Take home naloxone (THN) programs reduce mortality by training bystanders to respond to opioid overdoses. Clinical observation by the health care team at the Inner City Youth (ICY) program indicated that young adults appeared to enthusiastically participate in the THN program and developed improved relationships with staff after THN training. However, we found a dearth of literature exploring the experiences of young adults with THN programs. This study set out to address this gap and identify suggestions from the young adults for program improvement. The primary research question was “How do street-involved young people experience the THN Program in Vancouver, BC?”The study was undertaken at the ICY Program. Two peer researchers with lived experience of THN were recruited from ICY and were involved in all phases of the study. The peer researchers and a graduate student facilitated two focus groups and five individual interviews with ICY program participants using a semi-structured interview guide. Audio recordings were transcribed verbatim. The cut-up-and-put-in-folders approach was used to identify emerging themes.The themes that emerged were perceptions of risk, altruism, strengthening relationship with staff, access to training, empowerment, and confidence in ability to respond, and suggestions for youth-friendly training. These themes were then situated within the framework of the health belief model to provide additional context. Participants viewed themselves as vulnerable to overdose and spoke of the importance of expanding access to THN training. Following training, participants reported an increase in internal locus of control, an improved sense of safety among the community of people who use drugs, improved self-esteem, and strengthened relationships with ICY staff. Overall, participants found THN training engaging, which appeared to enhance participation in other ICY programming.Young people perceived THN training as a positive experience that improved relationships with staff. Participant recommendations for quality improvement were implemented within the provincial program.The online version of this article (doi:10.1186/s12954-017-0160-3) contains supplementary material, which is available to authorized users. Diagnostic and Statistical Manual of Mental Disorders (5th ed.) For many, opioids are their drug of choice. Young people in the ICM stream are eligible for a range of services, including psychiatric care, primary care, psychosocial rehabilitation, and supportive housing.Providence Health Care’s Inner City Youth (ICY) Program is a mental health and addiction team which support young people aged 16 to 24 years at the time of intake who are homeless or precariously housed in Vancouver, British Columbia (BC). To qualify for the Intensive Case Management (ICM) stream, young people present with moderate to severe mental illness and/or substance use disorders  depressants. Heroin, fentanyl, methadone, and hydromorphone are among the more commonly used opioids among ICY clients. In part due to opioid’s action as a CNS depressant, (which slows and even stops breathing) there is a relatively high prevalence of witnessing or experiencing overdose among people who use intravenous, non-prescription opioids , 2. SpecTake home naloxone (THN) programs involve providing naloxone and teaching people how to prevent, recognize, and respond to an opioid overdose, including seeking professional help, rescue breathing, and how to correctly administer naloxone . Most ovICY staff noticed that young adults appeared eager to participate in the THN program, and staff-client relationships seemed to be enriched after participating in the THN training. To date, studies on THN programs have predominantly focused on people with longer-term opioid use, and there is a lack of literature on the impact of THN training on young adults. This study set out to address this knowledge gap by investigating the experience of THN training among young adults at ICY who had a history opioid use. The authors also explored how participating in the THN program affected engagement in other aspects of mental health and addictions programming and collected suggestions on how to improve the THN program.The BC Centre of Disease Control (BCCDC) implemented the BC THN program in August 2012. The BCCDC develops the training materials and provides registered sites with free THN kits and training supplies for people who are personally at risk of overdose. Sites complete training and kit distribution records, and assist clients in filling out naloxone administration forms after a person has responded to an overdose event. The sites send all records to the BCCDC to collate. The program was found to be “easy to implement and empowering for clients” . The ICYA public health emergency was declared in British Columbia (BC) on April 14, 2016 by the Provincial Health Officer, due to a substantial increase in opioid overdose-related injury and death across the province . Recent THN programs effectively train people to respond to an overdose by using naloxone. Young adult participants articulated the need for easy access to THN, and this finding has been consistent across current press coverage on this topic . This stPrinciples of community-based participatory research (CBPR) informed the study design. CBPR supports the inclusion of the community members who are from the group that is being researched. Two peer researchers, with lived experience of THN, were recruited from young adults attending ICY. The peer researchers received training on research methods alongside the co-investigators. The “ladder of participation” is a model that measures peer involvement in CBPR from non-participatory and tokenized levels on the lower rungs, to active and equal involvement with researchers on the higher rungs. The research team strove to work as equal partners with youth researchers to ensure that peer involvement was on the higher rungs of the ladder. Therefore, shared decision-making was employed in all areas of the study, including design, interviewing subjects, data interpretation, and information dissemination. Peer participation in research increases relevance, and assists in more culturally appropriate data collection, analysis, and dissemination . We usedAt the time of the study development in December 2014, 103 individuals were enrolled in the Intensive Case Management stream of ICY; 34 (33%) of these were identified by their case manager as using opioids and 27 (79%) of these met DSM-5 criteria for moderate to severe opioid use disorder . DiagnosRecruitment occurred through posters, word of mouth, and announcements in ICY group sessions. Purposive sampling methods ensured participants were from the Intensive Case Management stream and met eligibility criteria of age 19–25 years, self-identified as having used opioids, had received THN training by an ICY team member, and included youth who identified as male and female. ICY follows youth who are 24 years old at the time of intake; however, young people may still be enrolled in the program at age 25 while planning transition to an adult service. Youth under 19 years were excluded from this study due to ethical concerns. Members of the research team who work as clinicians at ICY were not directly involved in participant recruitment or data collection. It was explicit that participation was voluntary and would not affect a participant’s access to clinical services. Interested young adults contacted a non-clinical team member to enroll and were provided with written informed consent prior to their participation. Participants completed a brief demographic questionnaire regarding age, gender, and recent substances used.Data were collected through focus groups and individual interviews conducted by peer researchers and a Masters of Public Health (MPH) student in July and August 2015. Interviews and focus groups took place in ICY offices and at the Granville Youth Health Centre, where participation was confidential and participants were familiar with the surroundings. Peer and staff researchers developed a semi-structured interview questionnaire. Participants were advised that mental health support was available if needed during or after the interview or focus group. Participants received a small honorarium of $20 CDN to compensate for their time and for sharing their experience and snacks were provided. , cocaine (n = 2), alcohol (n = 1), and benzodiazepines (n = 1).In total, 11 young adults participated in 2 small focus groups of 2 and 4 participants, and 5 individual interviews. Focus groups were small because not all enrolled participants arrived for the scheduled sessions. Young people who missed the focus groups were offered the option of an individual interview. Seven participants identified as male, four as female, and none identified as transgender; nine participants reported using opioids in the preceding week. Opioids reported used included heroin, hydromorphone, morphine, and methadone. Eight participants also identified using methamphetamine in the preceding week. Other substances participants reported having used in the previous week included cannabis  and self-efficacy (confidence in one’s ability to take action) . EmpowerPerceived threat:Perceptions of risk“-- it really kind of wakes you up and makes you realize that it’s real life and you’re kind of playing with fire sometimes.” Participant 3“Yeah, it’s just -- you can never really prepare yourself. It’s, I mean, you think going into it that you’re invincible and that you’re going to be able to notice when you’re going to start slipping into an overdose and that things are going to be okay for you, but you’re the same as everyone else. You can fall victim to the same casualty.” Participant 8Young adult’s understanding of overdose risk developed over time, and was influenced by close encounters with overdose. Participants said that personally experiencing or witnessing an overdose made them acutely aware of their vulnerability, which was a source of concern as they recognized themselves at personal risk of overdose.Perceived benefits:AltruismParticipant 2“You can save a person’s life by using this stuff because I had first-hand experience and I know that the stuff works.” “Because a family member close to me died from an overdose. And I kind of think of it as, like, in honor of her, you know.” Participant 9Throughout the interviews and focus groups, participants spoke a sense of altruism towards their peers, family, and community as reasons to carry naloxone and receive training in overdose response. Participants identified the ability to save other lives as a powerful motivator to participate in the training. They felt they had a responsibility to take care of other people who use substances, and they perceived this responsibility in a positive way.“I felt like I could actually do something to stop their overdose.” Participant 5THN training appeared to increase the sense of safety for the participants. They felt more aware of what to do in the event of an overdose, and they believed that naloxone would be effective.Relationships with staff“I think it, like, really [inaudible] reinforced and, like, people [ICY staff] are genuinely caring about us. And-you guys are a bunch of junkies, you don’t fucking need to, like-were actually, like, really gave a shit and were, like, considerate and polite.” Participant 6“I like that they’re [ICY staff] aware that not all drug users are, like, scum or anything. They treat us well. And they’re preparing us for like possible death and I like that it’s, like, harm reduction in general.” Participant 7“Well, we’re not looked down upon just because we use. And, like, stigma is not changing the relationship between a user and a non-user.” Participant 9Participants linked the training in overdose prevention to being genuinely cared for, valued, and respected by staff. They reported feeling that they were treated with compassion and not judged, which contrasted with their expectations to experience negative reactions linked to their drug use.“They [ICY staff]-- like, I guess they knew I was at a point where I was doing some pretty dangerous things. So they wanted -- didn’t want to see anything bad happen to me, so they really pushed for me to do the Naloxone training.” Participant 4“Like, it almost feels like a weight has been lifted or kind of like - I don’t know how to describe it, but when a layer has been, like, taken or, like, there’s an invisible wall that was broken. And we can now talk about something a bit more casually, even though it’s serious.” Participant 9Participants spoke about recognizing that ICY staff wanted to speak with them candidly about their substance use and harm reduction. Young adults expressed that the THN program provided them with a valuable skill, and improved their relationships with ICY staff. After THN training, they felt they could speak openly about issues that they previously were not comfortable discussing. Young people recognized that ICY staff were genuinely concerned and wanted them to be safe, which improved trust and helped them feel less self-conscious discussing substance use.Empowerment and improved self-esteem were reported by participants as perceived benefits of the program, but were also identified as improving confidence in one’s ability to take action and are therefore addressed in “self-efficacy” section.Perceived barriers and cues to action:Access and awareness of training“They should actually have, like, a fire extinguisher, a case, in every hotel [SRO] that people use drugs with Naloxone.” Participant 8“…the training should be a part of ICY. It should be mandatory for people who live in a hotel. You have a choice not to do it, but I totally recommend taking the training because I was totally oblivious to Narcan. I didn’t know what it was. I thought it was just a stimulant.” Participant 2Participants repeatedly spoke about the need to have increased access to naloxone and THN training. They suggested that ICY offers training universally to all clients, and that THN kits be available in public places. An example of this is the suggestion to keep naloxone in ‘hotels.’ (In this context ‘hotel’ refers to single room occupancies (SRO), which are low income housing units with shared bathrooms and cooking areas. SRO hotels are often low-barrier and first-stage housing for people who have been homeless.)Self-efficacy:Empowerment and improved self-esteem“Well, because you, like, before when you don’t have naloxone training, you don’t have a naloxone kit, when an overdose comes around and what can you really -- you can, like [inaudible] said, you can give a person CRP (sic) and pray and hope for the best. Whereas with naloxone you’re kind of given the power to try to do something about it.” Participant 8Participants were aware of the risk, but felt powerless to respond to overdose prior to the training. THN training increased their sense of agency.“So the ambulance came and they basically took over. They said ‘Great job. You could have saved his life, you did awesome. We’re going to take it from here.” Participant 3“It was very satisfying. Very, like, accomplishing. I was glad I had helped someone.” Participant 1Participants who had used naloxone previously talked about a sense of accomplishment and increased self-esteem. They felt empowered to be skilled in this intervention, and they recognized that this skill was valued and respected by peers, workers, family members, and other people in the community.Confidence in ability to respond“Yeah, well, I guess right after I first got it, I’ve never actually done it before so—you know, watching it on a video and getting a little piece of paper saying I can do it and having the little kit on me and actually being able to do it or two different things. Yeah, the first time I did it I was a bit scared. But, yeah, there was someone there try—you know, calming me down and, you know, making sure I was, like, okay. And I was on the phone with the paramedics or whatever.” Participant 1Mixed feelings were expressed by young adult participants about their comfort and confidence in their capability to respond to overdose following training. While some young people expressed confidence in their ability to respond to overdose, others stated that they felt somewhat underprepared. Interestingly, one of the participants who described feeling underprepared also reported having successfully reversed an overdose following the training.“They could have, like, you know, brought in a dummy or something and shown … what positions to put the person’s body or what to do to help them breathe or whatever.” Participant 1“It might be good to do a refresher every now and then.” Participant 3“The video was a bit dated.” Participant 8Participants provided concrete suggestions for ways to improve the training and make it more youth-friendly, such as updating the training video, using training dummies, and making refresher training available. Young adults felt these changes would make the THN training more practical and would increase their confidence in their ability to resuscitate someone from an overdose.Table Working within a framework of harm reduction, our primary research question was prompted by clinical observations that young adults appeared to positively engage with THN training. The community-based participatory research (CBPR) design intended to promote maximal involvement of service users, a pillar of harm reduction , in all Themes that emerged from the ICY study included perception of risk, motivation to take the training, empowerment, strengthening relationships with staff, access and importance of THN, and youth-friendly improvements. THN training increased a sense of safety at a time when the risk of overdose was high. Receiving THN training also fosters a sense of agency and increased self-esteem, with a newly acquired skill recognized by peers. This also seems to have influenced the client-clinician relationship, as young adults not only felt recognized by their clinicians but also were more willing to engage. Given the challenges of working with a young street-involved population, THN can serve as an important engagement tool.Study participants had several recommendations, in both policy and practice, for quality improvement. One specific benefit of using a CBPR design is the ease and speed with which participant recommendations can effect change and be quickly put into practice . SpecifiAnother important aspect of CBPR is the sharing of research findings in an accessible manner back to the community. A graphic booklet using direct quotes from this study illustrated by ICY participants was created and disseminated amongst youth, young adults, families, and service providers. Postcards using the same illustrations and quotes from the booklet and including information on how to recognize and respond to an overdose on the reverse side have also been developed and distributed .Limitations of this study include a small sample size and exclusion of youth under the age of 19. However, participants included males and females and reported varied duration of opioid use and a variety of other substances used. The dual roles of some research team members as researchers and staff clinicians in this study presented an ethical challenge of recruiting eligible young people while protecting their identity from researchers involved in their clinical care.Trustworthiness of the findings is enhanced by including experiential peers in the research and analysis processes. The peer researchers confirmed interpretation of the themes and helped to create relevant and acceptable knowledge disseminations tools. This study suggests that mental health and addiction programs that provide overdose response training empower street-involved young adults to care for their health and their communities. Programs that communicate respect and capacity help young people understand that they are valued, even if they continue to engage in risky behaviors. This approach to engagement could improve other health and harm reduction programs for this population.Previous findings of THN programs have shown that it is an effective harm reduction intervention. The findings from this qualitative study support additional benefits of THN programs in a street-involved young adult population as findings suggest improved safety, altruism, and empowerment, and improved self-esteem because of training. Other benefits include increased young adult engagement with health care staff that provide THN, and with other aspects of health care programming. The CBPR process also generated participant recommendations, which have been incorporated into the provincial and local THN initiatives.Additional file 1:Focus Group Questionnaire. (DOC 34 kb)Additional file 2:Individual Interview Questionnaire. (DOC 28 kb)


Although use of modern contraception is considered beneficial in lowering maternal and child mortality rates, the prevalence of contraceptive use remains low in the Democratic Republic of Congo. This study examined modern contraceptive use and its linkage to women’s autonomy.N = 6680). Logistic regression models were fitted to explore the relationship between women’s autonomy and modern contraceptive use.Data were drawn from the 2013–2014 Democratic Republic of Congo Demographic and Health Survey. We selected unsterilized and non-pregnant married women who have given birth in the last three years .The findings from this study indicate that it is not enough to provide women with educational and employment opportunities to increase the uptake of modern contraception, but also to enhance women’s assertiveness to make their own decisions regardless of their partners’ preferences within household settings. It is critical for government and other stakeholders to roll out programs aimed at reducing gender inequality and improving women’s autonomy in decision-making about reproductive health. As unintended pregnancy and short inter-pregnancy spacing are leading causes of maternal and child death in sub-Saharan Africa, use of modern contraception after delivery is considered a critical part of interventional efforts , 2. In tIn addition to these factors, women’s household decision-making autonomy  is also considered important in improving women’s assertiveness to negotiate reproductive and sexual health choices with their partners . AutonomAlthough these studies are important, the linkage between women’s autonomy and use of modern contraception is underexplored in the DRC. The country has been devastated by years of civil war and has one of the worse maternal and child mortality rates in the world . The intData for this study were drawn from the 2013–14 Democratic Republic of Congo Demographic and Health Survey (CDHS). The CDHS is a nationally representative dataset of women aged 15 to 49, implemented by Ministry of Monitoring, Planning and Implementation of the Modern Revolution, in collaboration with the Ministry of Public Health. The CDHS utilized a multi-staged sampling framework in which systematic sampling with probability to size was applied to identify Enumeration Areas from which households were chosen. A total of 19,097 women were initially identified at the time of fieldwork, and 18,827 women were successfully interviewed, with a response rate of 99%  recommenWomen were asked whether they were using any modern contraceptive method at the time of data collection, and we adopted this question as the dependent variable 0 = no; 1 = yes). The dependent variable was informed by the WHO reproductive health indicators guideline , suggest = yes. TThe independent variable for this study was “women’s autonomy,” which is a summative scale created with Principal Component Analysis (PCA). Specifically, PCA was used to construct a single latent scale with four questions that asked women about who usually has the final say in household settings on the following decisions: 1) obtaining their own health care, 2) making large purchases for daily needs, 3) visits to family and relatives, and 4) household expenditures . Cronbach’s alpha for this scale was statistically robust (α = 0.75). All indicators were loaded on a single latent scale construct with factor loadings ranged from 0.70 to 0.79. Higher values on this scale indicate that women have higher autonomy, while lower values indicate lower autonomy. This approach has been employed in previous studies see –26)..26]).In this study, two blocks of control variables were introduced, namely socioeconomic and demographic variables. Specifically, socioeconomic variables include level of education , household wealth quintiles , and employment status . Household wealth quintiles were constructed from a composite index based on the household ownership of consumer items, such as drinking water, car, and toilet facilities, among others. Moreover, we controlled for four demographic variables such as age of respondents (measured in completed years), province of residence , urban-rural residence , religious affiliations , and number of children .p is the probability that postpartum married women were using modern contraception, α is the constant, k is the total number of independent and control variables, β1, β2, …, βk are regression coefficients, and x1, x2, …, xkare independent and control variables [In addition to descriptive analysis of selected dependent and independent variables, logistic regression models were sequentially built. Specifically, we examined the bivariate association between women’s autonomy and use of modern contraception in Model 1, while Models 2 and 3 controlled for socioeconomic and demographic factors, respectively. This may be expressed as the following:ariables . MoreoveFindings from univariate analysis are shown in Table We explored percentage distributions of four questions related to women’s decision-making autonomy in Table Table In addition to women’s autonomy, there were other theoretically relevant variables significantly associated with use of modern contraception. For example, women with secondary  and higher education  were more likely to use modern contraception than those with no education. Similarly, women from the richest , richer , and poorer households  were more likely to use modern contraception than those from the poorest households. Also, compared to those in Kinshasa, women in Equateur , Kasai-Oriental , and Katanga  were less likely to use modern contraception. Women in rural areas were also less likely to use modern contraception than their urban counterparts .Within the unique context of prolonged conflict and strong patriarchy where husbands have persistent desire and preference for larger family size , we founIn addition to women’s autonomy, it is important to discuss other factors that were significantly associated with use of modern contraception. For example, attainment of higher levels of education was related to use of modern contraception. This lends support to Shapiro and Tambashe , suggestRelated to demographic factors, we found that province of residence strongly influenced women’s use of modern contraception. Despite the fact that the DRC has been ravaged by war and there still persists pockets of instability, the western provinces are the least affected and have a relatively better socioeconomic infrastructure and higher access to basic healthcare than the rest of the country , 29. In Similarly, women in rural areas were less likely to use modern contraception than their urban counterparts, reflecting wide rural-urban disparities in access to health care and level of awareness on modern contraceptive use. Additionally, patriarchy and other cultural values such as the strong desire for high fecundity dominant in rural settings may serve as barriers to the use of modern contraception . This isAlthough these findings may be useful for policymakers, there are noteworthy limitations. First, due to the cross-sectional nature of the CDHS, our interpretations of results are limited to statistical associations. Moreover, due to the sensitive nature of contraceptive use, the reliability of self-reported surveys such as the CDHS may be questionable with a possible underreporting issue. For future research, use of qualitative and longitudinal data may better explain the relationship between women’s autonomy and use of modern contraceptive methods. Despite these limitations, this study is one of few attempts to explore the effect of women’s autonomy on use of modern contraception in three years of post-delivery in the DRC.Understanding women’s autonomy as an important predictor of post-delivery modern contraceptive use is critical for informed policy on improved maternal and child health in the DRC. As suggested by our study findings, educational and employment opportunities alone may not be enough to increase the uptake of modern contraception. It is also important to enhance women’s assertiveness to make their own decisions regardless of their partners’ preferences within household settings. Therefore, it is critical for government and other stakeholders to roll out programs aimed at reducing gender inequality and improving women’s assertiveness in decision-making within households. In addition, it is suggested that interventional programs need to focus on providing universal access and awareness to modern contraceptive services, especially among women with low level of education, and those from poorer households in rural and conflict-affected areas in the DRC .


N = 2430), taste (39.4%), price (39.2%) and amount of nicotine (27.3%) were the most commonly cited reasons for choosing their brand of e-cigarettes. Those aged 15–24 were more likely to cite external packaging [adjusted prevalence ratio ] and design features  as important. As further legislation is debated and enacted enhanced regulation of price, design and marketing features of e-cigarettes may help to reduce the appeal of e-cigarettes.Data were analysed from the 2014 Special Eurobarometer for Tobacco survey. We estimated self-rated importance of various factors in the choice of both tobacco and electronic cigarettes (e-cigarettes) among tobacco smokers who had ever used an e-cigarette. Among ever users of tobacco and e-cigarettes ( Although response rates are not released by Eurobarometer, population weighting is applied to the data based on age, gender and area of residence, resulting in representative samples. The data are freely available to download.We analysed data from wave 82.4 of the Eurobarometer survey of 28 EU countries in November–December 2014, collected and funded by the European Commission.E-cigarette use was assessed with the question ‘Regarding the use of electronic cigarettes or any similar electronic devices , which of the following statements applies to you?’. Responses were: ‘You currently use electronic cigarettes or similar electronic devices ’; ‘You used them in the past, but no longer use them’; ‘You tried them in the past but no longer use them’; ‘You have never used them’; and ‘Don’t know’. Responses other than ‘You have never used them’ or ‘Don’t know’ were classified as ‘ever users’.Smoking status was assessed with the question ‘Regarding smoking cigarettes, cigars or a pipe, which of the following applies to you?’ Those who selected the response ‘You currently smoke’ or ‘You used to smoke but you have stopped’ were considered ‘ever-smokers’.Participants who had ever used e-cigarettes were asked ‘What are the factors you consider important in your choice of electronic cigarette or any similar device ?’ Respondents could choose multiple responses between ‘price’; ‘packaging’; ‘flavour’; ‘brand’; ‘type of electronic cigarette ’; ‘amount of nicotine’; ‘design or shape of the electronic cigarette or any similar device and its case’; and ‘marketed health claims’.Similarly, all ever-smokers were asked ‘How important is or was each of the following factors in your choice of brand of cigarettes? The price; the packaging; the taste of tobacco; the specific brand; the specific tastes such as menthol, spicy, fruity or sweet; the levels of tar, nicotine and carbon monoxide; the design or shape of the cigarette ’. Response options were dichotomized as important ; and not important . Both the ‘taste of tobacco’ and specific tastes were grouped together under the label of ‘taste’.Data were collected on participants’ age , gender , age at which they stopped full-time education  and whether they have had difficulties in paying bills during the last 12 months .n = 2430), as they were asked for the factors influencing the choice of both products.Analyses for this paper were restricted to respondents who had used both e-cigarettes and tobacco products in their lifetime .A total of 2712 individuals had ever used e-cigarettes and, among them, 2430 (89.6%) were ever-tobacco smokers. Among this group taste/flavours and price were the two most commonly reported factors influencing the choice of both tobacco  and e-cigarettes  . Health Respondents who identified price; packaging; flavour; brand; amount of nicotine; or design as important factors for the choice of cigarettes were more likely to identify the same factor as important for their choice of e-cigarettes, with aPRs ranging from 1.77 for flavour to 4.91 for packaging. Younger respondents were more likely to say that price, packaging, brand, design and type of e-cigarette were important compared with those aged 55 years or older. Price was more important to people who had difficulties paying bills [aPR 1.24 ], while design was more important to men and health claims more important to women.This secondary analysis of a representative sample of the EU population has found that, similar to tobacco, taste and price were the most important factors influencing choice of e-cigarettes, and that health claims were not as commonly cited. Despite the similarities, the criteria for choosing e-cigarettes were not identical to cigarettes, indicating that the approach for understanding this market may require further evaluation. The seeming greater receptivity of younger people to design and packaging features mimics findings from tobacco smoking, and indicates the importance of e-cigarette advertising,The finding that health claims were not cited as a common factor influencing the choice of e-cigarettes is surprising, as this has been a central part of marketing claims. Additionally, experiments in eliciting preferences have found this to be an important determinant of choice of these products.The Eurobarometer sample is representative of the EU population aged ≥15 years, therefore results can be generalized to the entire EU population, and comparisons made between different member states. The questions on choice of cigarettes and e-cigarettes had slightly different wording and so comparisons between these should be treated with caution. The closed nature of the questions also means that some possible important elements of choice were not reported. While we considered ever-users of e-cigarettes, we acknowledge that an analysis of regular users would provide more meaningful results; however, the number of regular users was low (∼300), thus limiting the value of such analyses. Finally the cross-sectional nature of this study means that causation cannot be inferred and we support calls for future longitudinal research into this area.Many of the factors behind the choice of e-cigarettes are similar to those for tobacco cigarettes, and this data suggests that taste and price are the most important factors influencing experimentation. Young people are more likely to be influenced by design and price of e-cigarettes than older people, which raises concerns regarding the degree to which these should potentially be regulated in the growing e-cigarette market.Supplementary data are available at EURPUB online.


Beyond a Shadow of a Diet is an easy-to-read 338 page guidebook on how to apply the Health at Every Size ® (HAES ®) to treat binge eating in a psychoanalysis setting, and divided into three parts, 1. ‘The Problem’, 2. ‘The Treatment’ and 3. ‘The Solution’.Part one is an excellent introduction to diet culture and its impact on binge eating, as well as on how the therapist may be complicit in the same culture. Much of this content may also be found in the book ‘Health At Every Size’ by Bacon .Part two outlines the principles of Intuitive Eating as described by Evelyn Trible, and gives tips to help clients adopt the approach, as well as to overcome obstacles, and manage emotions and poor body image, all through a psychoanalysis lens. Part three returns to diet culture, and the HAES(R) principles, and gives information on how clients may pursue health in a non-diet paradigm, mainly through giving references for further reading.The authors are two social workers, who both have over 20 years’ experience working in eating disorders using a psychoanalysis approach. The book benefits from their knowledge, many excellent examples from their extensive experience to illustrate how they have been treating binge eating disorder. It should be noted that their approach is not manualised, and therefore no studies have yet been done to evaluate the effectiveness of this approach.Overall, this book has a good brief introduction to HAES (R), but for more in-depth information on the science of HAES ®, readers may find the source material, such as the work by Linda Bacon and Evelyn Trible, more illuminating. Part two is where the true value of the book if found. There are so few books aimed at supporting the practioner in treating binge eating disorder, and this book has an in depth exploration of an alternative to Fairburn’s CBT-E . This is


In June 2015, Douglas Preston—amateur archaeologist, National Geographic journalist, and author of best-selling thrillers—entered an infusion suite at the National Institutes of Health sporting an “oozing crater, fiery red and disgusting to look at” on his left upper arm. Ensconced in the room's weirdly large chairs, the 61-year-old breathed deep, ready to receive his initial hit of amphotericin B. “It was a total anticlimax,” Preston later reported in “The Lost City of the Monkey God,” a fast-paced, often harrowing saga of a recent expedition to Honduras. Published this year, the book describes adventurers, scientists, photographers, soldiers, and ex-commandos who found tantalizing traces of a lost civilization in a jungle called La Mosquitia. Roughly two thirds of the entourage, more than thirty people, also contracted leishmaniasis.Leishmania brasiliensis infection, and the author also met NIH researcher David Sacks and inspected colonies of sandflies and leish-infected mice, I privately thanked “Inside Edition” for leading me to a perfect candidate for The Tropical Bookshelf.In January 2017, I learned of “The Lost City of the Monkey God” through an e-mail. Later that morning, could I travel to a nearby studio to provide expert perspective on leishmaniasis? a TV producer gamely asked. Well, no, I replied. But by now I was sufficiently intrigued to request the book from my library. Once I read the chapter in which Doctors Ted Nash and Elise O’Connell started to treat Preston’s Ciudad Blanca (White City)? If your answer is yes, Preston delivers. Then there’s 19th century banana baron Samuel Zemurray, AKA “Sam the Banana Man,” a one-time pushcart seller who eventually bilked both J. P. Morgan and the U.S. government. Long before the country became famous for narco-trafficking, Preston coolly reminds us, “the fruit companies left a dark colonist legacy that has hung like a miasma over Honduras ever since.”“Danger porn” is a term some have applied to Preston’s spellbinder, which certainly offers its share of edge-of-the-seat scares. But before considering Honduras’s bounty of vipers, jaguars, and quicksand, would you like to learn more about Theodore Morde, a Massachusetts-born journalist-cum-deceiver who first covered the Spanish Civil War, then traveled to Mosquitia to slake his lust for gold at the same time cabling fake accounts of a legendary st century. If the dense Mosquitia rainforest is Eden in ruins, there must be a snake, right? Oh boy, is there a snake. A fer-de-lance appears the same night Preston and company set up camp. Preston is the first to spy the savage viper, its eyes fixed, its tongue flickering. One-time jungle commando Andrew Wood then brandishes a machete and lops off the branch of a tree, swiftly forming a long, forked pole.“Keeping the neck pinned with the stick and his left hand,” Preston continues, “Woody crouched and seized it behind the head with his right hand. The snake’s body, thick as his arm, slammed against his legs, its dazzling snow-white mouth gaping wide, unsheathing inch-and-a-quarter-long fangs that pumped out streams of pale yellow liquid. As its head lashed back and forth, straining to sink its fangs into Woody’s fist, it expelled poison all over the back of his hand, causing his skin to bubble.”Back to the 21Following its decapitation, the snake’s head and neck continue to wriggle in one direction, while its muscular body crawls off in another. Egad.“As I crawled on board, my dismay deepened. The interior of the Cessna, once a rich velvetized fabric in burgundy, was now worn, greasy, and faded: much of the inside appeared to be held together with duct tape. It smelled of Eau de Old Car. Parts of the plane had been sealed with acrylic caulk, now peeling out in strings. As I tried to maneuver around the giant lidar box into the microspace provided, I bumped my elbow into a panel which fell off.”“I jammed myself behind the lidar box: no seat, my knees in my mouth. Juan Carlos was right in front of me. He was concerned about how I would fare; I sense he was worried I might get airsick and vomit down the back of his neck… The A/C on the plane was broken, he said; we would be sealed up in a metal tube, flying in full sun. The plane had no bathroom. If you had to go, you went in your pants. I tried to assure him I would be an exemplary passenger.”“Through it all, I peered out the window, transfixed. I can scarcely find the word to describe the opulence of the rainforest that unrolled below us. The tree crowns were packed together like puffballs, displaying every possible hue, tint and shade of green. Chartreuse, emerald, lime, aquamarine, teal, bottle, glaucous, asparagus, olive, celadon, jade, malachite—mere words are inadequate to express the chromatic infinities.”Although adventure is the signature hook of “The Lost City,” a near-lyrical passage marks Preston’s first sighting of a twenty-square-mile, unexplored tract called “Target One.” The aging Cessna from which the author stares is equipped with LIDAR  but hardly inspires confidence. Nonetheless, Preston desperately wants on. For ASTMH members who have braved similarly rustic aircraft in distant realms, the next excerpts may bring back memories:L. brasiliensis strain of a fellow Mosquitia traveler. Nash would eventually see five or six of the venturesome crew, he later told me, wryly adding: “I enjoyed taking care of these guys—they were great patients, kind of like Peace Corps volunteers. Of course it’s always tricky treating multiple people who are all yapping about each other at the same time they’re incredibly bonded.”Later we come to the book’s unexpected switchback: the point at which the adventurers have returned home and some of their lingering bug bites begin to morph into typical nodules, sores, and crusts of cutaneous leishmaniasis, a neglected disease which, every year, still afflicts one to two million people worldwide. Growing increasingly apprehensive about the possible metastatic spread of certain New World species, Preston first reaches out to Ravi Durvasala  in Albuquerque, New Mexico, then to Tom Nutman and Ted Nash at the NIH’s Laboratory for Parasitic Diseases. By then, Nash had already biopsied, cultured, and sequenced the It happened during the twenty-fifth year [1520] the plague began, oh my sons! First they became ill of a cough, they suffered from nosebleeds and illness of the bladder. It was truly terrible, the number of dead there were in that period. The prince Vakaki Ahmak died then. Little by little heavy shadows and black night enveloped our fathers and grandfathers and us also, oh my sons!... Great was the stench of the dead. After our father and grandfathers succumbed, half of the people fled to the fields. The dogs and the vultures devoured the bodies. The mortality was terrible… So it was that we became orphans, oh my sons! So we became when we were young. All of us were thus. We were born to die!Derring-do, drop-dead primeval beauty, and “white leprosy” notwithstanding, I found Preston’s closing chapters the most powerful. What actually happened to the inhabitants of Mosquitia? Today, while archaeologists continue to interrogate clues buried in forest, thicket, and vine, we can only guess the cause of their tragic demise. Most likely, Preston surmises, a newly-introduced virus took them out, as it did so many other indigenous Americans of that era. To evoke this cataclysm, he quotes from a manuscript found in 1844 in a remote Guatemalan convent. Written in the Mayan dialect of Cakchiquel, its original narrator was just a teen-aged boy when his world forever changed.Across the centuries, humanity keens. Snakes and sandflies are perilous, but what can be worse than an unseen, mass assassin?“There was then no sickness; they had no aching bones; they had then no high fever; they then had no smallpox; no stomach pains; no consumption… At that time people stood erect. But then the foreigners arrived and everything fell apart. They brought fear, and they came to wither the flowers.”Preston also shares a second contemporaneous account, originally written in Yucatec Mayan, which is at once touching, poetic, and far more explicit in linking European conquest with Native death and destruction.Basically, it boils down to this. I’m not really interested in normal people doing ordinary things. I’ve always been attracted to exploring how human beings react when they are placed in extraordinary or dangerous or life-threatening circumstances. That’s what my nonfiction is about and it’s also what my fiction is about. In nonfiction, I deal with exploration. In fiction, I write the thriller.Well, it’s a good question. You know, I think what started off as a dogged pursuit of a story became an obsession—or maybe a quasi-obsession. Because the more I looked at the story and the more I researched it, the more I realized that there was a lot of solid evidence suggesting truth behind this legend. In fact, almost all of the archaeological sites that have been found in Central America have been found by archaeologists who were led by indigenous people or by stories or legends about a city somewhere in the jungle. In the end, what we discovered was not just a lost city but a lost civilization that had once been great but was almost unknown because it was totally overshadowed by the Maya.The one moment that has really stayed with me is when we went in on the ground in 2015. On the second day, we discovered an immense cache of objects left at the base of a pyramid. And the first thing I saw was a jaguar head thrusting out of the ground. It was a major moment because, up to that point, it had all been theoretical. I mean, you see giant mounds and all kinds of evidence of occupation. But suddenly I felt like I was face to face with these long-lost people. The [jaguar] image had such power, such confidence, such vividness and artistic sophistication. That really brought home that this was a civilization of great interest and complexity that had somehow grown up in a very hostile jungle.For 15,000 or 20,000 years, ever since the first humans crossed the Bering land bridge and populated the Americas, it was a biological time bomb waiting to happen. These two populations had very different disease trajectories. When they finally met–and it was inevitable that it would happen at some point–there was going to be this absolute catastrophe. There was no preventing it. I mean, even if the Europeans or Spanish hadn’t [arrived]–well, the Africans or Asians would have. The same result would have occurred, which was an absolutely horrific series of pandemics that probably wiped out 90% of the population of the New World. What I tried in my book, as hard as I could, was to really imagine what it would have been like to experience a pandemic where 90% of the people die.I’ve always been interested in the Black Death and how it affected Europe and may have even triggered the Renaissance. I’m sure you know all the theories. But the Black Death at its worst caused 30% mortality except for a few pockets with 60% mortality. The 90% mortality isn’t just quantitatively more, it’s a qualitative jump because it destroys entire civilizations, languages, cultures, life cycles. It takes away everything you have.To be honest, I tend to be an optimist and to dismiss these sorts of things. I have spent most of my life backpacking in wilderness areas and climbing mountains and surviving in adverse conditions. So I thought to myself: well, this catalog of horrors is meant for people who have never been in a wilderness before. I’m going to be fine. Then when I got there and saw that it was not an exaggeration—that it was an extremely challenging and dangerous area—I thought, well, look, you know what? This is a place where human beings have not been in probably 500 years and we are not welcome here.It’s good for humans to be utterly humbled by nature every once in a while. That’s exactly what happened to us in this environment.Even if I knew I was going to get leish, I would still do it again. And I would also go back if they found something new. Here’s a bit of information that has not been published. Conservation International is down there and have found a species of bat that only lives in deep caves. One thing we know about this culture is that they bury their dead in caves. If these caves are a necropolis, there would be grave goods and all kinds of fascinating stuff that would open the door on this culture in a way that has never happened before.You know, I’ve had many encounters with poisonous snakes in my life. With rattlesnakes, I’ve been struck on my boot; then they bounced off, thank God. Anyway, I’m acutely aware of snakes and I actually like them. And a lot of snakes, really, are terrified—they just want to get away, even if they hit you and bite you. Fer-de-lance are different; they can strike and will often hit again. When I saw that fer-de-lance coiled in striking position, tracking me—I walked by it twice–I thought: wow, they’re very aggressive. Really, really bad. When I saw that snake, I was sobered.The British SAS guy who killed it, at the end when he’s washing the venom off his hands, said: “Nothing like that to concentrate the mind, is there?” If it hadn’t been such a scary moment, it would have been funny.I’ll be honest with you: the vipers were a lot scarier.Addendum: According to current estimates, snakebites kill more than 100,000 people per year. In an effort to reduce that number, WHO recently added venomous snake bites to its list of neglected tropical diseases.I just want to say how impressed I was with my experience at the NIH and its staff, doctors, and researchers, in particular Ted Nash, Elise O’Connell, and David Sacks. At NIH, our taxpayer dollars are being incredibly well spent for the benefit of the American people and the world. It’s a perfect example of government doing something so much better than private industry. Because government doesn’t have the financial and profit requirement that industry has… it can fund all kinds of far-reaching and important basic research that private industry can’t.


The contents of the guidelines for the use of non-benzodiazepines (Z-drugs) differ slightly between THE JAPANESE SOCIETY OF SLEEP RESEARCH and THE JAPAN GERIATRIC SOCIETY, and the recommended directions are conflicting. Therefore, we analyzed the use of the Japanese Adverse Drug Event Report database (JADER) for identifying adverse events (AEs) caused by Z-drugs and clarifying their occurrence trend and prognosis.2) results of data of elderly and non-elderly patients. Among AEs for which signals were detected in the elderly, we determined that those with lower signal values for non-elderly patients that were half the signal value of the elderly should be used with particular caution in the elderly. We also compared the prognoses.The signal value for comparison was calculated by using the proportional reporting ratio (PRR) and chi-squared test (χThe AEs with > 1 risk ratio (RR) in elderly and non-elderly patients were regarded as those that should be noted in the prognosis of AEs in elderly patients. Furthermore, 28 AEs were detected in elderly patients’ signals. In this study, in addition to movement disorders such as “falls” and “bone fractures,” identified by two academic societies, signal characteristics of the elderly were obtained for psychiatric disorders and eye disorders.There was no difference in prognosis, but these disorders could reduce the quality of life of patients. Therefore, we consider that in prescribing appropriate drug therapy for insomnia, attention should be paid to the occurrence of the AEs caused by the Z-drugs revealed by this study and the guidelines. Insomnia is defined as the inability to sleep or sleeplessness that lasts for at least 1 month under proper sleeping conditions, and is accompanied by intense daytime fatigue and decreased concentration, energy, drowsiness, and vigor. Recently, in Japan, 20 to 25% of adults have been reported to experience insomnia [Therefore, the “ Clinical guidelines for proper use of sleeping pills and drug withdrawal” of THE JAPANESE SOCIETY OF SLEEP RESEARCH states that the quality of evidence is “moderate” and the recommendation is “weak,” and it recommends the use of Z-drugs for elderly people who experience sleeplessness . AlternaThus, THE JAPANESE SOCIETY OF SLEEP RESEARCH evaluated “the presence or absence of drug use” and THE JAPAN GERIATRIC SOCIETY evaluated the “long-term use of drugs,” and although the contents of their guidelines differ, the recommended direction is contradictory .These guidelines are prepared using a method similar to that of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. In determining the recommendation level, there is also the challenge of insufficient documented proof, because the empirical evidence is not a research topic and the evidence is scarce because of the limited data on the elderly. Therefore, repeated discussions and voting by the research groups responsible for preparing guidelines have provided some evidence, which has been included in the guidelines even if it is not adequate .However, the members of the GRADE working group have pointed out that the original method of preparation used by THE JAPAN GERIATRIC SOCIETY did not follow the GRADE system. Specifically, issues were pointed out such as the fact that “evidence is not integrated with outcomes as the main body” and “the evaluation method of the quality of evidence is uncertain” . THE JAPFurthermore, the method used by THE JAPANESE SOCIETY OF SLEEP RESEARCH also points out the following problems by Okumura . These pTo use drugs appropriately, it is important to understand the adverse events (AEs) they cause. Signals based on the principle of disproportionality focusing on the difference in the number of reported cases of AEs are used as indicators of the safety of drugs. Signals are considered to be able to detect unknown AEs at an early stage, and numerous risk assessments have been reported –8. TheseTherefore, in this study, we used the Japanese Adverse Drug Event Report (JADER) database of a spontaneous reporting system (SRS) in Japan, to identify AEs caused by Z-drugs and analyze their trends.The JADER is a database of post-marketing surveillance and spontaneous reports collected by Pharmaceuticals and Medical Devices Agency (PMDA) as Japanese regulatory authority. This database is used for Japanese pharmacovigilance, and it is similar to the database for FAERS in the United States, and other countries for pharmacovigilance. The JADER database was downloaded from the website of PMDA. It consists of four datasets in csv format: patient demographic information (DEMO.csv), drug information (DRUG.csv), AE information (REAC.csv), and primary disease information (HIST.csv). In this study, data from patients registered in JADER from the first quarter of 2004 to the fourth quarter of 2015 were used. However, reports with missing information on sex, age, or primary disease, and where subjective terms such as “youth” and “elderly” were used, were excluded from the analysis data.The suspected drugs were the Z-drugs zolpidem, eszopiclone, and zopiclone. AE is registered in the JADER database as the preferred term (PT) of the Medical Dictionary for Regulatory Activities/Japanese version (MedDRA/J). In this study, the target AE was defined as the high-level group term (HLGT).Data on the age of patients in the cases registered in the JADER database are provided as data collected every 10 years in principle for privacy consideration. The definition of elderly and non-elderly patients has ambiguous and subjective parts, and the determination is challenging. According to the definition of the United Nations, elderly people are those over 60 years old. The World Health Organization (WHO) defines people over the age of 65 as elderly people, and in numerous countries, those 65 years and older are defined as elderly people. Therefore, in this study, similar to previous reports , 13, 14,2) values of elderly and non-elderly patients, respectively, using formula  .2 value [From the registered outcome information, “recovery” and “ light ” were classified as good prognosis. In contrast, “death,” “with sequelae,” and “unrecovered” were classified as AEs with poor prognoses. We created a 2 × 2 contingency table based on the elderly/non-elderly and good/bad prognosis of classified AEs and calculated the risk ratio (RR), the 95% confidence interval (CI), and χ2 value . As 0 ce2 value .11: 10, PRR: 21.3, χ2: 152.6, signal value: 8.1), impulse control disorders not elsewhere classified (NEC) , neurological| special senses and psychiatric investigations , injuries by physical agents , personality disorders and disturbances in behavior , neurological disorders of the eye , manic and bipolar mood disorders and disturbances , movement disorders (include parkinsonism) , enzyme investigations NEC , disturbances in thinking and perception , vision disorders , and ocular infections irritations and inflammations .We obtained data on 176,184 cases of oral drugs use by patients  excluding cases where information on sex and age were unclear from the analysis data table based on patient background factor. Of the 321 AEs, 28 were detected in elderly patients’ signals , four and three HLGTs were classified as psychiatric disorders and eye disorders, respectively Tables .Table 2NAmong the AEs for which signals were detected in the elderly, none led to poor prognosis in the elderly compared to the non-elderly Table . , enzyme investigations NEC, disturbances in thinking and perception, vision disorders, and ocular infections irritations and inflammations. Regarding the manifestation of these AEs, medical personnel including pharmacists need to pay attention to elderly patients administered Z-drugs.In this study, we found that following psychiatric disorders, AEs related to eye disorders were increasingly exhibited by the elderly. Among eye disorders, “blepharospasm”, which is a local dystonia is a problem recently identified as an AE of benzodiazepines and Z-drugs. Blepharospasm is considered to cause diseases that induce strong sensory hypersensitivity and lead to eyelid loss.Benzodiazepines and Z-drugs have been found to cause side effects that interfere with comfortable vision such as robust and persistent “dazzling,” “pain,” and “blurred vision.” Wakakura et al.  have warIn “benzodiazepine induced blepharospasm,” a few patients are aware of the dazzling, pain, and foggy feeling. However, in general ophthalmology, this disorder may be treated as dry eye or asthenopia, and patients may be considered nervous and fixated on their eyes, although they are thought to be healthy. Therefore, it is also important for a pharmacist who has a wide knowledge of drugs to confirm these observations .Analysis using spontaneous report databases such as the JADER used in this study could identify “AEs that are highly related to expression risk” and “AEs related to poor prognosis” in elderly patients. However, the spontaneous report database cannot provide the total number of patients using the target Z-drug. In addition, because the number of AEs registered does not correspond to the total number of patients who develop AEs, their incidence cannot be calculated. It should be noted that some AEs may be very rarely expressed despite their association with a higher risk of development in the elderly than in the non-elderly patients. Thus, there are certain limitations in analyzing the results of studies using data from spontaneously reporting databases, and further detailed clinical research would be required in the future. The WHO defines a safety signal as: is “Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously” , and it In this study, in addition to movement disorders such as “falls” and “bone fractures” recorded by “THE JAPANESE SOCIETY OF SLEEP RESEARCH” and “THE JAPAN GERIATRIC SOCIETY,” signals that are characteristic to the elderly were obtained for psychiatric disorders and eye disorders. These disorders are possible irreversible progressions of symptoms and could reduce the quality of life of patients. However, as they are concerned about in the report, eye disorders caused by benzodiazepine receptor agonists in Japan are not recognized as important adverse events in Japan. This study is a comprehensive analysis of adverse events, and more detailed analysis is required. However, in addition to each clinical practice guideline, attention must be paid to the manifestation of AEs caused by Z-drugs revealed in this study until more detailed analysis results are obtained.We consider that appropriate drug therapy for insomnia should be implemented by practicing side effect management. This would include considering individual patients and paying attention to the occurrence of Z-drug-induced AEs revealed in this study and the guidelines of each academic society. And we believe that this paper will contribute to future detailed side effects studies and proper use of Z-drugs.


As “-omics” data technology advances and becomes more readily accessible to address complex biological questions, increasing amount of cross “-omics” dataset is inspiring the use and development of integrative bioinformatics analysis. In the current review, we discuss multiple options for integrating data across “-omes” for a range of study designs. We discuss established methods for such analysis and point the reader to in-depth discussions for the various topics. Additionally, we discuss challenges and new directions in the area.  The past decade has witnessed tremendous advancements in biotechnology and computational performance that have provided vast amounts of new data and accompanying optimism for the burgeoning improvements to human health and disease treatment. It is now possible, and increasingly routine, for studies to test thousands to millions of molecular endpoints. However, as the dimensionality of these data increases, larger sample sizes are required, and studies are now being conducted on an unprecedented scale. We are now seeing an explosion of data in almost every area of disease and clinical research. These technologies are commonly referred to as “omics” technologies, related to the suffix “-ome,” defined as “all constituents considered collectively” . We now Although it is clear that data integration is required, methods for achieving this are far from systematic. The integrative genomics methodologies that are used to interpret these data require expertise in multiple different disciplines, such as biology, medicine, mathematics, statistics, and bioinformatics. Such interdisciplinary approaches require diverse expertise, either through extensive interdisciplinary training or through extensive collaborations. The accumulation of enormous quantities of molecular data has led to the emergence of “systems biology”—a branch of science that discovers the principles that underlie the basic functional properties of living organisms, starting from interactions between macromolecules. Integrative genomics is based on the fundamental principle that any biological mechanism builds upon multiple molecular phenomena, and only through the understanding of the interplay within and between different layers of genomic structures can one attempt to fully understand phenotypic traits. Therefore, principles of integrative genomics are based on the study of molecular events at different levels and on the attempt to integrate their effects in a functional or causal framework.http://www.ncbi.nlm.nih.gov/gene/), gene ontology (GO) (http://geneontology.org/), Ensembl (http://useast.ensembl.org), KEGG (http://www.genome.jp/kegg/pathway.html), HMDB (http://www.hmdb.ca/), MetaCyc (http://metacyc.org/), WikiPathways (http://www.wikipathways.org/index.php/WikiPathways), and DAVID (http://david.abcc.ncifcrf.gov/), and many others are also available. For data that is more granular than the “gene level” , methods for combining dependent univariate test statistics or p values are now available  are available, methods for genotype imputation [Commonly used approaches involve linking all markers at the genomic, proteomic, metabolomics, and other levels back to annotated genes. In general, this approach works sufficiently because well annotated and curated databases describing genes and their known biological functions are readily available, though the various sources of data can be a challenge for analysis. Examples of these databases include NCBI's gene database . As an or rates . The Corpriately . Now thaputation , 8 have However, some data types are not readily mapped to annotated genes and these annotation limitations are particularly noticeable for the newest “omics” technologies. Metabolomics, for example, has major gaps in annotation that limit integration potential and limit the utility of pathway based and integrative methods approaches . MetabolOnce the results are mapped to annotations in a database, various integrative analysis approaches can be taken. While “integrative analysis” and “systems biology” can be vaguely defined workflows, in the current discussion we will consider the analysis of at least two different types of omics data as integrative.The analysis can be restricted to molecular data (such as in expression quantitative trait loci (eQTL) studies, in which the relation between germ line variation and gene expression is investigated) or it can involve clinical outcomes  or intermediate phenotypes and biomarkers.While it is possible to design an analysis plan to ask a variety of interesting biological and clinical questions, there are a few themes that usually emerge. The first common objective of analysis is to understand molecular behaviors, mechanisms, and relationships between and within the different types of molecular structures, including associations between these and various phenotypes, such as clinical outcomes and pathways. The second objective is often to understand the taxonomy of diseases or other clinical traits, thereby classifying individuals into latent classes of disease subtype; and the third objective is to predict an outcome or phenotype for prospective patients. Some statistical methods are specialized to one type of question, and others can be used for several. Some of the tools, such as enrichment analysis, were originally designed to reveal features of genes and pathways, whereas others, such as integrative clustering, were designed to reveal features of patient subgroups; however, most of the tools discussed below can be applied to both. The statistical methods used can be unsupervised or supervised . Often these methods are used in conjunction with cross-validation or other model selection approaches to prevent overfitting.One of the most commonly used approaches, because of its ready application and interpretation, is sequential analysis. In sequential analysis, evidences  from distinct omics levels are used. This approach allows the confirmation or refinement of findings based on one data type, with additional analyses of further omics data obtained from the same set of samples. In this case, at least two types of omics data are analyzed, for example, copy-number variants (CNVs) and gene expression level data.t-test statistic) then these values can be combined, though there are challenges in how to create a combined p value to this intersection after proper controls for multiple comparison. Approaches for combining p values and permutation testing are suggested approaches.Typically, in sequential approaches, an analysis of each dataset is made independently of the others and produces a list of interesting entities (omics level variables), which are then linked to each other. For example, differentially expressed genes in one list are compared with each other and then with different CNVs that have been matched to the closest gene in a second list. Usually, the lists are intersected to find the genes that are confirmed in the analysis of each data type. Comparing ranks of each gene in each list leads to measures of concurrence. If each entity in each list has a value of association with the outcome of interest , only require a set of statistically significant endpoints  that test for enrichment in a set of endpoints known to be related to a biological process . SlightlMethods development is an incredibly active area of research, and promising new methods for integrating “-omics” data are on the horizon. The simplest of these approaches use different “-omics” technologies as “pseudo replication” across “-omes,” building on the simple overlap approaches discussed above. Specifically, sophisticated Bayesian approaches incorporate information from one “ome” as prior information to perform association analysis for other, distinct “omes.” Additionally, there are a number of clustering and network based analysis tools that do not rely on established knowledge bases and have the potential to discover new biology. However, these approaches have not been widely used due to the limited number of datasets amenable to such analysis , 13. An Although methods and data integration techniques are continuously evolving, there are several challenges that will need to be addressed in order for an integrative approach to become standardized and routine. From a statistical perspective, the most fundamental challenge in integrative analyses is dimensionality: taking more levels into account in the analysis tends to increase the dimensionality of the problem. Adding more layers of data or increasing the resolution of measurements increases the dimension of unknown parameters, which are often difficult to estimate, thereby making the overall inference weaker. This might seem paradoxical, as the purpose of taking multiple levels into account is precisely the opposite—to use more observations to obtain a more accurate picture of the biological system under study. In addition to the challenges described above with high dimensional data, a formidable quandary is how best to link data across omics platforms and different levels of biology. These relationships often produce “one-to-many” relationships, making causal relationships difficult to define.There are also a number of limitations in the data curation and quality control. In addition, at every step, there will be checkpoints of compatibility of the data, such as normalization to the same scale, sample selection from representative cohorts, adequate correction for technical batch effects, and use of different platforms. Constantly evolving technologies exacerbate this challenge.Additionally, the variety of study designs underlying individual “-omics” datasets poses a significant problem to integrating data across multiple studies. Many studies are cross-sectional and only capture a snapshot of what is actually a highly dynamic system . In addition, cohort differences due to individual study goals or available study populations may pose a significant barrier for integrating data. Even if the study designs are similar, different technology platforms have varying resolutions. Although genotype imputation has reduced this barrier in genome-wide association studies, a comparable tool does not exist for most “-omics” platforms. Pathway databases are continuously improving, but currently information related to tissue type, cell type, developmental stage , and diseased state is extremely sparse. We need methodological improvements that can address pathway topologies and feedback loops and methods to simulate data to benchmark pathway analysis methods.Another aspect of data integration and “omics” integration can be seen in the growing reliance on in vitro model systems and comparative genetics approaches with model organisms of disease. To date, there have been many successful examples of comparative genomics that implement a multiomics strategy to validate or replicate signals. For example, lymphoblastoid cell line models have shown success in finding gene and gene expression results that support clinical genetic results . ResultsAlthough it will take a tremendous effort from the research community to address many of these remaining challenges to “-omics” integration, there are useful methods currently available and no shortage of available “-omics” data. With the massive amounts of data that we have and are currently being generated, the challenge will now be to integrate these technologies to form a cohesive biological depiction of human disease, because only then can we claim to have considered all constituents collectively.An enormous challenge is also the functional validation of the in silico findings in relevant living biological systems, as well as the development of adequate in vitro functional studies to keep up with the increasing throughput by which candidates for validation are generated. It is still crucial to explore functions of thousands of candidate genes, proteins, and metabolomics to ascertain their value as risk factors, as predictive factors for therapy response, and as therapeutic targets.While integrative analyses are important in all areas of genetics and genomics, they are especially important for mapping and obtaining a better understanding for the biology of drug response. There are a number of study design limitations in pharmacogenomics, pharmacoproteomics, and pharmacometabolomics that force the use of integrative approaches to make reliable discoveries. In most omics applications, replication is considered the gold standard—where potential associations are tested in one dataset and significant signals are validated in independent data. Obtaining and properly using these data are a particular challenge for drug response studies due to limitations in study design; for example, such studies are frequently nested within clinical trials, where sample sizes are extremely limited or treatment strategies are not completely comparable to the initial study. Because of this, replication samples are not routinely available and replication across omics levels is the only available option for reinforcing the initial discoveries.Other opportunities for integrative approaches to address the needs in personalized medicine are in health monitoring. An example can be found in Chen et al. , where tA more fundamental understanding of the biological dynamics across omics datasets will enable us to better identify risk factors, refine disease diagnosis, predict therapeutic effects and prognosis, and identify new targets for therapy in personalized medicine. While the biological intuition of integrative “-omics” is clear, the real challenges are related to data integration, curation, and analysis. As we are moving towards an era in which the amount of data produced every year is increasing exponentially, methods to develop a deeper understanding of the biology of complex systems are crucial.


Can we exploit our burgeoning understanding of molecular evolution to slow the progress of drug resistance? One role of an infection clinician is exactly that: to foresee trajectories to resistance during antibiotic treatment and to hinder that evolutionary course. But can this be done at a hospital-wide scale? Clinicians and theoreticians tried to when they proposed two conflicting behavioral strategies that are expected to curb resistance evolution in the clinic, these are known as “antibiotic cycling” and “antibiotic mixing.” However, the accumulated data from clinical trials, now approaching 4 million patient days of treatment, is too variable for cycling or mixing to be deemed successful. The former implements the restriction and prioritization of different antibiotics at different times in hospitals in a manner said to “cycle” between them. In antibiotic mixing, appropriate antibiotics are allocated to patients but randomly. Mixing results in no correlation, in time or across patients, in the drugs used for treatment which is why theorists saw this as an optimal behavioral strategy. So while cycling and mixing were proposed as ways of controlling evolution, we show there is good reason why clinical datasets cannot choose between them: by re-examining the theoretical literature we show prior support for the theoretical optimality of mixing was misplaced. Our analysis is consistent with a pattern emerging in data: neither cycling or mixing is a priori better than the other at mitigating selection for antibiotic resistance in the clinic.Key words: antibiotic cycling, antibiotic mixing, optimal control, stochastic models. Now, if we give half the patients drug A and the half other receive drug B, which is a a, of patients are given drug A, and therefore the fraction p, of patients have a drug-A resistant infection and suppose q have a drug-B resistant infection, where a, that maximizes the likelihood of appropriateness of treatment.And what of the resulting evolutionary dynamics? This simple scenario says nothing about how our strategy should change as resistance evolves. So, to remedy this we make the situation a little more general: suppose a fraction, The patient fraction treated with A that exhibits a treatable, A-susceptible infection is a, which is a number between 0 and 1. Since the quantity a, this meansAntibiotic appropriateness is maximized when For the strategy defined in (1), As we this scenario knows nothing about individual patients, according to (1) it is optimal to treat everyone with the drug for which resistance is least likely, even though this is a population-wide strategy that will be sub-optimal for some individuals. We can, therefore, improve upon this solution by getting every individual treatment decision right which means having better information on individual circumstances, from antibiograms for example, but this realistic possibility is not part of our toy scenario.p and q will change over time as a result and we write p(t) and q(t) to allow this, t being time. Analogous reasoning shows that the definition of a in (1) should now be replaced by a time-dependent optimal strategy, We now seek the optimal strategy in the toy scenario if the pathogens are allowed to evolve in response to our behavior as clinicians. Variables p(t) or q(t) is the greater. Note also how this strategy tacitly requires that p(t) and q(t) can be estimated at all times and that it leads to the most appropriate treatment with probability T time units.Observe how The strategy analysis . This idanalysis . Clinicae clinic .β is that biasing constant. If we are free to optimize the fraction of appropriate treatments with respect to β we can determine an “optimal mixing strategy” that treats appropriately with probability β, this number is necessarily less than the optimal value a.k.a. maximal drug heterogeneity) is the strategy that sets And what of mixing in this toy analysis? A mixing protocol, a(t) with This seems clearcut, but things get interesting when we ask this: what is the worst strategy possible? Can we determine that too? This is the unfortunate case that gets the drug usage decisions wrong with maximal probability. So A (or B)-resistant infections are treated with drug A (or B) as often as possible. This occurs when we exchange So, to summarize, our scenario manifests the following “ordering property” in terms of which behavioral strategies select for resistance by giving appropriate or inappropriate antibiotic treatments: the best strategy available  is not possible once we begin to use the drugs. In other words, “theoretically optimal” does not necessarily mean “desirable” or clinically useful.Moreover, strategies that are optimal for one theoretical model need not be optimal for other theoretical models, let alone have value in the clinic. Indeed, it is only to be expected that different optimality criteria, and different modeling choices, will lead to different optimal strategies even in the same mathematical model.  Above we used the criterion of maximizing the likelihood of appropriate treatment within a patient cohort given that everyone is treated, but different performance criteria might have asked us to compromise on this. For example, if our criterion had sought to maintain longevity of the drugs, the optimal solution could well have drawn us into a tradeoff of treating fewer infected patients .The above scenario could be criticized in many different ways for a lack of realism, but do its predictions generalize to more sophisticated mathematical models? We address this question by applying the theory of optimal control and computational tools designed to solve dynamic programming problems  to the fI1 and I2 represent the densities of patients infected with drug 2- and drug 1-resistant strains, respectively, γ1 and γ2 are the clearance rates of infection when patients receive an appropriate antibiotic and m1 and m2 are the admittance rates of patients to the clinic infected by drug 2- and drug 1-resistant strains, respectively. Finally t = 0.Here I1 and I2 will be identical at all times. Moreover, if a definitive ranking of mixing and cycling were possible and clinically relevant, it would have to be robust to all reasonable variations of parameters in the model. We are therefore compelled to test whether, or not, our conclusions are robust to parameter changes in models like (3).Only the case dered in  whereas a(t) so that the totality of infected patient days T > 0 is some fixed observation time. Control theory tells us that the optimal strategy can be determined by solving the so-called Hamilton-Jacobi-Bellman (HJB) equation associated with (3) numerically. This numerical approach determines optimal controls as so-called “feedback laws” whereby Now, the optimal control problem for (3) asks us to find a function n φ [see  and suppSee θ depends on system parameters.However, when a would oscillate very rapidly between the deployment of either drug. While this phenomenon known as “chattering” would be irrelevant to the clinic, it could arise in theory if a mixing solution, whereby a = 1/2, were either very close to being optimal or else were optimal. However, as we discuss in the supplementary, this requires mathematical models to possess special symmetry properties.It must be noted that the strategies (1) and (4) do not preclude the optimality of antibiotic mixing, although this point is mathematically technical. This is because there could be theoretical cases where Although very simple, S is the proportion of patients in the hospital infected by a drug-susceptible pathogen, that R1 then represents the proportion of patients infected by a drug-1-resistant pathogen, similarly for R2, and then X is the proportion of uncolonized patients. The model is this:The first of these models, c2) the meanings of which are stated in τ1 and τ2 represent rates of use of drugs 1 and 2, where all patients are assumed treated with one of the drugs. This results in a constraint, τ a fixed constant that plays the role of “a” in our previous discussion. Following  to (6) and ask how it performs in relation to mixing.Now, in (6), ollowing  we seek Before doing this, we first generalize (6) so that the antibiotic usage protocol, tion see  online aThe second model we refer to is (7) below from ,Typical solutions that 7 different numerical realizations of stochastic versions of (6) and (7). However, There is an important difference between the reactive cycling strategies, and cycling, used in theory and cycling in the clinic. Although some clinical studies have utilized ideas that might be described as reactive cycling , 2006, wMoreover, clinical cycles of antibiotic prioritization and restriction vary considerably in duration, from one month , to threSo, when we simulated theoretical cycling strategies based on scheduled drug rotation of fixed cycling periods, we obtained a second performance histogram, part of which can be seen in Let us explain this feature more carefully. When differential equation models are used to examine the question of optimal antibiotic deployment, the two families of clinical strategies known as cycling (meaning scheduled rotation) and mixing  must exhibit comparable levels of drug resistance in the sense that their performance distributions can always be embedded into each other, with complete overlap of their performance ranges . This stshould we choose? This decision is critical to ultimate performance of that trial but there is no way of knowing how to optimize this choice a priori, just as there is no way of doing so in a mathematical model comparing mixing and cycling.All these arguments can be summarized by a single schematic, which is So why did prior theoretical studies  concludeρ1 and ρ2 for either drug, say, but suppose that were used in prior studies because an argument can be made that such assumptions engender a parsimonious, like-for-like comparison between two antibiotics with identical clinical effects whereby the only point of difference imposed in that model is that one cycles the drugs and another mixes them. This argument does seem appropriate to the question we are addressing, but it also leads to mathematical symmetries Ultimately, the technical, mathematical reason  for the http://goo.gl/Ztywjg; last accessed January 4, 2017). Meanwhile, trials continue, like the recent multinational study, the Saturn Project, that is said to be designed to “resolve an issue of high controversy (antibiotic cycling vs. mixing)” , whose authors recently stated this about their data:…there were no statistically significant differences in the prevalence of antibiotic resistance during mixing and cycling interventions.’‘So, mathematic models tell us that some of the difficulties of comparing mixing and cycling are inherent to the theory behind Niederman’s question. They cannot be resolved, not even within the solution sets of certain mathematical models, be they deterministic or stochastic. We should not, therefore, be surprised when clinical trials designed to rank cycling and mixing also prove inconclusive. After all, clinical trials cannot even begin to resolve performance distributions. This uncertainty likely contributes to the ongoing community debates as to the relative merits of cycling and mixing  maximizes antibiotic heterogeneity because drugs used in the past gain a low probability of being used in the future ;empirical treatment: a random drug is allocated to the patient but not changed thereafter ;scheduled rotation (periodic cycling): cycles of prioritization and restriction are fixed before any patients are admitted;periodic antibiotic monitoring and supervision (PAMS): the next patient admitted is treated with the antibiotic that maximizes the heterogeneity of drugs used so far (mixing);surveillance-based rotation: the drug estimated to have the lowest current prevalence of resistance from recent antibiograms is prescribed to all patients (the strategy from the toy scenario);Personalized(DNA-based) treatments: a rapid assessment is made of the genotype responsible for infection for every patient. Reassessments conducted during treatment yield a sequential monotherapy that maximizes drug appropriateness at all times, even if resistance emerges in the host during treatment.Based on this survey, the following protocols were simulated in the individual-based model:We do include multidrug resistance in this model but we do not implement combination therapy as it is not clear how to engineer a fair, like-for-like comparison of the performance of drug combinations in a theoretical test of mixing and cycling.In the absence of treatment, the length of stay (LoS) data are normally distributed whereas they are log-normally distributed when everyone is treated using empirical therapy . InteresWe conclude that information-rich, personalized protocols can outperform antibiotic cycling and mixing in some mathematical models but, we should emphasize, this conclusion will depend on nuanced model circumstances. For example, if all patients are infected with pathogens susceptible to both drugs, a personalized strategy will not outperform mixing because any treatment will be successful. At the other extreme in terms of the community prevalence of resistance, if multi-drug resistance has fixed in the pathogen in the community and so is present in all infections before patients begin their treatment, it will also matter little which treatment patients are given because none will work. However, before that stark situation arises, and somewhere in between these two extremes, our simulation data shows that targeting appropriate treatments at as many individuals as possible can outperform both mixing and cycling.Molecular Biology and Evolution online.Supplementary DataClick here for additional data file.