Yersinia pestis, is found in Asia, the Americas but mainly in Africa, with the island of Madagascar reporting almost one third of human cases worldwide. In the highlands of Madagascar, plague is transmitted predominantly by two flea species which coexist on the island, but differ in their distribution. The endemic flea, Synopsyllus fonquerniei, dominates flea communities on rats caught outdoors, while the cosmopolitan flea, Xenopsylla cheopis, is found mostly on rats caught in houses. Additionally S. fonquerniei seems restricted to areas above 800 m. Climatic constraints on the development of the two main vectors of plague could explain the differences in their distribution and the seasonal changes in their abundance. Here we present the first study on effects of temperature and relative humidity on the immature stages of both vector species.Plague, a zoonosis caused by We examined the two species’ temperature and humidity requirements under experimental conditions at five different temperatures and two relative humidities. By employing multivariate and survival analysis we established the impact of temperature and relative humidity on development times and survival for both species. Using degree-day analysis we then predicted the average developmental threshold for larvae to reach pupation and for pupae to complete development under each treatment. This analysis was undertaken separately for the two relative humidities and for the two species.S. fonquerniei taking on average 1.79 times longer to complete development and having a shorter time to death than X. cheopis under adverse conditions with high temperature and low humidity. Temperature had a significant effect on the development times of flea larvae and pupae. While humidity did not affect the development times of either species, it did influence the time of death of S. fonquerniei. Using degree-day analysis we estimated an average developmental threshold of 9 °C for S. fonquerniei, and 12.5 °C for X. cheopis.Development times and time to death differed significantly, with the endemic S. fonquerniei, is better adapted to cool temperatures than the exotic flea vector, X. cheopis. Future warming caused by climate change might reduce the area suitable for S. fonquerniei and may thus reduce the incidence of plague in Madagascar.While many vector-borne diseases are limited to warm, low-lying regions, plague in Madagascar is unusual in being most prevalent in the cool, highland regions of the country. Our results point towards the possibility that this is because the endemic flea vector,  Yersinia pestis, with rodents and their fleas as its principal hosts. Transmission of bubonic plague to humans occurs via the bite of an infected flea and if left untreated, it triggers serious illness with up to 55 % case fatality in human populations [Plague, a vector-borne, highly virulent zoonotic disease is still present today in Africa, Asia and the Americas. It is caused by infection with the bacterium ulations , 2. In mulations –6 and liulations . With 48ulations .Rattus rattus [Xenopsylla cheopis (X. cheopis), a cosmopolitan, exotic species, and Synopsyllus fonquerniei (S. fonquerniei), an endemic species. The two vector flea species coexist on the island, but occupy different niches, with X. cheopis found primarily on black rats within dwellings, while the endemic S. fonquerniei dominates the flea communities infesting rats living outdoors [S. fonquerniei appears to be absent [Plague is endemic in the highland region of Madagascar, above 800m of altitude. The reasons for such pronounced foci include unique host and vector dynamics, special climate features such as warm, wet austral summers and cool, dry winters as well as extreme poverty [s rattus , with twoutdoors . Below 8e absent .X. cheopis are low from April to December, whilst in rural areas numbers of adult S. fonquerniei increase during the cold dry season (from July onwards), peaking in September to January [In the central highlands of Madagascar, both human plague incidence and the abundance of the two flea vector species show seasonal cycles. Most human cases of plague are reported during the warm rainy season from October to March , 12. At  January .X. cheopis and S. fonquerniei within Madagascar, and the contrasting seasonal cycles may be driven by differences in climate susceptibility between the two species. The climate across Madagascar is described as unimodal tropical, with a hot rainy season from November to March and a cold dry season from April to October. To determine the temperature and relative humidity ranges for the experiment, information from micro-climate measurements inside burrows of the black rat (Rattus rattus) in the highlands of Madagascar was used. Previously published work by Sharif et al. on the development time of X. cheopis from India in 1949 in relation to temperature and humidity [X. cheopis, little is known about the biology of S. fonquerniei, and there is a critical need for information on the basic developmental constraints of the two flea vector species to provide further insight into plague epidemiology in Madagascar. Here we present the first study investigating the temperature and humidity needs of S. fonquerniei under experimental conditions, by examining larval and pupal development as well as survival. We provide original data on the effects of climate on the development and survival of the endemic S. fonquerniei and its counterpart X. cheopis.Like other ectoparasite species, flea distribution and abundance can be significantly affected by climatic variables. The immature stages of fleas develop in host burrows and are sensitive to air temperature and humidity, with effects on both development and survival times , 15. Thuhumidity  was alsoColonies of both vector species originated from adult fleas collected in 2001 from a total of 12 different highland regions of Madagascar. New specimens of both species from these regions were added every year until 2006. Since collection, they have been maintained in insectaria at the Medical Entomology unit, Institut Pasteur de Madagascar (IPM).The fleas were reared in covered glass jars, 1/4 filled with a 50:1 mixture of rice husk and dried beef blood for larval nutrition, at 27 ± 2 °C and 70 % ± 5 % relative humidity (RH). To obtain sufficient numbers of larvae for the experiment, recently fed, adult male and female fleas were transferred into glass jars containing 2 g of rice husk as a surface for oviposition. After 24 h the adults were carefully removed and the jars with the eggs were left to stand in the insectaria for 6 days. The jars were checked once a day until newly hatched larvae were detected; larvae were only collected once from each jar to ensure the same age of the specimens. In other flea species, the RH conditions under which the eggs are incubated do not affect the development time of larvae subsequently exposed to different conditions .n = 56) during the wet and dry season in villages reporting plague. In the dry season recorded burrow temperatures ranged from 17–22 °C and 65–81 % relative humidity while in the wet season burrow temperatures were between 23–28 °C and 84–94 % relative humidity. According to this information experiments were undertaken using incubators  at five temperatures , each at two RHs, 80 % and 90 %. Using a method described in detail by Winston and Bates [4)SO4, and sodium carbonate, NA2CO3, to 1.5 cm depth within airtight plastic boxes.Between 2008 and 2009, Easy Log data loggers  were used to record temperature and relative humidity inside rat-burrows  to ensure that the climatic conditions were maintained.S. fonquerniei  and X. cheopis (n = 750) larvae, up to 24 h old, were transferred onto halved ELISA-plates (NUNC MaxiSorp™ polystyrene 96 well), with one larva per well. Each well contained 5 mg of larval rearing medium . As a higher mortality rate became apparent, more S. fonquerniei larvae were reared than X. cheopis. Plates were placed on stands in the airtight boxes within the incubators and covered with fine nylon mesh to prevent escape during the first two days when the larvae are most active.Newly hatched Larval survival and cocoon formation  were noted daily. The developmental growth progress of the larval stages of both species was recorded every second day by placing the transparent ELISA plate under a microscope lit from below. Pupation indicated completion of the active larval stage. Larvae were observed until they either pupated or died, except for a small number which had still not pupated after twice the time taken by the majority of their counterparts; these individuals were assumed to have a developmental problem and, although still alive, they were excluded from the study population (2.74 %).After pupation, cocoons were individually transferred into 5 ml Eppendorfs and sealed with fine nylon mesh to prevent the adult flea escaping, once hatched. Each cocoon was then subjected to the same conditions as the larva before pupation. In some cases, however, cocoons were attached to the well, and could not be removed without risk of damage. In these cases, the wells were sealed with perforated Parafilm and maintained as for those in Eppendorfs. Eppendorfs and plates with cocoons were shaken gently every day to help stimulate emergence . Once emX. cheopis and 245/1288 (19.0 %) of S. fonquerniei), and to pupae that emerged as adults (258/521 (49.5 %) of X. cheopis and 77/245 (31.4 %) of S. fonquerniei). Temperature was log-transformed. LDTs and PDTs were tested for normal distribution using an Anderson Darling test. Outliers greater than the mean ± 2 SD were removed from the analysis. For each dataset, linear mixed effects models were first used to examine the effects of temperature and RH on development time of each species individually. There was a potential of non-independence of samples, as the individual larvae and pupae of one plate were likely to be from the same batch of eggs. To account for possible non-independence, plate was included as a random effect in all models. Subsequently, models were developed for the data of both species combined, with species as a fixed effect, and two-way interaction terms between temperature, RH and species. The purpose of the combined model was to examine differences in the effects of RH and temperature between species. Due to heterogeneity of variance in LDTs and PDTs between temperature treatments, a fixed variance structure as a function of temperature was used by applying a weights argument. This accounted for the larger variance in development times at lower temperatures. Model selection was based on the Akaike information criterion (AIC) [The data were divided into two sets for analysis: larval development time to pupation (LDT) and pupal development time to emergence (PDT). These analyses were restricted, respectively, to larvae that pupated successfully (521/750 (69.5 %) of on (AIC) . All staon (AIC)  in R 3.1To investigate the effect of species, temperature and humidity on the timing of death, survival analysis  was applA widely used method, degree-day analysis, was chosen to determine the thermal units needed by larvae to reach pupation, and by pupae to complete development , 27. ThiX. cheopis completed both development stages successfully and emerged as adults than the endemic S. fonquerniei. Sixty-nine percent of larval X. cheopis survived to pupation, and 34 % to adulthood. By comparison, only 19 % and 6 % of S. fonquerniei larvae reached the pupal and adult stages respectively. The male: female ratio of the emerged X. cheopis was 1: 0.79; that of S. fonquerniei was 1:2.5.Analysis of the raw data revealed that more individuals of X. cheopis were faster than S. fonquerniei at almost all temperatures, at both 80 %  and a significant interaction between temperature and RH .Overall the Kaplan Meier survivorship curves indicated that pis Fig. . In addiRH Table ; Fig. 2.S. fonquerniei larvae developed at 18 °C to include them in this analysis. At 32 °C the development time plateaued and thus the data was also excluded. Using the remaining 3 temperatures, the developmental threshold (intercept of the regression line and the x-axis) was 12.4 for X. cheopis and 9.3 for the endemic S. fonquerniei, a difference of 3.1 °C . Pupal development time was similar for the two species, but, as with larvae, pupal development in X. cheopis was significantly more sensitive to declining temperatures.m Sharif  and Mellm Sharif . There wX. cheopis survived longer at higher relative humidity, but no effect of temperature was detected. By contrast, survival times of larvae of S. fonquerniei were unaffected by relative humidity at low temperature, but at higher temperature they survived longer at higher relative humidity. Therefore, both species appear to survive longer at higher RH, but this is only true for S. fonquerniei when at higher temperature. This is consistent with an effect of desiccation on survival of the larvae of S. fonquerniei. Air is capable of holding more moisture at higher temperatures, and warmer, dry air is therefore more able to desiccate insects than cooler, dry air. This effect of increased temperature as a cause of desiccation and hence mortality is partially offset at higher relative humidity, as the warm air’s ability to desiccate is reduced.There were also differences between the species in the effects of temperature and humidity on survival time. Under laboratory conditions, larvae of S. fonquerniei than X. cheopis. This is perhaps not unexpected; given the restricted distribution of S. fonquerniei’s to the cool highlands of Madagascar, while X. cheopis is found throughout the island, and elsewhere. This may also be consistent with the presence of S. fonquerniei in outdoor rat burrows, while X. cheopis tends to be found only in burrows in houses which may be presumed to be warmer. Nevertheless, although S. fonquerniei is able to start developing at a lower temperature than X. cheopis, it requires a larger number of degree-days to achieve the same level of development (i.e. pupation).Converting the development times to development rates, and plotting the rates against temperature, indicates that the temperature threshold for development is substantially lower for S. fonquerniei, is found predominantly in the cooler highland regions of Madagascar [X. cheopis developed significantly faster than S. fonquerniei in all treatments except at the lowest temperature. Our results point towards the possibility that the endemic S. fonquerniei is better adapted to colder conditions found in the plague regions of Madagascar, while it may be outcompeted by X. cheopis in the warmer conditions that prevail in other parts of the island. This is supported by the degree-day analysis, estimating the developmental threshold of S. fonquerniei to be 3.1 °C lower than that of X. cheopis and thus giving the endemic S. fonquerniei an advantage in the colder highlands of Madagascar. However, due to the low number of larvae pupating at 18 °C, particularly for S. fonquerniei, there was only limited power to estimate lower development rates and thresholds and compare them between species.In terms of fleas, the endemic species, dagascar . Our resS. fonquerniei’s greater vectorial capacity [X. cheopis is thriving again in the warm summer months.The highland plague focus in Madagascar may be due to interplay between the two vector-species present above 800 m. capacity  and loweStenseth et al.  suggest S. fonquerniei, which has a high vectorial capacity for plague [X. cheopis in the coolest, highland parts of the country. This is also supported by findings of the highest abundance of S. fonquerniei in the cool and dry season [S. fonquerniei and/or more suitable for X. cheopis.A frequently cited impact of climate change is that increasing temperatures will enable many vector-borne diseases to spread from warm, low-lying areas to higher, upland regions that were previously too cold. There is a considerable body of evidence that climate change has enabled malaria, for example, to spread into highland areas of East Africa and South America . Plague r plague , survivey season . In thatS. fonquerniei, an important plague vector in Madagascar and a species endemic to that island. Previous studies on rodent fleas report species-specific effects of humidity and temperature on development times and adult survival [S. fonquerniei and compare them to those of X. cheopis. The range of temperatures and humidities used in this study was narrow and further laboratory work would be necessary to determine both the upper and lower developmental threshold temperatures for both species.The main aim of this study was to gather basic knowledge of the climatic constraints on the development of the flea survival , 16. ThiX. cheopis’ seasonal distribution patterns being determined by pre-imaginal development times [The results of this study are consistent with nt times .S. fonquerniei is better adapted to colder conditions found outdoors in the plague-endemic highlands. Our results suggest that a study with a wider range of temperatures and humidities and constant as well as fluctuating climate conditions would add valuable data and improve our understanding of the factors that determine the distribution of plague in Madagascar. In order to understand the vector-pathogen-host dynamics of plague an additional study evaluating the effects of different temperatures and RHs on plague transmission to mammal hosts by these flea species would be extremely valuable.Our results point towards the possibility that the endemic


Self-harm is a major public health issue in young people worldwide and there are many challenges to its management and prevention. Numerous studies have indicated that ADHD is associated with completed suicides and other suicidal behaviours . However, significantly less is known about the association between ADHD and self-harm.This is the first review of the association between ADHD and self-harm. A systematic PRISMA review was conducted. Two internet-based bibliographic databases (Medline and CINAHL) were searched to access studies which examined to any degree the association between, specifically, ADHD and self-harm.Only 15 studies were identified which investigated the association between ADHD and self-harm and found evidence to support that ADHD is a potential risk factor for self-harm.This association raises the need for more awareness of self-harm in individuals with symptoms of ADHD. Attention-deficit/hyperactivity disorder (ADHD), as defined by DSM-IV , is a syNomenclature used to describe acts of self-harm without fatal consequences varies considerably. For this review the terms deliberate self-harm (DSH), self-harm, self-mutilation, self-injury and self-injurious behaviour (SIB) are used interchangeably depending on the use applied in the paper discussed. DSH and SIB represent a significant health problem in the UK and are amongst the most common reasons for emergency hospital admission. Although international variation exists, findings from numerous community-based studies indicate that approximately 10% of adolescents report having self-harmed -12. SelfPrevious studies have shown a connection between ADHD and attempted and completed suicide in male adolescents and young adults -21, suicA previous systematic review  showed aFurther research is necessary to develop a mean of preventing adolescents from repeating self-harm, since several studies have shown that around 10–15% of children who self-harm are likely to repeat such episodes within a year ,29, someAlthough the focus of this systematic review is on ADHD and the outcomes, it is important to include a brief discussion of the crossover with medication and what is currently known. With the treatment of ADHD it is thus important to establish any associations between pharmacological treatments (such as atomoxetine and methylphenidate) and suicide-related events. Atomoxetine (Strattera®) is a selective norepinephrine  reuptake inhibitor. It is not a stimulant, and is indicated for use in patients with ADHD . MethylpHowever, a recent meta-analysis, the first focusing on five studies comparing suicide-related events in comparative randomised double-blind atomoxetine and methylphenidate clinical trials, found no significant evidence of a difference in risk between the two treatments . Given tThere is a need for greater understanding of the factors which contribute to self-harm. Identification of effective prevention initiatives and subsequent treatment strategies aimed at young people and those at particular high risk is clinically imperative. There is an urgent need to identify those populations at risk and to intervene proactively . The purInternet-based bibliographic databases (Medline and CINAHL) were searched to access studies which examined to any degree the association between, specifically, ADHD and self-harm rather than the association between ADHD and completed suicide, suicide attempts and suicide ideation. The search criteria identified below were entered in a number of other databases including PsycINFO. However, the Medline was chosen as the primary database because it returned more relevant articles. CINAHL was also used because it is the definitive research tool for nursing and allied health professionals. The process of eliminating non-relevant papers can be seen in the flowchart .Screening:In the first stage, papers were rejected which:self-harm as even less is known about this association.•investigated completed suicide, suicide attempts or suicide ideation as this review is specifically interested in the association between ADHD and •were not published in the English languageFor the next stage papers were rejected which:•were not studies that involved a sample of individuals with ADHD .In addition, review papers and book chapters which were clearly reviews were excluded and if relevant are referred to in the introduction. Full documents were obtained for the remaining records.Fifteen studies were found that explored or included an exploration of the association between ADHD and self-harm (one of which was a case study). Table Deane and Young  investigHinshaw et al.  conducteThe idea that ADHD may act as a risk factor for suicidal ideation and DSH was also investigated in a study based on adolescents from a general population sample  derived The effect of ADHD on substance-use disorder (SUD) as well as other behaviours such as SIB, suicide attempts and criminality is unclear which prompted the next study by Semiz, Basoglu, Oner et al. . A totalWehmeier, Schacht, Lehmann, Dittmann, Silva and March  were intDowson, Blackwell, Turner, Harvey, Malhotra, Robbins and Sahakian  examinedIn a more recent study by the same research group, Dowson and Blackwell  investigBen-Yehuda, Aviram, Govezensky, Nitzan, Levkovitz and Bloch  found anDiScala et al.  investigGoodman, Gerstadt, Pfeffer, Stroh and Valdez  examinedIzutsu, Shimotsu, Matsumoto, Okada, Kikuchi, Kojimoto et al.  exploredLam  found a Lam  investigLynch, Mills, Daly and Fitzpatrick  investigFulwiler, Forbes, Santangelo and Folstein  tested tThis review identified 15 studies which investigated the association between ADHD and self-harm (one of which was a case study design). All of these studies indicate an association between ADHD and self-harm which suggests that ADHD may be a potential risk factor for self-harm.It is important to consider the age of the individuals with ADHD in the studies which have been identified by this review (which investigated the association between ADHD and self-harming behaviours) given the literature which suggests that ADHD symptoms can sometimes change with age. Although ADHD symptoms frequently persist over time , maturatIt is also important to highlight the gender in the studies identified by this review given the gender differences seen in individuals with ADHD . The exiLooking at the gender in the group of interest across all fifteen studies it is clear that there are much higher numbers of males than females. This can be seen more clearly in Table The majority of the studies used samples of children (below the age of 18 years). Only three studies used a sample of adults (older than 18 years) -45, of wFrom the 15 identified studies in this review, seven were studies using a population with ADHD and measures of self-harming behaviour were then conducted ,48,52,53The importance of further research into the association between ADHD and self-harm is further highlighted by the studies (outwith this review) which have investigated the increased rates of suicide in individuals with ADHD. For instance, Barbaresi, Colligan, Weaver, Voigt, Killian and Katusic (2013)  investigThe conclusions that can be made regarding the strength of association between ADHD and self-harm are limited due to the relatively small amount of studies that have been conducted to date. In addition, the majority of these studies use small populations and some do not contain (or report on) control group findings. Publication bias is likely to be present as studies reporting no correlation are unlikely to be published . DifferiAnother limitation is the fact that data for the studies were collected retrospectively and then analysed for suicidal related events which exposes the studies to a degree of confounding bias, particularly in the studies where, for example, the Columbia Classification Algorithm for Suicide Assessment (C-CASA)  and the Computerized Suicide Risk Scale (CSRS) have not been delivered. Mapping any event to a specific code is possible, however, the potential for error is greater than if the scales were used prospectively. The use of these scales are often mandatory in trials. Additionally, the ability to separate self-harm as an entity from a suicide attempt is not always easy which is a potential confounding bias. In particular, Silverman, Berman, Sanddal, O’Carroll and Joiner (2007)  emphasisLastly, the influence of comorbidity is difficult to disentangle from the main findings, particularly for substance misuse and delinquency, prompting the need for further research using younger populations and those without co-morbidity .One study has shown some understanding of this relationship in their treatment strategies. Carminati, Deriaz and Bertschy  had goodDespite the contribution to our knowledge of self-harm behaviours to date, we remain unclear as to exactly why individuals engage in these behaviours and, even more importantly, we do not have in place effective methods of accurately predicting or reducing these behaviours as a consequence. Therefore, it is vitally important that risk factors for self-harm (such as symptoms of ADHD) are recognised and identified to produce more reliable risk level indicators.The author declares that she has no competing interests.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/14/133/prepub


Studies report the variable prevalence of attention deficit hyperactivity disorder(ADHD) in incarcerated populations. The aim of this meta-analysis was to determine theprevalence of ADHD in these populations.Primary research studies reporting the prevalence (lifetime/current) of ADHD inincarcerated populations were identified. The meta-analysis used a mixed log-binomialmodel, including fixed effects for each covariate and a random study effect, to estimatethe significance of various risk factors.versus diagnostic interview (and with retrospectiveyouth diagnoses versus current diagnoses). Using diagnostic interviewdata, the estimated prevalence was 25.5% and there were no significant differences forgender and age. Significant country differences were noted.Forty-two studies were included in the analysis. ADHD prevalence was higher withscreening diagnoses Compared with published general population prevalence, there is a fivefold increase inprevalence of ADHD in youth prison populations (30.1%) and a 10-fold increase in adultprison populations (26.2%). These individuals, who are often untreated, seem to have greater judicialcontact and pose higher risk within the criminal justice system. Compared with otheroffenders, they present with younger age at first contact, greater recidivism andinstitutional behaviour disturbance  the prevalence of ADHD in incarcerated youth and adult offenders,including differences by gender; (2) prevalence from studies applying screening tools anddiagnostic clinical interviews; (3) differences in prevalence obtained from retrospectivediagnoses from adults and youth prevalence obtained using a current diagnoses methodology;and (4) geographical differences.et al.The systematic review was performed in accordance with the Preferred Reporting Items forSystematic reviews and Meta-Analyses  and EMBASE (1988 to presentsegment), Datastar PsycINFO (unrestricted) and Social SciSearch , including the literature published between 1January 1980 and 3 May 2011; a citations update was performed on 21 June 2011 and extendedto 31 August 2012 in October 2012.Search terms were developed, refined and tested for relevance by cross-checking resultsagainst a list of known relevant articles provided by the lead author. The followingdescriptors were used in OvidSP EMBASE (1988 to present segment): ADHD; attention deficitdisorder; [EMTREE] crime; criminals; criminology; criminal behaviour; criminal justice;criminal law; court; criminal psychology; delinquency; juvenile delinquency; gang; legalevidence; legal procedure; police; legal liability; mandatory programs; violence; prisons;prisoner; probation; law enforcement; recidivism; jurisprudence; punishment; offender;drug abuse; drug misuse.Articles obtained from the final searches were first de-duplicated, then aninclusion/exclusion process was undertaken based on the following exclusion criteria:non-English language articles, articles published before 1980, animal studies, articlesthat were not peer reviewed (e.g. theses), and articles that obviously did not holdrelevance . Review articles pre-2006 were excluded, andpost-2006 reviews were kept with the sole purpose to examine bibliographies to check forany other articles not identified in the search; these review articles were not includedin the final prevalence calculation; only primary research articles were included.Articles with no abstract were also excluded unless the title or other information (e.g. key terms) suggested theymay hold relevance. The inclusion/exclusion review was first completed based ontitle/abstract/key words by four researchers, and if the relevance of an article wasunclear, the full text was retrieved before a final decision was made. Once the initialbulk of the inclusion/exclusion process was completed, abstracts were reviewedindependently by the lead author before full-text articles were retrieved. Anyuncertainties over including/excluding articles were discussed among the researchers and afinal decision was made once the full-text articles were reviewed.The full texts of included articles were retrieved for detailed evaluation againsteligibility criteria. Only the publications that focused on incarcerated/prisonpopulations and those that reported ADHD prevalence were selected. Studies that reportedresults on mixed gender populations were excluded as we aimed to separate the gendereffect in modelling.A data extraction sheet was developed in Microsoft Excel and pilot tested on 13 randomlyselected studies and refined accordingly. The publications were divided among fourresearchers (including two authors: D.M. and O.S.) who performed the data extractionindependently. Data were reviewed for consistency and any queries were resolved bydiscussion among the researchers and the lead author. The lead author also made the finaldecision whether to include/exclude data by reviewing the identified publications.et al.et al.et al.et al.etal.et al.The authors of 11 studies were contacted directly in personal communications to ascertainmissing information relating to age of the study population ; papers reporting youth data often cited 18 years as the upper limit of the agerange of participants. In those papers where an age range was given that spanned thiscut-off point (e.g. 15–28 years), the mean (or median if mean was not provided) was usedto define whether the study population should be listed as ‘youth’ or ‘adult’. For studiesreporting on (1) both genders separately, (2) both diagnostic criteria or (3) both studydesigns, information was recorded as two separate observations (‘study strata’) linked bythe study number. None of the studies reported separate results on more than one of thesethree characteristics and none reported on both age groups.For each included study, data were extracted into a data set containing: (1) studylocation (country of origin), (2) study sample size, (3) study population (including ageand gender), (4) diagnostic criteria (screening or diagnostic interview), (5) study design, (6) ADHD prevalence and (7) treatment (including prison management). We haveused the term ‘prison’ but included all individuals who were incarcerated, jailed orimprisoned, or similar descriptors. For the analysis, studies were grouped by age foryouth and adult offenders (see Supplementary Tables S1 and S2). It was noted that therewas no clear definition across publications on the age of an adult n = 13) included in this meta-analysis also reported aprevalence of childhood ADHD for the cohort (referred to as a retrospective diagnosis inthis study).For a diagnosis of ADHD to be given in adulthood, clinically significant symptoms musthave been present in childhood. Therefore, when assessing adults for ADHD, it is necessaryto establish whether they meet criteria for childhood ADHD, requiring them toretrospectively report on their symptoms . Someadult studies .Summary prevalence estimates were calculated for the meta-analysis. Observed prevalenceper study stratum was reported by age and gender groups. Model-predicted prevalence wasreported by the various model covariates together with their corresponding 95% confidenceintervals (CIs).yij is the number of patients with the response, pij is the ADHD prevalence and nij is the total number of inmates included in study i and on stratumj. As implemented here, the model made the following assumptions: (1)i represented a random study effect, assumed to follow a normal  distribution. The study effect was considered tobe the within-study logarithmic baseline prevalence, thus eliminating thestudy-specific effect from the other comparison estimates.study(2)ij represented the adjusted gender effect common to all patients in studyi and stratum j on the logarithm of prevalence.Similarly for ageij, diagnostic methodij, study designij and countryi. Countries were also grouped into regions in an attempt to obtain more stableestimates .genderGiven the observed level of interaction between gender, age group and diagnosticmethod, these three covariates were fully interacted in the model and were represented byeight indicator variables (one omitted as a reference group). Other interactions were alsotested for significance. Marginal estimates of prevalence (least-square means) for each ofthe covariates  and for their combinations were calculated byapplying the inverse logarithmic transformation to model predictors. To estimate thesensitivity of results to the diagnostic method, the model was refitted to a subset ofdata using diagnostic interview strata only (model 2). For the sensitivity analysis model(model 2), the aforementioned eight indicator variables for the interaction of gender, agegroup and diagnostic method were collapsed to four to capture the interaction ofage-by-gender group.A mixed log-binomial model was fitted for the observed prevalence in the study strata toestimate the significance of the various risk factors (model 1). Covariates collected forpredicting ADHD prevalence included gender, age group, diagnostic method, study design andcountry. The model included fixed effects for each of the covariates and a random studyeffect, and can be defined as follows: The models were fitted adopting a frequentist estimation approach using PROC GLIMMIX inSAS version 9.2 .et al.et al.et al.et al.et al.et al.et al.In total, 8520 publications were identified following the OvidSP Medline, EMBASE, Datastar,PsycINFO and Social SciSearch database search. Publications not specifically relating toADHD and criminality and duplicates between databases were excluded electronically, leaving325. Once further duplicates had been identified manually, 311 publications remained. Afurther 218 publications were excluded after further review as they did not report onsamples composed entirely of incarcerated/prison populations. Of the 93 articles remaining,a further 40 articles were excluded as they did not provide prevalence data on ADHD; 53publications included ADHD prevalence data. Three studies  and gender showing all data  and interviewdiagnosis strata  are presented in Overall, the observed ADHD prevalence in prison populations in all 42 studies (61 studystrata) was 21.3% . The observed ADHD prevalence in prison populations for inmates withan interview diagnosis  was 20.5% .p = 0.001). This suggested a high rate of false positives was beingidentified by screening tools, and thus subsequent reported analysis used prevalenceobtained only from diagnostic clinical interview data (i.e. model 2).Studies using screening for diagnosis had a significantly higher estimated ADHDprevalence of 43.3% (95% CI 33.2–56.4) compared with 25.5% (95% CI 20.0–32.4) obtainedfrom the subset of studies using a diagnostic clinical interview(p < 0.001) in studies with current diagnoses; ADHD prevalencefor current diagnoses was 21.7% (95% CI 17.5–26.9), compared with 36.4% (95% CI25.6–51.8) for retrospective diagnoses.ADHD prevalence was estimated to be significantly lower(p < 0.0001). ADHD prevalence ranged from 6.6% in Brazil; Europe had the highest estimated prevalence (32.1%),followed by North America (26.9%) and Other countries (17.6%).There were significant differences in ADHD prevalence estimated across countries(versus 26.1%(95% CI 19.3–35.2).Prevalence estimates for males with ADHD were not significantly different fromestimates for females with ADHD: 30.3% (95% CI 23.9–38.4) versus 26.2% (95% CI 18.4–37.5).Youth prevalence estimates were not significantly different from estimates for adults:30.1% (95% CI 22.1–41.1) Gender-by-age  comparisThere were no significant differences found within the clinical interview diagnosticgroups among the four gender-by-age groups.et al.This review presents a meta-analysis of 42 studies conducted in 15 countries thatprovides a reliable estimate of 25.5% as the prevalence of ADHD in incarceratedpopulations from studies using diagnostic clinical interview. Heterogeneity is likely tobe present in most meta-analyses as individual studies with the ‘same’ population andstudy characteristics are never identical with respect to both measured and unmeasuredfactors, which can lead to differences in outcome. For this reason, models that allow forheterogeneity are recommended . It seems important that all inmates are considered formental health screening, including ADHD, and those with positive screens be referred for aclinical assessment. What is unknown, however, is the rate of false-negative screens inthis population.In recent years, a high prevalence of psychopathology  has been recognized in prison inmates . It has been reported that theonset of offending is at a younger age for youth with ADHD, even as young as 10 years ofage , these differences were notsignificant. Europe had the highest estimated rate, followed by North America and thenOther countries. These variations may be due partly to study sample sizes: 70% (seven of10) of the diagnostic interview studies carried out in North America had sample sizes>200, compared with only 22% (two of nine) of European studies. The North Americanprevalence (26.9%) is closer to the prevalence obtained overall (by diagnostic interview)for offenders with youth and adult ADHD . Hence, theselarger samples may give an accurate estimate of prevalence.et al.et al.The differential may also reflect differences in the North American and European criminaljustice systems. Following the introduction of tougher laws and penalties surrounding drugcrimes by the US government, the number of inmates convicted of a drug crime rose by 1300%in the USA between 1980 and 2001 . However,female youths had similar prevalence to male youths . Thegeneral population prevalence indicates a 4:1 ratio of boys to girls with ADHD  compared withmale prevalence (n = 22), which may have given a restrictedrepresentation of the position. A recent study from Konstenius et al. had the lowest predicted ADHD prevalence whencomparing by age and gender . This suggests that incarcerated youths may remain in the criminal justicesystem because of repeat offending. Analysis of data from the Swedish National Registerfound that 36.6% males with ADHD were convicted of crime compared with 15.4% of females.Importantly, it was found that the use of ADHD medication reduced the risk of criminalityamong probands with ADHD: by 32% in men and 41% in women  is much lower thanthe observed ratio of 4:1 in youths with ADHD . Bias in study selection wasaddressed by delivering training on how to extract data from a random sample ofpublications, and each researcher checked and independently reviewed a random sample ofeach others’ papers for data interpretation consistency. Second, factors such as thereliability of ADHD diagnoses and differences in the criminal justice system between andwithin countries could have contributed to the broad ranges of prevalence observed in thisreview. The heterogeneity of samples used is also a potential source of variability andwas the reason for using a fitted model that assumed a fixed effect of measurable covariates but random study effects in the meta-analysis. In addition, onlythose publications since 1980 and in English were included.Overall, the estimated prevalence of ADHD in incarcerated populations is 25.5% based ondiagnostic clinical interviews. The ADHD prevalence was estimated to be significantly lowerin studies with current diagnoses compared with retrospective diagnoses. There was a largevariation in ADHD prevalence between countries, but this was no longer evident when groupedregionally. This systematic review and meta-analysis found, on average, a fivefold increasedprevalence of ADHD in youth prison populations (30.1%) and a 10-fold increase in adultprison populations (26.2%) compared with published general population prevalence . Female adults had a lower prevalence of ADHD, when compared by age andgender, than male adults. However, the risk for females was almost as high as that formales.


In this pilot study near-infrared spectroscopy (NIRS) neurofeedback was investigated as a new method for the treatment of Attention Deficit-/Hyperactivity Disorder (ADHD). Oxygenated hemoglobin in the prefrontal cortex of children with ADHD was measured and fed back. 12 sessions of NIRS-neurofeedback were compared to the intermediate outcome after 12 sessions of EEG-neurofeedback  and 12 sessions of EMG-feedback (muscular activity of left and right musculus supraspinatus). The task was either to increase or decrease hemodynamic activity in the prefrontal cortex (NIRS), to produce positive or negative shifts of SCP (EEG) or to increase or decrease muscular activity (EMG). In each group nine children with ADHD, aged 7–10 years, took part. Changes in parents’ ratings of ADHD symptoms were assessed before and after the 12 sessions and compared within and between groups. For the NIRS-group additional teachers’ ratings of ADHD symptoms, parents’ and teachers’ ratings of associated behavioral symptoms, childrens’ self reports on quality of life and a computer based attention task were conducted before, 4 weeks and 6 months after training. As primary outcome, ADHD symptoms decreased significantly 4 weeks and 6 months after the NIRS training, according to parents’ ratings. In teachers’ ratings of ADHD symptoms there was a significant reduction 4 weeks after the training. The performance in the computer based attention test improved significantly. Within-group comparisons after 12 sessions of NIRS-, EEG- and EMG-training revealed a significant reduction in ADHD symptoms in the NIRS-group and a trend for EEG- and EMG-groups. No significant differences for symptom reduction were found between the groups. Despite the limitations of small groups and the comparison of a completed with two uncompleted interventions, the results of this pilot study are promising. NIRS-neurofeedback could be a time-effective treatment for ADHD and an interesting new option to consider in the treatment of ADHD. Attention Deficit-/Hyperactivity Disorder (ADHD) is characterized by the main symptoms of inattention, hyperactivity and impulsivity, leading to deficits in social and/or academic functioning.In the model of prefrontal lobe executive functions according to Barkley , a deficNeurofeedback as a treatment for ADHD can be interpreted as a way to increase behavioral inhibition. Neurofeedback is commonly EEG-feedback of frequency bands or slow cortical potentials (SCP), measuring and feeding back electrical brain activity , measuring hemodynamic correlates of neural activity. Light in the near-infrared spectrum is absorbed to different amounts by oxygenated and deoxygenated hemoglobin allowing to determine relative concentration changes on the cortical surface  reasons: First, oxygenated hemoglobin was found to show the strongest correlation with the fMRI BOLD signal, probably because of its superior signal-to-noise ratio as compared to deoxygenated hemoglobin  was approved by all local Ethics Committees according to the Declaration of Helsinki. Written informed consent was obtained from parents and children.Inclusion criteria were age between 7;0 and 10;11 years and a full-scale intelligence quotient over 80  participated in the study. The diagnosis was confirmed with the supplement for ADHD  took part in the NIRS-feedback. For the EEG- and the EMG-group, 18 children were matched to the NIRS-group for gender, medication status and age . The children of these two groups were participants in a multicenter neurofeedback study  with a mean age of As additional screening instruments, all parents rated the child’s behavior on the Child behavior checklist  were assessed as main dependent variables. The parent-rated FBB-ADHS was the primary outcome. The FBB-ADHS is part of the Diagnostic System for Mental Disorders in Childhood and Adolescence .The childrens’ pediatricians or the childrens’ psychiatrists were asked to rate severity of psychopathology and improvement after treatment on the Clinical Global Impression Scale Guy, . This daNIRS-neurofeedback training consisted of twelve sessions within 4–6 weeks, with 2–3 sessions per week. Each session comprised three blocks of NIRS-neurofeedback. After the 12 sessions, children were instructed to practice their strategy for 3 weeks in attention-requiring situations at home or school, to facilitate the transfer to everyday life. In order to motivate the children, the whole training was accompanied by a token system in which the children could gain points and swap them for small toys. Tokens were given for good cooperation during a training session, independent of achievement.The basic parameters of the three trainings  were comparable. Each session lasted approximately 1 hour with 32 min effective feedback time. The visual layout of the feedback was identical. Compared to electrical brain and muscular activity, changes in hemodynamic activity are somewhat delayed and need more time to return back to baseline. In consequence, hemodynamic neurofeedback trials were designed with longer regulation and resting times  was placed over frontal and temporal areas and linked to a neurofeedback device (NeuroConn THERA-PRAX). For the measurement 46 optodes (44 NIRS channels) were used, arranged on two 3 × 5 probesets. The probesets were oriented along positions of the 10–20-system of electrode placement. The lowest row of both probesets was oriented frontally with Fpz as midpoint, while the second optode from occipital in the lowest row on each side was lying on T3 respectively T4  and one transfer block (without feedback object) each lasting 8 min. The blocks consisted of 40 regulation trials. One regulation trial comprised 2 s baseline measurement and 8 s regulation time . Nine Ag/AgCl ring electrodes were used, one at Cz, two at the right and left mastoid (A1 and A2), two central over and under the left eye, two at the left and right corner of both eyes and two at the right and left musculus supraspinatus above the shoulders.In the EEG-group the EEG-signal  was fed back, in the EMG-group the EMG-signal was fed back. The task in the EEG-group was to produce a positive or negative shift of the SCPs in comparison to the baseline. The task in the EMG-group was to increase muscle tension on the left side while decreasing it on the right side and vice versa in comparison to the baseline. At the end of a successful trial (= the object was flying at least 2 s of the last 4 s regulation time in the expected direction) a sun was shown on the screen as a visual reinforcer.For the FBB-ADHS, the SDQ and the KID-KINDL total scores were calculated according to the test instructions. A higher score in the FBB-ADHS implies more severe ADHD symptoms and a higher score in the SDQ implies a higher occurrence of associated behavioral symptoms, including hyperactivity. A higher score in the KID-KINDL implies a higher self-rated quality of life. For the two TAP subtests, medians of reaction times, standard deviations of reaction times and the numbers of commissions and omissions (only Go/NoGo) were assessed and analyzed. Higher medians of reaction times represent slower reactions; higher standard deviations of reaction times represent a higher variability of reaction times.post hoc analysis Wilcoxon signed-rank tests were conducted. Additionally, effect sizes were calculated IBM SPSS Version 20 was used for statistical analysis. Due to small sample-size, non-parametric tests were applied. Significance level was set to α ≤ 0.05. Friedman’s ANOVAS were conducted for comparisons within the NIRS-group  for the dependent variables. For post hoc Mann-Whitney U Tests, to ensure the general comparability of the three groups. To assess the pre-post effects of the twelve training sessions for each group separately, three Wilcoxon signed rank tests were conducted for the total scores of the FBB-ADHS comparing pretest and post test 1 within each group. Additionally, differences of the scores were calculated for each group , and these differences were compared between groups in a Kruskal-Wallis-Test.For the comparison of the three groups the initial values of parents’ and teachers’ ratings of the FBB-ADHD and the SDQ, the child-rated KID-KINDL and the performance data of the TAP subtests were compared with Kruskal-Wallis-Tests and For an overview of all medians and interquartile ranges for the dependent variables of the NIRS-group at all measurement points with test statistics see Table 2(2) = 6.59, p = 0.037; teachers: χ2(2) = 6.33, p = 0.042). In the post hoc analysis of parents’ ratings, ADHD symptoms significantly decreased from pretest to post test 2  as well as from pretest to follow-up test . There was no significant difference between parents’ ratings from post test 2 to follow-up test . The post hoc analysis of teachers’ ratings revealed a significant decrease of ADHD symptoms in teachers’ ratings from pretest to post test 2 , but not from pretest to follow-up test  or from post test 2 to follow-up test . For medians and interquartile ranges of FBB-ADHS total scores see Figure There are significant differences in the measurement points of the FBB-ADHS total score for the NIRS-group in parents’ and teachers’ ratings (parents: χ2(2) = 5.88, p = 0.053; teachers’ ratings SDQ: χ2(2) = 2.78, p = 0.249; childrens’ ratings KID-KINDL: χ2(2) = 2.00, p = 0.368). In the post hoc analysis there was a significant decrease in parents’ ratings of the SDQ total score from pretest to follow-up test . See Figure There were no significant differences in parents’ and teachers’ ratings of associated behavioral symptoms  and in childrens’ ratings of quality of life (KID-KINDL) for the three measurement points (parents’ ratings SDQ: χ2(2) = 8.97, p = 0.011), commission errors (χ2(2) = 12.96, p = 0.002) and medians of reaction times (χ2(2) = 6.91, p = 0.032). In the post hoc analysis there was a significant difference in the medians of reaction times from post test 2 to follow-up test , as shown in Figure post hoc analyses of the standard deviations of reaction times there was a significant difference between pretest and post test 2  as well as between pretest and follow up test  and from pretest to follow-up test , as shown in Figure For the subtest Go/NoGo significant differences were found for the three measurement points in standard deviations of reaction times (χ2(2) = 6.22, p = 0.045) and the standard deviations of reaction times (χ2(2) = 6.22, p = 0.045). In the post hoc analysis there were no significant differences for the medians of reaction times  and from pretest to follow-up test , see Figure z = −1.96, p = 0.050, r = −0.462), see Figure In the subtest Flexibility there were significant differences for the medians of reaction times . Post hoc analyses for the KID-KINDL showed significant higher quality of life scores in the NIRS-group in comparison to the EEG-group  as well as in comparison to the EMG-group , there was no difference between EEG- and EMG-group .There were no significant differences between groups in the pretest values of parents’ and teachers’ rating of the ADHD symptoms in the FBB-ADHS and in the teachers’ rating of associated behavioral symptoms in the SDQ  and the EMG-group .Within-group comparisons to assess the pre-post effect of the twelve sessions separately for each group revealed a significant difference in the parents’ rating of the FBB-ADHS only for the NIRS-group  = 2.72, p = 0.256).Comparing the three groups in the differences of parents’ ratings of the FBB-ADHS , there were no significant differences between the groups  was carried out.As primary outcome, parents’ ratings of ADHD symptoms in the NIRS-group were significantly reduced 4 weeks and 6 months after the training. Teachers’ ratings of ADHD symptoms showed a significant reduction 4 weeks after the end of treatment. Attention and impulsivity in the computer based attention test TAP improved significantly . According to these results, NIRS-neurofeedback might be as effective in reducing the main symptoms of ADHD, as it was shown before in randomized controlled studies for EEG-neurofeedback . This is comparable to effect-sizes of EEG-neurofeedback as reported in the meta-analysis of Arns et al. . Parents rated their satisfaction with the training on a six-item scale 4 weeks and 6 months after the training. They were asked to rate satisfaction with the training, satisfaction with the trainer, empathy of the trainer, trust in the training, trust in the competence of the trainer and recommendation of the training on a 7-point scale . The mean of parent satisfaction 4 weeks and 6 months after training was high . Additionally, parents were asked for adverse side effects in relation to measurement and training at all measurement points. No serious adverse events were documented. Two children reported to have had transient headaches directly after some of the training sessions, possibly caused by the fixation of the probe set. In conclusion, NIRS-neurofeedback seems to be a feasible and accepted intervention for children with ADHD.The general question of feasibility of NIRS-neurofeedback for children with ADHD can be answered by taking into account different variables. On the one hand, the technical implementation was possible; on the other hand, children and parents accepted the procedure. All nine children took part in all twelve sessions. At the beginning of each training session, motivation was rated on a 4-point smiley scale . The mean motivation over all sessions and children was high .NIRS-neurofeedback was effective in the reduction of the main symptoms of ADHD and possibly more time-effective in comparison to EEG-neurofeedback. However, this interpretation has to be confirmed, due to the fact that differences in improvement after the 12 sessions did not reach significance, and that the initial values in quality of life and associated behavioral symptoms of the groups differed. Moreover, a completed intervention was compared with two uncompleted interventions, based on the assumption of a more rapid improvement with NIRS neurofeedback, and the sample sizes were small. For future studies, sample sizes have to be enlarged and a randomized controlled design is mandatory. NIRS-neurofeedback could enlarge the treatment options for ADHD, with the possible advantage of being a shorter intervention in comparison to EEG-neurofeedback. The analysis of NIRS-data throughout the training will hopefully allow conclusions as regards to the learning of self-regulation and number of sessions needed. Birbaumer et al.  assume tAs a limitation it has to be taken into account, that medication could have a distorting effect on the results: seven of nine children in each group received a medication with methylphenidate during the training. The effects of medication were not assessable in this study. It might be possible, that symptom reduction only occurs in less impaired children or because medication allows a better training. Larger sample sizes, subgroups with medicated and unmedicated children are necessary to control for effects of medication. As an example, results of the multicenter study (comparison of EEG- and EMG-feedback), show that effects of neurofeedback were independent of medication NIRS-neurofeedback is a promising intervention for children with ADHD and can enlarge the range of options for a treatment of ADHD. Future studies should focus on randomized controlled designs. Especially the comparison with EEG-neurofeedback, and with its final rather than its intermediate outcome, is necessary to further support the assumption that NIRS-neurofeedback needs fewer sessions for comparable symptom reduction. It would also be important to clarify whether longer NIRS-neurofeedback training  yields further clinical improvement. For further development of NIRS-neurofeedback the identification of other possible feedback regions based on the growing number of NIRS-studies with children with ADHD is required. The prefrontal cortex plays a central role in ADHD. However, involving a greater database and identifying target regions according to symptomatology could lead to an evidence-based adaption of feedback protocols for individualized treatment of ADHD.Anna-Maria Marx, Adrian Furdea, Yvonne Fuchsenberger, Holger Gevensleben, Daniel Brandeis, Ann-Christine Ehlis and Andreas J. Fallgatter declare no commercial or financial relationships that could be construed as a potential conflict of interest. Ute Strehl was paid for public speaking by Novartis, Medice, Neuroconn, the German Society for Biofeedback and Akademie König und Müller. Martin Holtmann served in an advisory or consultancy role for Lilly, Shire and Bristol-Myers Squibb, and received conference attendance support or was paid for public speaking by Bristol-Myers Squibb, Janssen-Cilag, Lilly, Medice, Neuroconn, Novartis and Shire. Christine M. Freitag received one time speaker’s fees by Ely Lilly and Shire over the last 3 years. Tobias Banaschewski served in an advisory or consultancy role for Hexal Pharma, Lilly, Medice, Novartis, Otsuka, Oxford outcomes, PCM scientific, Shire and Viforpharma. He received conference attendance support and conference support or received speaker’s fee by Lilly, Medice, Novartis and Shire. He is/has been involved in clinical trials conducted by Lilly, Shire and Viforpharma. The present work is unrelated to the above grants and relationships. Prof. Rothenberger is member of an advisory board and speakers’ bureau of Lilly, Shire, Medice and Novartis. He got research and travel support and an educational grant from Shire and research support from the German Research Society. Where applicable, the above mentioned authors declare that the present work is unrelated to the above mentioned grants and relationships.


No case–control differences were found for the diffusion parameters investigated. This is the first report of a WM microstructural signature of autistic traits in ADHD. Thus, even in the absence of full disorder, ASD traits may index a distinctive underlying neurobiology in ADHD.Traits of autism spectrum disorder (ASD) in children with attention-deficit/hyperactivity disorder (ADHD) have previously been found to index clinical severity. This study examined the association of ASD traits with diffusion parameters in adolescent males with ADHD (n = 17), and also compared WM microstructure relative to controls (n = 17). Significant associations ( Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood-onset neurodevelopmental disorder, with a male:female prevalence bias of 2–3:1 in general population samples  has shown many brain abnormalities in ADHD  have been used to investigate correlation between clinical indices of phenotypic variability and diffusion metrics. Results have varied in terms of the measure used and the anatomical location where correlations were found. Whilst some studies have found associations between phenotypic measures and white matter microstructure   located in the right anterior corona radiata, right forceps minor, bilateral internal capsule and left cerebellum  were recruited. All were required to be right-handed as handedness and gender have independent associations with diffusion indices  HDx MR system. An 8 channel head coil was used. The ASSET factor was 2. TE was 87 ms and TR was 15–20 R–R intervals (i.e. 13.8–18.5 s assuming an average heart rate of 65 beats per minute). Data were acquired with a field of view of 230 × 230 mm with an acquisition matrix of 96 × 96 (subsequently zero-filled to 128 × 128 prior to the Fourier transform). Diffusion-weighted data were acquired with a twice-refocused spin-echo echo-planar imaging sequence giving whole oblique axial brain coverage, with 60 slices of 2.4 mm thickness aligned parallel to the anterior commissure-posterior commissure line. The b value was 1200 s/mmAll diffusion data processing was performed using ExploreDTI, version 4.8.2 , to ensure that their inclusion was not altering results.Participant characteristics of all those in the main analyses  are shown in Table p < 0.001) and full scale IQ . There was a significant difference in the distributions of age , with the ADHD group being slightly younger (difference in mean age = 1.3 years). There were also group differences in DSM-IV ADHD symptom scores  and SCQ score . Within both the ADHD and control groups, age was not correlated with either total ADHD or SCQ scores.There were significant differences between the 17 ADHD cases and 17 controls in the distributions of family income status , significant positive correlation was found between FA and autistic traits as indexed by SCQ score , correlations of diffusion parameters with summed socio-communicative scores and repetitive behaviour scores were tested separately. A similar pattern of results was seen as for total ASD score, but with associations being driven by socio-communicative scores with no contribution from repetitive behaviour scores. RD remained significantly negatively correlated with socio-communicative scores (p < 0.05), although correlations between FA and socio-communicative scores no longer quite reached significance (0.05 < p < 0.08).Given the observed correlations between FA/RD and total SCQ scores in the ADHD group, the relative contributions of SCQ sub-domain scores were examined post hoc. As social and communication sub-domain scores were highly cross-correlated . The addition of age as a covariate did not unmask any group differences and diffusion parameters showed no correlation with age across the total sample. Also, no age × group interactions on diffusion parameters were found. Results were unchanged when the two ‘remitted’ ADHD participants were excluded .The addition of IQ as a covariate into the initial case–control analysis  did not alter results.The correlation analysis of the association of ASD and ADHD traits with diffusion parameters in the ADHD group showed several areas where autistic traits were associated with altered tissue microstructure. When total SCQ score was decomposed into socio-communicative scores and repetitive behaviours, correlations seemed to be driven by the former, although they fell below significance for FA. However, variability in sub-domain scores will have been restricted because those with an ASD diagnosis were not included.decreases in FA in this area have been reported  correlation with autistic symptoms were seen for FA in the right posterior limb of the internal capsule including the corticospinal tract. This is an area where ADHD case–control differences have been reported  Imperfect matching at a group level on influential confounding variables such as handedness and gender could generate systematic differences between groups which cannot meaningfully be covaried out at the analysis stage. (2) ADHD, surplus to its core features, is associated with multiple, sometimes subtle, potentially dynamic cognitive, behavioural and developmental problems and it may be that these features are underpinned by altered WM development. (3) Withholding medication could predispose to movement during scanning, as could including younger children. Without rigorous compensation in processing, group level discrepancies in movement could generate spurious differences. There is evidence that distributions of certain case–control differences in WM microstructure in autism could be artefactual with the authors advising caution in interpretation of such findings  that typify clinic cases in the UK where health care is provided free of charge.Whilst current ADHD trait measures were assessed, current subtype was not, although inclusion of only those with a rigorously assessed lifetime diagnosis of ADHD-C ensured relative sample homogeneity. However, it is known that levels of ADHD symptom dimensions vary longitudinally so individuals can switch between subtypes , they would not be detected using TBSS. It may be that even with a comparable sample size to previous studies, this study did not have the power to detect effects given the multiple testing correction required. Although often reported as such, it is also not possible to infer a straightforward index of ‘connectivity’ from a voxel-averaged FA and diffusivity derived from the tensor, as the tensor model cannot resolve complex fibre architecture Jones . Hence tThe present results should be interpreted as preliminary, requiring further investigation and replication in bigger samples, especially in view of the small sample size and it not being possible to fully match groups on age and family income. With regards to the case–control results, studies with smaller or comparable sample sizes have found group differences (e.g. Tamm et al. This study is the first to report significant associations between tissue microstructure and autistic traits in ADHD and highlights the need for further investigation of the biological overlap of ADHD and ASD. Abnormal socio-communicative traits in ADHD appear to have association with the neurobiology of phenotypic variation in ADHD even in those who do not have a known ASD diagnosis. This highlights the need for clinicians assessing young people with ADHD to be vigilant to the potential impact of even sub-threshold socio-communicative difficulties.Whilst no case–control differences in young people with ADHD were found in this analysis, in view of the previous abnormalities found by standard structural, functional and diffusion imaging, findings from this analysis should not be taken as an assertion that the brain does not display abnormalities in ADHD. Rather, TBSS may not have had the sensitivity in this sample to detect residual case–control differences which may have been rendered less pronounced by medication and developmental effects. Also, more caution may be needed in the interpretation of the previously reported widespread changes in diffusion parameters, particularly with regard to heterogeneity of samples across studies and the multiple comparisons issue.


In this paper, a generation scheme for telecom band hyper-entanglement is proposed and demonstrated based on the vector spontaneous four wave mixing (SFWM) processes in optical fibers. Two kinds of two-photon states are generated, one is hyper-entangled in the degree of freedoms (DOFs) of energy-time and polarization, the other is hyper-entangled in DOFs of energy-time and discrete-frequency. Experiments of Franson-type interference, two-photon interference under non-orthogonal polarization bases and spatial quantum beating are realized to demonstrate the entanglement in energy-time, polarization and frequency, respectively. This scheme provides a simple way to realize telecom band hyper-entanglement, which has potential for large geographic-scale applications of quantum communication and quantum information over optical fibers. With entanglement in more than one degrees of freedom (DOFs) of photons, hyper-entangled photon pairs26789101114In this paper, we propose and demonstrate a scheme to generate 1.5 μm hyper-entangled photon pairs in optical fibers. Two kinds of hyper-entangled two-photon states are realized, one is hyper-entangled in DOFs of energy-time and polarization, the other is hyper-entangled in DOFs of energy-time and discrete-frequency. This scheme is based on the indistinguishability of the two vector SFWM processes in optical fibers, which are stimulated simultaneously by two pump lights with orthogonal polarizations and different frequencies. The experiments of Franson-type interferenceχ(3) nonlinearity, in which two pump photons are annihilated, while two photons are generated simultaneously. Traditionally, the photon with higher frequency is named as signal photon, and the other photon is named as idler photon. The energy conservation is satisfied in the SFWM processes, leading to the frequency relation of pω1 + pω2 = sω + iω, where pω1, pω2, sω, and iω denote the frequencies of the two pump photons, the signal photon and the idler photon, respectively. For an isotropic medium, the nonzero elements of the third order nonlinear tensor χ(3) are i, j ∈ {x, y, z}, x, y and z are three orthogonal coordinate directions. In optical fibers, the i ∈ {x, y} supports scalar SFWM processes, in which the annihilated pump photons and generated signal and idler photons are all polarized in the same direction. While, the i, j ∈ {x, y}, i ≠ j, may support vector SFWM processes. Two kinds of vector SFWM processes are shown in The SFWM is a kind of nonlinear processes caused by the In the proposed schemes for the hyper-entanglement generation in optical fibers, two orthogonally polarized continuous wave (CW) pump lights with different frequencies are injected into the optical fiber to stimulate the two vector SFWM processes simultaneously. The two processes are indistinguishable and coherently superposed, which is the basis for the hyper-entanglement generation. In each vector SFWM process shown in 81〉 and |Ψ2〉 are the states for the left and right processes in pω1 + pω2)/2 − iω = sω − (pω1 + pω2)/2, is the frequency detuning, where pω1, pω2, sω and iω are the frequencies of the two pump lights, the signal photon and idler photon, respectively. In an optical fiber without birefringence, the amplitudes of the two-photon states generated by the two vector SFWM processes are the same, which are denoted by ξ(Ω).where |Ψsω0 and iω0, respectively, which satisfy the relation of sω0 + iω0 = pω1 + pω2. The filter bandwidths for the signal and idler photons are the same and denoted by δ. If the bandwidth δ is narrow, the two-photon state at the two paths after the optical filter system can be expressed as0 is defined by Ω0 ≡ (pω1 + pω2)/2 − iω0 = sω0 − (pω1 + pω2)/2. ξ(Ω) is approximated to a constant ξ = ξ(Ω). The state |Ψ3〉 shows hyper-entanglement in DOFs of energy-time and polarization.sω0 and iω0 with bandwidths of δ, the discrete-frequency entanglement can be generated. If the bandwidth δ is narrow, the two-photon state can be expressed as0 is defined by Ω0 ≡ (pω1 + pω2)/2 − iω0 = sω0 − (pω1 + pω2)/2 and ξ(Ω) is approximated to a constant ξ = ξ(Ω). The state |Ψ4〉 shows hyper-entanglement in DOFs of energy-time and discrete-frequency.To generate hyper-entanglement in DOFs of energy-time and discrete-frequency, a polarization beam splitter should be used to route the generated photons by the two vector SFWM processes to two paths by their polarizations. The polarization relation of signal and idler photons in the vector SFWM processes ensures that the two generated photons in the same process would exit via the two paths separately. While, in each path the frequencies of the generated photons are not determined due to the indistinguishability of the two vector SFWM processes, leading to the frequency entanglement generation. Especially, if the frequencies of the signal and idler photons are defined by narrow band optical filters at The experiment setup for the demonstration of hyper-entanglement in energy-time and polarization is shown in To generate hyper-entanglement in energy-time and polarization, the generated photons are routed to two paths according to their frequencies by an optical filter module composed of cascaded commercial density wavelength division multiplexers (DWDMs). The central wavelength and full width at half maximum (FWHM) of the filter for the signal photons are 1549.32 nm  and 118 GHz, respectively. Those for the idler photons are 1555.75 nm  and 139 GHz, respectively [see Methods for more details]. Then, the selected signal and idler photons are detected by two NbN superconducting nanowire single photon detectors (SNSPDs)19The two SNSPDs are operated at 2.2 K in a Gifford-Mcmahon cryocooler. Since the detection efficiencies of the SNSPDs depend on the polarization of the injected photons, two fiber polarization controllers (FPCs) are used to maximize the detection efficiencies before the two SNSPDs. The detection efficiencies, timing jitters and dark count rates of the two SNSPDs are about 30%, 60 ps and 100 Hz. The detection events of the SNSPDs are recorded by a time correlated single photon counting module  with a bin width of 4 ps and time resolution of 12 ps rms. The small timing jitters of SNSPDs and high resolution of the TCSPC module ensure that a narrow time domain filter can be utilized in the coincidence measurement to suppress the impact of noise photons [see Methods for more details].UMZIt = 400 ps in time domain. The relative phase differences between the two arms of the UMZIs can be tuned by the voltages applied on the DPSK modulators, which are denoted by α and β, respectively. According to the FWHM of filters for signal and idler photons, the coherence time of the single photon wave packet of generated photons is about τ1 ~ 8 ps. On the other hand, the coherence time of the two-photon wave packets generated by the vector SFWM processes is determined by the coherence times of the two pump lights. Since the linewidth of one pump light is far larger than that of the other, the coherence time of the two-photon wave packets can be estimated by the coherence time of the pump light with wider linewidth, which is about τ2 ~ 0.2 μs. Hence, a Franson-type interference with high visibility can be expected under the condition of The experiment of Franson-type interference is realized to characterize the energy-time entanglement property, in which two unbalanced Mach-Zehnder interferometers (UMZIs) are used as the quantum state analyzer as shown in 5 Hz and 3.38 × 105 Hz for signal and idler photons, respectively . There are three coincidence peaks due to the arm length differences of the two UMZIs at signal and idler sides. The central coincidence peak is contributed by two cases, corresponding to that both photons pass through the long arms of the UMZIs and that both photons pass through the short arms of the UMZIs, respectively. The two cases are indistinguishable and their states are coherently superposed, showing the property of energy-time entanglementα when β is fixed at 6.38 rad or 7.29 rad, respectively. The interference visibilities are calculated by curve fitting. The interference visibilities for net coincidence counts are 99 ± 1% for both β = 6.38 rad and β = 7.29 rad. For the raw coincidence counts, the interference visibilities are 84 ± 1% for both β = 6.38 rad and β = 7.29 rad. During the measurement, the single side count rates are almost unchanged under different relative phase differences of the two UMZIs, showing that the fringes are induced by the energy-time entanglement rather than the interference of single photons. Either the measured visibilities for the net coincidence counts or that for the raw coincidence counts are higher than The experiment results for the energy-time entanglement are shown in sθ and iθ, respectively. Firstly, sθ is set to 0 and iθ is set to π/2 rad, then the fiber polarization controllers are adjusted to maximize the coincidence counts. By this process, the detecting directions of the two polarization analyzers are collimated. iθ is varied and sθ is set to 0 or −π/4 rad. It is shown that the single side count rates are almost independent on the angle of polarizer, indicating that photons at single sides are not polarized in some specific direction. sθ = 0 and 96 ± 1% under sθ = −π/4 rad. For the raw coincidence counts, the visibilities are 88 ± 1% under sθ = 0 and 89 ± 1% under sθ = −π/4 rad, respectively. Both the measured visibilities for the net coincidence counts and that for the raw coincidence counts are higher than 71%The entanglement property on the DOF of polarization is explored by the two-photon interference under two non-orthogonal polarization bases, using two polarization analyzers as the quantum state analyzer, which is shown in The experiment setup for the demonstration of hyper-entanglement in energy-time and frequency is shown in β = 6.38 rad and 99 ± 1% under β = 7.29 rad, respectively. For the raw coincidence counts, the interference visibilities are 91 ± 1% for both β = 6.38 rad, and β = 7.29 rad. Either the measured visibilities for the net coincidence counts or that for the raw coincidence counts are higher than The energy-time entanglement is also demonstrated by the experiment of Franson-type nonlocal interference. The quantum state analyzer for this experiment is similar with the one shown in To demonstrate the discrete-frequency entanglement property, an experiment of spatial quantum beating is realized utilizing the quantum state analyzer shown in τ is the delay times between signal and idler photons at the 50:50 PM-FC, V is the visibility of the spatial quantum beating fringe. ω2 is the frequency difference between the signal and idler photons. f(τ) is a normalized function determined by the transmission spectra of the optical filters for the signal and idler photons. In the experiment, the optical filters have flat top and steep falling edges  can be approximated by a sinc function, f(τ) = sin(ω1τ)/ω1τ. ω1 = 2π × 112 GHz and ω2 = 2π × 788 GHz. Both of them are close to the values calculated by the transmission spectra of the optical filters for the signal and idler photons, which are ω1,0 = 2π × 118 GHz and ω2,0 = sω0 − iω0 = 2π × 800 GHz, respectively. The differences between the fitting results and the calculated values may be due to that the two pump frequencies (pω1 and pω2) and central frequencies of the optical filters for signal and idler photons (sω0 and iω0) have a small mismatch. The interference visibility is V = 91 ± 3% for net coincidence counts. For the raw coincidence counts, the visibility is 85 ± 3%. According to Ref. The experiment results of the spatial quantum beating are shown in 17In the experiments shown in this paper, although the interference visibilities for the raw coincidence are all higher than the criterion for entanglement, they are limited by noise photons mainly generated by the spontaneous Raman scattering. In our experiments, two methods have been applied to suppress the impacts of the spontaneous Raman scattering. On one hand, the optical fiber is cooled to 77 K by liquid nitrogen bath to reduce the Raman noise photon generation rates26It is worth noting that when the two pump lights propagate through the optical fiber, scalar SFWM processes by single pump light would also be stimulated. Since the frequency relations among the pump lights and generated signal and idler photons in the scalar processes are different from those of vector SFWM processes, the scalar processes have no contribution on the hyper-entanglement generation if proper optical filters are used to select signal and idler photons. Hence, in this scheme the scalar SFWM processes only introduce noise photons at both sides without correlation, like the noise photons generated by the spontaneous Raman scattering. Our previous workβ = 6.38 rad and β = 7.29 rad. Its property of polarization entanglement is demonstrated by the two-photon interference under two non-orthogonal polarization bases, with fringe visibilities (for net coincidence counts) of 94 ± 1% under sθ = 0 and 96 ± 1% under sθ = −π/4 rad, respectively. The other is hyper-entangled in DOFs of energy-time and discrete-frequency. The property of energy-time entanglement is also demonstrated by the Franson-type interference, with fringe visibilities (for net coincidence counts) of 98 ± 1% under β = 6.38 rad and 99 ± 1% under β = 7.29 rad, respectively. Its property of frequency entanglement is demonstrated by the experiment of spatial quantum beating, with a fringe visibility (for net coincidence counts) of 91 ± 3%. This scheme provides a simple way to realize telecom band hyper-entanglement, which has potentials for long distance distribution over optical fiber, preferred in large geographic-scale applications of quantum communication and quantum information.As a summary, we proposed and demonstrate a generation scheme for telecom band hyper-entanglement based on vector SFWM processes, which are stimulated by two orthogonal polarized CW pump lights with different frequencies. Two kinds of hyper-entangled two-photon states are generated. One is hyper-entangled in DOFs of energy-time and polarization. Its property of energy-time entanglement is demonstrated by the Franson-type interference with fringe visibilities (for the net coincidence counts) of 99 ± 1% for both In the experiments, the optical filters for signal photons, idler photons and pump lights are realized by cascading 4 DWDMs, respectively, which are commercial devices for optical communication. The insertion losses of these filters are all lower than 2 dB. Their isolations at adjacent channels are larger than 120 dB, estimated by the parameters of each DWDM device and the fact that commercial DWDM devices have very high return loss. For non-adjacent channels, their isolations are even much higher. The transmission spectra of the filters for signal and idler photons are shown in In the experiment, under the CW pumping configuration, the generation rate of noise photons in optical fibers, including those by the spontaneous Raman scattering and those by the scalar SFWM processes, is much higher than that of entangled photon pairs by vector SFWM processes. A narrow time domain filter is applied in the experiment to suppress the impact of noise photons. To measure the coincidence counts and accidental coincidence counts, the detection events of the two SNSPDs are delivered to the trigger port and signal port of the TCSPC, respectively. The event sent to the trigger port starts the timer in the TCSPC. The event sent to the signal port stops the timer in the TCSPC, forming a start-stop event. In the measurement, a histogram is carried out by the statistics on the spans of recorded start-stop events. If the start-stop event is generated by an entangled photon pair, its span should be a fixed value, which is determined by the travel time difference of the two photons to the two SNSPDs. On the other hand, the spans of the start-stop events due to noise photons are random in time. Hence, the contribution of entangled photon pairs can be discriminated in the histogram and selected out by a time domain filter. It can be expected that the narrower the time domain filter, the better the noise suppression, however, the peak for the coincidence counts would be extended by the timing jitters of single photon detectors and the TCSPC module, which provides a limit to the filter width. Comparing with the single photon detectors based on APDs , SNSPDs have far lower timing jitters. In the experiment, the timing jitters of the two SNSPDs are 60 ps, respectively, and the timing jitters of the TCSPC is 12 ps. Such low timing jitters of SNSPDs and the TCSPC support a time domain filter width as narrow as 80 ps, leading to a high suppression of the impact of noise photons on coincidence count measurement.S.D. designed and performed experiments, analyzed data and wrote the manuscript. L.J.Y., J.J.W. and W.J.Z. performed experiments. W.Z. designed experiments, analyzed data, wrote the manuscript and supervised the project. L.X.Y. and Y.D.H. supervised the project and edited the manuscript.


Cotesia rubecula was previously shown to inhibit melanization in the host hemolymph by blocking activation of prophenoloxidase to phenoloxidase, a key enzyme in melanin formation. Similar to other SPHs, Vn50 consists of a clip and a protease-like (SPL) domain. Protein modeling demonstrated that Vn50 has a very similar structure to known SPHs and functional analysis of Vn50 domains expressed in insect cells indicated that neither of the domains on its own has an inhibitory effect on melanization.Endoparasitoid wasps inject a variety of components into their host hemocoel at oviposition to facilitate successful development of their progeny. Among these are venom proteins which have been shown to play crucial roles in host regulation. A serine protease homolog (SPH)-like venom protein from  The pt al. 200 presenteCotesia rubecula (Hymenoptera: Braconidae) which binds to proPAP, PAP, proPO and PO and inhibits activation of PO by competing with host SPHs for binding to proPO [Endoparasitoids introduce a mixture of components during oviposition, including calyx fluid proteins, venom components, and symbiotic viruses and virus-like particles such as polydnaviruses . These ato proPO ,9. Unlikto proPO . Vn50 isto proPO .H. diomphalia as a template [To investigate if Vn50 has a similar structure to SPHs, tertiary structure predictions were generated using ESyPred3D v1.0 . The modtemplate ; therefoSpodoptera frugiperda Sf9 cells according to the manufacturer's instructions (Nitrogen). The corresponding coding regions for the two domains were first amplified with PCR by incorporating the restriction sites for direct cloning into the transfer vector pFastBac-HTa. For efficient secretion of the proteins, the coding sequences for the secretion signal of the honey bee, Apis mellifera, melittin gene  were inserted into the transfer vector after which the corresponding Vn50 constructs were cloned. To confirm expression of the proteins, media were collected 72 h after infection and reduced in volume to approximately a tenth of their original volumes using a rotary evaporator and were run on a Western blot. The blot was then probed with an anti-Vn50 polyclonal antibody [To find out whether either of the Vn50 domains on their own have the PO inhibitory function, we expressed the two domains separately as well as the full-length Vn50, using the Bac-to-Bac baculovirus expression system in antibody  used as th instar Pieris rapae larvae were surface sterilized in 70% EtOH before bleeding from a proleg into 100 μL of ice-cold phosphate buffered saline (PBS). This was then centrifuged for 5 min at 800 × g and the supernatant (plasma) was transferred into a fresh tube. A 20 mM solution of L-3,4-dihydroxyphenylalanine (L-DOPA) in PBS was prepared immediately before use in order to avoid the effects of auto-oxidation. For each replicate, 10 μL of hemolymph was mixed with 10 μL of protein and 80 μL of L-DOPA. A control without hemolymph was also included to correct the data for auto-oxidation. Absorbance was measured at 485 nm each 10 min for 300 min.Following confirmation of expression of the proteins, they were affinity purified from the medium collected from cells 72 h after infection using Ni-NTA agarose beads (BioRAD) that specifically bind to the 6× His-tag. These were then used for melanization assays. To provide hemolymph for the assays, 4P < 0.0001 One-way ANOVA). The RNase III control, SPL domain only, clip domain only and a mixture of SPL and clip domains all showed increases in absorbance similar to the control (mock-infected) . The results suggested that only the full-length Vn50 was successful in inhibiting melanization activity and that the expressed domains were not able to bind to proPO in an inhibitory fashion like Vn50, but also that they were unable to increase levels of melanization. Therefore, cleavage of Vn50 into the two domains is not all that is missing in Vn50 compared to other SPHs and the close interaction of the clip and protease domains is important in the activity of SPHs.Absorbance readings for the control (mock-infected) showed a significant increase in melanization compared to the full-length Vn50 which showed only slight melanization  who published the crystal structure of PPAF-II, a clip-domain family SPH [The activation of proPO to PO in the process of melanization is of major importance in the melanization process . Usuallyt al. 200 who publ2.Protein modeling showed that Vn50 has a very similar 3D structure to a known SPH (PPAF-II) with determined crystal structure, and functional analysis of Vn50 domains (clip and SPL) indicated that neither of the domains on its own has an inhibitory effect on melanization. These results give us deeper insight into two effects. Firstly, they reinforce the findings of past studies that emphasized the importance of the close interactions between the SPL and clip domains of SPHs and that this is essential for their activity. Secondly, they show the need for this interaction for successful binding to proPO and support the past assertion that Vn50's inhibitory activity is through competing with SPHs for the binding of proPO.