Reproduction on Film.Reproduction is one of the most persistently generative themes in the history of science and cinema. Cabbage fairies, clones and monstrous creations have fascinated filmmakers and audiences for more than a century. Today we have grown accustomed not only to the once controversial portrayals of sperm, eggs and embryos in biology and medicine, but also to the artificial wombs and dystopian futures of science fiction and fantasy. Yet, while scholars have examined key films and genres, especially in response to the recent cycle of Hollywood ‘mom coms’, the analytic potential of reproduction on film as a larger theme remains largely untapped. This introduction to a special issue aims to consolidate a disparate literature by exploring diverse strands of film studies that are rarely considered in the same frame. It traces the contours of a little-studied history, pauses to consider in greater detail a few particularly instructive examples, and underscores some promising lines of inquiry. Along the way, it introduces the six original articles that constitute  The capacious and slippery term reproduction itself can refer to a biological and social process of human procreation, or to a mechanical process of copying images now closely associated with the Marxist philosopher Walter Benjamin's classic essay ‘The work of art in the age of mechanical reproduction’ (1935).A Machine for Recreating Life (1924–1933).Reproductive metaphors abound in discussions of cinema. The ‘birth’ of cinema is typically dated to 1895. Like the other creative arts, cinema has its founding ‘fathers’  and ‘mothers’ (Alice Guy-Blaché). Like all cultural endeavours, filmmaking has been likened to a collaborative, creative enterprise akin to making babies. Film has allowed women and men to ‘give birth’ metaphorically, as directors, and literally, as actors. Films have a What to Expect When You're Expecting (2012), the first Hollywood movie to be based on a pregnancy advice manual, has been winding and bumpy, with significant detours along the way. The canon of reproductive film includes some of the best-loved and most controversial artefacts in the history of the cinema. The relevant scholarship is extensive, but often organized by genre, analytically focused on the narrative content of fiction films – and the types of representation embedded therein – and scattered in disparate studies on a range of more discrete topics, including sex education, genetics and eugenics.Beyond metaphors and language, reproductive science, technology and medicine have developed especially since the early 1900s alongside techniques of capturing, displaying and analysing moving images. For over a century, embryologists, obstetricians and scientists and medical professionals of other kinds have made movies for purposes of research, teaching and propaganda. Meanwhile, the mass-market products of lucrative entertainment industries have made previously taboo reproductive experiences, practices and technologies more publicly visible than ever before. The road to Vanity Fair, contributed to an increasingly public culture of reproduction.Baby Boom (1987), Three Men and a Baby (1987) and Look Who's Talking (1989)  .5 InflueReproduction on Film will begin to answer this and other questions.Taking film – broadly conceived to include cinema, television, video and digital imaging – as the case study, this special issue explores the highly generative confluence of biological reproduction and mechanical reproduction. It also considers the production and circulation of moving images in relation to a broader visual and material culture of research, teaching and communication that has included – and continues to include – a diversity of publication formats, from three-dimensional models to illustrated textbooks, scientific journals and magazines, to name just a few.Reproduction on Film examine developments mainly in Britain and the United States, from around 1910 to the present. In this introduction we take a somewhat broader view, both geographically and chronologically. Beginning in the late nineteenth century, we first examine early genres and editing techniques that produced newborn babies from behind cabbage patches and out of thin air. Dwelling on the silent period, we consider Soviet avant-garde filmmaker Sergei Eisenstein's career-defining engagement with a foetus, and the impact of this encounter on his theory of animation. We next investigate the promises and constraints of biological and medical cinematography, particularly in relation to the manipulation of time and motion; embryologists used time-lapse techniques to accelerate otherwise imperceptibly slow developmental processes, while obstetricians learned how to pause their films in order to make rapid surgical manoeuvres intelligible to students. Turning to genres that blurred the boundaries between entertainment and education, we consider the shock of the birth scene in ‘exploitation’ and avant-garde cinema before concluding with a glance at the mainstreaming of reproduction in cinema as well as the related media of television, video and streaming. Overall, we propose that moving images not only have significantly shaped the scientific understandings, private experiences and public cultures of reproduction, but also have done so in media-specific ways.The six contributions to Prior to the ‘birth of cinema’ in 1895, a variety of nineteenth-century mechanical devices and display techniques, as well as music hall and fairground attractions, offered appeals similar to those that would soon become associated with the Lumière cinematograph, a portable hand-cranked device that served as both camera and projector: optical toys such as the zoetrope (the ‘wheel of life’) ‘animated’ the inanimate, panorama paintings immersed the viewer in another space, magic-lantern projectors were indispensable in medical education, and mechanical postcards added a kinetic movement to a simple message.faire-parts de naissance) equally politely premised upon the folk notion of babies emerging from cabbage patches, they would be sent by new parents to friends and relations , which survives, and Their First Baby (1911), now lost. None of this work was as unusual or as comic as Madame Has Her Cravings (1906), in which an insatiable pregnant woman is driven to steal increasingly inappropriate foodstuffs, including herring from a tramp and absinthe from a café. The film ends with her giving birth in a cabbage patch, in a trick cut. to life . A non-tc.1913).Artistic Creation (1901) the London trick filmmaker Walter Booth has a lightning sketch artist transform a drawn infant into living one in a single cut , a film about congenital syphilis and ‘eugenic marriage’, and Whatsoever a Man Soweth (1917), a British War Office production about a young Canadian soldier who learns of the ‘grave evils’ of syphilis.Variety critic worried that ‘vivid portraits of defectives’ in The Black Stork (1916), a highly publicized film that advocated eugenic infanticide, ‘would cause birth defects if pregnant women were allowed to see them’.Moral panic about venereal disease and racial degeneration resulted in the production during and after the First World War of numerous ‘social hygiene’ films. These included The Strenuous Life; or, Anti-race Suicide (1904).The Over-Incubated Baby (1901) parodied the popular ‘incubator baby sideshow’, while The Miraculous Waters (1914), an Italian film, seemed to cheekily endorse infidelity as the ‘cure’ for a childless marriage after hydrotherapy fails to restore the husband's potency.Kid Commotion (1935), a slapstick benshi or narrated ‘silent’ film originally titled Birth (Out of) Control, cast Shigeru Ogura, Japan's Charlie Chaplin, as an unemployed father and midwife for a day.Bed and Sofa (1927) humorously depicted a ménage à trois – a woman and two men – in a Moscow flat and frankly depicted a visit to a private abortion clinic.Some directors responded to moralizing propaganda with satirical films of their own, such as Edwin D. Porter's spoof of eugenics, Man with a Movie Camera (1929), edited by his wife Yelizaveta Svilova, cross-cut documentary childbirth footage with that of a funeral procession.The Soviet avant-garde, too, found inspiration in reproduction. Dziga Vertov's experimental classic Battleship Potemkin (1925) and the development of montage theory, in his later years Eisenstein developed a devotion to Disney cartoons and a posthumously published theory of animation that corresponded to it.The Misery and Fortune of Women (Frauennot-Frauenglück), a health education film that warned of the dangers of illegal, unprofessional abortion and promoted the wonders of hygienic medical childbirth, caesarean section, blood transfusion and surgical abortion.Celebrated for The rejection of the constraint of form, fixed once and for all, freedom from ossification, an ability to take on any form dynamically. An ability which I would call ‘plasmaticity’, for here a being, represented in a drawing, a being of a given form, a being that has achieved a particular appearance, behaves itself like primordial protoplasm, not yet having a stable form, but capable of taking on any and all forms of animal life on the ladder of evolution.The experience was to inspire Eisenstein's theory of the plasmatic, which he defined as follows:Snow White and the Seven Dwarfs (1937). For Eisenstein, the unfixed cartoon character was full of foetal potential. He imagined animation itself as a kind of quickening, bringing the non-living to life, animating the inanimate. This understanding of animation, prompted by the encounter between a Soviet filmmaker and a Swiss foetus in 1930, persists in the literature to this day.In application, he meant the metamorphic quality of animation – the ‘stretch and squash’ that characters performed, the water-balloon physiology of the dwarfs in Research Films in Biology, Anthropology, Psychology, and Medicine, ‘is one of the characteristics of life: it begins with the penetration of the ovum by the spermatozoon and ends with last cytoplastic streaming of the cells. Both have been registered on motion picture film’.Movement, proclaimed Anthony Michaelis in his encyclopedic Beginning in the late nineteenth century, embryologists created and consulted standardized images of ‘normal’ embryological development for a range of invertebrate and vertebrate species. Organized into stages, series and tables, these visual standards organized a discipline and have sustained developmental biology to this day.The Development of the Fertilized Rabbit's Ovum (1929), a celebrated time-lapse film by American embryologist Warren H. Lewis, compressed seventy-two hours of development into fourteen minutes of projection time.In contrast to sea urchins and other invertebrates, vertebrate embryos posed additional challenges for would-be cinematographers, including obtaining rarer and more fragile specimens as well as keeping them alive during often lengthier periods of development. Time magazine favourably reported on Hooker's research on ‘living abortuses’ in 1938.Magnified, moving images of embryos revealed much that was previously hidden, but there were limits to how much manipulation an embryo could stand. The later stages of mammalian development were particularly resistant to filming. As for human embryos, the additional, specific challenge of sourcing foetal material (from abortions or miscarriages) ‘precluded any films of their developmental stages’.The Fight for Life (1940), a documentary about DeLee's own maternity ward. DeLee's approach was highly distinctive, not least because of the way he extended the engineering concept of ‘streamlining’ to childbirth, but he was not the first obstetrician to take up cinematography. A decade earlier, Paris obstetrician Victor Wallich had produced a series of short obstetric teaching films.In contrast to the developing embryo, the process of delivery and childbirth was comparatively amenable to medical filmmaking. In this issue Caitjan Gainty examines the efforts, in the late 1920s, of Chicago obstetrician Joseph DeLee to transform the birthing room into a film studio, as well as his later objections to Eléments d'obstétrique, were illustrated with enlarged photographs of short strips of film to show in a few frames the stages of an operative movement.In 1916 Wallich recorded various interventions, including forceps delivery, performed on a mannequin, which, in contrast to the living patient, enabled the interior movements of the operations to be visualized. Later editions of his popular textbook, Human Reproduction (1947) and Encyclopaedia Britannica's Biography of the Unborn (1956), combined documentary footage, animated drawings, X-ray photographs and models to depict intrauterine life. These were nominally produced for married parents, but other films were intended for more specialist audiences.Birth and the First Fifteen Minutes of Life (1947), which showed the ‘removal of the placenta’, was made available ‘only to advanced classes in psychology and medical students in groups under the leadership of a physician or a senior member of a psychological faculty’.The advent of portable and less expensive 16 mm projectors, as well as non-flammable celluloid film stocks, facilitated the instructional uses of films, especially after the Second World War.Between 1930 and the late 1950s, as David A. Kirby demonstrates in this issue, American film censors treated the biological reality of human reproduction as sacred but horrific; they believed that pregnancy and childbirth should be celebrated but not seen, and feared that realistic portrayals would put young women off pursuing motherhood.So-called exploiteers appropriated and exhibited medical footage, including of childbirth, before general audiences in theatrical venues typically reserved for entertainment films. In so doing, they challenged the boundaries between educational and obscene visual materials that medical professionals, the film industry and censor boards worked hard to maintain. Exploitation films traded in forbidden spectacles and ‘bad taste’. Low production costs, alternative distribution networks and distinctive marketing techniques set them apart from major studio releases. These titillating films, which flourished at the height of the Hays Code, showcased nudity, sex, drugs, abortion and childbirth, but stopped short of hard-core pornography. In contrast to stag films, which were technically illegal, were always short (one or two reels), depicted actual non-stimulated sex, and were shown privately to men only, exploitation films were legal, often feature-length, and shown openly to mixed audiences.Going to an exploitation film was often a carnival-like event because of the extrafilmic practices that accompanied the show. Lectures, slide presentations, the sale of pamphlets or books on the picture's topic, and the presence of uniformed ‘nurses’ to attend to those who might faint due to the ‘shocking’ sights became a major part of the exploitation film experience.Whereas major studio releases typically opened with four hundred prints in the 1930s or 1940s, ‘exploiteers’ would strike no more than fifteen or twenty prints of any given film, but these could remain in circulation for decades.The Birth of a Baby (1938) proclaimed, ‘See a baby born before your very eyes!’The Birth of a Baby was presented to general audiences under the auspices of the American Committee on Maternal Welfare, an umbrella group consisting of several reputable medical and public-health associations.Time praised the ‘absorbing example of visual education’ and Variety judged that it was ‘not in the class with so-called sex films’.The Birth of a Baby went on to become one of the most controversial films of the 1930s: ‘The cinema explodes the stork myth’, proclaimed journalist Geraldine Sartain. ‘Almost overnight’, she claimed, ‘The Birth of a Baby became the most discussed picture since The Birth of a Nation’.As birth control became more socially acceptable in the 1930s, attention shifted to the ‘mystery of birth’, and the direct promise of the spectacle of childbirth became a frequent advertising tactic. For instance, publicity material for The Birth of a Baby was sparked not directly by the film itself, but indirectly by a photo-essay in Life magazine on 11 April 1938 (The Birth of a Baby played in cinemas for some twenty years and inspired imitators like Childbirth from Life (c.1938), Life (1938), Childbirth (1940) and The Birth of a Child (1938), the last of which provoked a ‘series of suits and countersuits’.A major debate over ril 1938 . The magChildbirth: Normal Delivery (1950), screened in 1953 at Cinema 16, that the medical film depicted ‘the actual birth of a baby so graphically that the baby seems to leap simultaneously into the world and through the screen at the audience’.The exploitation circuit was not the only route whereby obstetric films found non-medical audiences. In 1947, Austrian émigré Amos Vogel and his wife Marcia established Cinema 16 in New York City. Though better known today for cultivating the first American audience for European and home-grown experimental art films, the Vogels also programmed medical and scientific films, alongside documentaries, propaganda and other oddities. Cell division, sexual development and childbirth were consistently among their favourite themes.The Private Life of a Cat (1944), Alexander Hammid and Maya Deren, the first power couple of American avant-garde cinema, documented the arrival of their pet cat's kittens in their West Village apartment.To film her, it was necessary to only place her box more in the open, so I could get around with my camera. She seemed to mind little that her box was near the window – contrary to the belief that cats give birth only in dark places. The strong lights I needed turned on only for a few seconds necessary to take each shot. At first she disliked this, but when delivery got under way she was too busy to mind … almost none of the film is staged. Usually, I waited for the cats to do what I knew they would do from habit, or often I waited for a surprise, as in the case of the father seeing his children for the first time. My only contrivance was placing the kittens where I wanted them, making them look one way or the other by some noise, motion, or food. The film was taken over a period of four weeks … some seemingly consecutive shots were in reality taken days apart. Others, like the delivery, are seen in almost the same actual continuity.In Popular Photography similarly praised Hammid as a ‘sensitive and original thinker-with-the-camera’ and his film as ‘unusual’, ‘absorbing’, ‘charming’ and ‘instructive’. It did not remark on the birth scene one way or another, but did laud the ‘marvellous sequences in which the kittens take their first faltering steps, and lurch along as uncoordinated as any new-born baby’.Film as a Subversive Art (1976), state censors banned the film in 1948 ‘as “indecent” because of its moving birth sequences’.Vogel's programme notes praised the film, singling out the delivery scene: ‘Birth is shown as a tender, yet painful miracle, the very objectivity of portrayal robbing it of all sensationalism’.Panorama made headlines around the world when it broadcast footage of an ‘actual birth’ for the first time. In this issue Salim Al-Gailani recovers the history of the production, distribution and screening of the footage, originally intended for use in antenatal classes, in the context of heated debates over ‘natural childbirth’. Meanwhile, just as censorship was beginning to relax, experimental filmmakers found new ways of pushing boundaries, including by visually exploring the sexual and reproductive human body.That even the birth of kittens was censored in the late 1940s provides some indication of the degree to which norms have changed since then. Human reproduction, however, is a somewhat different story. In 1957, BBC TV's flagship current affairs programme Window Water Baby Moving (1959), by pioneering experimental filmmaker Stan Brakhage. This intentionally silent, ambient study of his wife Jane's pregnancy and the birth of their first child Myrrena has become part of the canon of experimental film.In contrast to the no-longer controversial birth of kittens, the spectacle of childbirth still has the power to shock. Take, for example, Village Voice, ‘On the screen probably for the first time ever in film history: a woman gives birth to a child. We see it all. The woman is ecstatic. And so is the father. The audience is totally totally silent’.Reactions were strong and began in pre-production, well before the film was even edited, much less projected for the first time. The Kodak laboratory where Brakhage had his film developed threatened to notify the police and only released his footage when Jane's doctor wrote a letter. Of the New York premiere in December 1959, film critic Jonas Mekas wrote for his column in the L'opéra mouffe (1958), Gunvor Nelson's Kirsa Nicholina (1969) and Marjorie Keller's Misconception (1977).L'opéra mouffe as the ‘notebook of a pregnant woman unafraid to show what pregnancy really looks like’ , a still more controversial landmark in the history of experimental film.Window Water Baby Moving, she acknowledged Brakhage's ‘unique … willingness to focus on the actual birth’. ‘You must understand’, she later recalled, ‘there were no precedents that we know of – only medical and pornographic models’.Performance artist and filmmaker Carolee Schneemann responded somewhat differently to Brakhage's provocation. She worried that Brakhage's ‘male eye replicated or possessed the vagina's primacy of giving birth’. Moreover, she ‘wanted to see “the fuck,” lovemaking's erotic blinding core apart from maternity/paternity’. The result was Schneemann's own sexually explicit Window Water Baby Moving was surely not the medical training film that Jane's doctor had bargained for, it is all the more remarkable that thousands of 8 mm prints circulated in maternity clinics in the 1960s, where it often screened on a double bill with George Stoney's All My Babies (1952), a lyrical documentary about midwifery in the American South.Window Water Baby Moving remains a ‘rite of initiation’ for students, who, as another film scholar recently remarked, ‘tend to respond to it as either the “most beautiful” or the “most obscene” film they have ever seen’.Considering that Window Water Baby Moving. As Brakhage later recalled,is a monster!’ I had never seen a newborn baby before and thought this was a deformed monster, and I remember the thought passing through my head, ‘Then I will make a monster film!’ and continued to film in a kind of rage. Of course, it turned out much happier than that.Jane had German measles at three months, and in those days, they thought this meant there was a much higher chance of giving birth to a monster. We were always concerned about that. When I first looked through the camera at the baby emerging, I thought, ‘This It is worth dwelling on a final, little-remarked aspect of Frankenstein (1931) or Island of Lost Souls (1932), the Cold War reinvigorated the genre, which traded old fears for new ones about radioactive fallout, mutation and degeneration.Several features of this eye-opening anecdote merit discussion. First, the disease. The couple's concerns were not in fact unfounded. As was already suspected in the 1950s, contracting rubella (German measles) in pregnancy does increase the risk of giving birth to a malformed child and highly mediatized epidemics of the disease would soon after play a significant role in the liberalization of abortion law in the United States and other countries.A Taste of Honey (1961) to Up the Junction (1968), British ‘kitchen sink’ cinema looked to recent novels and stage plays for gritty narratives about unmarried pregnancy and abortion; Ken Loach's Poor Cow (1967) opened with documentary footage of childbirth.Prudence and the Pill (1968), a comedy film based on a novel and folk tale about a daughter taking her mother's contraceptive pills and replacing them with aspirin, resulting in the mother becoming pregnant.As with graphic nudity, sex and other taboos, reproduction on screen has become something of a cliché: part of a broader liberalizing trend across a wide range of mainstream media that really got going in the 1960s and 1970s.Life magazine and then in Swedish photographer Lennart Nilsson's global bestseller, A Child Is Born.Georgy Girl (1966), a British film that also features the same pair watching childbirth on television and reading Dr Benjamin Spock's leading pregnancy advice manual, Baby and Child Care (2001: A Space Odyssey (1967).Rosemary's Baby (1968) and Alien (1979), bookended a decade obsessed with the unsettled and increasingly contested contents of the womb.The public visibility of human embryos increased when colour pictures appeared on 30 April 1965 on the cover of ild Care . The phoin utero videography, most notoriously in The Silent Scream (1984), while infertility experts made television documentaries about the ‘miracle’ of IVF.The Fly (1986) incorporated pregnancy, miscarriage and abortion into storylines about genetic contamination and monstrous hybridity.The Handmaid's Tale (1990) to Children of Men (2006), continued to evoke abiding concerns about reproductive control.Alien franchise is still going strong, with the most recent instalment, Alien: Covenant (2017), continuing to engage in a sophisticated way with reproduction, from embryo to fully grown monster. The Handmaid's Tale lives again as a critically acclaimed television series, provoking fresh discussion on the enduring relevance of its source material, the 1985 dystopian novel by Canadian author Margaret Atwood.In the 1980s, after several Western countries had legalized abortion and the first ‘test-tube babies’ had been born, ‘pro-life’ activists mobilized I Love Lucy.The Kids Are All Right (2010), an independent film about a married lesbian couple who meet the sperm-donor father of their children, to Two 4 One (2014), a crowdfunded film about a transgender man who accidentally becomes pregnant, unconventional family forms have inspired new takes on older themes, queering reproduction on film.So much has changed since Lucille Ball made prime-time history in 1952 as the first pregnant actress to play a pregnant character, on the popular American comedy series 16 and Pregnant and Channel 4's One Born Every Minute.One Born Every Minute were recently filmed watching their televised births for the spin-off miniseries I Was Born on One Born. As recently as the 1980s, in contrast, home movies were still a novelty and the birth of a child could stimulate parents to purchase their first Polaroid instant-film camera or video camcorder.Depictions of pregnancy and childbirth on television have become a commonplace, including on so-called reality programmes such as MTV's Companies, meanwhile, offer ‘keepsake’ ultrasound scans, displayed on large LCD screens, and recorded to DVD, ‘usually with a soundtrack of the client's choice’.Reproduction on Film began as series of public film screenings and discussions, activities that have fed back into the research process in ways that film appears to facilitate most effectively. This introduction has explored some of the media-specific hopes and fears associated with the history of reproduction in cinema, and on television and video: the potent realism of the moving image, its fraught visual politics, and the disruptive power of innovative distribution networks – from roadshows to the Internet – to collapse boundaries between genres. Focusing on one neglected medium always throws taken-for-granted features of other media into relief, and reproduction, as a theme, seems to have an intensifying effect. It opens up resonant issues, from the manipulation of scale, time and motion in research and teaching to the contested visual communication of biological and medical subjects to laypeople. From postcards to time-lapse, cabbage fairies to IVF, communication technologies and reproductive technologies have structured the stories we tell about making or not making babies. The rest of this special issue will set the stage for further exploration of a vast and still mostly uncharted history.


Parkinson’s disease (PD) is a progressive neurodegenerative condition that has genetic susceptibility, aging, and exposure to certain chemicals as risk factors. In recent decades, epidemiological and experimental studies have investigated the role of pesticides in the development of PD, in particular that of the herbicide paraquat. Here, we, therefore, aim to systematically review the association between paraquat exposure and PD.Observational studies  eligible for this systematic review will enroll any participant who was occupationally and/or environmentally exposed to paraquat. Experimental studies, including in vivo and in vitro assays designed to assess neurotoxicological endpoints or mechanisms of paraquat neurotoxicity, will also be eligible. Outcomes of interest include the following: PD diagnosis; neurobehavioral, biochemical, and/or morphological alterations; and cellular, biochemical, and/or molecular pathways to oxidative stress. Using terms to include all forms of paraquat combined with PD, the following electronic databases will be searched: PubMed, EMBASE, LILACS, Toxnet, and Web of Science, without restrictions as to language, year, or status of publication. A team of reviewers will independently select potential titles and abstracts, extract data, assess risk of bias, and determine the overall quality of evidence for each outcome using the Office of Health Assessment and Translation (OHAT) approach for systematic reviews and evidence integration. Dichotomous data will be summarized as odds ratios, and continuous data will be given as mean differences, both with their respective 95% confidence intervals.This is the first time that the OHAT systematic review protocol will be applied to investigate a possible causal association between exposure to paraquat and PD. Results from this study could serve as basis for regulatory agencies to define paraquat levels of concern, supporting its risk assessment process.PROSPERO CRD42016050861The online version of this article (doi:10.1186/s13643-017-0491-x) contains supplementary material, which is available to authorized users. It is common, though, that environmental health studies have some differences regarding outcome assessments and exposure definitions that could be an obstacle to formal statistical meta-analysis . The het × 100%) , 47. HetStatistical analysis will be conducted using the Comprehensive Meta-Analysis STATA software (version 10.1). If considerable heterogeneity is detected among studies, meta-analysis will not be indicated and results will only be presented in tables or in a narrative synthesis. However, if heterogeneity does not exceed 75%, we will use random effects meta-analysis , which iSubgroup analysis will be conducted to investigate possible heterogeneity causes and other risk factors that could be potential cofounders. Studies will be allocated into groups according to common characteristics, as described below. The outcomes are assessed to determine if exposure caused a significant effect due to a specific feature. For human studies, subgroup analyses will be conducted for different exposure periods (<5 years vs. ≥5 years), co-exposures to other pesticides also related to PD , different comorbidities , different age groups , and presence or absence of family history of PD.For experimental animal studies, subgroup analyses will be conducted for dose , duration of paraquat exposure in multidose studies, and routes of administration .If there are enough studies, we will develop sensitivity analyses to explore robustness of the results for each type of study design “e.g., observational studies  vs. experimental animal studies, cohort vs. case–control vs. cross-sectional” and studies with low risk of bias vs. those with high risk of bias.The certainty of the evidence for each outcome will also be rated at high, moderate, low, or very low, using an adapted version of the Grading of Recommendations Assessment, Development and Evaluation system (GRADE) . To dateAvailable studies on a particular outcome will be initially grouped by key study design features that guarantee that the paraquat exposure preceded and was associated with the development of the signs and symptoms of parkinsonism . Each grIn this adaptation of GRADE, experimental studies begin as “high certainty” of the evidence, cohort studies as “moderate certainty,” case–control studies as “moderate or low certainty,” and cross-sectional studies as “low certainty” of the evidence. This initial rating could be downgraded by the presence of risk of bias, imprecision, unexplained inconsistency, indirectness, and publication bias . If therOn the other hand, the presence of a large magnitude of effect, a dose–response gradient, recognition of confounding factors that could underestimate or overestimate the effect and consistency among studies with different designs could upgrade the certainty of the evidence . After tFive descriptors will be used to rate the level of evidence: “high,” “moderate,” “low,” “inadequate evidence,” and “evidence of no health effect.” The first three descriptors  used in the previous step to indicate the certainty of the evidence will be directly converted into levels of evidence. However, if the level of certainty is “very low” or no evidence is identified, the level of evidence will be considered “inadequate” .The descriptor “evidence of no health effect” that indicates that paraquat is not related to PD in humans or in rodent models will be considered only when the level of certainty is high .For proper categorization of paraquat in one of the five categories of hazard  , evidencAmong the factors that can support biological plausibility and increase the hazard classification, the magnitude of the effect, the dose–response gradient, and the direct and indirect consistencies between outcomes from studies with different biological levels  will be considered. On the contrary, hazard classification may be reduced by the identification of risk of bias, unexplained inconsistencies between studies with related outcomes, non-relevance of the paraquat mechanism of toxicity to humans and dose levels not relevant to real human exposure.Current systematic review protocols are primarily based on randomized clinical trials for evaluating the efficacy of healthcare interventions –54. WithResults that could arise from the present study could serve as basis for regulatory agencies to define paraquat levels of concern (LoC), once the real human levels of exposure and the relevance of its mechanisms of neurotoxicity are known. Hazard identification is the early stage of the risk assessment process, which takes into account information such as LoC and exposure levels for regulatory purposes . The sys


Bullying is a major problem in schools and a large number of studies have demonstrated that victims have a high excess risk of poor mental health. It may however also affect those who are not directly victimized by peers. The present study investigates whether peer victimization among classmates is linked to internalizing problems, self-esteem, and life satisfaction at the individual level, when the student’s own victimization has been taken into account. The data were derived from the first wave of the Swedish part of Youth in Europe Study (YES!), including information on 4319 students in grade 8 (14–15 years of age) distributed across 242 classes. Results from multilevel analyses show a significant association between classes with a high proportion of students being victimized and higher levels of internalizing problems, lower self-esteem, and lower life satisfaction at the student level. This association holds when the student’s own victimization has been taken into account. This suggests that peer victimization negatively affects those who are directly exposed, as well as their classmates. We conclude that efficient methods and interventions to reduce bullying in school are likely to benefit not only those who are victimized, but all students. Bullying and peer victimization in the school setting is a problem that often has severe consequences for the exposed student’s mental health ,2,3,4 anWhen an individual student develops psychological problems because he or she is victimized, it can be seen as an individual-level effect: the victimization has consequences for the mental well-being of the individual who is directly exposed. However, the existence of peer victimization in the school setting can also have consequences for the overall school climate, and thus ‘spill over’ onto the mental well-being of the surrounding peer group. Students who participate in, witness, or are simply aware of such bullying behaviors in their class are likely to sense that the social climate is unfriendly and may also become worried that they, for example, might be the next victim. The ‘concentration’ of peer victimization in a class may, in this way, lead to poorer mental well-being among classmates who are not directly exposed. Further, the more common peer victimization is, the higher is the risk that students who are not victimized themselves will become aware of or witness such situations and be affected. The mere fact that peer victimization is known of or observed in the immediate environment can thus be seen as a marker of “ambient threat” in the school setting  (p. 386)Accordingly, in classes where peer victimization is common, students who are not yet victimized may perceive a potential risk of becoming a future target. This may lead to elevated levels of stress, a more negative self-perception, and poorer general well-being. However, to the best of our knowledge, only a small number of empirical studies have hitherto investigated contextual effects of bullying among classmates and students’ mental well-being, i.e., whether the occurrence of bullying in a class is linked to students’ mental well-being even when adjusting for peer victimization at the student level. Using data from the Stockholm School Survey of students in grade 9 (15–16 years of age), Modin and Östberg  found thThe purpose of the present study is to analyze whether the prevalence of peer victimization at the class level is related to students’ internalizing problems, self-esteem, and life satisfaction when peer victimization at the student level has been taken into consideration. To this end, we will employ survey data material from grade 8 students (aged 14–15 years) in schools in Sweden. In grade 8 in Swedish schools, classes constitute relatively well-defined units and the students in a class attend most lessons together. Our hypotheses are:Hypothesis 1 (H1).A high occurrence of peer victimization at the class level is positively associated with students’ internalizing problems, over and above the individual-level association.Hypothesis 2 (H2).A high occurrence of peer victimization at the class level is associated with lower self-esteem among students, over and above the individual-level association.Hypothesis 3 (H3).A high occurrence of peer victimization at the class level is associated with lower life satisfaction among students, over and above the individual-level association.n = 5025 distributed over 251 classes in 129 schools). Additional information about students’ household characteristics was collected through parental questionnaires and register data. More information about the sampling procedure, the data collection and the data material is available elsewhere (www.cils4.eu)  statements?”: “I have a lot of good qualities”, “I have a lot to be proud of”, and “I like myself just the way I am”. The response categories were “Strongly agree”, “Agree”, “Neither agree nor disagree”, “Disagree”, and “Strongly disagree”. The five-point scale was coded so that for each item, “Strongly agree” was given the value of 4 and “Strongly disagree” the value of 0. Since the three items were correlated  they were added to a form an index with the range 0–12. The distribution was heavily skewed towards higher values in that more students tended to have high self-esteem. Accordingly, we constructed an ordinal scale measure with three categories of about equal size .Life satisfaction was captured by the question “On a scale of 1 to 10, where 1 is very unsatisfied and 10 is very satisfied, how satisfied are you with your life in general?” The distribution of this measure was heavily skewed towards higher values since more students tended to rate their life satisfaction as high. We constructed an ordinal scale measure with three categories of as similar size as possible .Peer victimization was measured by the question “How often have the following things happened in the last month?” followed by the statements: “I was scared of other students”, “I was teased by other students”, and “I was bullied by other students”. The response alternatives were: “Every day”, “Once or several times a week”, “Less often”, and “Never” (coded 3–0). The three items have a good internal consistency . Responses from the three items were added to form an index ranging from 0 to 9, with higher values indicating greater exposure to harassment. Students with values >1 standard deviation above the mean were classified as being subjected to harassment. This strategy was adopted from earlier studies that used the KIDSCREEN social acceptance subscale which is based on items similar to the ones used here ,20.Peer victimization at the class level was calculated as the proportion of students in each class who were classified as being victimized by peers (measured in %). To detect potential non-linear associations, the continuous measure was subsequently divided into three categories of about equal size, in order to distinguish classes with a relatively low, intermediate, and high occurrence of peer victimization.Sex was based on information from the student questionnaire, with the categories boy and girl, respectively.Age was the year when the student filled in the survey  minus the student’s birth year.Family structure was based on information in the student questionnaire about whether or not the student lived with two custodial parents in the same household. This was included as a control variable since earlier research has shown that adolescents not living with two custodial parents in the same have a higher risk of both peer victimization  and of pParents’ occupational status was included as a control variable since household socioeconomic conditions have been shown to be linked with a higher risk of peer victimization ,24 as weImmigrant background was included as a control variable since earlier studies based on the same data material have demonstrated that peer victimization is less commonly experienced by second generation immigrants than among the Swedish majority  and thatThe Regional Ethical Review Board of Stockholm has given ethical approval to the project (2010/1557-31/5).The study uses multilevel analysis, which is appropriate since the data structure is hierarchical, with students nested in classes. The software is Stata version 13.1. We performed two-level linear regression models of internalizing problems (using the ‘xtmixed’ command) and two-level ordered regression models of self-esteem and life satisfaction (using the ‘meologit’ command), respectively. To account for differences in sampling probabilities we used a sampling weight in the descriptive analyses. In the multilevel regression analyses we adjusted for stratum .In the analyses, we first estimated whether exposure to peer victimization was predictive of internalizing problems, self-esteem and life satisfaction after control for sociodemographic background characteristics (student level). These analyses are presented in Models 1. Next, we added class-level proportions of peer victimization to the model to investigate if there was any additional disadvantage for individual students of being part of a class context where peer victimization is common . These analyses are presented in Models 2.A description of the data is provided in p < 0.001) as well as lower self-esteem  and lower life satisfaction  than those who were not victimized. Model(s) 2 further demonstrate that the proportion of classmates who were victimized by peers—independently of class size, individual victimization, and the variables adjusted for in Model 1—was significantly associated with all three outcomes in the expected direction. Thus, a relatively high concentration of peer victimization in the class was predictive of more internalizing problems , lower self-esteem  and lower life satisfaction  than among students exposed to lower concentrations of peer victimization in the class. For life satisfaction, students in the intermediate category of class-level victimization  tended to report lower life satisfaction than students in classes where there was a low level of peer victimization.To assess whether the patterns in p < 0.01; for self-esteem OR = 0.99, p < 0.01; for life satisfaction OR = 0.99, p < 0.05) (not presented).As an additional check (not presented), we also performed analyses of the continuous measure of class-level peer victimization, i.e., the proportion of students in a class who reported to be victimized (ranging between 0 and 47%) instead of the three categories. For all three outcomes, the estimate of the continuous measure was statistically significant , data not presented). Since these additional checks showed very similar results to those displayed in In the ordered multilevel regression models, the parallel lines assumption  was not met. Therefore, to check the robustness of the findings, we also performed binary logistic multilevel models with dichotomous versions of self-esteem and of life satisfaction. For self-esteem, we compared students with low vs. intermediate/high self-esteem, as well as those with low vs. high self-esteem . Both analyses produced results similar to the ones from the ordered multilevel regression analysis: students in classes in the highest of the three peer victimization categories were less likely to report intermediate/high or high self-esteem than those in the lowest third (data not presented). Similarly, for life satisfaction we compared students with low vs. intermediate/high life satisfaction, as well as those with low vs. high life satisfaction . In both analyses, results were similar to the ones produced in the ordered multilevel regression model , in accordance with previous studies that have used the same data material ,24: a stUsing Swedish survey data collected from students in grade 8 aged 14–15 years), the present study shows that the class-level concentration of peer victimization was linked to higher levels of internalizing problems as well as to lower self-esteem and lower life satisfaction, even when peer victimization at the individual level was adjusted for. Thus, our findings indicate that there are contextual effects of peer victimization among classmates with potentially harmful implications for the class as a whole. The effect sizes, although not as resolute as at individual-level, were not negligible. The strongest associations were found at the individual level, with students who themselves were victimized reporting more internalizing problems, lower self-esteem and lower life satisfaction than their classmates who were not victimized. This corroborates findings from earlier studies ,3,4,5,6.–15 yearsWhere the contextual effects of peer victimization are concerned, the present study confirms and extends previous research. By analyzing three important aspects of well-being—internalizing problems, self-esteem, and life satisfaction—we conclude that the class-level concentration of peer victimization, over and above individual victimization, is negatively linked not only with emotional  and psycThe data were based on a survey conducted among students in schools with high response rates   . One limBoth the current study and earlier research into the contextual effects of bullying are based on analyses of Scandinavian data ,12,13. SThe finding that the prevalence of peer victimization in Swedish classes is related to poorer mental well-being not only for those who are victimized themselves but for all students is highly important from a policy perspective. These results help us to understand peer victimization and bullying as group phenomena and how negative emotions and reactions related to the prevalence of peer victimization appear to ‘spread’ among students. Conversely, it is also important to note that students in classes with relatively low concentrations of peer victimization tend to report more positive outcomes. We can therefore conclude that effective measures to combat peer victimization and bullying will benefit all students.


Compared to other disciplines and sectors, the epidemiological and medical communities have been slow to turn their interest to the climate impacts on health , 2. EmbaWhy is this so?The first argument, which is often put forward, is the lack of valid and reliable health data in these countries, most of which are low or middle income. We hear this argument frequently from climate scientists, as well. Fortunately, this problem can be solved: high quality, long-term (up to 60 years), retrospective, mortality data sets do exist, comprising more than four million observed person-years , 4.The second set of arguments is of more methodological nature. 1) our classical epidemiological tools, comparing exposed and control groups with respect to a risk factor are often not applicable, given the pervasiveness of climate change and the lack of control groups. (2) Climate change comprises different pathways, all of which have quite different health impacts: temperature, precipitation, ocean changes  and air pollution. our clasWhat are some pathways to solve these problems?One is about human brainpower: We need to interest and “enroll” the sharpest scientific minds into this scientific challenge. Unfortunately, we do a bad job at teaching the topic in a systematic way at our universities, West, East, North and South: my last count was 5 accredited formal short courses of 1–3-weeks durations worldwide on “climate change and health”. Massive Open Online Courses (MMOCs) can quickly disseminate knowledge and convey skills. However, the current four MOOCS on the topic are introductory or policy-focused and do not provide research skills. This, however, is the focus of a new MOOC on “Research Methods for Studying Climate Change Health”. This course is currently being developed by scientists of various disciplines from 7 universities: Harvard, Heidelberg, Charité Medical School (Berlin), the London School of Hygiene, Nottingham, Paris Descartes/Sorbonne-Cité, and Umeå. Theses universities are joined by the INDEPTH-network.org, as well as the Potsdam Institute for Climate Change Impact Research (PIK). The course is targeted to doctoral students and postdocs from everywhere wishing to study the impact of climate change on a disorder. The course will provide access to the type of long-term data-sets in (sub-)tropical countries, which I described in the second para above. In addition, participants will learn the required (to be adapted) tools in quantitative health sciences as well as an understanding of key tools from other disciplines .There are other road blocks: particularly our young colleagues are often put off by the lack of project funding in the area of climate change and health. Research funding organizations need to raise the number and volume of their calls in this arena. Often, the topic falls through the disciplinary “silos” of funding institutions: environment, health. Importantly, funders should not evaluate proposals as much on the PI’s past track records in this field, as this is a new research frontier and even the senior scientists in this field—globally maybe only two dozen—do not and cannot have a long publication track records in this field.Journals, in turn, must accept that innovative research has higher risks, that interdisciplinary research is often penalized in reviews, due to “serial” evaluations by specialized scientists.Finally, academic institution need to step up to the task and create careers, from junior research groups to senior positions. As an example: in Germany, there is currently not a single chair for “Climate change and health”.


Detecting associations between an input gene set and annotated gene sets  is an important problem in modern molecular biology. In this paper, we propose two algorithms, termed NetPEA and NetPEA’, for conducting network-based pathway enrichment analysis. Our algorithms consider not only shared genes but also gene–gene interactions. Both algorithms utilize a protein–protein interaction network and a random walk with a restart procedure to identify hidden relationships between an input gene set and pathways, but both use different randomization strategies to evaluate statistical significance and as a result emphasize different pathway properties. Compared to an over representation-based method, our algorithms can identify more statistically significant pathways. Compared to an existing network-based algorithm, EnrichNet, our algorithms have a higher sensitivity in revealing the true causal pathways while at the same time achieving a higher specificity. A literature review of selected results indicates that some of the novel pathways reported by our algorithms are biologically relevant and important. While the evaluations are performed only with KEGG pathways, we believe the algorithms can be valuable for general functional discovery from high-throughput experiments. Modern molecular biology has been revolutionized with the emergence of high-throughput experimental technologies such as microarrays and next-generation DNA sequencing. While many exciting discoveries have been made by data-driven analysis of such whole-genome data sets, an important problem that many biologists face everyday is how to interpret such large-scale data sets. A typical output from such a high-throughput experiment is a list of genes that are observed to be associated with a certain phenotype, such as those differentially expressed in tumors compared to normal tissues. In contrast to the easiness in obtaining the gene list, the bottleneck usually lies in understanding the meaning of the genes and generating new testable hypotheses with the hope to reveal the underlying molecular cause of the phenotype.p-value cutoff, e.g., 0.05, is then applied to select the annotated gene sets that share a statistically significant overlap with the input gene set. ORA is very easy to implement, and the idea behind it is straightforward to biologists. A popular extension of ORA, known as the Gene Set Enrichment Analysis (GSEA) [Biologists are knowledge-driven. A principled way to interpret such gene lists is to compare them with a database of well-annotated gene sets, such as biological pathways. For example, one of the most widely used approach, Over Representation Analysis (ORA) , counts s (GSEA) , tries tBoth ORA and GSEA depend on the availability of trusted gene annotations, such as gene ontology (GO) or metabolic pathways, which limits their applicability to only well annotated species. In addition, gene annotations in databases such as GO or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway may be strongly biased by some classes of genes or phenotypes that are popular targets, such as cancer. More importantly, it is becoming more and more well known that such enrichment-based analyses, including both ORA and GSEA, have very low discriminative power, as they treat genes as independent functional units. In reality, genes function in a highly coordinated way. For example, two gene sets may share few genes but can be involved in similar functional pathways, or they can represent two sub-modules of the same pathway. Common enrichment-based analysis may not be able to detect the relationship between gene sets.To address the aforementioned issues, several studies have proposed the use of biological networks, such as protein–protein interaction (PPI) networks, as a more unbiased tool to investigate the biological meaning of gene sets ,4,5,6. TAnother strategy, which seems to be more successful in practice, is to combine both biological networks and pathways in an analysis. For example, Alexeyenko et al. proposed a network-based method to investigate the associations between input gene sets and annotated gene sets by counting the number of network links between members of two gene sets . Later, In this paper, we propose two network-based pathway enrichment analysis algorithms, NetPEA and NetPEA’, for conducting a network-based pathway enrichment analysis. Our algorithms consider not only shared genes but also gene–gene interactions. The two algorithms share some common features to identify hidden relationships between an input gene set and pathways, but each uses a different randomization strategy to evaluate statistical significance and, as a result, emphasize different pathway properties.The remainder of this paper is organized as follows. We present the details of the two algorithms and the data sets in We propose two network-based pathway enrichment analysis algorithms, NetPEA and NetPEA’. NetPEA treats gene interactions as important as shared genes, while NetPEA’ is devised to find hidden causal pathways that are not enriched within the input gene set.The two algorithms share their first step to calculate similarity scores between the input gene set and pathways based on their “closeness” on a PPI network, measured by a random walk with restart procedure. The two methods then adopt different randomization strategies as their background models to evaluate the statistical significance of the similarity scores. NetPEA uses randomized gene sets as its background; NetPEA’ employs randomized gene sets and randomized networks as its background. Both algorithms take gene interactions into account but focus on different pathways. Considering not only shared genes but also interacting genes, NetPEA extends the search scope of ORA, and therefore it reports more significant pathways. On the other hand, NetPEA’ attempts to de-emphasize pathways that are considered statistically significant simply because of their overlaps with the input gene set, and, as a result, it is able to identify pathways that are within close proximity to the input genes but do not have a significant overlap with them. As shown in V denotes the vector of initial node values; p represents the restart probability, which indicates the probability for random walkers to jump back to their starting nodes (fixed at 0.5 in this study); M is the PPI network transition matrix; and Sn is a vector of all nodes in the network, which is used to measure the similarities between each node in the network and nodes in the input gene set after n rounds of propagation. At the very beginning, S0 is initialized with V. After a period of time of propagation, Sn reaches some dynamic balance and the node values converge and become stable. For each pathway, we take the average of its member gene values as its similarity score to the input gene set.To evaluate the statistical significance for pathways to achieve such similarity scores, we introduce two algorithms based on different randomization strategies.z-scores for pathway significance. D is the similarity score using gene set of interest as input, while R is a set 1000 similarity scores taking randomized gene sets as inputs.NetPEA only randomizes the input gene set, in which we randomly choose the same number of genes as the input gene set to calculate the similarity score for each pathway. After we repeat this randomization 1000 times, we then get 1000 similarity scores for each pathway as its background. Equation  is used z-scores. As the distribution of the z-scores roughly follows a normal distribution, we also convert the z-scores to p-values under a normal distribution assumption. We then select pathways with z-scores greater than 1.65, which corresponds to a p-value 0.05, as statistically significant pathways.We rank the pathways in descending order according to their NetPEA’ randomizes both the input gene set and PPI network to calculate the statistical significance of the associations between the input gene set and annotated gene sets. To randomize the network, we rewire the network connections randomly but ensure all nodes in the network maintain the same degrees as in the original PPI network. Repeating this rewiring 10 times, we have 11 networks including the original human PPI network. For each network, we perform a random walk with a restart procedure to calculate the similarity scores between the true input gene set and each of the annotated gene sets. This is also repeated for 1000 randomized input gene sets.z-score of the association between an input gene set and each annotated gene set is calculated by Equation  of 1000 similarity scores taking randomized gene sets and randomized networks as input. Similarly as in NetPEA, we rank all pathways according to their z-scores, and use a cutoff 1.65 to select statistically significant pathways.The Equation . For eacDR are close to DN. As a result, the z-score for this particular pathway will be “corrected” and becomes insignificant in NetPEA’ compared to that in NetPEA. Therefore, we expect NetPEA’ to report less pathways than NetPEA but, at the same time, be able to promote the ranking of the true causal pathways, which may not be ranked high in NetPEA or other overlap-based methods.Consider that there is a modest overlap between an input gene set and a particular pathway, and that none of the genes in the input gene set, other than those overlapping, are located within close proximity to the pathway genes in the PPI network. In this case, the expected values in the vector The annotated gene sets used in this study are from KEGG pathways . We testValidation of associations between genes sets is difficult because of the lack of ground truth and the biases inherent in different evaluation standards. To evaluate the performance of our methods and have a fair comparison with the existing ones, we adopted and designed multiple evaluation methods.z-score. Moreover, some between-pathway associations found by NetPEA are also reasonable. For example, the top three pathways associated with “DNA replication” are “DNA replication”, ”mismatch repair”, and “nucleotide excision repair”, while the top three pathways associated with “chemokine signaling” are “hemokine signaling”, “cytokine–cytokine receptor interaction”, and “gap junction”.To validate that our algorithms can indeed identify the most relevant pathways, we first used KEGG pathways as input genes to identify the most significantly associated KEGG pathway for each pathway. The rationale is that each pathway should have a closer relationship with itself. Indeed, NetPEA ranks each pathway itself as the most enriched pathway with a very significant On the other hand, NetPEA’ ranks the pathway itself as the most enriched pathway only for 62% pathways, and ranks the pathway itself in the top 10% for 91% of pathways. The deviation from the ground truth is because NetPEA’ is intended to explore hidden pathways by de-emphasizing pathways that are considered significant simply because of their overlaps with the input gene set. Indeed, for a number of cases where the input gene set itself is not ranked as the top gene set, we found evidence of the association between the reported top gene set and the input gene set, such as “maturity onset diabetes of the young” and “methane metabolism”. Note also that the association between the two pathways is not significant according to NetPEA.For four data sets that we have access to the coupled microarrays and ranked gene lists, we applied GSEA to rank the pathways and we use the rankings as benchmarks. GSEA is a benchmark widely used to validate gene set rankings, and  uses it We apply our algorithms, NetPEA and NetPEA’, to each of the data sets mentioned in p-values. p-value ratio (NetPEA/ORA) is less than 0.001; As NetPEA’ is devised to complement NetPEA, it provides new significant pathway information that is not present in the results of ORA or NetPEA. Compared to information in p-values of the overlap under the hypergeometric distribution using 208 total KEGG pathways as background. It is well known that the agreement is often poor between different high throughput experiments concerning the same disease performed by different groups. Among other reasons, this is because many of the genes identified by these experiments are caused by downstream effects, which can vary significantly among experiments. It is reasonable to assume that if indeed we can find true causal genes/pathways, agreement between experiments will be improved. Therefore, for the genes identified from the two breast cancer data sets and the two lung cancer data sets, we compare the significant pathways from different data sets reported by NetPEA, NetPEA’ and ORA. We calculate the ratios of common significant pathways to the total number of unique significant pathways identified from the two experiments as well as the Checking whether pathways ranked at the top by one method are also ranked at the top by other methods can provide additional confidence to biologists and help biologists to narrow down new hypotheses to test. Here we use two cross verification methods, positive cross verification and negative cross verification, to compare our algorithms with ORA, EnrichNet and GSEA. For positive cross verification, we examine how many pathways out of the top 20 by one method appear in the top 20 pathways determined by all the other methods. For negative cross verification, we checked how many pathways out of the top 20 by one method are ranked below the top 100 by the other three methods. We verify NetPEA and NetPEA’ separately because if we verify them together they may vote for each other, which would provide biased, favorable results for our algorithms.Compared with As shown in z-score 3.5 . For the Leukemia down-regulated gene set, both NetPEA and NetPEA’ rank “folate biosynthesis” as the most significant pathway (z-score = 5.0 and 6.5 respectively), while the same pathway is ranked 22nd in EnrichNet and has a p-value 0.05 in ORA. A search through the literature confirms that the relationship between the pathway, “folate biosynthesis”, and leukemia can be verified [Another good example is the Leukemia up-regulated input gene set, where NetPEA’ ranks the pathway “chronic myeloid leukemia” 4th with a significant p-value > 0.05) include “pathways in cancer” for the p53 up-regulated gene set, “steroid hormone biosynthesis” and “sphingolipid metabolism” in Parkinson’s disease, “natural killer cell mediated cytotoxicity” in diabetes, as well as “MAPK signaling”, “ERBB signaling”, “PPAR signaling”, “focal adhesion” and “ECM receptor interaction” for various cancer gene sets, to mention a few.Other verifiable significant associations that are identified by our methods but missed by both EnrichNet (rank > 30) and ORA . The two algorithms apply different randomization strategies to evaluate the statistical significance of the associations and often return complementary results. Compared to the well-adopted over representation analysis (ORA), our methods extend beyond overlap-based comparison, and as a result they are able to identify more significant pathways, report more common pathways shared by different gene sets of the same diseases and gain more GSEA support on the pathways rankings. Compared to another network-based approach, EnrichNet, our algorithms usually report fewer false negative pathways, have a better discriminative power and provide statistical significance. We demonstrate that novel significant pathways reported by our algorithms are biologically meaningful and are confirmed by previous publications. In the future, we plan to extend the methods to be applied to multiple heterogeneous terms and contexts.


In the last decade, clinical staging model of schizophrenia 2 has been increasingly recognized and early intervention is regarded as a promising strategy. The fact that early intervention for psychosis involves providing treatment in the critical period, i.e, at around the onset of the condition, has reminded us of how little we know about the developmental neuroscience of adolescence and how important it is to incorporate knowledge of adolescent brain development into schizophrenia research.3 Human adolescence is much longer than that in non-human primates, and is the stage of life in which the cerebral neocortex matures, thereby promoting human-specific self-regulation.3 Schizophrenia might be reconsidered as a developmental disorder of self-regulation in adolescence.Although schizophrenia was first described as dementia praecox by E. Kraepelin more than a hundred years ago, assuming a neurodegenerative origin, neurodevelopmental hypothesis of schizophrenia 4 tightly coupled with subjective well-being, has recently been emerging from the user’s point of view for providing a life worth living , which is about building a life that is satisfying, fulfilling, and enjoyable. Could personal recovery, a subjective (first-person) concept, be solely pursued through spiritual, ethical, and human rights/social capital approaches? Would the neuroscientific understanding of personal recovery be impossible? We believe it is possible. We should make efforts to scientifically characterize the conceptual framework of personal recovery, so that users, family members, caregivers, and professionals can understand and contribute to the users’ personal recovery and subjective well-being.Major outcomes indicating clinical remission or recovery in schizophrenia have been symptomatology, neurocognition, and objective social functioning. However, the concept of “personal” recovery,How do we achieve this? First, we should scientifically redefine a person’s “value.” Here, “value” refers to individuals’ way of facing the world, which both consciously and unconsciously drives their long-term actions throughout the course of their lives. While childhood is associated with trans-generational, passive incorporation of parental values, adolescence is characterized by social interactions with peers. Through such influences, a person’s value is internalized and personalized to become “personalized value,” on which the person can rely to actively make decisions on his/her own life in the long term.To understand the neural basis of “personalized value,” its development can be modeled as the psychological process in which adolescents acquire the ability to control the conflict between learned value and actual behavior by using self-regulation, including meta-cognition and language (inner-speech). Here, we should consider the “real-world” as the field where an individual develops a personalized value to live his/her own life. We may hypothesize a spiral model where active interactions with the real-world influence value development, which then shapes patterns of action in life, in turn inducing plasticity in the brain circuit. Furthermore, use of a life-course epidemiologic approach is important to understand how personalized value is developed in adolescence and how it influences later life. By integrating the brain, real-world, and life-course approaches, we will be able to deepen the conceptual framework of personalized value and then develop psychosocial intervention strategies to cultivate it.5 Thus, schizophrenia research is in the frontline of the value-based approach,6 which has been recently proposed in the “beyond evidence-based medicine” approach.Schizophrenia is a disorder with adolescent onset for which functioning in the real world may have a long-term impairment. We can incorporate the concept of “personalized value” into schizophrenia research by combining the areas of developmental psychology and neuroscience in adolescence with developmental psychopathology in schizophrenia. This approach will be important to scientifically conceptualize and realize personal recovery, which may also be important to understand the concepts of “person-centered” approach and “democratizing” clinical research.


Established in 2011, BrowZine is a “Journal Enhancement Platform” owned by Third Iron. Usable from a desktop, laptop, or mobile device, the journal browsing service allows users to create a custom electronic journal library of their favorite journals. BrowZine does not change the journal reading experience but helps users discover and organize their favorite journals in a library’s existing electronic journal collection.With a variety of available subjects and subcategories , BrowZine is not limited to health sciences libraries. Brow-Zine’s predictive search can be used multiple ways: searching by subject, title, or ISSN. In subject browsing mode, the user can either view all available journals in a specific subject area or further limit to a specific discipline within that subject area.As an example, through the reviewer’s institutional access, “Biomedical and Heath Sciences” can be limited to dentistry, health care services, nutrition, veterinary science, or any of the additional seventeen subcategories . From thBrowZine uses a custom 3-tier taxonomy  of more Appropriate for students, physicians, faculty, and librarians, BrowZine is useful for anyone who wants to browse journals on an intuitive platform. BrowZine markets itself to academic libraries, medical libraries, and corporate information centers, so the user possibilities are seemingly endless. According to the Third Iron website, BrowZine is used at nearly 500 libraries and information centers in 16 countries [Finding a champion in the institution is important, because BrowZine can be relatively challenging to market. It is difficult to adequately describe the product to potential users on a library’s website, which makes product demonstration crucial. But because many of BrowZine’s intended users are busy clinicians, reaching members of this group to provide one-on-one demonstrations might be an impossible task. In addition to the strategy of recruiting several clinicians or faculty members to help promote the service to their students and colleagues, libraries can use marketing tools provided by Third Iron to promote the product: a LibGuide, widgets, images, and several printable posters.BrowZine’s features can be tailored to suit users’ preference. In addition to simply browsing favorite journals, users can create reading lists; save articles; share articles through Twitter, Facebook, LinkedIn, or email; and export citations to Zotero, Mendeley, BibTex, or EndNote. Articles can also be saved in BrowZine under My Articles. Clicking on the article’s title will automatically connect users to an article’s full text using the library’s existing linking tool.Perhaps BrowZine’s most notable feature is My Bookshelf. My Bookshelf consists of four colored rooms, or “bookcases,” that hold sixteen titles each (four on each “shelf”), for a total of sixty-four individual journals. The user can change titles of bookcases and shelves to aid in organization. Any journal can easily be added to My Bookshelf from the journal’s table of contents page by clicking “Add to My Bookshelf.” When the desktop application is open, BrowZine pushes out badge alerts for each journal title to indicate the number of unread articles.Another useful feature of BrowZine is the ability to integrate the product into LibGuides. Examples include widgets directing users to predetermined subject collections, an A–Z search box, and tables of top journals with access to each title’s current issue. Third Iron has created its own LibGuide with resources and instructions for successfully adding BrowZine to a library’s existing LibGuide. New for 2017 is BrowZine’s application programming interface (API) functionality: the Journal Availability API and the Search Results API are currently available, and late 2017 will see release of the Article in Context API.BrowZine’s mobile application  can be downloaded for Apple, Android, and Kindle Fire using each device’s respective store. Once a BrowZine username and password have been created, the app syncs easily with the desktop version. Similar to the functionality of the desktop version, the app can be set up to push alerts when new content is added to favorite journals.BrowZine works with EZProxy, WAM proxy, OpenAthens, and virtual private network (VPN) authentication systems. A “Pairing Service” is also available for libraries without remote authentication. BrowZine can sync with most existing A–Z systems, including Serial Solutions 360, OCLC WorldCat, TDNet, Alma, and ProQuest Intota.Generally, new users should not require a great deal of training to use BrowZine. The service is easy to learn, and users should be able to create a BrowZine username and password and easily build collections on their own.Although the product is intuitive, BrowZine offers several options for technical support, if the need arises. Support is available through email, or one may visit the Knowledge Base, an extensive bank of questions and answers covering general questions for users, information for publishers, video tutorials, and frequently asked questions about library configuration and working with library holdings. 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An increasing number of patients bring Internet-based health information to medical consultations. However, little is known about how physicians experience, manage, and view these patients. This study aimed to advance the understanding of the effects of incorporating Internet-based health information into routine medical consultations from physicians’ perspectives, using a qualitative approach.Six focus groups were conducted with 48 family physicians practising in Toronto. The data were analyzed using qualitative methods of content analysis and constant comparison, derived from grounded theory approach.Three overarching themes were identified: (1) perceived reactions of patients, (2) physician burden, and (3) physician interpretation and contextualization of information. Physicians in our study generally perceived Internet-based health information as problematic when introduced by patients during medical consultations. They believed that Internet information often generated patient misinformation, leading to confusion, distress, or an inclination towards detrimental self-diagnosis and/or self-treatment. Physicians felt these influences added a new interpretive role to their clinical responsibilities. Although most of the physicians felt obliged to carry out this new responsibility, the additional role was often unwelcome. Despite identifying various reactions of patients to Internet-based health information, physicians in our study were unprepared to handle these patients.Effective initiatives at the level of the health care system are needed. The potential of Internet-based health information to lead to better physician-patient communication and patient outcomes could be facilitated by promoting physician acknowledgment of increasing use of the Internet among patients and by developing patient management guidelines and incentives for physicians. Internet access is rapidly changing the landscape of health information. In North America, 80% of the general population currently accesseshealth information on the Internet for themselves, family, or friends ,2. MoreoSurveys of physicians have explored the impact of Internet-based health information on physician-patient relationships ,8. In a A series of focus groups with family physicians was designed to explore physicians’ opinions of and experiences with patients who brought Internet-based health information to routine medical consultations. Focus groups allow for participant interaction, and, hence, they create a cueing phenomenon which leads to greater insight as to why certain beliefs and opinions are held. This unique feature of focus groups is not found in face-to-face interviews or questionnaires .The focus groups were co-facilitated by a trained moderator and a member of the research team using standard moderation techniques  and an oParticipants wererecruited by telephone by a local recruitment firm whose database contains demographic information on more than 50000 persons in the greater Toronto area. This firm maintained a registry of health professionals volunteering for research. The study was approved by the Research Ethics Boards of St. Michael’s Hospital and York University. All participants provided written informed consent and were compensated with a modest sum for their time, in keeping with local standards for focus groups.The focus groups were tape-recorded and transcribed verbatim. The data were analyzed using qualitative methods of content analysis and constant comparison, derived from grounded theory approach . This meSix focus groups were conducted with 48 family physicians, with an average of 10 participants per group (range 8-12), between April and October 2002. Participants, of whom 54% were male, had been practising for 6 to 27 years, and were encountering approximately 125-149 patients per week on average. All physicians had active practices in the greater Toronto area.Three overarching and interrelated themes were identified: (1) perceived reactions of patients, (2) physician burden, and (3) physician interpretation and contextualization of information. Within the theme of interpretation and contextualization, the sub-themes of physician roles, resistance, and strategies were identified .Dominant views as well as provocative dissenting views are presented below for each theme. Support for our interpretation is provided by including particular quotations from the data that most clearly illustrated the analytic points. From here onward, we refer to Internet-based health information as “Internet health information.” The abbreviations “FG 1,” “FG 2,” “FG 3,” and “FG 4” refer to the four focus groups, and “pg” indicates the page location of the quotes in the transcribed files.Physicians distinguished various patient reactions to the Internet health information brought to medical consultations. Broadly, some patients were perceived to have emotional reactions (confusion or distress) to the Internet health information, while others were perceived to have used the information for self-educationon pre-established medical conditions or for self-diagnoses with or without self-treatment. The latter group was discussed as challenging despite its small size.Patients with emotional reactions were perceived as being either “confused” or “distressed.” Physicians attributed patient confusion to their limited ability to evaluate, personalize, and interpret abundant Internet health information. Physicians identified these patients as needing clarification of the information brought to the visit:FG 3, pg 2Patients who do come with information, I find they are more confused than anything else and they come for clarification.FG 2, pg 2They [patients] are getting full of rather stupid facts in many cases, which they do not know how to interpret, which are usually misinformation.In other instances, Internet health information resulted in patient distress, which was perceived by physicians as patient “anxiety,” “worry,” “nervousness,” panic,” or the patients feeling ‘overwhelmed” or “sicker.” For this cluster of patients, physicians attributed their distress to such factors as the sheer volume of Internet health information, blind faith in or acceptance of Internet data , and/or the inability to critically evaluate the personal relevance of the information:FG 4, pg 3They are bringing up sort of obscure articles and stuff about different conditions, and some of them are pretty scary.… They think everything is happening.FG 6, pg 11It makes them sicker, because they get too worried about what their problems are.Physicians favorably perceived those patients who used Internet health information for educating themselves about their pre-established medical conditions. The self-educators were perceived to introduce the Internet information into the medical visits for confirmation, without challenging physicians’ expertise.FG 5, pg 4I think there’s one situation where the Internet is useful. If the person has the diagnosis, and they want to find out more, educate themselves…, I find that’s actually helpful in cases where…it’s not time-consuming for me.Patients were perceived as “challenging” when they used Internet information for self-diagnosis or self-treatment or to test the knowledge of physicians. The Internet was deemed simply another potential source of misunderstood health information for the challenging patients who were also described as adversarial, professional, difficult, or neurotic. Some physicians perceived these patients as lacking trust in their provider. Physicians often discussed having to defend their diagnosis or treatment plans, with feelings ranging from anger to frustration . However, a few physicians discussed how patients felt distressed and needed help after making self-misdiagnoses.FG5, pg 10If they’re, however, using it to diagnose, then I think that’s where the problem lies….FG 4, pg 14You may disagree with whatever disease that they’ve come in with all this research on.... I think it’s like putting the cart before the horse.... They’re ahead of you and not on the right track.FG 5, pg 9I find that they are testing me on how up-to-date I manage to be.FG 1, pg 5Part of the therapeutic relationship is the trust and the belief that the doctor will make you better. You don’t have that, you have lost a great portion of your therapy.Physicians discussed several difficulties arising from the introduction of Internet health information into the medical consultations. Expressions such as “awkward,” “tough spot,” “hard time,” “headache,” “nightmare,” “annoying,” “irritating,” and ‘frustrating” indicate the magnitude and nature of the difficulties and the accompanying sense of burden such information placed on physicians.Concerns about the quality and quantity of health information on the Internet were common. Physicians linked their uncertainty about websites to their lack of information about recommended health sites andthe instability of websites over time.FG 1, pg 2I can’t answer for a lot of their questions about the validity of the sites that they’ve received information from….FG 1, pg 3I would like to be able to send them to a site that I know is, has reliable information. And I’m not at a point where I have that yellow page book for sites that are approved or somehow controlled.Time constraint was a major issue for these physicians. They discussed having limited time to deal with Internet-derived “volumes of pages” or “scrolls” of questions that patients bring to their visits. In only a few instances did physicians think Internet health information could actually be time-saving. “Big lists” of questions were particularly problematic and a cause for cynicism among some physicians:FG 5, pg 13As soon as that list comes out I panic…[because of] time constraints and everything else.FG 1, pg 3I do not mind patients coming in with information, but it is very hard if they present you with a package of, you know, 60 sheets.... Time is really at a premium, so it makes it very difficult.Furthermore, some physicians acknowledged their limited Internet skills and attributed this to a lack of time to advance their computer skills. This was predominantly discussed among older physicians who seemed reluctant to spend time on learning this new technology:FG 5, pg 8One of the frustrations is, knowledge takes time, and it’s fairly busy, in a busy practice, to just keep up and current in all areas.FG 3, pg 10All the graduates [are] now using these technologies. So, it’s not that it’s too expensive for us as physicians. It’s that we are caught in this transition in terms of “I do not feel comfortable, the time to learn it.”There were, however, a few instances of “rare conditions” and “travel medicine” when physicians thought that Internet information brought by patients into medical consultations had been helpful in making a diagnosis or identifying an appropriate referral.FG 6, pg 12We [family physicians] do not know everything. Then, it can’t be challenges, actually “teach me” sometimes.FG 1, pg 3I had a patient…I didn’t know the diagnosis, something getting off a ship and having vertigo and some problems that ensued. The ENT doctor did not know…and in her search on the Web she found the diagnosis and found a single physician in Ontario. She ended up getting a referral by me….Many physicians viewed putting Internet health information in context for patients  as part of their responsibility and role. Physicians generally believed they were in the best position to explain, synthesize, and contextualize information because of their training:FG 6, pg 7I think for many patients they don’t have the wherewithal to assimilate this sort of information and come up with the appropriate response.... Part of our role is to explain that to them.... They don’t have the background knowledge that we have in order to put it into proper perspective.The specific roles of physicians in relation to the contextualization and interpretation of Internet health information varied depending on the responses of patients to that information. For those patients perceived by physicians as self-educators, the work of the physicianwas generally limited and sometimes actually reduced.However, for distressed or confusedpatients who took an uncritical stance toward the information, physicians discussed having the significant task of educating them by putting the information into its proper context. Physicians perceived this task as time-consuming, and, hence, a burden on their routine clinical responsibilities:FG 5, pg 1Similar experience where the patients are coming informed with information from the Internet, and sometimes from good sources and sometimes from more anecdotal, personal Web pages where the information may not be entirely correct. Then, you have to do lots of damage control and try to not disinform but try to undo and re-educate.,physicians described doing substantial work in justifying and, at times, even defending their own diagnosis and treatment recommendations or in “debunking” incorrect information. In having their expertise challenged, some physicians felt they were at risk of “losing face” and/or being “put on the spot”:For patients who used Internet for self-misdiagnosis or self-treatmentFG 4, pg 3Some of my patients come in with a diagnosis...convinced in their minds that this is what they have. Then you’re almost put on the defensive sometimes as to why you think otherwise, or why maybe they should be looking elsewhere for what are their symptoms. So, it’s more of a challenge.Importantly, not all physicians embraced the role of interpreter, and there were indications of resistance from some to discussing Internet health information with any patient:FG 3, pg 1Most of them [patients] know it’s annoying to me when they do it [bring in Internet downloads], so they don’t.FG 3, pg 3I just sort of stick with what I know and what I do and how I practice.The excerpt above highlights the fact that, in some instances, not only is the physician resistant to Internet health information, but his or her patients are aware of this resistance. Older physicians seemed more resistant:FG 3, pg 11A lot of people do not take new patients. So, we are going to grow old with our patients. And they’re gonna get used to our ways and we’re gonna [get] used to theirs.FG 5, pg 14I think a lot of it is dependent on the age of the physician…. The older physicians are paternalistic and…do not feel comfortable when a patient comes in with an article….Physicians discussed various strategies they had adopted in order to cope with Internet health information introduced by patients during medical consultations. These strategies included recommending reliable websites, asking for a follow-up visit, or expressing limited knowledge on specific details:There is nothing wrong with saying, “You know what? I do not see a lot of this but I am going to find out for you.” They have huge time commitment and an emotional commitment to whatever it is they’ve brought in. So, I’ll say, “Leave it with me for a couple weeks and let me think about it.” And I’ll usually look it over, probably not while they’re there, not that minute. Notably, some physicians discussed strategies of “firing” the patient, referring patients to specialists, or charging for extra time. These strategies have the potential to undermine the physician-patient relationship.FG 4, pg 9Well, frankly, we’re paid for [the] visit. So, if your patient [is] having a $15 visit, you’re not going to sit for 15 minutes going through all this, you’re going to get them out of the office.FG 3, pg 4If they come in and it’s too much and it’s too specialized…I let them slug it out with the specialist. They’re paid very special money to do this kind of work.FG 4, pg 13Maybe we can bill our patients privately for extra time to review research with them, if we can choose to do that or not do that.FG 5, pg 7They’re coming back [with Internet information]. It requires a little looking into. If you’re tired, of course, you’ll probably just fire them…if they’re really belligerent.Physicians in our study generally perceived Internet health information as problematic when brought by patients to medical consultations. They believed that Internet information generated patient misinformation, leading to confusion, distress, or an inclination towards detrimental self-diagnosis and/or self-treatment. Physicians felt these undesirable but common influences of Internet health information added a new interpretive role to their clinical responsibilities. Although most of the physicians felt obliged to carry out this new responsibility, the additional role was often unwelcome. Despite identifying various reactions of patients to Internet health information, physicians in our study were unprepared to handle these patients.Despite the patient-perceived benefits of bringing Internet health information into medical consultations ,5,6, phyPerceptions of consultations being too demanding were further compounded by physicians’ uncertainty about website validity, alack of incentives to contextualize the Internet health information for patients, and limited access to up-to-date resources. The scepticism expressed by physicians about the quality of health information on the Internet is in accordance with existing empirical studies . NeverthIn our study, physicians’ perceptions of difficulties in adopting their new role of contextualization and interpretation seemed to vary according to their perception of patients’ reactions to Internet health information. This possible inter-relatedness should be examined in future research.Many academic and nonacademic institutions have recently begun to train health care providers to critically evaluate Internet materials available to patients . HoweverFirst, there is a need to increase the awareness of health care providers about the Internet-generated “reversed” information asymmetry . Today, Second, training programs for health care providers need to enhance physicians’ understanding of patients’ perspectives on Internet information. For instance, patients with serious sickness are more likely to ask their physician about Internet health information . Also, pThird, time-pressed physicians require tangible incentives to undertake the new role of contextualization and interpretation. Alongside monetary incentives, which require progressive structural changes in health care services, other incentives targeting professional “pride” should be considered. These include recognition in the form of certificates, award nominations, or credits for continuing medical education on information technology. The incentives should particularly target those health care providers who graduated beforethe inclusion of information technology in health care training programs.”use of the Internet among patients entails an inherent risk of ignoring less resourceful people.Finally, patient-focused strategies related to Internet health information could complement physician-patient communication. Health care institutions could actively develop general patient guidelines on how to optimize the usefulness of Internet health information in physician-patient encounters. However, educating the public to apply evaluation criteria in a critical appraisal of the health information available on the World Wide Web, as proposed by others ,24, is aThe study has some limitations. We used a convenience sample of urban physicians, which limits the generalizability. Physicians in our study seemed to have highly negative attitudes toward the influence of Internet health information on physician-patient relationships compared to prior physician surveys. Possible explanations include the cuing phenomenon of focus group methodology, use of prompts in the discussion guide, metropolitan sample of family physicians, and/or individual characteristics of the participants, such as number of years since graduation. Future research studies should examine physicians’ perceptions by speciality, geographic location, and practice years. Nevertheless, our study findings represent the tip of the iceberg.The dramatic increase in patient access to Internet health information of varying quality influences physician-patient relationships. We identified several factors that will need to be addressed in order for this information to be optimally integrated. Effective initiatives at the level of the health care system are needed. The potential of Internet health information to lead to better physician-patient communication and patient outcomes could be facilitated by promoting physician acknowledgement of an increasing use of Internet health information by patients and by developing patient management guidelines and incentivesfor physicians.