being aware that HIV transmission is very unlikely with UVL ; and having the application language set as Portuguese  and Thai  UVL was also positively associated with older age ; being aware that HIV transmission is very unlikely with UVL ; and having recently gotten an STI screen or STI treatment . Compared to English‐speakers, respondents who set their application language to Portuguese  or Thai  were more likely to report having UVL. Having UVL was not associated with sexual position or role preferences and relationship status. Factors associated with PrEP use, ART use and UVL are presented in Table 4Our study examined factors associated with PrEP use, ART use and UVL in a large, international sample of gay and bisexual men who are the users of the popular gay social networking app Hornet. The sample size and median age of Hornet users offered a unique window into the sexual health of a population that is at elevated risk for STIs, including HIV. Ten percent of study participants reported being HIV‐positive. HIV prevalence among gay and bisexual men reported from other online convenience samples range from 12% to 30% Low PrEP use among study participants is not surprising. Although the PrEP landscape has changed dramatically since 2016 when Hornet surveyed its users through the Blue‐Ribbon Boys initiative, PrEP is still not broadly available, especially in low and middle‐income countries ART utilization and viral suppression rates reported by study participants are higher than previously reported among men who have sex with men in other studies Language differences we found in multivariate analyses are not surprising given the limited availability of PrEP at the time of the study. For example, there is no national PrEP policy or guidance in Thailand and PrEP availability is limited to pilot studies, with additional limited accessibility among gay and bisexual men with private insurance Age differences in ART use and UVL reinforce previously reported age disparities in access to services between younger and older men who have sex with men Study participants who reported having had an STI test and/or treatment and reported awareness about the link between viral load and HIV transmissibility were significantly more likely to report ART use and UVL. These findings highlight the critical role sexual health services can play in facilitating access to HIV‐related education and services. Moreover, awareness about risk minimalization may play key role in PrEP and ART uptake 4.1Our study had several strengths and limitations that are important to note. The study sample of Hornet users was conveniently recruited, restricting generalization of study findings. Online convenience samples can create a selection bias towards gay and bisexual men who have better access to the Internet Another limitation from this study is the missing data from the sexual health outcomes of interest. As mentioned, our analysis was restricted to individuals who provided information about these outcomes. It is possible that this approach has introduced a selection bias toward participants who are more comfortable discussing their sexual health and this group may be different from broader Hornet users who were excluded. In addition, due to the anonymized nature of this study, we are unable to compare our participants with Hornet users who declined to participate. Therefore, we do not know if there are significant differences between our sample, and those who declined to participate. Nevertheless, because our survey invitation was extended via the use of the Hornet app, we speculate that individuals with unlimited data plans and/or have reliable wi‐fi access  were more likely to participate in the study. Hence, our findings may likely overestimate self‐reported PrEP or ART use and HIV viral suppression among men who have sex with men.5Study findings underscore the importance of STI testing and treatment sites as entry points for encouraging PrEP and ART use. Information about HIV transmissibility and viral load should be integrated into tailored HIV prevention messages and educational campaigns. Moreover, sexual health programmes should be designed with age disparities in service access and utilization in mind. Structural‐level factors like national HIV policies may be influencing availability and utilisation of important prevention tools, like PrEP. As illustrated by this study, gay social networking apps offer important opportunities to rapidly collect data and disseminate tailored prevention messages. Online social networking applications should be better studied and utilized to more fully leverage their contribution to sexual health promotion among men who have sex with men Authors have no competing interests to declare.GA is the principal investigator of the Blue‐Ribbon Boys study and was the lead writer. GMS is a co‐principal investigator, led all data analysis and co‐wrote the methods and results reported here. SA, AG, KM and SH are co‐ investigators who assisted with the overall design of the study and offered feedback to the draft manuscript.


Endobronchial ultrasound (EBUS) is indispensable when it comes to evaluation of mediastinal lesion and staging of lung cancer. The incorporation of endoscopic ultrasound using an echobronchoscope (EUS‐B) further extends this capability to the paraoesophageal and subdiaphragmatic structures. When combined, EBUS with EUS‐B increases the diagnostic yield. Both procedures can be done in a single session and by a single operator; this translates into an overall reduction in the healthcare cost. Endobronchial ultrasound (EBUS) has been established as an important minimally invasive procedure for the investigation of mediastinal lesions and the staging of lung cancer. When combined with endoscopic ultrasound with bronchoscope‐guided fine‐needle aspiration (EUS‐B‐FNA), the technique allows for the augmentation of diagnostic potentials and increased precision in staging procedures.We describe three cases of lung malignancy that employed three distinct applications of endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) and EUS‐B‐FNA. The first and second cases were performed at the National University of Malaysia (UKM) Medical Centre. The third case originated from Sarawak General Hospital.A 65‐year‐old man presented with a four‐week history of chronic cough and progressive dyspnoea. The computed tomography (CT) scan of his thorax revealed left lower lobe collapse with consolidation, presence of mediastinal lymphadenopathy (ML) and the absence of distant metastasis Fig. . EBUS wa2: 141 mmHg, partial pressure of carbon dioxide: 123 mmHg, and HCO3−: 21.3 mmol/L). A CT scan of the thorax was carried out to assess the suspicion of a widened mediastinum on the chest radiograph and confirmed the presence of a large, right‐sided heterogeneous pulmonary lesion with numerous ML. All lesions had multiple large, ill‐defined, scattered necrotic areas. We carried out a thorough review of the CT images to determine suitable non‐necrotic areas for aspiration , subcarinal (7), hilar (10R and 10 L), and interlobar (11R and 11L). A combination of EUS‐B and EBUS improves in‐depth staging of lung cancer with better patient tolerance and access to evaluate upper paratracheal stations 2R and 2L), the left lower paratracheal station (4L) and possibly the left adrenal gland by a single operator during one session R and 2L,R and 4L,The first case shows that EUS‐B compliments EBUS for lung cancer staging purposes and also serves as an alternative for challenging cases that require prolonged procedural time or a high amount of sedation. In contrast to the bronchus, endosonography through the oesophageal route causes significantly less coughing and oxygen desaturation. This improves patient tolerance and diagnostic yield, alleviating the concern of “tissue is the issue” and fear of inadequate samples. These results are even more apparent when dealing with patients with poor lung function.Another advantage of EUS‐B is that it provides access for evaluation of mediastinal lesions adjacent to the oesophagus. Novel usage of EUS‐B for the diagnosis of centrally located intrapulmonary lesions has been described The second case demonstrated the practicality of EUS‐B when performed in a critically ill patient. As a result of the widespread areas of necrosis, endobronchial aspiration attempts at stations 7 and 4R only showed scanty material when examined by our cytotechnician. In addition, the narrowed left and right main bronchus and carina, which was distorted from external compression, prevented further assessment. When EUS‐B was employed in the area chosen prior to the procedure, the surrounding structures and necrotic areas of the mass were identified and avoided during aspiration. So, when EBUS‐TBNA fails, EUS‐B can provide a beneficial reduction of further unnecessary procedures and an overall reduction in the cost of treatment.The third case depicts EUS‐B used in the evaluation and sampling of abnormal lesions which are not accessible by linear EBUS or radial EBUS. Utilization of EUS‐B in this case also averted unnecessary complications.In the advent of EUS‐B, computed tomographic‐guided aspiration of centrally located lesions could possibly become a procedure of the past. Compared to its use with peripherally located lesions, CT‐guided aspiration of central lesions can be technically more challenging. In addition, assessment of central lesions by EUS‐B precludes potential complications, such as bleeding, iatrogenic injury to the surrounding organs, and, importantly, pneumothoraces attributed to radiologically guided sampling of centrally located mediastinal or pulmonary lesions With the growing evidence of the utility of EUS‐B, pulmonologists who are experienced in performing EBUS should explore and acquire the technical skills and competency needed to extend the diagnostic boundaries of echo‐endoscopes. A structured training programme could be the catalyst necessary to realize the full potential of both EBUS and EUS‐B.Appropriate written informed consent was obtained from all three patients for the publication of this case series and the accompanying images.Video S1. EUS‐B procedure for case 2.Click here for additional data file.


Infants as young as 2 months can integrate audio and visual aspects of speech articulation. A shift of attention from the eyes towards the mouth of talking faces occurs around 6 months of age in monolingual infants. However, it is unknown whether this pattern of attention during audiovisual speech processing is influenced by speech and language experience in infancy. The present study investigated this question by analysing audiovisual speech processing in three groups of 4‐ to 8‐month‐old infants who differed in their language experience: monolinguals, unimodal bilinguals (infants exposed to two or more spoken languages) and bimodal bilinguals (hearing infants with Deaf mothers). Eye‐tracking was used to study patterns of face scanning while infants were viewing faces articulating syllables with congruent, incongruent and silent auditory tracks. Monolinguals and unimodal bilinguals increased their attention to the mouth of talking faces between 4 and 8 months, while bimodal bilinguals did not show any age difference in their scanning patterns. Moreover, older (6.6 to 8 months), but not younger, monolinguals (4 to 6.5 months) showed increased visual attention to the mouth of faces articulating audiovisually incongruent rather than congruent faces, indicating surprise or novelty. In contrast, no audiovisual congruency effect was found in unimodal or bimodal bilinguals. Results suggest that speech and language experience influences audiovisual integration in infancy. Specifically, reduced or more variable experience of audiovisual speech from the primary caregiver may lead to less sensitivity to the integration of audio and visual cues of speech articulation. Increased attention to the mouth was observed between 4 and 8 months in monolinguals and unimodal bilinguals, but not in bimodal bilingual infants with Deaf mothers.Audiovisual incongruence of speech articulation increased visual attention to the mouth in older (6.6–8 months), but not younger (4–6.5 months) monolinguals.Audiovisual incongruence did not influence face scanning in bilingual infants (4–8 months), which may indicate increased tolerance to articulatory inconsistencies and imprecision.Multi‐modal speech processing in infancy requires sufficient audiovisual speech experience.1A few weeks after birth and several months before they begin producing canonical babbling, infants can perceptually integrate audio and visual cues of speech articulation. Indeed, from 2 months of age, infants look longer at a face articulating a phoneme that they can hear as opposed to a face articulating a different phoneme  as her preferred mode of communication, the speech and language experience of her hearing infant is likely to differ from that of hearing infants of hearing mothers in several ways. (1) First, hearing infants with Deaf mothers experience a signed language processed mainly in the visual modality (e.g. BSL), and a spoken language processed mainly in the auditory modality (e.g. spoken English). Because these infants are exposed to two languages in different modalities—signed and spoken—they are often referred to as ‘bimodal bilinguals’. On the other hand, the term ‘unimodal bilinguals’ is commonly used in the literature to describe bilinguals exposed to two spoken languages. This terminology does not deny the multimodal nature of speech perception and the crucial importance of audiovisual speech integration, but aims to emphasize their difference from bimodal bilinguals who are exposed to two languages processed in very different sensory systems. (2) Moreover, the language produced by a Deaf mother to and around her infant is likely to comprise less audiovisual spoken language than that of a hearing mother. A Deaf mother may use sign language in many of her daily interactions in the presence of her infant. Many Deaf signing individuals also use speech to communicate with hearing people, but the extent to which they actually ‘voice’ their speech and produce sound, as opposed to silently mouth, is extremely variable , withdrawal (n = 1), failure to reach looking time criteria  or prior inclusion of a sibling (n = 2). Infants were from three groups with different language experience: 28 monolingual infants with hearing parents , 22 unimodal bilingual infants with hearing parents  and 23 bimodal bilingual infants with a Deaf mother . Age did not differ between groups (F(2) = 0.182; p = 0.834). Monolingual infants were only exposed to English. Both parents were hearing and only used one language. Unimodal bilinguals were frequently and regularly exposed to English and one or more additional spoken language(s). The combination of languages varied between infants and there were 18 different additional languages in this study. All infants in this group had a hearing bilingual/multilingual mother. Fifteen unimodal bilingual infants also had a bilingual/ multilingual father, and seven had a monolingual father. None reported hearing deficits in any immediate family members. Exposure to each language was estimated by using an English adaptation of the language exposure questionnaire designed by Bosch and Sebastián‐Gallés (p = 0.376). Bimodal bilinguals were recruited through social media and websites specifically aimed at the Deaf community. Most infants were born at term (37 to 42 weeks gestation), except for two infants born slightly before term (34–36weeks) . Infants had no hearing problems (except for one infant's mother reporting glue ear) or vision problems (except for one infant's mother reporting a suspected squint), no history of seizure or other serious mental or physical conditions according to their parents. Deaf families were geographically spread across the whole of Great Britain, while infants with hearing parents came mostly from London and surrounding areas. Travel expenses were reimbursed, and a baby T‐shirt and certificate of participation were offered to families. All parents gave informed consent prior to participation, after explanations of the study in English or BSL depending on the parents’ preferred mode of communication by fluent members of the research team. This study was approved by UCL and Birkbeck Research Ethics Committees and conforms to the Declaration of Helsinki.Seventy‐three hearing infants between 4 and 8 months contributed data to the present study. A further 21 infants participated in the study but were excluded due to equipment malfunction or failure to calibrate , three eye‐tracking tasks  and behavioural measures . The whole protocol usually required between 1.5 to 3 hours per infant, including resting, napping, and feeding time. Only data from the McGurk task are reported in the present article.Infants were invited to participate in the larger During the McGurk task, infants sat on their parent's lap in a dimly lit room about 60 centimetres from a TobiiT120 eye‐tracker . Infant gaze position was calibrated with colorful animations using a 5‐point routine. Infant's gaze and behaviour was monitored throughout the study via camera and Tobii Studio LiveViewer. The parent's view of the stimulus monitor was obscured to avoid interference with infant behaviour.2.3Infants were presented with short videos of a female native English speaker repeatedly articulating /ba/ or /ga/. These stimuli have been used previously and are described in detail elsewhere  = 1.690; p = 0.192). A Mouth‐to‐Face and Eyes‐to‐Face ratio was calculated for each condition and each participant.For each trial, the total looking time was extracted using Tobii Studio in three regions of interest: eyes region , mouth region  and entire face   = 17.385; p < 0.001; ƞ2 = 0.201] was found, suggesting, as would be expected on the basis of our exclusion criterion, that babies with more included trials generally spent longer looking at faces . A significant Group effect  was also observed. Bimodal bilinguals (p = 0.001) and to some extent unimodal bilinguals (p = 0.076) spent more time looking at faces than monolinguals. There was no difference between the two groups of bilinguals (p = 0.573). Looking time to the entire face did not correlate with percentage of English exposure in the two groups of bilinguals .A univariate ANOVA was performed on looking times to the entire face with 3 Groups and Included Trials as a covariate. A significant effect of Included Trials  was observed, which confirmed a general attentional shift from the eyes to the mouth with age. No significant Condition effect or interaction were observed.A repeated measures ANOVA was performed on Mouth‐to‐Face and Eyes‐to‐Face ratios with 5 Conditions  × 2 Regions (Mouth and Eyes) × 3 Groups , while Age and Included Trials were added as covariates  = 13.01; p = 0.001; ƞ2 = 0.161].To explore the impact of audiovisual congruency on looking times to the mouth, data were merged into Congruent (/ba/ + /ga/) and Incongruent articulations (Fusible + Non‐Fusible).F = 3.495; p = 0.043; ƞ2 = 0.184] was significant. In older monolinguals, incongruent articulations were associated with a higher percentage of looking time at the mouth . Unimodal bilinguals  and bimodal bilinguals  showed no Congruency effect.Given (1) the robust age effect in these analyses, (2) the fact that very different patterns of visual scanning of talking faces have been observed in infants before and after 6 months  = 2.332; p = 0.030; ƞ2 = 0.116]. A one‐way ANOVA examining Condition in each of the older groups separately showed a significant Condition effect in monolinguals , but not in unimodal bilinguals , nor in bimodal bilinguals . Post‐hoc t tests revealed that older monolinguals looked longer at the mouth when processing incongruent than congruent articulations . No difference was found between congruent /ba/ and congruent /ga/ (p = 0.777), between the two incongruent conditions (p = 0.159) or between silent and non‐silent conditions .These same analyses performed with 5 Conditions  × 3 Groups  revealed no significant effect or interaction in the younger group. In the older group, a significant Condition × Group interaction was found [4The present study aimed to assess the role of language experience in shaping the development of audiovisual speech integration. Visual attention to faces articulating syllables with congruent, incongruent and silent auditory tracks was studied in three groups of 4‐ to 8‐month‐old infants with different language experience: monolingual infants, unimodal bilingual infants (infants exposed to two spoken languages) and bimodal bilingual infants (hearing infants with Deaf parents).non‐fusible condition in younger infants (5‐month‐olds)  show a trend towards an increase in looking time to the mouth in unimodal bilinguals compared to monolinguals. It is also important to note that the stimuli used in the present study were very different from the ones used by Pons and colleagues. Fluent infant‐directed speech may elicit different levels of attention and different processing strategies than repeated syllables.Unimodal bilingual infants have different experience of speech and language compared to monolinguals as they are exposed to two different auditory phonological systems. Like monolinguals, unimodal bilingual infants showed an attentional shift towards the mouth and away from the eyes between 4 and 8 months. The predicted increase in attention to the mouth compared to monolinguals was not observed in this study, but a general increase in looking time to the entire face was observed. Increased attention to the mouth might have been observed if a larger proportion of younger infants (around 4 months) had been part of the present sample. Indeed, Pons and colleagues (2015) found increased attention to the mouth in unimodal bilinguals compared to monolinguals at 4 months, while no difference was observed at 8 months. Similarly, the data from our youngest group of infants . The target phonemes /b/ and /g/ may be extracted from different phonetic populations for different unimodal bilinguals. A detailed examination of phonetic and phonological differences between monolinguals and unimodal bilinguals is not possible given the large number of alternative languages in the present study and it is unclear how these differences could influence the present results. For this reason, it would be interesting to perform the same task in a more defined group of unimodal bilinguals all experiencing the same combination of languages and phonological systems.Infants with Deaf mothers experience bimodal bilingualism, and the audiovisual spoken language provided by their primary caregiver is likely to differ in quantity and phonetic properties from that provided by a hearing caregiver. All these factors have undetermined effects on the development of audiovisual speech processing. In the present study, a general increase in looking time to talking faces was observed in bimodal bilinguals compared to monolinguals. Since sign language communication requires visual attention to the signer, Deaf mothers use various strategies to obtain visual attention from their infants (Woll & Kyle, Moreover, no relationship was observed between bimodal bilinguals’ age and the percentage of time they spent looking at the mouth and eyes of talking faces. This finding contrasts with the attention shift towards the mouth between 4 and 8 months observed in monolinguals and unimodal bilinguals in the literature (Lewkowicz & Hansen‐Tift, The results of the present study also suggest reduced sensitivity to audiovisual congruency in bimodal bilingual infants compared to monolinguals. Indeed, both younger and older bimodal bilinguals showed undifferentiated visual scanning patterns to faces articulating audiovisually congruent and incongruent syllables. This pattern is similar to the one observed in younger monolinguals, yet older monolinguals increased their attention to the mouth in the case of incongruent audiovisual cues of articulation. This suggests an immaturity in the way bimodal bilinguals integrate audiovisual cues of articulation, which could be due to a reduced experience of audiovisual spoken language or an increased variability in speech production from their primary caregiver. Whether this apparent immaturity in audiovisual speech processing in hearing infants with Deaf mothers represents a transient developmental delay in early infancy or the beginning of a different developmental trajectory of speech processing remains to be seen.Taken together, the results of the present study indicate that early speech and language experience influences the integration of audiovisual speech in infancy. Monolinguals appeared to be more sensitive to audiovisual incongruences in the second half of their first year, while this increase in sensitivity to audiovisual incongruences after 6 months was not observed in unimodal bilinguals and bimodal bilinguals with Deaf parents. Moreover, a shift in selective attention to the mouth of talking faces was progressively observed between 4 and 8 months in monolingual and bilingual infants with hearing parents, while no eyes‐to‐mouth shift with age was observed in infants with Deaf parents who may experience a reduced amount of audiovisual speech from their primary caregiver. We conclude that multi‐modal speech processing in infancy requires sufficient audiovisual speech experience.


The side‐to‐side anastomosis was considered a promising approach to create an intrathoracic esophagogastrostomy in the minimally invasive esophagectomy, with advantages over the side‐to‐end anastomosis with aspects of no need for additional mini‐thoracotomy and lower occurrence of stenosis. The hand‐sewing anterior aspect of the anastomosis is technically challenging in the thoracoscopic Ivor Lewis esophagectomy. Here we introduced our initial experience to facilitate this approach by using the surgical robot and barbed suture.A retrospective study of all patients underwent robot‐assisted Ivor Lewis esophagectomy with side‐to‐side esophagogastrostomy from February 2016 to September 2018 was performed. The technical details are described in this paper.A total of 37 patients  were successfully treated with completely robot‐assisted Ivor Lewis esophagectomy. The median total surgical time was 340 minutes including 65 minutes to perform the anastomosis. Median estimated blood loss was 120 mL and the length of hospital stay was 10 days. There was no 90‐day mortality. Three patients suffered anastomotic leakage , who were successfully treated without reoperation.Our initial results imply that it is technically feasible to perform intrathoracic gastroesophageal anastomosis by taking advantage of a robotic system and knotless suturing. Since February 2016, we have been performing minimally invasive Ivor Lewis esophagectomy (MILE) with the da Vince Si System. Here, we introduce our initial experience of intrathoracic side‐to‐side esophagogastrostomy with a linear stapler and report the short‐term outcomes.22.1During February 2016 to September 2018, a total of 37 patients diagnosed with esophageal carcinoma in the lower third and gastroesophageal junction underwent robot‐assisted Ivor‐Lewis esophagectomy by one medical team experienced in both minimally invasive esophagectomy and robotic surgeries. The patient demographics and perioperative parameters were collected from the institutional database, and the short‐term follow‐up was completed by return visits or telephone calls. Descriptive statistics for continuous variables are reported as median (range) and categoric variable as percentage and frequency. The study protocol was approved by the applicable institution review board of West China Hospital, Sichuan University. Written informed consents were obtained from all 37 patients.2.2The operation was performed in two stages during the same period of anesthesia using a single‐lumen endotracheal tube. First, in the reverse Trendelenburg position, the stomach mobilization and lymph nodes dissection were completed with a four‐arm robotic platform  as previously reported.In the second stage, the patient was repositioned in a left semi‐prone position. Four robotic ports and one assistant port are placed as shown in Figure After the circumferential mobilization of thoracic esophagus and dissection of paraoesophageal tissue, we start to fashion anastomosis by transecting the thoracic esophagus at the level of the azygos arch with the monopolar curved scissors Figure . The gasHemostasis was checked, and the right hemithorax was irrigated with normal saline. A 28‐F chest tube was inserted into the thoracic cavity through the camera port, and an 18‐F silicone tube was placed in postmediastinum behind the gastric conduit through the port for robotic arm 2.2.3Total parenteral nutrition was used in the first 4 days after operation and the oral intake began at postoperative day (POD) 3 to POD5 with a liquid diet, to which was added Methylene blue to explore potential anastomotic fistula. With the absence of leakage, the drainage tube would be removed at POD7 to POD10. All patients were discharged once oral feeding could be tolerated.32. A total of eight patients with local advanced esophageal cancer underwent neoadjuvant therapy in this case. The median total surgical time was 340 minutes, with 165 minutes for the thoracic phase and 65 minutes required to create anastomosis. The estimated blood loss ranged from 50 mL to 160 mL, with a median of 120 mL. The median length of hospital stay was 10 days. Postoperative pathology shows that there were 26 cases of squamous carcinoma, nine cases of adenocarcinoma, one case of neuroendocrine carcinoma of and one case of small‐cell carcinoma. All patients had negative margins. Postoperative complications were classified according to Esophagectomy Complications Consensus Group (ECCG) guidelines.The demographic, intra‐ and peri‐operative data of all 37 patients are listed Table . In summA total of three patients suffered postoperative anastomotic leakage. All three fistulas were developed at the anastomosed area, and no airway fistula or enterocutaneous fistula occurred in this series. Anastomotic fistula in two patients was confirmed by methylene blue which was drained from the thoracic cavity and mediastinum. The other anastomotic fistula was diagnosed by digital gastrointestinal radiography. All three patients were successfully treated by drainage and/or irrigation without reoperation.During the follow‐up period for 3 to 16 months, stenosis occurred during the 16th month after discharge in one patient, and another patient died at the 12th month postoperatively as a result of neoplasm recurrence.4Considering its advantages including low stricture rates and absence of need for an extra minithoracotomy to insert the stapler, the side‐to‐side anastomosis has been considered a promising approach in the MILE. However, technical difficulties in endoscopic suturing may hinder the extensive adoption of this procedure. The application of a surgical robot may find a way out of this dilemma by significantly improving the surgeon's ability to suture even in deep and narrow anatomical sites such as the posterior mediastinum. Actually, the robot‐assisted suturing was so facilitating that a hand‐sewing anastomosis was achievable even in the posterior aspect of the anastomosis for low tension in anastomosis.Triangular stapling is another anastomotic technique totally using linear staplers, which is reported being associated with a decreased rate of anastomotic complications.The knotless barbed suture appears to be ideal for endoscopic suturing according to the literature and our own experience.Although creating a gastric conduit intracorporeally would cause less trauma in the abdominal phase of robot‐assisted Ivor‐Lewis esophagectomy, we still chose to complete it extracorporeally through a 7‐cm incision in the upper abdomen. Therefore, we irrigated the gastral cavity before anastomosing. Due to the barrier resulting from a mass of esophageal carcinoma, sometimes the nasogastric tube cannot be placed in the proper location. This led to a poor preoperative preparation where a mass of content remained in the gastral cavity. Under such circumstance, gastric content would leak from the orifice of the gastric tube to the abdominal cavity during anastomosis, which is one of the major sources of intrathoracic abscess and postoperative contamination in previous years in our center. Since adoption of irrigation before anastomosis, we recorded a decrease in postoperative intrathoracic abscess.After creating the posterior part of anastomosis with linear stapler, we stitched the anterior defect from two corners and combined at the midpoint, which was different from the typical end‐to‐end modus operandi. During operation, we found that the surgical viewing became worse from the midline to the corner, and this problem was aggravated when sewing up the corner. We speculated that starting at each corner and finishing the suturing at the midline could ameliorate this problem.There are three postoperative fistulas in our cohort: one presumed cause is the compromised blood perfusion associated with the longer esophageal stump in the side‐to‐side approach compared with hand‐sewn or end‐to‐side anastomosis. HodariThis study contained several limitations: first, due to the limitations of retrospective study, generalizations of several results were subject to potential bias; second, only 37 patients were included in this study, therefore, a prospective study with large sample size is recommended. Notwithstanding these limitations, we believe that, with such advantages of robotic surgery, clinical outcomes of robotic Ivor Lewis esophagectomy can be further promoted after completion of the learning curve.In summary, the utilization of surgical robot and barbed suture could facilitate the creation of intrathoracic anastomosis in MILE. It seems to be a promising alternative to open or traditional thoracoscopic surgery.The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.The technical difficulties may hinder the extensive adoption of the side‐to‐side anastomosis in the minimally invasive Ivor Lewis esophagectomy. Our initial results imply it is technically feasible to perform intrathoracic gastroesophageal anastomosis by taking advantage of the robotic system and knotless suture.


Women who had experienced preeclampsia during pregnancy had a significantly decreased risk of premenopausal breast cancer (hazard ratio (HR) =0.67, 95% confidence interval (CI): 0.49–0.90) and of HER2‐enriched tumours , but there was no association with overall  or postmenopausal  breast cancer risk. Risk reductions among premenopausal women were strongest within 20 years since the last pregnancy with preeclampsia. Hyperemesis was associated with a significantly increased risk of HER2‐enriched tumours , but not with other intrinsic subtypes or breast cancer risk overall. These results provide evidence that preeclampsia is associated with a decreased risk of premenopausal and HER2‐enriched breast cancer and that hyperemesis, although not associated with breast cancer risk overall, may be associated with raised risk of HER2‐enriched tumours.Preeclampsia and hyperemesis gravidarum are pregnancy complications associated with altered sex hormone levels. Previous studies suggest preeclampsia may be associated with a decreased risk of subsequent breast cancer and hyperemesis with an increased risk, but the evidence remains unclear. We used data from the Generations Study, a large prospective study of women in the United Kingdom, to estimate relative risks of breast cancer in relation to a history of preeclampsia and hyperemesis using Cox regression adjusting for known breast cancer risk factors. During 7.5 years average follow‐up of 82,053 parous women, 1,969 were diagnosed with invasive or  What's new?Although the link of preeclampsia and hyperemesis gravidarum with altered sex hormone levels is well established, relatively little is known about the association of these pregnancy complications with breast cancer risk. Here, the authors found that a history of preeclampsia decreased the risk of premenopausal breast cancer and tumors enriched for the receptor tyrosine‐protein kinase HER2. In contrast, hyperemesis gravidarum increased the risk to develop HER2‐enriched tumors, pointing to nuanced differences of sex hormone alterations during pregnancy with respect to breast cancer subtypes and menopausal status. BMIbody mass indexCIconfidence intervalERoestrogen receptorHER2human epidermal growth factor receptor 2HRhazard ratioUKUnited KingdomBreast cancer is the most common type of cancer among females worldwide and has a hormonal aetiology. During pregnancy, breast tissue is exposed to hormonal surges including of oestrogen and progesterone, which may be related to the transient increased risk of breast cancer after pregnancy, followed by a decreased risk long‐term.Preeclampsia is a disorder characterised by the onset of hypertension and proteinuria in the second half of pregnancy, affecting around 2–8% of pregnancies,Hyperemesis gravidarum (hereafter referred to as ‘hyperemesis’) is characterised by severe nausea, vomiting and faintness in the first half of pregnancy. It has been hypothesised that it could be associated with a raised risk of maternal breast cancer via elevated estradiol levels in pregnancy.We therefore examined the association between history of preeclampsia and hyperemesis and maternal risk of breast cancer in women within the Generations Study, a large prospective cohort study in the UK, in which detailed information on pregnancies, breast cancer risk factors and breast cancer characteristics was available.The Generations Study is a cohort study of over 113,700 women from the United Kingdom (UK), aged 16 years or older, designed to investigate the aetiology of breast cancer. Questionnaire information and informed consent were gained at recruitment since 2003. The first follow‐up questionnaire (2½ years after recruitment) was completed by 99% of non‐deceased participants, the second (6 years after recruitment) by 96%, and the third (9½ years after recruitment) by 94% of those recruited long enough ago to have entered this round of follow‐up. The study was approved by the South East Multi‐Centre Research Ethics Committee and has been described in detail previously.Breast cancers occurring in the cohort were identified from recruitment and follow‐up questionnaires and spontaneous reports to the study centre, and where necessary from ‘flagging’ at the National Health Service Central Registers . Confirmation of diagnosis was obtained from UK cancer registries, pathology reports and correspondence with patients' general practitioners.Information on pregnancies was collected in the recruitment and second follow‐up questionnaires. Participants were asked if they had experienced preeclampsia or hyperemesis gravidarum , and about birth outcome, gestational length, offspring sex and birth weight at each of their pregnancies. Age at first and last pregnancy and time since last pregnancy with preeclampsia and hyperemesis were calculated using information from individual pregnancies.Information on menopausal status and age at menopause was obtained from the recruitment and second follow‐up questionnaires, in which women were asked how old they were when their periods stopped completely . For women who did not provide an age at menopause but who reported that they became postmenopausal during follow‐up, we defined menopausal age to be the youngest of either the woman's age at the questionnaire at which she first reported that she was postmenopausal or age 50.in situ breast cancer, and were either parous (defined as pregnancies of ≥26 weeks resulting in a live birth) at recruitment or became parous during follow‐up. The recruitment cut‐off at December 2013 was selected because at the time of analysis the second follow‐up was virtually complete, two‐thirds had reached the third follow‐up, and we had ‘flagging’ information to June 2017 for these recruits. Participants entered risk at the date of return of their recruitment questionnaire, or if they were nulliparous at recruitment and became parous during follow‐up, the date of first delivery, and were censored at the earliest of: first invasive or in situ breast cancer; death; most recent follow‐up questionnaire (depending on date of recruitment), if completed, or the date the most recent follow‐up questionnaire was due if cancer and vital status was known from ‘flagging’; or the date of the last completed questionnaire, if lost to study follow‐up. We additionally censored at the first age of having a twin or higher‐order birth, since such births are associated with higher hormone exposures.The analytic cohort in our study is based on all women who were recruited to the Generations Study before 31 December 2013, did not have a previous diagnosis of invasive or in situ breast cancer, or prophylactic mastectomy. Women who remained nulliparous throughout follow‐up  and women who had a twin or higher‐order birth before entry to the study  were excluded from the analysis. The analytical cohort included 82,053 women who were either parous at baseline questionnaire  or became parous during follow‐up  and therefore entered follow‐up at their first parous birth. Three hundred and twenty nine women were censored at their first twin or higher‐order birth during follow‐up. During follow‐up, 1.2% of women died. Of the remainder, cancer and vital status was known for 97.4% from completion of the relevant follow‐up questionnaire, and a further 2.4% from ‘flagging’ at the National Health Service Central Registers. The remaining 0.2% were lost to follow‐up at an earlier date. The follow‐up completeness  was 99.7%. There were 1,969 incident breast cancers during follow‐up , of which 99.6% were confirmed through national cancer registration or medical records and the remaining eight cases were self‐reported with treatments that implied breast cancer. ER information was available for 91.2% of breast cancers , and of these 83% were ER positive.During 2003–2013 the recruitment questionnaire was completed by 106,628 study participants who had no previous invasive or The median age at recruitment was 49.0 years (inter‐quartile range: 39–58) and participants contributed an average of 7.5 years of follow‐up. Characteristics of the participants overall and by preeclampsia and hyperemesis history are given in Table ptrend = 0.29) across the number of pregnancies with preeclampsia. Risk reductions for premenopausal women were significant for women whose first preeclamptic pregnancy was at ages 25 or over , or whose last preeclamptic pregnancy was at ages under 30 years , or during the 20 years after the last preeclamptic pregnancy . The risk of premenopausal breast cancer was also significantly reduced for preeclampsia experienced at a first  or a last pregnancy . The relative risk of premenopausal breast cancer in relation to a history of preeclampsia remained significantly decreased when the analyses were restricted to invasive breast tumours only (Supporting Information Table S1). For postmenopausal breast cancer, there was no significant association of risk with any of the above preeclampsia variables.Women who reported a history of preeclampsia during a pregnancy had a similar risk of breast cancer overall compared to parous women who had never experienced preeclampsia  , nor with subdivisions of this, except for a positive association in women aged under 25 years at their first preeclamptic pregnancy . Ever having had preeclampsia was associated with a significantly decreased risk of human epidermal growth factor receptor 2 (HER2)‐enriched breast cancer , but there was no association with other intrinsic subtypes (Table Relative risks with respect to preeclampsia were similar for ER positive and ER negative tumours Table . Risk ofpint = 0.23 and pint = 0.67). Relative risks with respect to preeclampsia did not vary significantly according to whether the subject also had a history of hyperemesis, or vice versa (pint = 0.21) (Supporting Information Tables S2 and S3).Relative risks with respect to preeclampsia did not vary appreciably according to whether the subject's mother had experienced preeclampsia at the subject's birth Table . The relptrend = 0.44) or time since last hyperemetic pregnancy (ptrend = 0.83), and no association with the age at hyperemetic pregnancy or with hyperemesis at first or last pregnancy. Relative risks did not vary by menopausal status at follow‐up, or ER status or invasiveness of breast cancer (Supporting Information Table S4). Risk of HER2‐enriched breast cancer was significantly raised in women who had experienced hyperemesis , but there was no association with other intrinsic subtypes of breast cancer  Table . There wIn this large prospective investigation, women who experienced preeclampsia during a pregnancy were at significantly reduced risk of breast cancer at premenopausal ages and of HER2‐enriched breast cancer. Risk reductions amongst overall, ER positive and invasive breast cancers were observed during the 20 years since the last pregnancy with preeclampsia, with strongest reductions observed amongst premenopausal women, but not in those who last experienced preeclampsia >20 years after the pregnancy with preeclampsia. We observed no significant associations of breast cancer risk with a history of hyperemesis except for a significant positive association with HER2‐enriched breast cancer.in situ breast cancer, in accord with the only previous study that analysed this.The literature on breast cancer risk in women with a history of preeclampsia is inconsistent. Some studies have reported an inverse association,6 and IGF1RPotential mechanisms for risk reductions in breast cancer for women with a history of preeclampsia could be due to lower levels of oestrogenset al.et al.et al.Although there is no evidence to suggest an association between sex of the offspring and long‐term risk of breast cancer in pregnancies without complications,Since a maternal history of preeclampsia in the pregnancy leading to the subject's birth is a risk factor for experiencing preeclampsia in the subject's own pregnancy,An adverse effect of hyperemesis on breast cancer risk has been proposed because of reported higher estradiol levels in pregnancies with hyperemesis.To our knowledge there have been no previous investigations of risk by tumour intrinsic subtypes of breast cancer in relation to history of preeclampsia or hyperemesis. We found that the strongest associations for both pregnancy complications were for HER2‐enriched tumours. Risk of this type of breast cancer was reduced in women with a history of preeclampsia, which is associated with lower levels of estriol,While there are several strengths to our study, including its large size, prospective design, high completeness of follow‐up and quality of covariate data, we are dependent on self‐reported history of preeclampsia and hyperemesis, although collected prior to breast cancer diagnosis and therefore unbiased by outcome. Registry‐based cohort studies have been based on records of women hospitalised for pregnancy‐complications, therefore reflecting confirmed diagnoses, but did not have complete data on other important breast cancer risk and lifestyle factors. In the Generations Study extensive pregnancy and other breast cancer risk factor data were collected and our analyses were adjusted for a wide range of potential confounders.In conclusion, our results suggest that preeclampsia is associated with a decreased risk of breast cancer at premenopausal ages and of HER2‐enriched breast cancer. We did not find evidence that a history of hyperemesis was associated with breast cancer risk overall, but there was a positive association with the HER2‐enriched subtype.Supporting Information TableClick here for additional data file.


SWAN) reconceptualizes each diagnostic criterion for selected DSM‐5 disorders as a behavior, which can range from high (strengths) to low (weaknesses). Initial development focused on Panic Disorder, Social Anxiety, Major Depression, and Disruptive Mood Dysregulation Disorder.The Extended Strengths and Weaknesses Assessment of Normal Behavior , and Receiver Operating Characteristic (ROC) curves were used to assess and compare the performance of E‐SWAN and traditional scales.Data were collected from 523 participants (ages 6–17). Parents completed each of the four E‐SWAN scales had symmetric distributions. IRT analyses indicate the E‐SWAN subscales provided reliable information about respondents throughout the population distribution; traditional scales only provided reliable information about respondents at the high end of the distribution. Predictive value for DSM‐5 diagnoses was comparable to prior scales.In contrast to the traditional scales, which exhibited truncated distributions, all four E‐SWAN bidirectional scales can capture the full spectrum of the population distribution of behavior underlying DSM disorders. The additional information provided can better inform examination of inter‐individual variation in population studies, as well as facilitate the identification of factors related to resiliency in clinical samples.E‐ Myriad questionnaires are available for measuring psychiatric illness dimensionally , there is generally a high degree of agreement between the SWAN and traditional scales  – a framework that extends the general methodology of the SWAN to other psychiatric disorders. Consistent with the SWAN, the clinical wisdom embodied in the DSM‐5 was taken as the departure point to develop each E‐SWAN scale. Four disorders were chosen to provide a sampling of challenges that can arise in the conversion of DSM symptoms to dimensional probes. Major Depressive Disorder and Social Anxiety were chosen for their high prevalence in the general population  that enabled comparison of E‐SWAN results with those obtained using equivalent unidirectional questionnaires in the same individuals. Item response theory analyses, showing in what area of the latent trait the scale scores are reliable enough to provide information about the subjects, are included to demonstrate the added value of the information obtained via the E‐SWAN. Additionally, we obtained informant and self‐report data via the Prolific Academic platform to verify the bidirectional distributional properties of the E‐SWAN in an independent sample with distinct characteristics (n = 250).The present work makes use of initial data obtained in the Child Mind Institute Healthy Brain Network (CMI‐HBN) sample  in which the behavior is actually taking place. As a result, we changed the questionnaire to ask each question separately for each of the settings . In the first step of the E‐SWAN construction process, complex criteria such as this are broken down into multiple items Figure .Some DSM diagnoses have conditional criteria that cannot easily be translated into abilities or strengths. For example, Panic Disorder criteria are mostly physiological symptoms experienced during a panic attack. To address this, we first developed three questions focused on the presence and severity of panic attacks (phrased as ‘moments of intense fear or discomfort’). We then ask the parent to rate how well their child is able to regulate the physiological symptoms while experiencing ‘a moment of intense fear or discomfort’. This allows us to potentially capture what prevents a panic attack in one individual in the same context that elicits a panic attack in another individual.To promote standardization across current and future E‐SWAN assessments, we focused on ensuring that all questions met specific criteria. In particular, we focused on three criteria: clarity, precision, and general applicability. Clarity means that each item is straightforward and easy to understand – not vague, confusing, or complex. To meet this goal, we used simple language characteristic of a sixth‐grade reading level. Precision means that each question is specific, asking only about one behavior in one setting. We did not include multiple behaviors in one item. To meet this goal, several of the original questions were broken down into multiple questions. General applicability means that the questions do not require cultural or contextual knowledge. To meet this goal, the scale was constructed including input for item development and review from individuals with different cultural backgrounds.https://www.chesapeakeirb.com/). Prior to collecting data, written informed consent is obtained from participants’ legal guardians and written assent obtained from the participant and all methods were performed in accordance with the relevant guidelines and regulations.Data were collected from 523 participants  of the CMI‐HBN . Users were screened based on having a child in the 6.0–17.0 age range. Parents then completed four questionnaires anonymously through a Google survey. This sample had a younger mean age (8.75) than the CMI‐HBN sample, and a more balanced male to female ratio, with slightly more females (115:135). These respondents completed the E‐SWAN questionnaires only and were given a small monetary compensation. Additionally, we collected 250 adult self‐report surveys . Because all data were collected anonymously, through a platform designed for research data collection, no IRB oversight was required for this sample. Exemption from IRB oversight was approved by the Chesapeake Institutional Review Board. Participants using the Prolific Academic website are required to agree to the Terms of Service notification ( https://prolific.ac/assets/docs/Participant_Terms.pdf) before being allowed to complete surveys. Per the IRB exemption, no additional informed consent was required.To confirm the generality of distributional properties for the E‐SWAN, additional data were collected from 250 parents through Prolific Academic  Cronbach's alpha coefficients for individual scale items, and between scores on the corresponding scales, to measure internal consistency within and between scales, and (b) Omega reliability for each of the scales, (c) Pearson correlation coefficients. All questionnaire items for each domain were included in these analyses. Internal consistency analysis was performed without scaling. To further examine the added value of measuring both strengths and weaknesses, for each questionnaire, we subdivided participants into those with mean E‐SWAN scores greater for strengths, or negative scores, based on the scoring convention (E‐SWAN mean score < 0) and those with mean E‐SWAN scores greater for weaknesses, or positive scores (E‐SWAN mean score > 0), and then calculated Cronbach's alpha and Pearson correlation coefficients again for each of the two groups. Finally, we tested whether correlations between E‐SWAN scales and traditional scales vary as a function of E‐SWAN score using quantile regression, which assesses whether the correlation between two instruments is the same for varying levels of a latent trait  and Confirmatory Factor Analysis (CFA). We followed three analytical approaches.All questions for a given domain together  as a single unidimensional IRT model. This analysis aims to directly compare the level of information provided by unidirectional and bidirectional scales using the same latent trait. Prior to this analysis, ‘sufficient’ unidimensionality of the total item pool for each domain was assessed by inspecting the ratio of the first eigenvalue to the second eigenvalue using scree plots. Domains with ratios greater than or equal to 3 to 1 were considered sufficiently unidimensional to relate to a single construct  modeling all questions for each domain together in a bifactor model and; (b) modeling all scales separately . Detailed descriptions of these additional approaches, and results, can be found in the To determine the ability of E‐SWAN scales to predict DSM‐based diagnoses in the CMI‐HBN sample, and their comparability to traditional scales, we generated Receiver Operating Characteristic (ROC) curves for all scales using clinician consensus diagnoses from the KSADS  – not just at the high end as unidirectional scales. Finally, we demonstrated the ability to generate both parent and self‐report questionnaires using the E‐SWAN framework. Consistent with the data from CMI‐HBN participants, our online sample from PA yielded a symmetric distribution, although shifted slightly to the left , as would be expected given the differences in recruitment strategies.Inspired by the SWAN, we developed and tested a generalized framework for constructing questionnaires to assess the full range of behavior underlying DSM symptoms, when considered as an endpoint of a dimension. When compared to the unidirectional scales, the E‐SWAN scales exhibited distributional properties that were symmetric rather than highly skewed or truncated. As predicted, for each trait, a strong correspondence was noted between the E‐SWAN scores and traditional scale scores among individuals at the high  end, but not at the low end. IRT analyses suggested that in contrast to traditional scales, the E‐SWAN subscales exhibited good discrimination and reliability across the full latent trait ; the neuroimaging literature already has examples of this when we think of the age‐related changes in the neural correlates of constructs such as intelligence and reading abilities  that allows raters to consider a given ability in the context of the population, with the added information related to direction of an extreme strength as well as an extreme weakness. Thus, the average is being used as a reference for measurement, not a standard to aim for. Second, it is important to note that some ‘strengths’ at an extreme or in isolation can actually be deleterious, at least in some contexts. Arguably, it is the combination of measured strengths and weaknesses that is most informative regarding the status of a child. We believe properties of the E‐SWAN allow for just that; researchers can look for multivariate profiles that engender higher or lower function, rather than just a given strength in isolation, which can be a plus or minus depending on the larger context. Third, given that E‐SWAN items are directly related to the content of DSM 5 criteria, the framework is not all inclusive with respect to strengths and weaknesses that may be relevant to psychiatric illness. However, we do believe that the using the DSM 5 criteria to define content does ensure the relevance of this dimensional approach for evaluation of psychiatric disorders. Fourth, a higher number of response options and a higher number of items might increase the amount of information from one instrument if compared to another; therefore, the amount of information provided by both instruments is not necessarily comparable. However, our main interest in this analysis is not to compare the amount of information from each scale, but to investigate the area of the latent trait from which each instrument provides information. We hypothesized (and documented) that E‐SWAN scales capture information about the full latent trait, whereas the legacy measures only capture information from one end of the latent trait, from individuals with a high level of symptoms.http://www.eswan.org, licensed Creative Commons (CC) BY 4.0 to encourage maximal dissemination and application of the questionnaires. It is our hope that other investigative teams will join in the effort to create the full range of E‐SWAN questionnaires encompassing all major psychiatric syndromes.In the spirit of collaboration and open science, all E‐SWAN questionnaires are freely available for use and can be accessed at Myriad questionnaires are available for measuring psychiatric illness dimensionally. However, the vast majority are based on detection of the presence of problematic behaviors and symptoms.The Strengths and Weaknesses Assessment of ADHD Symptoms and Normal Behavior (SWAN) provides a potentially valuable model for bidirectional questionnaire design.The methodology of the SWAN was extended for the E‐SWAN to address four additional DSM‐5 disorders; Depression, Social Anxiety, Panic Disorder, and DMDD.The E‐SWAN bidirectional scales can capture the full spectrum of the population distribution of behavior underlying these DSM disorders.The additional information provided by the E‐SWAN can better inform examination of inter‐individual variation in population studies, as well as facilitate the identification of factors related to resiliency in clinical samples.Appendix S1. Modeling and results of psychometric approaches 2 and 3.Table S1. t test results comparing mean scores between CMI‐HBN and prolific academic samples.Tables S2–S17. More information on psychometric approaches 2 and 3.Figure S1. E‐SWAN items.Figure S2. Prolific academic parent report and HBN parent report.Figure S3. Quantile regression plots.Figure S4. Scree plots for jointly modeled scales.Figures S5–S7. More information on psychometric approaches 2 and 3.Figure S8. ROC curves for all scales.Figure S9. Distribution of E‐SWAN scores by diagnosis.Figure S10. Distribution of SDQ prosocial scores by E‐SWAN score quintile.Click here for additional data file.


RNAs are emerging as potent and multifunctional regulators in all biological processes. In parallel, a rapidly growing number of studies has unravelled associations between aberrant noncoding RNA expression and human diseases. These associations have been extensively reviewed, often with the focus on a particular microRNA (miRNA) (family) or a selected disease/pathology. In this Mini‐Review, we highlight a selection of studies in order to demonstrate the wide‐scale involvement of miRNAs and long noncoding RNAs in the pathophysiology of three types of diseases: cancer, cardiovascular and neurological disorders. This research is opening new avenues to novel therapeutic approaches.Noncoding  AD, Alzheimer's diseaseALS, amyotrophic lateral sclerosisAPP, amyloid precursor proteinBDNF, brain‐derived neurotrophic factorCARL, cardiac apoptosis‐related lncRNACLL, chronic lymphocytic leukaemiaCRP, C‐reactive proteinEC, endothelial cellFTLD, frontotemporal lobar degenerationHCC, hepatocellular carcinomaHD, Huntington's diseaselncRNAs, long noncoding RNAsmiRNA, microRNAMPTP, 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridineNATs, natural antisense transcriptsncRNA, noncoding RNANSCLC, nonsmall cell lung cancerPD, Parkinson's diseaseSMA, spinal muscular atrophyCompletion of the Human Genome Project has revealed that protein‐coding genes comprise only about 1.5% of the human genome. In fact, two large‐scale consortia, the Encyclopedia of DNA elements (ENCODE) and the Functional Annotation of the Mammalian Genome (FANTOM) have shown that the majority of genome is transcribed and produces a wide spectrum of noncoding RNA species (ncRNAs) Noncoding RNAs can be classified, according to their size: short RNAs are < 200 nucleotides (nts) in length and include small interfering RNAs (siRNAs), piwi‐interacting RNAs (piRNAs) and microRNAs (miRNAs) Caenorhabditis elegans regulates lin‐14 through its 3′ untranslated region (3′UTR) The discovery of miRNAs dates back to 1993, when two laboratories independently reported that a small noncoding RNA transcript lin‐4 from The biogenesis of miRNAs Fig.  has beenMiRNAs attenuate the expression of their target genes by hybridizing, either completely or partially, to complementary binding sites located in the 3ʹUTR of target mRNAs. This leads to mRNA degradation and/or translational inhibition Bioinformatic predictions suggest that human miRNAs regulate over 60% of transcripts. Given that a single miRNA can regulate the expression of over one hundred mRNAs Long noncoding RNAs are a large and diverse class of transcribed RNAs that lack functional open reading frames, though exceptions have been described Long noncoding RNAs function through heterogeneous mechanisms Fig. , conferret al. via the Mediator complex to establish a stable transcription initiation process Certain lncRNAs have enhancer‐like properties. Orom A special class of lncRNAs are the antisense lncRNAs (NATs) that are transcribed from the opposite strand of a protein‐coding gene locus In the sections below, we highlight a nonexhaustive selection of examples that demonstrate the wide‐scale involvement of miRNAs and lncRNAs in the pathophysiology of cancer, cardiovascular and neurological disorders.MiRNAs play various roles in processes underlying human malignancies, including sustaining proliferation, resistance to apoptosis, angiogenesis, invasion and metastasis. Altered miRNA expression patterns found in cancer have been attributed to genomic abnormalities  Calin and associates were the first to describe a role of miRNAs in cancer, when they reported that miR‐15 and miR‐16 are dramatically downregulated in the majority (68%) of patients with B‐cell chronic lymphocytic leukaemia (CLL) due to deletions or mutations on the 13q13.4 chromosome http://clinicaltrials.gov/ct2/show/NCT01829971). It was given intravenously in patients with primary liver cancer or other selected solid tumors or hematologic malignancies. However, the trial was halted after immune‐related severe adverse events were reported in some of the patients. MiR‐26a is an example of a miRNA whose expression is lost in hepatocellular carcinoma (HCC). It regulates the cyclins D1 and D2, which control cell cycle arrest, as well as ULK1, a critical initiator of autophagy that promotes apoptosis More than 50% of human tumours carry loss of function mutations in the tumour suppressor protein TP53 (p53) via siRNAs suppressed established human xenograft tumours in mice The let‐7 miRNAs represent a large family of miRNAs that plays an important role in stem cell division and cell differentiation CIP1 and p57KIP2 thereby enhancing cancer cell growth Many miRNAs are found expressed at higher levels in tumours and can be seen as oncogenes. They promote tumour development by inhibiting tumour suppressor genes and/or genes that control cell cycle, cell differentiation and apoptosis. c‐Myc is an important oncogene that transactivates several miRNAs including the miR‐17~92 and miR‐106a~363 clusters in vivoMiR‐221 and miR‐222 (miR‐221/222) are two highly homologous miRNAs, which are significantly overexpressed in several types of human malignancies et al. via Tet‐Off and Cre‐recombinase technologies developed clinical signs of haematological malignancies. MiR‐21‐overexpressing tumour cells were found to invade the peripheral blood, and other organs. Once miR‐21 expression was switched off, the tumours regressed, partly due to the activation of apoptosis There is considerable evidence that miR‐21 has oncogenic properties, being involved in regulatory pathways of proliferation, apoptosis and metastatic potential On the list of prominent tumour‐promoting miRNAs is miR‐155, which originates from the B‐cell integration cluster, also known as MIR155HG (miR‐155 host gene). Aberrant expression of miR‐155 has oncogenic potential in several types of haematological malignancies Long noncoding RNAs have been shown to influence many of the pathways which drive malignant transformation. For instance the lncRNA MALAT1  is found to be highly expressed in many tumours The Hox transcript antisense intergenic RNA known as HOTAIR is a lncRNA which is transcribed from the HOXC locus. It is considered a biomarker for the prognosis of certain cancers: higher levels of the RNA have been found in colorectal, liver, pancreatic, breast and gastric cancers The lncRNA neuroblastoma associated transcript‐1 (NBAT‐1) was identified as an independent prognostic biomarker, predicting clinical outcome of neuroblastoma patients The lncRNA ANRIL shows increased expression in NSCLC tissues, and this correlates with stages of tumour–node–metastasis and the size of tumours in vivoThe oncofoetal lncRNA H19 is an important factor in both embryonic development and tumorigenesis. It is upregulated in a series of cancer types, where it reportedly accelerates cellular proliferation rates and increases the resistance of tumour cells to stress et al. Cardiovascular disease and complications thereof are a leading cause of morbidity and mortality worldwide. The myocardium can undergo remodelling in response to external stressors. However, chronic activation of remodelling processes, such as hypertrophy and fibrosis, can result in multiple cardiovascular diseases, including myocardial infarction, cardiomyopathies and heart failure. Ikeda via the CXCL12‐CXCR4 pathway Several miRNAs play key roles in vascular development and angiogenesis. For example miR‐24 has a role in cardiac vascularization MiR‐208 is selectively expressed in cardiomyocytes, and is highly expressed in autopsy samples of infarcted heart tissue from patients with myocardial ischaemia via C‐reactive protein (CRP) Zidar and associates have reported that downregulation of miR‐150 is involved in the pathology of ventricular rupture after myocardial ischaemia The neurologic‐enriched miRNA miR‐212/132 family becomes activated during heart failure et al. MiR‐1 is most abundantly expressed in heart and plays essential roles in cardiogenesis and in physiological cardiac function. Jayawardena et al. have recently discovered a new lncRNA – Chast (for ‘cardiac hypertrophy–associated transcript’) – that promotes cardiac remodelling and hypertrophy in mice. Antisense‐mediated degradation of Chast attenuated pathological cardiac remodelling, as it was shown by in vivo gain‐ and loss‐of‐function experiments in mice Next to miRNAs, lncRNAs also play important roles in cardiovascular disease. In fact, data from deep sequencing demonstrated that compared to mRNA and miRNA expression profiles, lncRNA expression profiles are more sensitive to different heart failure aetiologies and that altered lncRNAs reflect increased susceptibility to coronary artery disease, myocardial infarction and heart failure Besides its role in cancer, the lncRNA MALAT1 is also linked to cardiovascular disease: silencing of MALAT1 reduces capillary growth in a mouse model of hind limb ischaemia The lncRNA GAS5 (growth arrest–specific 5) is another regulator of hypertension‐related vascular remodelling et al. Ounzain The lncRNA cardiac hypertrophy related factor, is substantially elevated in response to hypertrophic stimulation by angiotensin II in cardiomyocytes Finally, the lncRNA myocardial infarction–associated transcript (MIAT) is highly expressed in heart and foetal brain tissue. Polymorphisms in MIAT that were identified by genome‐wide association studies are a risk factor for myocardial infarction Neurodegenerative diseases are hereditary and sporadic conditions which are characterized by progressive dysfunction and the death of neurons. According to the neuronal populations afflicted, these disorders can lead to disturbances in motor, cognitive and/or behavioural performance of affected individuals. They include diseases such as Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Huntington's disease (HD) and others.via an adeno‐associated‐virus; AAV2‐SYN), levels of miR‐155 are significantly increased. However, miR‐155 knockout mice models transduced with AAV2‐SYN, exhibit a remarkably decreased proinflammatory response, without a loss of dopaminergic neurons via targeting Nlrp3 expression and inhibiting NLRP3 inflammasome activation in a MPTP‐induced PD mice model MiRNAs display specific temporal and spatial patterns of expression during embryonic neural development and in adult brain via decreased miR‐106b levels Expression of the miR‐29a/b‐1 cluster is significantly decreased in the brains of patients suffering from sporadic AD, displaying abnormally high levels of BACE1 protein via its involvement in the ubiquitin–proteasome systems, gliosis, and the CREB pathway.Huntington's disease is an autosomal‐dominant disease that is caused by an expansion of CAG trinucleotide repeats located in the exon 1 region of the huntingtin gene. MiR‐196a has emerged as a protective miRNA in the context of HD. Overexpression of miR‐196a leads to a reduction of mutant huntingtin (HTT) and the formation of pathological aggregates in HD models of human embryonic kidney cells and mouse neuroblastoma cells. In HD transgenic mice overexpressing miR‐196a, suppression of mutant HTT in the brain shows attenuated neuropathological progression, manifested by reduced nuclear, intranuclear and neuropil aggregates as well as late‐stage behavioural phenotypes via its target mTor. The local axonal translation of mTor is reduced in SMN‐deficient neurons, and this can be restored by inhibition of miR‐183. Importantly, inhibition of miR‐183 expression in the spinal cord of an SMA mouse model prolongs survival and ameliorates motor performance of SMN‐mutant mice MiR‐183 has been shown to contribute to the pathology of SMA Aberrant lncRNA expression is linked to the onset and progression of several neurodegenerative diseases. For instance BACE1‐AS is a NAT that is transcribed from an intron of the β‐secretase‐1 (BACE1) gene in antisense direction. Its expression is elevated in subjects suffering from AD and in APP transgenic mice TDP‐43 is a nuclear RNA‐binding protein that forms inclusion bodies in frontotemporal lobar degeneration (FTLD) and ALS. The binding of TDP‐43 to MALAT1 and NEAT1_2 lncRNAs is increased in human FTLD brains compared with healthy controls in vitro and in vivoThe ubiquitin carboxy‐terminal hydrolase L1 gene (UCHL1) is closely related to brain function and neurodegenerative diseases. An antisense transcript of UCHL1, UCHL1‐AS promotes translation of UCHL1 The constellations of physiological processes which orchestrate life are subject to intricate control. MiRNAs and lncRNAs have emerged as ubiquitous RNA molecules capable of modulating all cellular processes. In particular, ncRNAs have drawn great attention partly for their putative roles in the pathology of many diseases. In many of the cases highlighted in this Review, in which we have limited the discussion to three types of diseases, the links between ncRNAs and disease pathologies came to light through their aberrant expression in disease cells or tissues. It is noteworthy that some ncRNAs  appear to contribute to more than one pathological mechanisms. In some of these cases, the miRNA‐disease association is sufficiently strong (i.e. possibly causative) that the miRNA represents a potential drug target or a therapeutic entity (e.g. miR‐106 and let‐7 respectively). The availability of potent pharmacological tools for use in animal models of these diseases and/or in clinical trials will ultimately clarify their value in distinct therapeutic applications