Youth under the age of 25 are at high risk for HIV infection. While pre‐exposure prophylaxis (PrEP) has the potential to curb new infections within this population, it is unclear how country‐specific laws and policies that govern youth access to sexual and reproductive health (SRH) services impact access to PrEP. The purpose of this review was to analyse laws and policies concerning PrEP implementation and SRH services available to youth in countries with a high HIV incidence. To the best of our knowledge this is the first systematic assessment of country‐level policies that impact the availability of PrEP to adolescent populations.We conducted a review of national policies published on or before 12 June 2018 that could impact adolescents’ access to PrEP, SRH services and ability to consent to medical intervention. Countries were included if: (1) there was a high incidence of HIV; (2) they had active PrEP trials or PrEP was available for distribution; (3) information regarding PrEP guidelines were publicly available. We also included a selected number of countries with lower adolescent HIV incidence. Internet and legal database searches were used to identify policies relevant to adolescent PrEP (e.g. age of consent to HIV testing).Fifteen countries were selected for inclusion in this review. Countries varied considerably in their respective laws and policies governing adolescents’ access to PrEP, HIV testing and SRH services. Six countries had specific polices around the provision of PrEP to youth under the age of 18. Five countries required people to be 18 years or older to access HIV testing, and six countries had specific laws addressing adolescent consent for‐ and access to‐ contraceptives.Adolescents’ access to PrEP without parental consent remains limited or uncertain in many countries where this biomedical intervention is needed. Observational and qualitative studies are needed to determine if and how adolescent consent laws are followed in relation to adolescent PrEP provisions. Intensified efforts to amend laws that limit adolescent access to PrEP and restrict the establishment of national guidelines supporting adolescent PrEP are also needed to address the epidemic in this group. Laws include age of consent to sexual intercourse, medical treatment, contraceptives and HIV testing. We also include a review of PrEP national guidelines and adolescent PrEP directives. For this purpose, three sources of information have been triangulated including a review of policies, a review of current country‐specific guidelines, and an analysis of country surveillance and programme monitoring data.22.1We used the following inclusion criteria to select countries: (1) the country had a high incidence of HIV; (2) the country had either active PrEP trials or PrEP was available for distribution; and (3) information regarding PrEP guidelines were publicly available. Our search for policies related to adolescents’ access to PrEP focused largely on countries with the highest burden of adolescent HIV and a select sample of Western countries where PrEP is available. Western countries were selected to explore how countries that have a comparatively low incidence of adolescent HIV, but have a well‐resourced healthcare infrastructure, may address PrEP access among adolescents. We used the WHO and the United Nations’ definition of adolescence, which is classified as the period in human growth and development that occurs after childhood and before adulthood from ages 10 to 19 years 2.2We conducted an Internet search for national policies related to adolescent PrEP use, its availability, and adolescents’ ability to consent to medical treatment in the identified countries using the following key words: [“Pre‐exposure prophylaxis OR PrEP”] AND [“Policy” OR “Strategies” OR “Guidelines”] AND [“Adolescent” OR “Youth” OR “Child” OR “Teen”]. We specifically targeted reports by the WHO, the President's Emergency Plan for AIDS Relief, and PrEPwatch.org, a website that tracks the global availability of PrEP and ongoing medication trials 2.3Countries were divided equally among the four coders . We extracted information regarding age of majority, national guidelines and policies for adolescent PrEP, age of consent to SRH services (i.e. contraceptives and HIV testing), medical treatment and diagnostic laws, and PrEP availability. These data were documented in tabular form in Microsoft Excel for analyses. The research team met to discuss findings and exchange information, and adjusted search strategies as necessary.3We identified 15 countries for this review. The majority of the countries identified are in Eastern and Southern Africa, and South Asia. Table 3.1Age of consent to sexual intercourse is 18 years in seven countries (47%) with some countries’ consent laws differing by type of partnership  or gender. For example, according to Indonesian law, men can consent to sex with a woman at 19 years and women can consent to sex with a man at 15 years. Two countries (13%) have laws that prohibit sex with anyone under 15 years. Unlike the other countries in this review, age of consent in the Ukraine is a range between 14 and 17 years and is based on pubertal development.3.2Laws in seven countries (47%) do not specify an age of consent to medical treatment or the age is unclear. The age of consent to medical treatment in most countries is 18 years. In the Ukraine, people 14 years and older could access SRH services; however, to date, these services do not include PrEP. Other countries’ laws include stipulations for people under 18 years to consent to medical treatment. For example, in the United Kingdom (England) people under 16 years can consent for medical treatment, but it is at the provider's discretion to determine whether they understand the treatment and can provide consent. France is the only country to explicitly include PrEP as part of medical treatment, but their law requires parental consent for medical treatment in people under 18 years.3.3Although the majority of countries in this review have national healthcare directives for access to contraceptive services, only six countries (40%) have specific laws addressing adolescent consent for‐ and access to‐ contraceptives. For example, Ukrainian law requires legal guardian or parental consent for anyone aged 14 to 18 years to access SRH services, while Indonesian law restricts access to contraceptives to anyone who is not married.3.4All 15 countries have national guidelines or laws for age of consent for HIV testing. Age limits range from 12 to 18 years. Of the countries with age limits, five countries (42%) require people to be 18 years or older to consent to HIV testing, while four countries (33%) require those under the age of 18 years who are not married, pregnant or a parent themselves to have parental consent for an HIV test.3.5Table Ten countries (66%) have national guidelines for PrEP to assist providers with patient care. Of these, six countries (60%) include specifications for people under the age of 18 years. For example, in the Ukraine, PrEP can be provided to people 14 years and older who are at risk for HIV. In Australia, guidelines do not list a specific age limit for PrEP; rather, guidelines offer considerations for side effects, health benefits and risk of HIV infection when providing PrEP to adolescents. In South Africa and the UK, national guidelines recommend that PrEP be offered to adolescents who are members of key populations (e.g. young MSM and young women).3.6Currently, indications for PrEP including initial and follow‐up prescribing and testing recommendations are the same for adolescents and adults Despite these concerns, PrEP represents a promising biomedical intervention for addressing the global adolescent HIV epidemic. With the onset of regulatory approval of adolescent PrEP in the United States, understanding the laws which govern access and adherence to PrEP is a necessary and critical next step Most countries in this review have written national guidelines for implementing PrEP. Many of these guidelines include directives for key populations such as at‐risk adolescents. However, age of consent laws requiring parental consent for HIV testing and medical treatment undermine these directives. Adolescents may be unwilling to disclose their sexual activity to their parents because of fear, sexual stigma and discomfort Across laws and national guidelines, classification of PrEP as biomedical HIV prevention rather than HIV treatment is inconsistent. This inconsistency has implications for provider prescribing behaviours due to ethical and legal differences between HIV prevention and treatment options, challenges identifying appropriate PrEP‐eligible patients and cost barriers for youth under 18 years Our review identified age of consent laws that differ by an adolescent's age, gender and sexual orientation and laws that criminalize same‐sex sexual activity. Discordant age of consent laws that criminalize consensual sexual activity among adolescents drives HIV risks and are barriers to accessing SRH services, including PrEP 4This study provides a review of age of consent laws and PrEP initiatives based on a comprehensive internet and legal database search; however, we did not review case law or grey literature that were not available in English. This review did not examine sociocultural drivers of policy such as religion or HIV stigma, nor did we examine the structure of various healthcare delivery systems. Analysis of these factors is beyond the scope of this review and should be considered for future research as they may influence laws and guidelines on PrEP. Lastly, this review reports age of consent laws as written. We are not able to determine how these laws are implemented, how closely providers follow these laws, or if they truly impact access to SRH services including PrEP provisions for adolescents. These limitations lead to some uncertainty about adolescent PrEP implementation in light of current age of consent laws.The degree to which youth have access to PrEP remains unclear in many countries where this biomedical intervention is needed. Given that adolescent HIV is acquired chiefly through sexual transmission, scaling up PrEP among adolescent populations could significantly curb new infections within this population. This review identifies a number of ambiguities in current laws that may influence the provision of PrEP to youth, and a need for further consideration of adolescent‐specific PrEP issues. Adolescents at substantial risk of HIV are excluded from services for multiple reasons including their age, lack of information on SRH services, discriminatory attitudes of service providers, gender inequality and sexual orientation criminalization. Intensified efforts to modify national and sub‐national laws related to adolescent informed consent are needed to ensure that policy constraints associated with adolescent PrEP are minimized. It is imperative that policy makers, policy implementers, providers and advocates meaningfully engage youth in devising strategies to address the structural  challenges of implementing adolescent PrEP programmes. More support for providers is needed in order to facilitate trustful and empathetic relationships with their adolescent patients The authors have no conflicts to disclose.TT conceived and designed the study, conducted data collection and analysis, wrote sections of the paper, and reviewed and approved the final draft of the manuscript. KTB conducted data collection, drafted the introduction and implication sections, and reviewed and approved the final draft of the manuscript. TR conducted data collection, drafted the methods section, edited the manuscript and reviewed and approved the final draft of the manuscript. JCS conducted data collection, edited the manuscript, and reviewed and approved the final draft of the manuscript.


Tsogolo la Thanzi (TLT) was designed to study how young adults navigate sexual relationships and childbearing during a generalized HIV epidemic. TLT began in 2009 with a population‐representative sample of 1,505 women and 574 men between the ages of 15 and 25 living in Balaka, southern Malawi, where regional adult HIV prevalence then stood at 15 percent. The first phase (2009–11) included a series of eight interviews, spaced four months apart. During this time, women's romantic and sexual partners enrolled in the study on an ongoing basis. A refresher sample of 315 women was added in 2012. Seventy‐eight percent of respondents were re‐interviewed in the second phase of TLT (2015), which consisted of follow‐up interviews approximately 3.5 years after the previous interview (ages 21–31). At each wave, detailed information about fertility intentions and behaviors, relationships, sexual behavior, health, and a range of sociodemographic and economic traits was gathered by means of face‐to‐face surveys. Biomarkers for HIV and pregnancy were also collected. Distinguishing features include: a population‐representative sample, closely spaced data collection, dyadic data on couples over time, and an experimental approach to HIV testing and counseling. Data are available through restricted data‐user agreements managed by Data Sharing for Demographic Research (DSDR) at the University of Michigan. Tsogolo la Thanzi means “Healthy Futures” in the Chichewa language. The study is comprised of two phases: TLT‐1 (2009–11) and TLT‐2 (2015).TTLT‐1 was designed to understand how young adults in Malawi navigate childbearing and related life‐course events while avoiding HIV or contending with its consequences. The study focused on young men and women aged 15–25 in 2009 who comprise a birth cohort that grew up during the HIV epidemic and suffered particularly high rates of orphanhood (Monasch and Boerma The study team fielded a follow‐up survey (TLT‐2) in 2015 to examine how the relationships between HIV and fertility identified in TLT‐1 might be changing in light of the rapidly changing HIV‐treatment context. To illustrate the magnitude of these changes, rates of HIV testing rose nationally from 7 percent and 15 percent of women and men, respectively, reporting ever having been tested for HIV in 2004 to 83 percent of women and 70 percent of men in 2015  and in the United States from the Office for Research Protections at The Pennsylvania State University and the Social and Behavioral Sciences Institutional Review Board at the University of Chicago.Malawi is a pronatalist country wherein childbearing is critically important to achieving full adulthood  radius of Balaka's main market. The catchment area includes a train station, a bus depot, a hospital and two smaller district health centers, a cotton “ginnery,” dozens of religious congregations, and about 100 villages of various sizes. The listing exercise enumerated urban town residents and residents of rural villages well outside of town, and went beyond the listing of regular households and their members to include all individuals living in boarding schools and “rest houses”  within the catchment area. The core sample was drawn as a simple random sample of 1,562 women between the ages of 15 and 25 in the catchment area of whom 1,505 completed a baseline interview (96.4 percent response rate). Reasons for nonparticipation were refusal (N=30), not found (N=17), and language or mental health problems (N=10). Out of 614 men sampled in this same age‐range, 574 (93.5 percent) completed a baseline survey. Reasons for nonparticipation among men included: not found (N=21), refusal (N=11), and language or mental health problems (N=8).TLT was powered to study the relationship between childbearing and HIV among women. The smaller core sample of men facilitates comparisons by gender at this same stage of the life course and provides a benchmark for understanding the selective aspects of the male‐partner sample (described below). The random sample of men also provided some “cover” for the romantic partners enrolled in the study; without them, it would have been too obvious that the men in the study had all gotten there because of their relationships with female respondents.Table Because both HIV infection and pregnancy are dyadic phenomena, TLT was designed with a focus on couple‐level dynamics. Many of the behaviors of interest occur before marriage, thus TLT widened its lens to include not just spouses of women in the sample (a common approach in couples’ studies) but also women's partners at much earlier stages of a relationship. During their first interview, and at all subsequent interviews, women answered detailed questions about their sexual and romantic relationships and then recruited the male partners they named into the TLT study by providing them with tokens that had unique identifiers. Female respondents shared these tokens with their male partners, and the men subsequently enrolled themselves in the study by coming to the TLT research center . Research staff confirmed the relationship through an initial conversation with the male partner at the reception area in the research center and then again based on his reports about his relationships during the survey itself. On a few occasions, the data from male partners were excluded from the study when they were identified as “imposters”—such as one case in which the respondent had passed the token to her brother, rather than her romantic partner. Male partners had a median age of 26 years at enrollment and ranged in age from 13–62.Immediately following Wave 8, the study team added a refresher sample of 315 female respondents  to TLT‐1. Drawn from the original 2009 sampling frame to offset attrition, the refresher sample also provides a comparison sample against which analysts can identify potential panel‐conditioning effects within the study.TLT‐1 (2009–11) featured an intensive design wherein the core sample of female and male respondents were interviewed every four months for eight waves . During TLT‐2, women again recruited current male partners using tokens. Male partners from TLT‐1 were only included in TLT‐2 if they were still in a relationship with a female respondent. Male partners who appear in both the TLT‐1 and TLT‐2 datasets can be followed longitudinally across study phases using a single, unique identifier.In 2015, TLT‐2 successfully re‐interviewed 80 percent of women and 71 percent of men in the core sample. A bivariate analysis of sample retention can be found in Table Respondents gave consent at the time they were recruited for the study, before each interview, and before biomarker collection. Unmarried men and women aged 15–17 in the core sample enrolled in the study only after the study team obtained informed consent from a parent or guardian and assent from the minors themselves.Malawian interviewers, trained extensively by the TLT research team and certified by Malawi's Ministry of Health to conduct HIV testing and counseling (HTC), conducted the interviews in Chichewa. Rather than following the standard household‐survey approach, which is often impacted by bystanders and interruptions .At each wave, female respondents were asked to take an hCG pregnancy test. The acceptance rate ranged between 84 and 94 percent across waves; the main reason for refusal was menstruation. Table During TLT‐1, HIV testing and counseling was offered using a randomized experimental design in which the frequency of HIV testing was manipulated to allow researchers to examine the impact of HTC on a variety of behavioral and socioeconomic outcomes. At their baseline interview in 2009, core‐sample respondents were randomized into three groups, with male partners subsequently assigned to the same group as their nominating partner: one‐third would receive HTC at every interview, one‐third would receive HTC at Waves 4 and 8; and the final one‐third would not get tested at TLT until Wave 8. All respondents were offered HTC at TLT‐2. At Wave 1, HTC uptake among respondents offered testing was 85 percent for women and 78 percent for men (core sample and partners). In 2015, 93 percent of women and 91 percent of men consented to HIV testing. HTC used rapid HIV tests and followed the protocol set by the Malawi Ministry of Health and used by local clinics.Among core‐sample respondents, HIV prevalence in 2009 Wave 1) was 1.7 percent among men and 6.0 percent among women. By 2015 (TLT‐2), prevalence had increased to 3.8 percent for men and 15.2 percent for women Figure . Women's was 1.7 pregnancy questionnaire that asked about when and how they found out they were pregnant, how they reacted emotionally, prenatal health behaviors, and antenatal testing for HIV. In waves that followed a birth, women also completed a postpartum questionnaire, which asked about their delivery, postnatal behaviors, and infant's health. Over the course of the study, the TLT research team tracked respondents who had migrated, re‐interviewing those who had moved to other districts when possible. During TLT‐1, most tracking was done within the district; however, at Wave 8 and TLT‐2, migrants were followed throughout Malawi. When respondents truly could not be interviewed because of migration, interviewers conducted a migration autopsy with a family member or neighbor who knew the reasons for migration and the respondent's destination. Twenty‐one respondents in the core and refresher samples died during the study period; to gather information about these deaths, interviewers conducted verbal autopsies with a family member or neighbor.Following the core questionnaire and biomarker portions of the study, women with new and ongoing pregnancies completed a TLT data are designed to facilitate two types of dyadic data analysis. TLT collected data from women and men in relationships over time, capturing relationships as they formed, strengthened, and dissolved. Time‐varying, couple‐level linking files can be used to match data from TLT women to the corresponding data from the men they referred to the study. Additionally, all respondents were asked to report on up to three ongoing partnerships at each wave. These self‐reported partnerships can be followed longitudinally over TLT‐1 using a partnership‐link file—even if the partners themselves never enrolled in the study.Detailed data from a population‐based sample in an HIV‐endemic context over timeAn intensive design with respondents interviewed every four months during TLT‐1A randomized, experimental approach to HIV testing and biomarkers for HIV status that mean researchers can study the impacts of knowledge of one's status as well as have data on respondents’ HIV status and incident HIV infectionsA biomarker for pregnancyDynamic, dyadic data on couples over timeTLT's distinguishing features differentiate it from other studies in the region and make it useful to public health researchers and social scientists working in a variety of disciplines. Specifically, the study includes:https://scholar.google.com/citations?user=OFx9oPIAAAAJ&hl=en.Key findings have centered on the changing HIV treatment context  (Beegle and Poulin https://www.icpsr.umich.edu/icpsrweb/DSDR/series/767).TLT data are available through Data Sharing for Demographic Research (DSDR) within ICPSR at the University of Michigan (http://tsogololathanzi.uchicago.edu.Because of deductive disclosure concerns, all files are released under restricted‐use access agreements. More detailed information about the TLT study including survey instruments, documentation guides, a data key, a user forum, and links to open‐access versions of many publications are available on the TLT website:


Hepatic sinusoidal obstruction syndrome during oxaliplatin‐based chemotherapy has been shown to be associated with severe steatohepatitis. Gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid‐enhanced magnetic resonance imaging may identify various features of hepatic sinusoidal obstruction syndrome, even when the lesion cannot be differentiated from sinusoidal obstruction syndrome by other imaging tools. Abdominal computed tomography scan showed splenomegaly without any other abnormal finding. However, multi‐imaging modalities including gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid‐enhanced magnetic resonance imaging showed the presence of cracked hypointensity of peripheral right hepatic lobule in the hepatobiliary phase.A 54‐year‐old woman with a history of chemotherapy against advanced gastric cancer with distant metastases in the liver and para‐aortic lymph nodes presented with acute‐onset epigastric pain and hematemesis. The patient received oxaliplatin‐based chemotherapy for metastatic gastric cancer for six months. We planned palliative gastrectomy against hematemesis from gastric cancer after evaluating distant metastatic lesions. Multi‐imaging modalities including gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid ‐enhanced magnetic resonance imaging (EOB‐MRI) showed the presence of cracked hypointensity of peripheral right hepatic lobule in the hepatobiliary phase Figure . AbdominThe authors declare no conflicts of interest in association with the present study.All of the authors have read and approved the manuscript. SK: collected, analyzed, and interpreted the patient disease data and edited the manuscript. Kazuma Kobayashi and Kengo Kanetaka: supervised the patient treatments and the research project. SO: pathologist and participated in the diagnosis of sinusoidal obstruction syndrome. SE: participated in the discussion and approved the final submission of this manuscript.The publication of present study was in accordance with the ethical standards of our institution.Consent for publication: Informed consent was obtained from the patient and her family in this report.


Perceiving one's own weight status as being overweight is a likely motivation for weight loss. However, self‐perceived overweight status has also been found to be associated with overeating and weight gain. This study examined whether weight stigma concerns explain why individuals who perceive their weight status as overweight are at increased risk of overeating.N = 1,236) in which we assessed whether weight stigma concerns explain the cross‐sectional relationship between perceived overweight and overeating tendencies.We conducted two survey studies of United States adults  to 58.6% (Study 2) of the variance in the relationship between perceived overweight and overeating tendencies.Weight stigma concerns may explain why perceiving one's own weight status as overweight is associated with an increased tendency to overeat. The failure of individuals with overweight to accurately identify their weight status has been highlighted as a cause for concern, as it is presumed that this failure might lead to ineffective weight management. In support of this idea, studies have demonstrated that self‐perception of overweight is associated with attempted weight loss and weight loss intentions among adults and adolescents of overweight status One reason why self‐perception of overweight may be associated with overeating is because of the widespread stigma attached to larger body sizes Although self‐perception of overweight has now been shown to be associated with overeating among female adolescents f2 ≥ 0.02) for each pathway of our proposed test of indirect effect using bias‐corrected bootstrap models while accounting for covariates Our analytic sample size in Study 1 provided sufficient power to detect small effect sizes  and weight (pounds), which were converted to metric measures to calculate BMI (kilograms per meter squared). Presence of chronic illness was assessed with a single yes or no item.Consistent with previous research Weight stigma concerns were assessed using the Weight Stigma Concerns Scale To assess overeating tendencies, participants completed a measure of stress‐induced overeating. Participants were asked to indicate the extent to which they typically engage in the following behaviors when stressed: “eating more than usual to enhance my mood” and “eating more of my favorite foods to enhance my mood” Participants completed the Neuroticism subscale of the Mini International Personality Item Pool Depressive symptoms were assessed using the 10‐item Center for Epidemiological Studies Depression Scale An adapted version of the Perceived Everyday Experiences with Discrimination Scale In Study 1 and Study 2, we collected additional self‐report questionnaires for the purpose of other research questions, and these are reported in full in the online Supporting Information.After providing informed consent, participants completed the demographics and perceived weight measures. Measures of weight stigma concerns, perceived weight discrimination, neuroticism, depression, and stress‐induced eating were then completed on randomized consecutive pages of the online survey. The survey included four attention checks, and participants who failed to answer them properly were screened out of the questionnaire. Participants were provided with a small monetary reward upon completion of the questionnaire. Ethical approval was obtained from the University of Liverpool Ethics Committee.The PROCESS macro for SPSS  with 5,000 bootstrap samples We also conducted two tests of conditional indirect effects using the PROCESS macro for SPSS (model 59) to test whether participant gender or the accuracy of perceived overweight  moderated the indirect effect of perceived overweight on stress‐induced overeating through weight stigma concerns in the fully adjusted analyses.f2 ≥ 0.03), oversampling for participant exclusions. We recruited 804 United States adults via Amazon Mechanical Turk to complete a study on “the relationship between weight, personal characteristics, and wellbeing.” Of the 804 participants, 97 were excluded because they failed an attention check, 40 perceived their weight as being underweight, 14 reported implausible BMIs, and 4 participants reported an age of <18 years old, leaving an analytic sample of 649.We powered Study 2 to be able to detect the effects observed in Study 1  and a good test‐retest reliability (r = 0.72) Physical activity was assessed using a single‐item measure , which has been validated against other widely used physical activity questionnaires, showing moderate positive correlations , and in turn, weight stigma concerns were a significant predictor of stress‐induced overeating . Perceived overweight  had a significant indirect effect on stress‐induced overeating via weight stigma concerns , with weight stigma concerns explaining 31.8% of the variance in the relationship between perceived overweight and stress‐induced overeating. In the fully adjusted model , suggesting that gender did not moderate the indirect effect of perceived overweight on stress‐induced overeating via weight stigma concerns. For weight perception accuracy, the index of moderated mediation was not significant , indicating that weight perception accuracy did not moderate the indirect effect of perceived overweight on stress‐induced overeating via weight stigma concerns.Weight stigma concerns partially explained the relationship between perceived overweight status and overeating. A limitation of Study 1 was that although our measure of overeating has been shown to prospectively predict increased weight gain P < 0.001), and weight stigma concerns significantly predicted uncontrolled eating . There was a significant indirect effect of perceived weight on uncontrolled eating via weight stigma concerns , and weight stigma concerns explained 58.6% of the variance in the relationship between perceived overweight and uncontrolled eating. In the fully adjusted model , suggesting that gender did not moderate the indirect effect of perceived overweight on uncontrolled eating via weight stigma concerns. For weight perception accuracy, the index of moderated mediation was not significant , indicating that weight perception accuracy did not moderate the indirect effect of perceived overweight on uncontrolled eating via weight stigma concerns.Individuals who perceive their weight status as overweight are more likely to overeat and gain more weight than those who do not perceive their weight status as overweight In line with Hunger et al. In both studies, weight stigma concerns only partially explained the cross‐sectional association between self‐perception of overweight and overeating. Therefore, it is likely that there are other factors explaining this relationship. Internalized weight stigma may be an important factor to consider in future research. Individuals who perceive their weight status as overweight may internalize negative stereotypes about larger body sizes, and this negative self‐perception may lead to emotional overeating In the present research, we replicated our findings across two studies using different measures of overeating tendencies and found consistent results across analyses that controlled for a range of potentially confounding psychological variables. A limitation of the present studies is that they were cross‐sectional, which precludes causal inference. For example, we cannot rule out reverse causality in the relationships we tested, and it is possible that a third unmeasured variable may explain the observed pattern of findings. The measures of overeating tendencies used in Study 1 have been shown to prospectively predict weight gain The results of these two cross‐sectional survey studies suggest that weight stigma concerns may explain why perceiving one's own weight status as overweight is associated with an increased tendency to overeat. Click here for additional data file.


Lay summaries:2 have been linked to changes in ion gradients and neurotransmitter function. To explain how relatively small changes in ion concentrations could have such profound neural effects, we propose that a vicious cycle can be triggered that amplifies the initial disturbance.The altered behaviours of fish exposed to elevated CO 2 levels. These disturbances have been linked to altered ion gradients and neurotransmitter function in the brain. Still, it seems surprising that the relatively small ionic changes induced by near-future CO2 levels can have such profound neural effects. Based on recent transcriptomics data, we propose that a vicious cycle can be triggered that amplifies the initial disturbance, explaining how small pH regulatory adjustments in response to ocean acidification can lead to major behavioural alterations in fish and other water-breathing animals. The proposed cycle is initiated by a reversal of the function of some inhibitory GABAA receptors in the direction of neural excitation and then amplified by adjustments in gene expression aimed at suppressing the excitation but in reality increasing it. In addition, the increased metabolic production of CO2 by overexcited neurons will feed into the cycle by elevating intracellular bicarbonate levels that will lead to increased excitatory ion fluxes through GABAA receptors. We also discuss the possibility that an initiation of a vicious cycle could be one of the several factors underlying the differences in neural sensitivity to elevated CO2 displayed by fishes.Maladaptive behavioural disturbances have been reported in some fishes and aquatic invertebrates exposed to projected future CO It is of course possible that other neural mechanisms are involved in the behavioural alterations seen in fish exposed to elevated CO2. For example, A receptor reversal’. However, no plausible mechanistic link between elevated CO2 and altered neural function has been proposed for such alternative explanations. Glutamate receptors, for example, are linked to Ca2+ and/or Na+ channels, so unlike the GABAA receptor that gates Cl− and HCO3− fluxes, there is no obvious reason why they would be affected by pH regulatory responses to elevated CO2. Similarly, altered electrical responses of the olfactory organ seen during acute high-CO2 exposure in sea bass (Dicentrarchus labrax)   in spiny damselfish (Acanthochromis polyacanthus) , developmental (from hatching to 5 months) and transgenerational exposure to hypercapnia  and moving it into synaptic vesicles (VGAT and CLCN3). Furthermore, we found reduced expression of mRNA for the transporter protein GAT1 responsible for removing extracellular GABA from synapses  behaviourally affected by elevated CO2 found elevated mRNA levels of GABAA alpha-subunits, which are major subunits present in all GABAA receptors (Oncorhynchus kisutch) exposed to elevated CO2  and some species do not seem to be affected at all , especially when swimming at high speed (i.e. at high metabolic CO2 production rates) where blood pCO2 approached 1 mm Hg  are not behaviourally affected by elevated CO2 . By contrast, behavioural lateralization was affected by elevated CO2 in polar cod (Boreogadus saida) (2 in the habitats they commonly occupy and thus have different GABAergic responses to high CO2 (3− concentrations and gradients, will retain normal GABAergic function. However, failure to defend internal pH could bring other problems. For example, it is noteworthy that Atlantic cod is one of the few species of fish for which projected future CO2 levels have been found to directly impact larval development (2 compared with other fishes and the absence of behavioural effects, because the changes in Cl− and HCO3− could be too small to induce a significant change in GABAergic function.One would expect that the alteration of ion gradients needs to reach a threshold for triggering a self-amplifying vicious cycle altering GABAergic function. 2 exposure and lingers on for several days after the exposure has ended (2 is needed to trigger and/or sustain the vicious cycle, then this could also explain recent findings showing that daily cycling of water pCO2 has less behavioural effects in fish than a maintained high CO2 level (To conclude, the vicious cycle that we describe here can explain why relatively small initial disturbances in neuronal ion gradients after a few days become manifested in neural dysfunction severe enough to cause an array of behavioural alterations. A self-amplifying cycle that involves changes in gene expression and ultimately protein synthesis may take some time to be fully expressed, which can explain why the behavioural disturbances are not seen until after 2–3 days of high-CO2 responses should prove useful for testing hypotheses about the relationship between altered behaviours and changes in GABAergic function caused by elevated CO2. More comparative studies on more species and life stages would of course be most welcome as they would allow us to better identify and examine the patterns and processes that determine the neural sensitivity to elevated CO2. Experimentally, finding signs of the vicious circle we propose here could involve transcriptomic and proteomic studies. It would be desirable if these could be linked to measurements of ion and pH regulatory variables in blood and brain tissue, although this will be difficult in small individuals. Future studies could adopt new technologies that allow a more fine-scale approach, such as single-cell transcriptomics to examine the responses of specific cell types in discrete brain regions rather than whole brain tissue. Direct electrophysiological recordings of effects of elevated CO2 on neural functions, which have only rarely been done (The variation between species and life stages in CO2 affects fish behaviour, and how this links to variation in responses among species and habitats, will help establish where and when future ocean acidification conditions could impact fish populations. For iconic and/or high value species, such as salmon (2 levels such that any effects on behaviour are optimal for production.Understanding the physiological mechanisms by which elevated COSchunter_et_al_Suppl_Table1_coz100Click here for additional data file.


Genetic knockout of the serotonin reuptake transporter (SERT) potentiates serotonin signaling and increases crypt‐cell proliferation, neuroplasticity, and mucosal surface area. However, it remains unknown whether these changes occur throughout the small intestine and whether they increase nutrient absorption. We hypothesized that serotonin‐mediated mucosal growth would occur throughout the intestine and would increase enterocyte mass and absorptive function. Following institutional approval, intestinal segments spanning the bowel were harvested from 10 to 12 week‐old SERT knockout (SERTKO) and wild‐type (WT) C57Bl/6 mice. Histologic sections were used to measure villus height (VH), crypt depth (CD), and crypt proliferation index (CPI). Plasma citrulline was measured colorimetrically. Glucose and peptide absorption in isolated segments of small bowel were calculated using a previously described method for quantification after luminal instillation of substrate. At baseline, morphometric (VH/CD) and proliferative (CPI) parameters varied from jejunum to ileum. Enhanced 5‐HT signaling significantly increased plasma citrulline levels and morphometric/proliferative parameters in all regions analyzed. Glucose absorption in WT mice varied throughout the small intestine, and SERTKO mice demonstrated significant increases in the middle and distal bowel. WT peptide absorption was similar throughout the small bowel, and SERTKO mice had significant increases in the proximal and distal bowel. Enhanced serotonin signaling results in increased morphometric and proliferative parameters throughout the small intestine, and results in increased enterocyte mass and intestinal absorptive function. These data further advance the concept that the serotonin system is an attractive therapeutic target for increasing functional intestinal mucosa. Enhanced serotonin signaling in the murine enteric nervous system stimulates mucosal growth throughout the small bowel, but most significantly in its distal segments. Importantly, these anatomic changes are associated with evidence for greater enterocyte mass that translates into increased glucose and peptide absorption. Taken together, these findings suggest enteric serotonin acts as a mucosal growth factor supporting the concept of enteric serotonin signaling as a potential therapeutic target. Short bowel syndrome (SBS) is the most common cause of intestinal failure (IF) and is responsible for significant morbidity and mortality  is the most abundant neurotransmitter in the intestine and has been implicated in a wide range of physiologic processes in the gastrointestinal tract  mouse model. Previous data using this model have shown enhanced mucosal morphometric parameters (villus height and crypt depth) resulting in increased mucosal surface area as well as increased crypt cell proliferation and neuroplasticity in the ileum, all while maintaining normal physiologic cellular composition of the ileal mucosa, including the number of 5‐HT‐producing enterochromaffin cells . Yale University’s IACUC is governed by applicable Federal and State regulations, including those of the Animal Welfare Act (AWA), Public Health Service (PHS), and the United States Department of Agriculture (USDA) and is guided by the U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research and Training.The serotonin reuptake transporter (SERT) molecule is a high‐affinity transporter of 5‐HT and responsible for its signaling inactivation by way of intracellular transport. SERT knockout mouse models have been generated by deletion of this gene, which results in decreased signaling inactivation of 5‐HT and thus enhanced 5‐HT effects. Wild‐type (WT) and SERT knockout (SERTKO) mice were bred on a C57BL/6 background at the Yale Animal Resource Facility at Yale School of Medicine. All animals were housed in a pathogen‐free environment with a 12‐h light/dark cycle with food and water ad libitum. 10‐ to 12‐week‐old male mice were used for all experiments. Animal weights were recorded at the start of the experiments.2 asphyxiation followed by confirmation of death with cervical dislocation.Fasting mice received inhalational anesthesia . Depth of anesthesia was monitored by monitoring of respiratory rate and by toe‐pinch looking for reaction from the mouse every 5 min during the procedure. Euthanasia was performed using COUsing six mice from each group (WT and SERTKO), 2 cm segments from the proximal jejunum, distal jejunum, proximal ileum, and distal ileum were procured and fixed in 10% Neutral Buffered Formalin. These were then paraffin‐embedded and histologic sections created. Standard immunohistochemical protocols were used to create H&E and chromogenic slides for measurements of morphometric and proliferative parameters, respectively. Examiners were blinded to the samples at the time of measurements.For chromogenic slides used to calculate crypt proliferation index (CPI), a mouse monoclonal primary antibody against Ki67 at 1:250 dilution  followed by DAB substrate  was used as per manufacturer’s protocols and counterstained with hematoxylin. CPI was then calculated as the percentage of Ki67‐positive cells within the total number of crypt cells. Crypts were counted if a single epithelial cell layer was present from crypt‐villus junction to crypt‐villus junction, and at least a portion of the adjacent villi were present. At least 10 crypts per group were counted, and used to calculate the mean CPI.Morphometric parameters included villus height (VH) and crypt depth (CD). At least 20 villi and crypts were measured per group. Villi were chosen for measurement when intact from crypt‐villus junction to crypt‐villus junction and central lacteal present. Crypts were measured when intact from crypt‐villus junction to crypt‐villus junction and at least partial visualization of adjacent villi present.µL samples were collected and placed in BD serum separator microtainers  for isolation of serum for analysis. Citrulline was measured using a commercially available colorimetric assay kit .Serum citrulline is a known and validated biomarker for enterocyte mass  is a fluorophore‐conjugated peptide molecule used previously as a reporter molecule for peptide transport . Groups were compared using Student’s t‐test with Starting weights did not significantly differ between experimental groups, and mean ± SD weights for WT were 21.6 ± 3.2 g and SERTKO were 20.0 ± 3.8 g. At baseline in wild‐type animals, morphometric (VH and CD) and proliferative (CPI) parameters varied throughout the small bowel, with a trend toward decreased morphometric and proliferative parameters moving from proximal to distal bowel , while our genetic knockout model deletes the same SERT gene targeted by SSRIs. Most of the intestinal effects of SSRIs relate to their effect on GI motility. The effect of genetic deletion of SERT in our SERT knockout mice was initially concerning for possible developmental issues, but no major defects were observed and survival was not impacted (Bengel et al. Here we investigated whether 5‐HT‐mediated mucosal growth would result in increased enterocyte mass and mucosal absorptive function. We hypothesized that increases in intestinal mucosal growth in SERTKO mice previously observed in the distal small intestine would occur throughout the small bowel, and that this would logically result in increases in enterocyte mass and in mucosal absorptive function.We found that at baseline, WT morphometric and proliferative parameters vary throughout the small bowel, with the largest measurements occurring in the proximal small bowel and the lowest in the distal bowel. When we compared morphometric and proliferative parameters of SERTKO animals to WT, we found significant increases in all measured parameters throughout all areas of the bowel. This is in agreement with previous findings from our laboratory, although our previous work did not find a difference in the proximal small bowel (Park et al. Interestingly, the largest increases were seen in the distal small bowel of SERTKO mice, and this may be explained by the parameters observed in WT mice. Given that the villi and crypts in the proximal bowel of WT mice are large at baseline, the capacity for enhanced 5‐HT signaling to increase these parameters is presumably less. Conversely, enhanced 5‐HT signaling results in substantial increases in the distal bowel, where WT parameters are low at baseline. These data support our hypothesis that enhanced 5‐HT signaling stimulates mucosal growth in all areas of the small intestine, with the greatest capacity for change in the distal bowel.in vivo increase in total enterocyte mass, and support the concept of enhanced 5‐HT signaling as a therapeutic target to add new enterocytes and thus potentially functional intestinal mucosa. Further analysis was thus directed at determining absorptive function of these mice.We next assessed whether this increase in presumably functional intestinal mucosa would result in increased serum citrulline in SERTKO animals. Serum citrulline is a non‐protein amino acid demonstrated in multiple reports to be a reliable biomarker for enterocyte mass (Crenn et al. To evaluate for absorption, we utilized a previously described method of isolated intestinal segments to measure carbohydrate and peptide absorption in SERTKO mice compared to WT (Sullins et al. These data are the foundation for our planned experiments in clinically relevant settings. For example, we plan to investigate the utility of enhanced serotonin signaling on mucosal growth and absorption following small bowel resection, which is known to result in intestinal mucosal adaptation as well as changes in the microbiome (Tappenden In conclusion, we have determined that mice with enhanced 5‐HT signaling have increased intestinal mucosal growth throughout the small bowel, and this growth results in increased serum markers for enterocyte mass as well as increased glucose and peptide absorption. These data are critical for supporting the concept of targeting the serotonin signaling system in the small bowel to stimulate the growth of functioning intestinal mucosa. In this setting, 5‐HT acts as an intestinal growth factor rather than a neurotransmitter, and further study is warranted to define the complex mechanisms involved in this signaling pathway with a broader goal of developing new therapies for the treatment of short bowel syndrome and intestinal insufficiency.The authors have no conflict of interest to report.


To develop a training program designed to meet the specific needs of medical physicists as they transition into a clinical role with direct patient care responsibilities.UC San Diego School of Medicine and incorporates training techniques that have been shown to be effective in improving communication skills. The program emphasizes experiential, practice‐based learning over didactic presentations.The training program was designed in collaboration with the faculty at the UC San Diego School of Medicine, 2) Communication Strategies for Radiation Oncology, which consists of two, 2‐hour sessions designed to provide trainees with patient communication skills that are specific to patient interactions in radiation oncology, 3) Simulated Patient Interactions, in which trainees perform mock physicist‐patient consults with trained patient actors, 4) Faculty‐Observed Patient Consults, and 5) a Case‐Based Treatment Toxicity Course. A competency assessment mechanism was also developed to provide a clear set of objectives and to guide trainer feedback. The training program is comprised of 5 components: 1) a 1‐day Clinician‐Patient Communication Workshop run by the The training program that we have developed incorporates an array of established education techniques and provides a comprehensive, accessible, means of improving medical physicists’ patient communication skills. In contrast to the extensive training received by physicians,Here, we describe a training program that was developed to meet the specific needs of medical physicists as they transition into a clinical role with direct patient care responsibilities.2The training program incorporates established techniques for improving patient communication skills. It emphasizes experiential, practice‐based learning over didactic presentations and includes role‐playing and Simulated Patient interactions.2.1The medical physics training program utilizes a Physician Assessment and Clinical Education Workshop which is a 1‐day event offered through the UC San Diego School of Medicine. It is designed specifically to improve physician–patient communication and employs a structured approach to training communication skills based on four main concepts — engagement, empathy, education, and enlistment.2.2This course consists of a series of two, 2‐hour sessions designed to provide trainees with patient communication skills that are specific to patient interactions in radiation oncology. The sessions combine brief lectures with moderated, practice‐based group interactions.The essential components of a physicist–patient consult.How to introduce yourself to a patient.Review of a list of common questions from patients.Strategies for answering patient questions effectively.Re‐enactments of positive and negative physicist–patient interactions followed by group discussion.A one‐on‐one role‐playing exercise where each physicist plays the role of a patient during an encounter with a medical physicist.Topics covered are:2.3Widely used in medical education, Simulated Patient interactions have been shown to be effective in improving clinical communication skills.Simulated Patient characteristics and demeanors are withheld from trainees before the simulated physicist–patient consult. An important aspect of this exercise is for the trainees to practice assessing a patient's informational needs and comfort level with technical language while using patient‐appropriate language throughout the consult.Trainees perform consults with both Simulated Patients. Each consult is scheduled for 30 minutes. A trainer is present in the room during the consult to assess the trainee's clinical communication competencies using the form shown in Table 2.4Trainees conduct actual physicist–patient consults with a medical physicist mentor present in the room. The medical physicist mentor assesses the trainee's clinical communication competencies using the same clinical communication competency form. Trainees meet with the medical physicist mentor prior to, and immediately after, the consult to discuss the interaction.2.5Medical faculty in our department run a case‐based course that describes common treatment toxicities. Classes occur once per month over the course of a year and cover common toxicities for breast, genitourinary, gynecological, brain, pediatrics, lymphoma, head and neck, gastrointestinal, and lung cases. Toxicity presentation, progression, and likelihood of resolution are discussed. Medical physicist trainees take this course for the purpose of equipping them with the knowledge to better prepare for understanding likely medical questions from patients and to help them effectively communicate toxicity concerns to the attending radiation oncologist.Figure 3A series of clinical communication competencies, shown in Table Trainee did not attempt to display the specific competency.Trainee attempted to display the specific competency but missed some key elements.Trainee displayed mastery of the specific competency.Clinical communication competencies are assessed at two time points: (a) during the Simulated Patient interactions, and (b) during the Faculty‐Observed Patient Consults. A three‐point scoring system was developed for this assessment, defined as follows:Trainees are deemed competent to perform physicist–patient consults on their own when they score a three in all competency categories.4If direct patient care responsibilities for medical physicists are to see widespread adoption, appropriate training programs will need to be implemented in medical physics residency programs. This raises several important questions: (a) How will educators prepare for developing and running such a training program?, (b) How much clinical experience should a resident have prior to starting the training?, and (c) Is there sufficient time in a 24‐month residency to incorporate this type of training?To address the first question, we propose to offer a series of “train‐the‐trainer” workshops where residency directors would acquire the experience and materials required to implement a similar training program in their own residency programs. Ultimately this work could be taken over by relevant committees within the AAPM. In response to the second question, we believe that training should begin as early as possible. Given there is sufficient oversight and that the competency assessment described in this work is adhered to, there is little risk of putting residents in situations where they would have insufficient clinical experience to successfully interact with patients. With respect to whether there is sufficient time in a 24‐month residency program, we believe that this new role for medical physicists is of sufficient importance that time must be made to ensure adequate training of residents. Perhaps programs could reduce the amount of time spent doing monthly, or patient‐specific, QA to make time for this type of training.5The concept of training medical physicists to be patient‐facing professionals is new to the field of radiation oncology. The training program that we have developed incorporates an array of established education techniques and provides a comprehensive, accessible, means of improving medical physicists’ patient communication skills. It was created in conjunction with a phase II clinical trial, recently conducted at our institution, where board certified medical physicists established independent professional relationships with patients. The results of that phase II trial showed decreases in patient anxiety and increases in patient satisfaction.Additional trainees are currently going through the program in preparation for a prospective randomized phase III clinical trial. This cohort of trainees will complete the training program before the end of 2018. A formal evaluation of the program is ongoing and will be submitted for peer review after the current trainees have completed the program and are routinely participating in physicist–patient consults.The authors have no other relevant conflicts of interest to disclose.


ISAAC) measured the global prevalence of symptoms of asthma in children. We undertook comprehensive analyses addressing risk factors for asthma symptoms in combination, at both the individual and the school level, to explore the potential role of reverse causation due to selective avoidance or confounding by indication.Phase Three of the International Study of Asthma and Allergies in Childhood  individual level exposure data and (b) school level average exposure , in two different age groups. In individual level analyses, reverse causation is a possible concern if individual level exposure statuses were changed as a result of asthma symptoms or diagnosis. School level analyses may suffer from ecologic confounding, but reverse causation is less of a concern because individual changes in exposure status as a result of asthma symptoms would only have a small effect on overall school exposure levels.There were 131 924 children aged 6‐7 years  with complete exposure, outcome and confounder data. The strongest associations in individual level analyses (fully adjusted) were for current paracetamol use , early life antibiotic use  and open fire cooking . In school level analyses, these risk factors again showed increased risks.There were 238 586 adolescents aged 13‐14 years  with complete exposure, outcome and confounder data. The strongest associations in individual level analyses (fully adjusted) were for current paracetamol use , cooking on an open fire  and maternal tobacco use . In school level analyses, these risk factors again showed increased risks.These analyses strengthen the potentially causal interpretation of previously reported individual level findings, by providing evidence against reverse causation. We have done this in two ways. Firstly, we have conducted a “standard” analysis using the individual level exposure data for each risk factor . However, for some risk factors the cross‐sectional nature of the study means that such analyses may be subject to “reverse causation” if individual level exposure statuses were changed as a result of asthma symptoms or diagnosis. This may occur due to selective avoidance (eg if the child's mother stops smoking because the child has developed asthma) or “confounding by indication” (eg if exposures such as paracetamol or antibiotics are taken in response to symptoms which are related to the subsequent development of asthma).As schools were the level of sampling in ISAAC, we have therefore conducted a second set of analyses using the school level average reported exposure  to each risk factor to attempt to avoid or minimize such biases. School level analyses may suffer from ecologic (community‐level) confounding, but reverse causation is perhaps less of a concern because individual changes in exposure status as a result of asthma symptoms would only have a small effect on overall school exposure levels. It is therefore of considerable interest to compare the individual level and school level analyses.If reverse causation due to confounding by indication was exerting a major influence on the individual level associations, we would expect the associations to be much reduced at the school level. Conversely, if there was reverse causation due to selective avoidance, we would expect a stronger association at the school level, although this could also be due to contextual factors operating at the school level. Consistency of findings at the two levels thus provides indirect evidence against reverse causation and against strong contextual factors.Biases may differ in different parts of the world, for example breastfeeding is more strongly associated with socio‐economic status in high‐income countries than in low‐ and middle‐income countries,22.1http://isaac.auckland.ac.nz).ISAAC Phase Three methods have been described in detail elsewhere2.2We considered the outcome of wheeze in the last 12 months, defined by a positive response to the question “Has your child/have you had wheezing or whistling in the chest in the past 12 months?” In many countries in the world, we find that most asthma (based on symptoms) has not been diagnosed, which is why ISAAC is based on symptoms. The ISAAC symptoms questionnaire validates well against doctor‐diagnosed asthma.The environmental questionnaires in the two age groups did not contain identical questions, so it was not possible to examine the same set of potential risk factors in each age group. In addition, we restricted our analyses to the risk factors which had shown associations with wheeze in the last 12 months in previous analyses at the individual level. For the younger age group, we included paracetamol use in the first year of life and in the past 12 months,Most of the above risk factors were parameterised as binary variables from “yes/no” questions in the environmental questionnaire. The exceptions were as follows: paracetamol use in the past 12 months (at least once per month vs less than once per month), truck traffic (seldom or more frequently vs never), fast food consumption (once per week or more vs less than once per week), television viewing (at least 1 hour per day vs less than 1 hour per day) and birth weight (less than 2.5 kg vs at least 2.5 kg). Full definitions are in Sex was self‐reported as male/female, and the highest level of maternal education was recorded as primary, secondary, tertiary or missing/not stated.Gross National Income (GNI) as of 2002 was obtained from the World Bank website2.3To be included in the analysis for a particular age group, centres had to include at least 1000 individuals and to have a response rate of >60% for children and >70% for adolescents. Analyses were conducted separately in the two age groups. Within each age group, schools with fewer than 10 individuals were excluded from the analysis.All analyses were conducted using mixed effect (multilevel) logistic regression models. The four‐level hierarchical nature of the data  was acknowledged by allowing random intercepts at levels 2, 3 and 4 in individual level models and by including random intercepts at levels 3 and 4 in school level models. Centres were self‐selected, whereas schools were randomly sampled within centres, making school the preferred level of analysis. Sex and maternal education were adjusted for as individual level confounders in all models.Three different modelling approaches were used: (a) individual level, (b) school level and (c) hybrid fixed effects.Individual level models related the individual level outcome to each individual level risk factor within schools. School level models related the individual level outcome to the school level average exposure  of each risk factor. In these models, the estimated OR corresponding to the school level prevalence of the risk factor can be interpreted as the effect on the individual outcome of attending a school where all children are exposed compared to attending a school where no one is exposed.Within each approach, models were fitted for: (a) each exposure of interest using the sub‐sample who had data present for wheeze, sex, maternal education and the given exposure (the “maximum sample”), (b) each exposure of interest using the sub‐sample who had data present for wheeze, sex, maternal education and all exposures of interest (the “common sample”) and (c) each exposure of interest mutually adjusted using the sub‐sample who had data present for wheeze, sex, maternal education and all exposures of interest (the “common sample”).The extent of collinearity in the mutually adjusted models was examined by comparing the standard errors in the mutually adjusted model and the minimally adjusted model fitted to the same sub‐sample.Additionally, we ran the fully adjusted analyses separately for “affluent” and “non‐affluent” countries. We then separately tested for effect modification of each risk factor by country‐level affluence.Analyses were conducted using Stata version 14.33.1The 6‐7‐year‐old participants included 221 280 children from 75 centres which met the initial data quality criteria (at least 1000 children and a response rate of >60%). Of these, 212 480 children  were from schools with at least 10 children and had data present for wheeze, sex, maternal education and at least one of the exposures of interest so contributed to the analyses for one or more exposures (the “maximum sample”), with 131 924 children  having data present for all analysis variables (the “common sample”). See the data flowchart , early life antibiotic use  and open fire cooking  were maintained (Table P < 0.001) of effect modification at the individual level for early life exposure to cats , early life exposure to farm animals  and current paracetamol use  (Table S4).In the analyses stratified by country‐level affluence Tables , there wP = 0.04) of effect modification of current paracetamol use . However, there was little evidence of a difference between affluent and non‐affluent countries for the associations of wheeze with cat and farm animal exposure in the first year of life. Several risk factors showed greater effect modification in the school level analysis than in the individual level analysis: maternal tobacco , antibiotics in the first year of life  and paracetamol use in the first year of life .When using the school level prevalence Table , there w3.2The 13‐14‐year‐old participants included 362 048 adolescents from 122 centres which met the initial data quality criteria (at least 1000 adolescents and a response rate of >70%). Of these 350 915 adolescents  were from schools with at least 10 adolescents and had data present for wheeze, sex, maternal education and at least one of the exposures of interest so contributed to the analyses for one or more exposures (the “maximum sample”), with 238 586 adolescents  having data present for all analysis variables (the “common sample”). See the data flowchart  and maternal tobacco use  were maintained. Although the evidence for an association with cooking on an open fire was reduced, the point estimate was comparable to that in the individual level analysis  (Table P < 0.001) at the individual level that paracetamol use in the last 12 months was more strongly associated with wheeze in affluent countries  than non‐affluent   Table . There w2) Table .4A number of papers have been published describing the association of asthma symptoms with individual level risk factors in ISAAC Phase Three.The associations we present here at the individual level Table  generallSecondly, previous ISAAC Phase Three publications have adjusted for sex but not for socio‐economic status at the individual level, whereas we included individual level maternal education as a socio‐economic indicator in all models. Although maternal education is problematic to interpret as a socio‐economic indicator across diverse study centres from different countries and cultures, it is more likely to be valid for adjustment of socio‐economic confounding within local communities, such as school catchment areas, which is how it is used in our multilevel analyses.Thirdly, previous ISAAC publications have adjusted for selected confounders , whereas we took a more comprehensive and harmonized approach in constructing our fully adjusted model. Comparison between the minimally adjusted and fully adjusted results in Table A potential drawback of including multiple variables in a single model is a reduced sample size due to missing covariate data. About one‐third of the 6‐7‐year‐olds and about one‐quarter of the 13‐14‐year‐olds were excluded from the fully adjusted model due to incomplete risk factor information. However, comparison of results from the maximum sample with those from the common sample shows that findings were generally very similar for the subset of respondents with complete covariate data, suggesting that valid conclusions can be drawn from the “common sample” dataset.It should also be noted that, whilst early life exposures are less prone to reverse causality than current exposures, recall errors (which may be biased with respect to disease status) are perhaps more likely to have affected early childhood exposures in an interview conducted when the child was 6‐7 years old.An innovative feature of this paper is the presentation of associations of school level prevalence of risk factors with individual level wheeze. This type of population‐level analysis is potentially vulnerable to the “ecological fallacy,”The school level associations shown in Table The observed consistency of findings at the two levels provides indirect evidence against reverse causation and against strong contextual factors. Furthermore, since the spectrum of unmeasured confounders is likely to be different at the individual and population levels, consistency of results between the two levels provides additional reassurance against unmeasured confounding. Therefore, on both counts, cross‐level consistency strengthens the evidence for a causal relationship at the individual level.Such cross‐level comparisons Table  show a cISAAC Phase Three findings for paracetamol in the first year of life have also been debated.Another risk factor which might be prone to reverse causation  is cat exposure in infancy. Here, the school level association is somewhat stronger than the individual level association in the minimally adjusted models, as would be predicted from avoidance bias. However, after full adjustment the estimated associations are very similar.In the older age group, we found associations with paternal tobacco smoking which differed in direction between the individual‐ and school level analyses. This was a surprising finding which we have been unable to satisfactorily explain.Finally, stratified analyses identified some risk factors whose effects seemed to differ by country‐level affluence Tables . In the In conclusion, these multilevel analyses generally confirm previously reported child‐level findings for wheeze in ISAAC but, importantly, they provide additional evidence in favour of direct (rather than reverse) causation. This is the first comprehensive analysis of school level associations, which may be particularly relevant to public health policies, which aim to prevent asthma symptoms by modifying environment, lifestyle or medication use among whole communities, rather than individual children or their families.All authors declare no conflicts of interest. Click here for additional data file.


Objectives. To explore if sensory information is abnormally processed and integrated in focal hand dystonia (FHD) and if surround inhibition phenomena are operating during sensory-motor plasticity and somatosensory integration in normal humans and in patients with FHD. Methods. We looked at the MEP facilitation obtained after 5 Hz repetitive paired associative stimulation of median (PAS M), ulnar (PAS U), and median + ulnar nerve (PAS MU) stimulation in 8 normal subjects and 8 FHD. We evaluated the ratio MU/(M + U) ∗ 100 and the spatial and temporal somatosensory integration recording the somatosensory evoked potentials (SEPs) evoked by a dual nerve input.  Surround inhibition is a system that sharpens sensation by creating an inhibitory zone around the central core of activation. In the motor system, this mechanism probably contributes to the selection of voluntary movements, and it seems to be lost in dystonia. Conclusions. The inhibitory integration of somatosensory inputs and the somatosensory inhibition are normal in patients with focal dystonia as well as lateral surrounding inhibition phenomena during sensory-motor plasticity in FHD. FHD had two main abnormalities: first, the amount of facilitation was larger than normal subjects; second, the spatial specificity was lost. The MU/(M + U) ∗ 100 ratio was similar in healthy subjects and in FHD patients, and the somatosensory integration was normal in this subset of patients Dystonia is a motor disorder characterized by sustained involuntary muscular contractions resulting from cocontraction of antagonistic muscles and overflow into extraneous muscles . Focal hIn addition, it is well known that dystonia is characterized by a defective somatosensory processing within the somatosensory system  associatSeveral stimulation protocols can be used to test, noninvasively, plasticity within the somatosensory motor system. One of the most established protocols is the paired associative stimulation (PAS) where a magnetic stimulus is coupled with contralateral peripheral nerve stimulation . This prWe have characterized a new conditioning fast PAS protocol that requires only two minutes of induction called 5 Hz rPAS  which prThe aim of the present study was to evaluate the spatial integration of somatosensory inputs during sensory-motor plasticity phenomena, evaluated with 5 Hz rPAS, in healthy subjects and in patients with focal hand dystonia. To achieve this goal, we compared the amplitude of MEPs obtained after the 5 Hz rPAS protocol induced by stimulating the median and ulnar nerves simultaneously (MU) vs the MEP amplitude values being obtained from the arithmetic sum of the 5 Hz rPAS protocol elicited by stimulating the same nerves separately (M + U), looking at the amount of suppression induced by dual nerve simultaneously stimulation. Moreover, we evaluated the spatial and temporal somatosensory integration recording the somatosensory evoked potentials (SEPs) evoked by a dual nerve input to investigate the contribution of lateral inhibition in the somatosensory system. Indeed, previously, Tinazzi and coworkers proposed the MU/(M + U) ∗ 100 as a marker of lateral surround inhibition evoked by a dual input in the somatosensory system , but the amount of facilitation was different between the two groups, as revealed by the time × group interaction . This effect was produced by a larger increase in MEP amplitude in dystonic patients compared to controls. We found no time × group × conditioning interaction because all the three types of intervention induced an increase in MEP amplitude in both dystonic patients and controls   ∗ 100 after the 5 Hz rPAS between dystonic patients and controls in the APB muscle. In both groups, indeed, the percentage of inhibition was around 50%   can induce long-lasting plastic changes in cortical excitability of both dystonic patients and normal subjectsIn keeping with previous findings, focal hand dystonia patients had two main abnormalities. First, associative plasticity after PAS25 was enhanced compared to normal subjects; second, the spatial specificity was lost so that facilitation was observed in both median and ulnar innervated musclesThe inhibitory integration of somatosensory inputs as well as the somatosensory inhibition are normal in patients with focal dystoniaSurround inhibition phenomena are normal in focal dystonia when applying PAS-induced sensory-motor plasticity protocolFour main findings clearly emerge from this study:Our results confirm that 5 Hz rPAS at an interstimulus interval of 25 ms can promote lasting changes in cortical excitability. Considering that rPAS aftereffects are long lasting, reversible, and topographically specific , this prInhibitory integration of somatosensory inputs as well as the somatosensory inhibition phenomena evaluated in our population of dystonic patients did not show any abnormalities compared with the ones of normal subjects. These findings support the idea that the temporal and spatial integration along somatosensory pathways are normal at least in focal hand dystonia, and this could explain the normal integration of the simultaneous median-ulnar nerve stimulation after PAS. On the other hand, our data confirm again that in focal hand dystonia there is a clear abnormality in sensory-motor plasticity as indexed by the loss of spatial specificity after PAS that may account for the creation of abnormal motor engrams. PAS topographical specificity has a different mechanism since the afferent stimulation is not dual and is probably related to the alteration of inhibitory phenomena within motor cortex which are lost in dystonia. These results can be apparently in contrast with the previous findings of Tinazzi and coworkers and Frasson and coworkers , 9. IndeIn conclusion, the data of the present study suggest, in contrast with previous ones, that surround inhibition along somatosensory pathways are intact in FHD. In addition, we demonstrated that surround inhibition is also normal during the induction of sensory-motor plasticity phenomena. These results may suggest that, at least in FHD, spatial and temporal processing of sensory inputs are normal in patients with FHD despite the well-known alterations of spatial and temporal tactile discrimination, which are related to dysfunction in somatosensory cortex (S1) –29. In a


In this sensing system, the graphene woven mesh is embedded inside ionic polymer membrane to interact with mobile ions and to trace their movements. The migration of mobile ions inside the membrane induces an electrical signal on the mesh and provides the information regarding ion distribution, which is proven to be highly correlated with the bending deformation of the actuator. Using this integrated self‐sensing system, the responses of an ionic actuator to various input stimulations are precisely estimated for both direct current and alternating current inputs. Even though the generated displacement is extremely small around 300 µm at very low driving voltage of 0.1 V, high level accuracy (96%) of estimated deformations could be achieved using the self‐sensing actuator system.Here, inspired by mechanoreceptors in the human body, a self‐sensing ionic soft actuator is developed that precisely senses the bending motions during actuating utilizing a 3D graphene mesh electrode. The graphene mesh electrode has the permeability of mobile ions inside the ionic exchangeable polymer and shows low electrical resistance of 6.25 Ω Sq A graphene mesh electrode having high ion permeability and electrical conductivity is adopted as a self‐sensing ionic soft actuator inspired by mechanoreceptors in the human body. The graphene mesh electrode provides electrical signals sensitive to ion migration inside the polymer electrolyte without blocking their movements and is used to predict the bending deflection of the actuator. The main drawback of ionic soft actuators is their unpredictable responses and highly nonlinear behavior.In fundamental studies, the mechanical displacement of ionic actuators is usually measured through external sensors, such as laser sensors or strain gauges. However, parallel implementation of external sensors with an actuator is not possible in real applications because of cost and space limitations. Accordingly, some research groups are focusing on the fabrication of self‐sensing actuators, in which sensing and actuation are integrated within a single component for real‐time monitoring of the actuator movement. Most of the currently available mechanisms of self‐sensing actuators require the simultaneous measurement of the electrical resistance along the actuator electrode during actuation. When the actuator is stimulated, one of the electrodes will be stretched while the other is compressed. Since the electrical resistance varies with the effective length of the electrodes, one is able to measure the bending deformation in the form of curvature or tip displacement.However, inferring the resistance values by measuring the voltage drop along an electrically active component is an intricate task.In principle, various kinds of mechanoreceptors in the human body work by changing the ion equilibrium in receptor cells.A 3D graphene woven mesh is a perfect candidate for the design of an ion‐permeable sensing electrode due to its liquid permeability and high electrical conductivity. An established way to monolithically assemble graphene woven mesh at a large scale is to grow graphene by chemical vapor deposition (CVD) method on metallic meshes.In this study, we propose a self‐sensing ionic soft actuator utilizing 3D graphene woven mesh as a signal collector. This graphene mesh electrode is composed of a monolithic network of hollow graphene tubes assembled in a mesh‐type architecture. The high electrical conductivity of graphene, along with its chemical stability, facilitates a neat and stable data acquisition during the deformation of the actuator. In addition, the wavy pattern of graphene tubes in the mesh‐type structures renders this electrode flexible and stretchable, which are crucial requirements for implementation in ionic soft actuators. The proposed graphene mesh is a plane weaved mesh that contains multiple arrays of large holes. While collecting data, the graphene mesh electrode does not impede ion motion, such that ions can freely migrate under the imposed electric field. Not only is this measurement technique beneficial in estimating the mechanical deformation of soft ionic actuators, but it could also be employed for measuring the ionic conductivity of polymer membranes and for real‐time monitoring of ion migration within ionically conductive polymers.22.1Scheme+) into the neuron cell. The presence of extra Na+ ions alternates the potential of the neuron cell and provides the action potential for firing the neuron (Scheme The sensing mechanism of the proposed self‐sensing actuator is inspired by the reception function of human mechanoreceptors. As shown in n Scheme a.m hydrochloric acid (HCl) solution. Through layer‐by‐layer casting, the as‐prepared graphene mesh was later embedded inside a Nafion/1‐Ethyl‐3‐methylimidazolium tetrafluoroborate (EMIM‐Bf4) membrane. Using drop casting, the graphene‐embedded membrane was then sandwiched between two poly polystyrene sulfonate (PEDOT:PSS) layers as actuator electrodes. More details about material synthesis and fabrication steps can be found in the Experimental Section and Supporting Information. In the aforementioned layout, the embedded graphene mesh acts as a sensing electrode that apprehends ion movements within the polymer electrolyte membrane, without hindering the ions' migration. Indeed, large holes (≈160 µm) in the graphene mesh provide a path for ion migration, such that ions can freely move in response to the applied electric field  woven mesh was selected as a template for growing the graphene layer. The CVD method is based on catalytic growth of graphene; among a variety of transition metals, Ni has been shown to be a promising substrate for growing multilayer graphene because it allows for growth of large‐scale crack‐free graphene.FigureThe as‐prepared graphene mesh was first characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). SEM images in GI/I2D) in Raman spectra. Based on the literature, the intensity of the G and 2D peaks of graphene can be used for determining the number of layers.−1) to that of the 2D peak (at around 2750 cm−1) increases. As illustrated in Figure GI/I2D ratio does not notably vary through the surface, signifying that the thickness of graphene remains similar on the whole surface. These mapping data indicate uniform graphene growth through CVD, which results in enhanced electro‐mechanical properties of the sample. Figure −1) at all four points. Since a D peak in Raman spectra is an indication of defects in graphene sheets, the absence of this peak at all points reaffirms the growth of high quality graphene.To further examine the uniformity of the synthesized graphene, Raman spectra were captured from a 10 µm × 10 µm area of the sample. Figure Figurem HCl solution (a highly oxidative medium). As explained earlier, the sample was then subjected to 1000 CV cycles in EMIM‐Bf4/Acetonitrile solution (0.5 m) to inspect the chemical stability of the graphene mesh in the electrochemical reactions that might be involved in the actuation process. The elemental mapping of this sample did not show a meaningful change in the oxygen content when compared with the sample before CV  on three samples: graphene coated Ni mesh right after CVD, pristine graphene mesh after etching with Ni, and graphene mesh after being subjected to 1000 cycles of cyclic voltammetry (CV). The results of these analyses are presented in V Figure c. This cFigure−1 even at 180° bending deformation. This resistance value is prominent when compared to other previously reported graphene electrodes, pointing at a high electrical conductivity of the proposed electrode.Thereafter, employing layer by layer casting of the Nafion/EMIM‐Bf4 5:3 wt) solution and drying, the graphene mesh electrodes were embedded inside electrolyte membrane. To study the effect of the graphene mesh on the mechanical properties of the electrolyte membrane, a tensile test was conducted. As illustrated in Figure  wt solutFollowing the characterization of the proposed composite membrane, the actuator was fabricated by drop‐casting of PEDOT:PSS electrodes on both sides of the membrane. Details about actuator fabrication steps and wiring of the electrodes are provided in the Experimental Section, as well as Supporting Information. The SEM image taken from the cross‐sectional view of the actuator is displayed in Figure 2.2FigureAfter preparation, the actuator was tested for sensing‐actuation performance by applying an input electric potential across its electrodes. While performing the actuation test, we measured the absolute potential at the embedded graphene mesh electrode and the tip displacement of the actuator by a laser sensor to provide a reference value. To better illustrate the sensing mechanism, a schematic diagram of the proposed self‐sensing actuator is provided in Vin), one of the actuator electrodes experiences an absolute potential of zero (anode), while the other electrode experiences an absolute potential of Vin (cathode). This potential difference generates an electric field through the membrane, which induces an absolute potential on the graphene mesh electrode, located between the actuator electrodes. Such an induced potential is a fraction of the input voltage, and it depends on the location of the mesh with respect the anode. At the same time, the electric field inside the electrolyte membrane causes the differential migration of the cations and anions, which, in turn, generates a uneven charge distribution along the thickness of the membrane that manifests into a varying electrical potential on the graphene mesh electrode . As sketched in Figure By applying a constant input potential  and ions‐induced potential (Vion). These signals are also shown in Figure Consequently, the sensing signal can be decomposed into its contributions: the electrodes‐induced potential :A closer look at Figure By substituting Equation SM is the estimated tip displacement of the self‐sensing actuator. Beyond supporting evidence by the circuit model, the proposed explanation can be grounded in the distributed model of Nemat‐Nasser and Li,By multiplying the ions‐induced signal by another constant, one can estimate the actuator displacement.C1 and C2 can be estimated from one set of signals acquired from a specific input stimulus and then utilized to explore other inputs. Figure Employing linear regression, the coefficients SM) and only use it for DC inputs. To adjust the model for dynamic inputs, a phase shifting term could be added, by considering a differential form of the static model (see Supporting Information)DM and δSM are the tip displacements of the actuator estimated through the dynamic and static Models, respectively. In this equation, ω is the frequency of the harmonic input potential, while φ is the phase delay of the static model. As in the static model, the coefficients C1 and C2 along with the phase shift φ in the dynamic model can be estimated from regression for a specific input potential and then used for other inputs.While the proposed model works adequately for DC inputs, it shows sluggish performance for dynamic inputs such as AC voltage. As shown in Figure FigureAs shown in C2 and phase shift φ needed to be modified for each case, implying the frequency‐dependency of these parameters. As illustrated in Figure C2 and φ are described by logarithmic functions with respect to the frequency of the input stimulation. This could be expected due to interplay of damping and inertia effects in the actuator, which is modulated by the excitation frequency.The other influential parameter affecting the estimation model is the frequency of the input voltage. Figure In addition to sine wave inputs, the as‐prepared self‐sensing actuator was also tested for square wave and triangle wave inputs Figure e,f. SimiIn order to inspect the life‐time stability of the proposed self‐sensing actuator, the samples were again tested after 2 months to check if their performance is degraded or not. However, as presented in Figure S17, Supporting Information, no meaningful change was observed neither in output displacement of the actuator nor in sensing signal. After 2 months, the sensing signal was still very neat and clean without any noise or disturbance.3Inspired by mechanoreceptors in the human body, we developed an innovative self‐sensing ionic soft actuator using graphene woven mesh electrode. The proposed 3D graphene electrode showed outstanding multi‐functional attributes, such as flexibility, high electrical conductivity, and ion permeability. Embedding a high‐quality graphene mesh inside the electrolyte membrane could afford a novel self‐sensing ionic actuator that could precisely measure the displacement during actuation. In the suggested bio‐inspired sensing mechanism, the sensing signals were generated by mobile ions inside an electrolyte membrane, similar to various types of mechanoreceptors in the human body. The signals, collected by graphene mesh, contained the information regarding the distribution of ions within the membrane and was properly correlated with the bending deflection to estimate the tip displacement of the actuator. Using the sensing data, semi‐empirical models were proposed to estimate the tip displacement for both static and dynamic electrical stimulations. These static and dynamic models properly predicted the tip displacement of the actuator at a variety of input potentials.The obtained results offer compelling evidence in favor of this newly designed self‐sensing actuator. Not only can the proposed graphene mesh electrode and sensing mechanism be used for new types of self‐sensing actuators, but also for many other applications, such as measuring ionic conductivity of polymer membranes or monitoring ion movement inside solid‐liquid electrolytes in real‐time. Further investigation of this approach could pave the way for rigorous electrochemical studies of electrolytic membranes that could improve our understanding of ions' interactions.4Graphene Mesh Synthesis: A plane woven Ni mesh with a pore size of 155 µm was selected as a template for graphene growth. Ni mesh substrates were cut into 1 cm × 4 cm samples and washed with ethanol. The substrates were lunched in a long quartz tube (1.5 m) and heated to 1000 °C in ambient pressure and Ar atmosphere (1000 s.c.c.m.). After reaching the reaction temperature, the samples were kept in this condition to remove the oxides and other impurities from the surface. In order to initiate the growth, reaction gases  were flowed into the tube while decreasing Ar flow rate to 400 s.c.c.m. After 10 min, the H2 and CH4 flows were stopped and the furnace was removed from the samples to swiftly cool them to room temperature. The Ni substrate was etched from graphene coated samples using 3 m HCl solution while keeping samples in the oven (80 °C) for 24 h. Afterward, floating graphene samples were washed with DI water three times to remove the acid and then dried by freeze‐drying technique at −50 °C and 14 Pa pressure.Fabrication of Self‐Sensing Actuator: First, Cu foil was attached to one end of graphene mesh using silver paste. Then, the electrolyte solution was prepared by dissolving 3 g Nafion and 1.8 g EMIM‐Bf4 in 30 mL Dimethylacetamide (DMAc). To achieve a well‐dissolved solution, the mixture was stirred in an oil bath (80 °C) for 24 h. Then, 2 mL of the electrolyte solution was casted in a circular glass Petri dish (diameter: 55 mm) and dried in the oven to remove the DMAc. Afterward, the as‐prepared graphene electrode was placed on the dried membrane and 0.5 mL of the electrolyte solution was drop‐casted on the graphene mesh and dried to fix the mesh in that position. Another 4 mL of electrolyte solution was casted on the dried membrane to fully embed the graphene mesh electrode inside the membrane. After obtaining the membrane with embedded graphene mesh, it was sandwiched between actuator electrodes by drop‐casting DMSO/PEDOT:PSS (5 vol%) on both sides of the membrane. Finally, the actuators were cut into favorable sizes and the sensing‐actuating measurements proceeded.Material Characterization: Micro‐scale surface morphology of the graphene mesh and cross‐sectional view of the actuator were obtained using a Field Emission Scanning Electron Microscope (Magellan400) made by the FEI Company. This microscope was equipped with an Energy‐dispersive X‐ray spectroscopy system that was used for elemental mapping of the samples. Nano‐scale surface morphology and cross‐sectional views of graphene sheets were obtained using a Field‐emission transmission electron microscope (300 kV Tecnai G2 F30 S‐Twin) made by the FEI Company. High‐resolution images of the graphene mesh embedded in the electrolyte membrane were captured using an optical microscope (ECLIPSE LV100D‐U) made by the Nikon Company. Raman spectra analysis was carried out using a High‐Resolution Raman Device (LabRAM HR Evolution Visible‐NIR) made by HORIBA. Mechanical properties of electrolyte membrane were determined using a Universal/Tensile Test Machine (AGS‐X) made by SHIMADZU Corporation. Two‐probe resistance measurement of the graphene mesh was executed on a Keithley Multimeter (DMM7510).Actuation Measurements: To perform the sensing‐actuating measurements, the as‐prepared actuator was clamped at one end using two electrodes that were connected to the power supply in order to transfer the driving input voltages to the actuator electrodes. The sensing signal was collected from the graphene mesh electrode at the same end. The tip displacement of the actuator was recorded at the free end using a High‐Accuracy Laser Displacement Sensor (LK‐H080) produced by KEYENCE Corporation. All signals were simultaneously acquired using a Data Acquisition System  made by National Instruments.The authors declare no conflict of interest.SupplementaryClick here for additional data file.