Low birthweight is a widely used indicator of newborn health. This study investigates the association of birthweight <2.5 kg (LBW) with a wide range of factors related to geo-demographics, maternal health and pregnancy history in public hospitals at Peshawar, North West Frontier Province (NWFP) Pakistan. It is noted that that Low birthweight may arise for two different reasons, one related to gestational age and the other corresponding to births that are small for gestational age (SGA).n = 1039) were collected prospectively between August and November 2003 in a cross-sectional survey of four public hospitals in Peshawar, NWFP-Pakistan. Crude and adjusted odds ratios were used to investigate the factors affecting incidence of LBW, by multivariate logistic regression. Gestational age was included as an explanatory variable therefore the additional covariates identified by model selection are expected to account for SGA.Data on geo-demographics, maternal health indicators, pregnancy history and outcome scores for newborn babies and their families , maternal health (anaemia) and pregnancy history (abortion/miscarriage) were significantly associated with the incidence of LBW observed at the four hospitals surveyed in Peshawar. These results indicate that cultural factors can adversely affect the incidence of SGA in this area of Pakistan. Across the world, neonatal mortality is 20 times more likely for low birthweight (LBW) babies compared to heavier babies (≤ 2.5 kg). It is aIn a literature survey, de Onis et al (1998) found that IUGR babies are at increased risk of perinatal mortality and morbidity, i.e. sudden infant death syndrome, poor cognitive development and neurologic impairment, cardiovascular disease, high blood pressure, obstructive lung disease, diabetes, high cholesterol concentrations and renal damage in adulthood . Such baThe incidence of LBW  is estimated to be 16% worldwide, 19% in the least developed and developing countries and 7% in the developed countries. The incidence of LBW is 31% in South Asia followed by Middle East and North Africa (15%), Sub-Saharan Africa 14%) and East Asia and Pacific 7% [% and EasIn South Asia the incidence of LBW is 36%, 30% in Bangladesh and India, and 19% in Pakistan . In PakiPeshawar is the capital of the NWFP Province of Pakistan, where the health care facilities are used by the people of Settled areas of NWFP, and Federally Administered Tribal Areas of Pakistan  including Afghan refugees since 1979. The diversity in area-status , ethnicity (Afghan refugees/Pakistani) and differential in overall geo-demographics factors suggest a need to investigate LBW in Peshawar. The current study derives an explanatory multivariate regression model for LBW, that includes gestational age as an independent covariate. The remaining selected covariates are thus interpreted as explanatory of incidence of LBW under the category of SGA. Therefore, this prospective public hospital-based study in Peshawar focuses on LBW to investigate associated explanatory factors beyond gestational age. These factors contribute towards the explanation of the observed births that are SGA (including preterm and non-preterm SGA births).Data were collected in a cross-sectional prospective survey on maternal and paternal geo-demographic factors, maternal health and pregnancy history (MHPH) and neonatal outcome from all public hospitals  in Peshawar during August to November 2003 through clinicians on duty.The research reported in the paper was approved by the Research Ethics Committee of Liverpool John Moores University, with reference number 02141. Approval was granted prior to the commencement of data collection by questionnaire. Verbal consent was obtained from each mother recruited for this study.The data comprise questionnaire responses collected from 1,039 single birth mothers from a total of 2286 mothers delivered during the study period irrespective of birth-status and gestational age. The volunteer clinicians for this study collected data as per their usual shifts i.e. day time one week and night time the next. This gave us 45.5% of the available data. As far as possible all consecutive births during the duty periods were recruited into this study, resulting in only 4.5% records returned entirely empty. This may have been through refusal by the patient to take part in the study or an inadvertent omission on the part of the duty clinician.Women were interviewed by the clinicians in local languages at admission in the reception, with the exception of emergency admissions, when they were interviewed in the labour room. The factors were recorded on a pre-designed questionnaire validated by health professionals during a pilot study in the same hospitals.Five factors were collected as continuous measures, which were later banded into categorical measures according to the previous literature Table  and 2. TThe category of LBW was defined as less than 2.5 kg . Gestatith percentile (<10th percentiles) and upper 10th percentiles (>90th percentiles) of birthweight.The reliability of the estimates of gestational age was further investigated using a descriptive table showing the incidence of observations grouped by birthweight and gestational weeks, shown in the form of a normogram in Figure A comparison of the profile of birthweight against gestational age with those listed in ,21 showsFrom the covariates originally collected, twenty were used for the initial analysis, to keep at least 5 events (LBW) per factor, as there are 101 occurrences of LBW in the data. This ratio of events per variable is on the threshold of acceptability for the size of the pool of covariates prior to initiating the variable selection process, as recommended in the literature .There were two levels of data analysis, Crude odds of LBW babies in different categories were calculated to identify the significant factors at univariate level . MultivaThe interpretation of main effects and interactions was aided by calculating a one-way table of predicted means for each significant main effect, and a two-way table of predicted means for each significant (two-way) interaction, using the statistical package GenStat . These wThe results are for data from 1039 birth episodes, prospectively sampled in the four public hospitals in Peshawar. The overall incidence of LBW <2.5 kg) was found to be 9.9%. However, the crude odds of LBW in all geo-demographic factors  , 17.8 (18/101) were preterm and small for gestational age  and 40.6% (41/101) were full term and SGA. Among the total LBW, 58.4% (59/101) were SGA, and 40.6% (41/101) were appropriate for gestational age  were preterm and appropriate for gestational age  area of residence and history of anaemia, and (ii) gestational age and abortion/miscarriage Table .The adjusted odds ratios reinforce the earlier results from univariate analysis, showing that five factors significantly increase the incidence of LBW, namely Afghan refugees compared to Pakistani mothers, consanguineous compared to non-consanguineous births, and teenage compared to middle age mothers Table . A furthThe estimated predicted probability of LBW (PPr), obtained by marginalising over all of the explanatory variables, for single and interactive effects, respectively, are entirely consistent with the expectations from the values of the adjusted odds-ratios. The predictive analysis confirmed the significant independent effects already noted for teenage mothers, Afghan refugee mothers and consanguineous births, effect of anaemia in Tribal areas, and abortion/miscarriage on SGA Table .This study has been conducted in public hospitals that cover only 9%  of the total births, whereas the majority 91% of the deliveries take place at home (78%), or in private hospital/clinics etc (13%) . There iIn the present study abortion/miscarriage was used to include induced and spontaneous abortion, "due to the taboos and sensitivity associated with reporting an induced abortion". It was Considering the reliability of the study, this study found that some of the factors, i.e. consanguinity, low family income, maternal and paternal education and non-fresh water areas, diabetes, hypertension, anaemia and abortions are comparable with other reports for population or population-based studies. However, the high ratio of mothers from Tribal areas 24% in this study, compared to the total female Tribal population 15%  in this The motivation behind this study is to collect data on low birthweight in NWFP, starting from the four public hospitals available for the general public in Peshawar. This study provides baseline information and a start to debate low birthweight from public hospitals in this region, which could help with possible intervention regarding maternal and newborn health in the future. It is an observational study which generated a sample surveying all but a very small proportion of consecutive births attended by the clinicians who agreed to take part. While this reduced the overall sample size, the duty patterns alternated between day and night and so the stratification of sampling by clinician does not indicate any factor likely to introduce bias into the results of the study.The overall incidence of LBW in this study at Peshawar (10%) was half that of recent studies 19%–23%) in Lahore and Karachi ,9 and th%–23% in Among the total LBW, 59% were SGA, and 41% appropriate for gestation  compared to full term babies without any abortion/miscarriage (Table The incidence of low birthweight reported in this study is less than one-half of the overall figure for Pakistan. However, there is significant variation among groups of mothers with specific combinations of geo-demographic factors, maternal health indicators and pregnancy history.The effect of anaemia and previous abortion/miscarriage in Tribal areas compared to Settled areas, and the independent effect of Afghan refugee status on birth weight need further investigation to identify the root causes of adverse pregnancy outcomes in Tribal areas and Afghan refugees.Health awareness programmes delivered by health workers in the villages, at educational institutions and through a concerted media campaign regarding the effect of consanguinity, teenage mothers, abortions and anaemia could be helpful in reducing the adverse pregnancy outcomes.The findings of this study are specific to public hospitals in NWFP-Pakistan. However they show value in registering with the hospital during pregnancy and potential value in improving data collection methods, perhaps by electronic means, to support the design of targeted public health interventions and monitoring of their effectiveness. Further studies on LBW in private hospitals and clinics, together with studies of home deliveries, are also needed in order to extend the scope of the present work on LBW in this region.The authors declare that they have no competing interests.SB carried out the survey, fitted the multivariate statistical model, and led the interpretation of the results and the writing of the paper. PJGL and KMcK provided supervision during the conception, design and statistical analysis. LM supervised the public health context of the work, during the conception and design of the survey as well as interpretation of the results. RP modelled the predictions using GENSTAT and verified the statistical integrity of the analysis. All authors read and approved the final version to be published.The pre-publication history for this paper can be accessed here:


Children with attention-deficit/hyperactivity disorder (ADHD) often experience problems with education, interaction with others and emotional disturbances. Families of ADHD children also suffer a significant burden, in terms of strain on relationships and reduced work productivity. This parent survey assessed daily life for children with ADHD and their families.This pan-European survey involved the completion of an on-line questionnaire by parents of children (6–18 years) with ADHD (ADHD sample) and without ADHD (normative population sample). Parents were questioned about the impact of their child's ADHD on everyday activities, general behaviour and family relationships.The ADHD sample comprised 910 parents and the normative population sample 995 parents. 62% of ADHD children were not currently receiving medication; 15% were receiving 6–8 hour stimulant medication and 23% 12-hour stimulant medication. Compared with the normative population sample, parents reported that ADHD children consistently displayed more demanding, noisy, disruptive, disorganised and impulsive behaviour. Significantly more parents reported that ADHD children experienced challenges throughout the day, from morning until bedtime, compared with the normative population sample. Parents reported that children with ADHD receiving 12-hour stimulant medication experienced fewer challenges during early afternoon and late afternoon/early evening than children receiving 6–8 hour stimulant medication; by late evening and bedtime however, this difference was not apparent. ADHD was reported to impact most significantly on activities such as homework, family routines and playing with other children. All relationships between ADHD children and others were also negatively affected, especially those between parent and child (72% of respondents). Parents reported that more children with ADHD experienced a personal injury in the preceding 12 months, including those requiring the attention of healthcare professionals. Although 68% of parents were satisfied with their child's current treatment, 35–40% stated that their child's ADHD symptoms needed to be more effectively treated during the afternoon and evening.This parent survey highlights the breadth of problems experienced by ADHD children and the impact throughout the day on both activities and relationships. Therefore, there is a need for treatment approaches that take into account the 24-hour impact of the disorder and include all-day coverage with effective medication. Attention-deficit/hyperactivity disorder (ADHD), which is estimated to affect 4–12% of school-aged children, is one of the most common neurobehavioural disorders of childhood ,4. AlthoADHD is associated with an increased risk for accidents among children ,12. CompAs they reach adolescence, children with ADHD are also at an increased risk for cigarette smoking and substance abuse -18. FurtWhilst debilitating for the child, ADHD has also been shown to adversely impact on parents' quality of life, placing a substantial burden on the family as a whole. Indeed, families of children with ADHD have been consistently shown to experience more difficulties than families of nondisabled controls ,19. ThesAlthough the financial burden of ADHD has not been fully evaluated, it has been demonstrated that individuals with ADHD exhibit increased use of mental health, social and special education services ,22. Resu®)  and amfetamines) or the non-stimulant atomoxetine (Strattera®) ,25, and ®) . MPH is ®) -32, as w®) . The sel®) -36. To d®) . To addrAn on-line, parent-completed questionnaire was designed with input from both experts in the field of child psychiatry and paediatrics and experienced ADHD advocates. The primary aim of the survey was to examine the experiences of parents with a child with ADHD and the degree to which their child's ADHD impacts on both the daily life of the individual child and the family as a whole.The survey was also designed to explore the differences in behaviour between children with ADHD receiving stable medication (> 3 months), children with ADHD not on medication and children without ADHD. As such, this questionnaire was completed by a sample of parents with children with ADHD and a general population sample of parents with children without ADHD (normative population). Parents of children with ADHD were questioned about the impact of their child's ADHD in three key areas: (i) everyday activities both 'in the home'  and 'outside the home' (e.g. leisure and family activities); (ii) general behaviour ; and (iii) family relationships . Similarly, parents in the normative population sample were questioned about their non-ADHD child's general behaviour and their behaviour in relation to everyday activities and family relationships.All questions contained in the survey were multiple choice and answered using a 7-point scale. This survey also addressed the times of day at which the children were perceived by their parents to be affected by their ADHD Table . On averOverall, parents from ten European countries  were invited to participate in the survey. This survey was sponsored by Janssen Cilag and conducted by Harris Interactive, an experienced market research company. The survey was conducted in accordance with guidelines set by the European Pharmaceutical Market Research Associations and the Market Research Society.st March to 11th April, 2007.Parents of children with ADHD were drawn from an independently sourced sample via third party sample providers, who had identified households within their panel  where one or more of the children in the household had ADHD . To supplement this sample group, additional respondents within the sample providers' panel were also invited to participate in a screening questionnaire. Parents of children with ADHD were surveyed between 1th June to 21st June, 2007.A sample of parents with children without ADHD were drawn from the Harris pan European panel, which comprised of approximately 3 million households across Europe, and was representative of the general population within Europe in terms of age, gender and socio-economic status. Parents of children without ADHD were surveyed between 4Both the ADHD and normative population surveys were conducted on-line and potential respondents were screened on a number of selection criteria. For the ADHD survey, parents were required to have a child (or children) aged 6–18 years, with a confirmed diagnosis of ADHD that had been made by a designated healthcare professional. Parents also had to live in the same household as the child with ADHD. Due to the fact that atomoxetine has a substantially different mechanism of action from stimulant medications, parents whose child with ADHD received atomoxetine were excluded from participating in the ADHD survey. In addition, given that one of the objectives of this survey was to investigate the impact of stimulant medication on afternoon behaviours, parents whose child with ADHD only received a once-daily dose of an immediate-release stimulant medication, were also excluded from the ADHD survey. In those instances where parents had more than one child with ADHD, parents answered questions with reference to their eldest child with ADHD. For the normative population survey, respondents also had to have a child (or children) aged 6–18 years and had to live with the child (or children). For parents with more than one child, the survey was completed with reference to the eldest child. In both surveys (ADHD and normative population surveys), data was collected and analysed for young (6–10 years) and older children (11–18 years). Gender was not considered as a specific issue during the design of the survey and as such gender was not controlled for in either the ADHD or the normative population survey samples.Overall, invitations to participate in the survey were sent to 122 069 parents , after which 25,280 parents were enrolled to the screening questionnaire. Following completion of the screening questionnaire, 910 parents were enrolled in the ADHD survey and 995 parents in the normative population survey  or non-parametric (chi-square) tests as appropriate, carried out at the 5% significance level. Wincross (version 7.0) was used for this analysis. Data was analysed separately for the two groups (ADHD survey parent sample and normative population parent sample).Responses to the surveys were received from 1905 parents   versus older (11–18 years) children, revealed few differences on the impact of ADHD on everyday activities, general behaviour and family relationships as recorded by parents. Therefore, data is presented here for the entire ADHD age sample (6–18 years).Overall, parents reported that their children with ADHD find the whole day challenging. An analysis of parent's responses revealed that a reasonably high percentage of children with ADHD and children without ADHD experienced challenges with the morning routine . However, over the course of the day, parents reported that children with ADHD consistently experienced greater challenges as observed during the morning , at lunchtime , during the early afternoon , late afternoon/early evening , late evening  and at bedtime .When results were analysed for medicated versus non-medicated children with ADHD, a significantly higher percentage of children receiving stimulant medication experienced challenges with the morning routine compared with non-medicated children . With the exception of the early afternoon period, where a greater percentage of non-medicated children experienced challenges compared with medicated children , few other differences were observed by parents between the medicated and non-medicated ADHD groups during the course of the day.For medicated children with ADHD, parents reported that those receiving 12-hour stimulant medication experienced greater challenges with the morning routine than those receiving 6–8 hour stimulant medication. However, as the day progressed, children receiving 12-hour stimulant medication experienced less challenges than children receiving 6–8 hour stimulant medication, although parents noted a trend for children receiving 12-hour stimulant medication to exhibit more challenging behaviour in the late evening and at bedtime Figure .As part of this survey, parents were asked whether, on an average week day, their child's ADHD affected various everyday activities: meal-times, homework, playing alone, playing with other children, following family routines, individual leisure activities and group leisure activities. Overall, parents reported that ADHD is adjudged to impact negatively on all measured activities. In particular, compared with the normative population sample, a significantly higher percentage of children with ADHD were described as being considerably more challenged in the areas of homework , following family routines  and playing with other children . When questioned at which times during the course of the day (lunchtime to late evening) these three activities were most affected in children with ADHD, parents reported that homework and playing with other children were most affected during the early afternoon and late afternoon/early evening, whilst following family routines was most affected during the late afternoon/early evening and late evening periods . With regards to the times of day that homework and the following of family routines were most affected, a similar pattern emerged for both medicated and non-medicated children with ADHD, with parents reporting that both activities were most affected during the early afternoon and late afternoon/early evening periods. Playing with other children was reported by parents as being most affected during the early afternoon and late afternoon/early evening period. However, compared with non-medicated children with ADHD, a higher percentage of medicated children with ADHD experienced problems in the late afternoon/early evening periods as assessed by their parents .Overall, parents reported that ADHD impacted negatively on all relationships asked about: child-parent, parent-parent, child-sibling(s), child-other children and child-other adults. However, compared with the normative population sample, parents in the ADHD sample reported that the three relationships that were most affected were those between the child and parent , the child and their sibling(s)  and the child and other children . When questioned at which times during the course of the day (lunchtime to bedtime) these three relationships were most affected, parents reported that they were affected over the whole time period assessed. Compared with the normative population sample, parents in the ADHD sample described the child-parent relationship as being most affected during the late afternoon/early evening  and late evening periods . Likewise, compared with the normative population sample, the child-sibling(s) relationship was also described by parents as being most affected in the late afternoon/early evening  and late evening  periods. Finally, compared with the normative population sample, the child-other children relationship was described by parents as being most affected in the early afternoon  and late afternoon/early evening  periods.For children with ADHD, there was no effect of medication status on the relationships assessed, with parents reporting that the relationships between the child and parent, the child and their sibling(s) and the child and other children were similarly affected amongst medicated  and non-medicated children with ADHD . From lunchtime to early evening, there were no significant differences between medicated and non-medicated children with ADHD, in terms of the impact of their behaviour on the child-parent or child-sibling(s) relationship. However, compared with non-medicated children with ADHD, parents reported that a higher percentage of medicated children with ADHD experienced behavior that affected the relationship with their parents during the late evening  and at bedtime . Likewise, parents reported that the percentage of children with ADHD whose behaviour affected the relationship with their sibling(s) was significantly higher in the group receiving medication at bedtime . Over the course of the day, no significant differences were reported by parents between medicated and non-medicated children with ADHD with regards to the impact of their behaviour on their relationships with other children.When questioned about the types of behaviour displayed by their children with ADHD, parents reported a range of typical ADHD-related behaviours in their children Figure . In partWhen results were analysed for medicated versus non-medicated children with ADHD, medication status did not significantly alter the proportion of children who exhibited typical ADHD-related behaviours. According to parental assessments, the percentage of children with ADHD reported to display noisy and disruptive behaviour, disorganised behaviour and excessively demanding and attention-seeking behaviour were comparable between the medicated  and non-medicated groups . With regards to the times of day that such behaviours occurred, parents reported that noisy or disruptive behaviour was displayed by similar proportions of medicated and non-medicated children with ADHD throughout the day, except at bedtime, when this was significantly more frequent in medicated children . No significant differences in disorganised behaviour were reported by parents between medicated and non-medicated children with ADHD during the early afternoon, late afternoon and late evening periods; however, parents reported that disorganised behaviour was significantly more frequent in medicated children with ADHD at lunchtime  and at bedtime . Excessively demanding or attention-seeking behaviour was recorded by parents in a similar percentage of medicated and non-medicated children with ADHD over the course of the day.Parents were also questioned about the number of personal injuries experienced by their children with ADHD. Compared with the normative population sample, parents reported that a significantly greater percentage of children in the ADHD sample  experienced a personal injury in the last 12 months. In addition, an analysis of parent's responses suggest that children with ADHD experience a greater number of injuries that required the attention of a primary care physician or paramedic  and a visit to hospital .Medication status, as assessed by parents with an ADHD child, did not have a great impact on the number of injuries. Overall, there were no significant differences between medicated and non-medicated children with respect to percentage of medicated children with ADHD experiencing a personal injury in the last 12 months , average number of total injuries , injuries that required the attention of a primary care physician or paramedic , injuries that required a visit to the hospital  or injuries that required a stay in hospital . However when results for the injuries that required a stay in hospital were analysed separately for those receiving 6–8 and 12-hour stimulant medication, parents reported that children receiving 12-hour medication had significantly less injuries than those receiving 6–8 hour medication  were not receiving medication at the time of this survey  to 7 ('extremely satisfied').Overall, parents were 'reasonably satisfied' with their child's medication, with 68% of parents recording a score of 5, 6 or 7 on this scale. When results were analysed for children receiving 6–8 hour stimulant medication and 12-hour stimulant medication, 71% of parents reported that they were reasonably satisfied with their child's 6–8 hour stimulant medication and 63% were 'reasonably satisfied' with their child's 12-hour stimulant medication, as recorded by a score of 5, 6 or 7 on this scale. Only 4% of parents (3% of parents whose ADHD child was receiving 6–8 hour stimulant medication and 5% of parents whose ADHD child was receiving 12-hour stimulant medication) recorded a score of 1, indicating that they were 'not at all satisfied' with the ADHD medication their child was receiving.As part of this survey, parents with an ADHD child treated with stimulant medication were also asked whether there were any particular times of the day (lunchtime to late evening) when they felt that their child's symptoms needed to be better controlled. Overall, 47% of parents felt that their child's symptoms needed to be better medicated in the early afternoon. An additional 41% of parents felt that there was a need for improved medication in the late afternoon/early evening period, whilst 37% also reported a need for more effective medication during the late evening period.Results from this large European parent survey demonstrate that parents report that ADHD has a significant impact on the child and their family, affecting school work, peer relationships and family relationships. Importantly, parental assessment in this survey clearly highlights that all times of the day are challenging for children with ADHD, with the afternoon/evening period at least as problematic as the school day. Of note, parents reported that typical behaviours associated with ADHD  consistently peaked during the late afternoon/early evening period. In line with this finding, a range of everyday activities  and a number of important relationships  were also reported by parents to be affected during the course of the afternoon and evening.Of note, the majority of children with ADHD in this survey (62%) were not currently receiving medication. This may be due in part to a European tradition that medication treatments for ADHD should be reserved for those with more severe symptoms and impairments. This may also be related to a number of concerns that have arisen regarding the use of stimulant medication for children with ADHD, especially in younger children. These range from ethical objections to utilising medication to modify children's behaviour  to conceAlthough there is a misconception that ADHD is a condition that primarily affects children whilst at school (e.g. their school grades), which results in some physicians focusing solely on the impact of ADHD on school activities, results from this parent survey highlight the importance of treatment throughout the full active day. Indeed, when questioned directly, approximately half of parents reported the need for a medication that extends into the early afternoon and late afternoon/early evening periods. Moreover, the observation by parents that there was a trend for children with ADHD receiving 12-hour stimulant medication to experience more challenges during the morning routine, in the late evening and at bedtime may reflect that these children are those with the most severe ADHD, with pronounced disturbances late in the day, whose symptoms require medication coverage over the full course of the active day. However, it is important to note that individual treatment plans for children with ADHD may take into account not only the severity of symptoms and the ensuing daily challenges, but also the context (e.g. consequences and settings) of symptoms and the impact of these symptoms on daily functioning. Indeed, it has been suggested that the primary focus of assessment of ADHD should be on functional behavioural assessments of impairment such as identifying impaired domains of functioning, operationalizing target behaviours within these domains and implementing treatment measures such as Individualised Target Behaviour Evaluation. Such assessments will identify environmental contexts and socially valid target behaviours (not DSM-IV symptoms of ADHD) and facilitate treatment planning .Interestingly, although specific parent enquiry demonstrated a significant degree of challenging behaviours, many parents who participated in this survey reported reasonable satisfaction with their child's current ADHD treatment. These results highlight that, by asking about specific activities at different times of the day, physicians may be able to elicit better information from parents that may guide individual medication decisions and optimize treatment across the day.®, Ritalin LA®, Metadate CD® and Concerta XL®. Results from a number of studies have demonstrated that these long-acting MPH formulations improve the behavioural and attention-related symptoms of ADHD over the course of the day [Given the importance of considering the treatment of ADHD symptoms outside of the school environment, there has recently been great interest in the use of longer acting stimulant preparations. Current international guidelines for the management of ADHD recommend the use of long-acting formulations to reduce the need for in-school dosage and the likelihood of diversion . To date the day -31. In a the day ,29,45. CThere are several limitations of this survey that must be noted. Due to the design of the survey, the core selection criterion for ADHD was based solely on the diagnosis made by a dedicated healthcare professional. Moreover, unlike clinical trials in which all attempts are made to standardise the research setting, surveys are conducted in the real world under circumstances that can not be fully controlled. In addition, because the data reported here are based on parental reports of the impact of their child's ADHD on everyday activities, general behaviour and family relationships, the accuracy of these reports may be subject to recall bias, subjective reporting by parents and other types of response errors. In particular, parents may have been unwilling to indicate whether their child engaged in behaviours contrary to the generally accepted norms of society, thereby reducing the reliability and validity of some of the results. Of note, parental assessment in this survey showed relatively small differences between medicated and non-mediated children with ADHD, in terms of the impact of their condition on everyday activities, general behaviour and family relationships, and the times of day reported by their parents as challenging. This may be due to the fact that this was an observational study and that the two ADHD groups (medicated and non-medicated ADHD children) were not matched for severity-of-illness. In addition, no information was available on the dosage of medication and medication compliance in the ADHD treatment group. Concerns regarding the use of stimulation medication for children with ADHD have been raised across Europe . This contributes to wide variations in prescribing practices across Europe. Consequently, comparisons between medicated and non-medicated children with ADHD observed in this naturalistic survey are somewhat difficult to interpret. A further limitation of this survey is that children with ADHD receiving the non-stimulant medication Strattera, or who only received one dose of an immediate-release stimulant medication, were excluded from the survey, and therefore the results presented may not generalize to these children. Overall, this was a large European survey with broad selection criteria, a factor that should be noted when interpreting the results. In the future, additional studies or surveys could employ different recruitment strategies and designs in order that they can provide clearer, accurate and precise results. In particular, future studies should consider the validity of the ADHD diagnosis and provide more stringent selection criteria. In addition, analyses designed to critically evaluate the impact, on the course and outcome of ADHD, of a range of variables including gender, severity-of-illness, dosage of medication and/or behavioral treatment and treatment compliance are required. Such analyses may help identify and predict which children with ADHD may respond more optimally to different treatments. However, despite these limitations, the data gathered during this parent survey provides clinicians with a wealth of information on the effect of ADHD and its medication on the everyday life of affected children and their families.Results from this parent survey demonstrates both the breadth of problems experienced by children with ADHD, as well as alerting physicians to a range of factors that should be considered in the management of children with ADHD. Importantly, by highlighting that children with ADHD experience challenges throughout the day, with the afternoon/evening period at least as problematic as the school day, this survey illustrates the importance of medication throughout the full active day. To assist both children with ADHD and their families, such medication should include a range of behavioural interventions as well as pharmacological treatments that can provide full-day coverage of symptoms. This will help children with ADHD achieve their full potential at home and at school, and with their families and friends. These results also reinforce the need for good quality medication management in order to derive maximum benefit from pharmacological treatments.ADHD: attention-deficit/hyperactivity disorder; MPH: methylphenidate.DC has been an advisory board member for Cephalon, Eli Lilly, Janssen Cilag, Shire and UCB and has received research funding from Eli Lilly and Janssen Cilag.CS is a consultant for Alicia Koplowitz Foundation, EINAQ, Eli Lilly, Janssen-Cilag, Juste, Otsuka/Bristol-Myers Squibb, Pfizer and Shire and has been a speaker for ADHI, Admirall-Prodesfarma, APNADAH, AstraZeneca, ASTTA, Bristol-Myers Squibb, Eli Lilly, Esteve, GlaxoSmithKline, Janssen, Novartis and Solvay. Cesar Soutullo has received research funding from Abbott, Alicia Koplowitz Foundation, Bristol-Myers Squibb, Eli Lilly, Navarra Department of Health, Novartis, Pfizer, Solvay, Shire, Spanish Department of Health, Stanley Medical Research Institute-NAMI and royalties from DOYMA, Editorial Médica Panamericana, EUNSA, Grupo Correo and Euro RSCG Life Medea.CA has been a speaker for Janssen-Cilag and participated in a German Survey for Eli Lilly.UP is a consultant for Swiss Medic and Canton Bern and has been a speaker for Eli Lilly, Pfizer, Novartis, Janssen-Cilag, Solvay Pharma, Vifor AG and Canton Bern. Ulrich Preuss has been an advisory board memeber for Eli Lilly, Janssen-Cilag, Lundbeck and Canton Bern and has research contracts with Eli Lilly, AstraZeneca and Canton Bern.TL has been an advisory board member for Janssen Cilag.MS has been an advisory board member for Janssen Cilag.JB is a consultant, advisory board memeber and a speaker for Janssen Cilag BV, Eli Lilly, Bristol-Myer Squibb, UCB, Shire, Medice and Pfizer.All of the authors participated in a series of Advisory Board Meetings to assist with the design and development of the survey questionnaire. The authors worked together to analyse the results from the survey and interpret the findings. All authors participated in the development of the manuscript, including the writing and editing.All authors proof read the manuscript and approved the manuscript prior to submission.


The objective of this study was to assess the effects of atomoxetine on treating attention-deficit/hyperactivity disorder (ADHD), on reading performance, and on neurocognitive function in youth with ADHD and dyslexia (ADHD+D).Patients with ADHD (n = 20) or ADHD+D (n = 36), aged 10-16 years, received open-label atomoxetine for 16 weeks. Data from the ADHD Rating Scale-IV (ADHDRS-IV), Kaufman Test of Educational Achievement (K-TEA), Working Memory Test Battery for Children (WMTB-C), and Life Participation Scale for ADHD-Child Version (LPS-C) were assessed.Atomoxetine demonstrated significant improvement for both groups on the ADHDRS-IV, LPS-C, and K-TEA reading comprehension standard and composite scores. K-TEA spelling subtest improvement was significant for the ADHD group, whereas the ADHD+D group showed significant reading decoding improvements. Substantial K-TEA reading and spelling subtest age equivalence gains (in months) were achieved for both groups. The WMTB-C central executive score change was significantly greater for the ADHD group. Conversely, the ADHD+D group showed significant phonological loop score enhancement by visit over the ADHD group. Atomoxetine was well tolerated, and commonly reported adverse events were similar to those previously reported.Atomoxetine reduced ADHD symptoms and improved reading scores in both groups. Conversely, different patterns and magnitude of improvement in working memory component scores existed between ADHD and ADHD+D patients. Though limited by small sample size, group differences in relation to the comparable changes in improvement in ADHD symptoms could suggest that brain systems related to the therapeutic benefit of atomoxetine in reducing ADHD symptoms may be different in individuals with ADHD+D and ADHD without dyslexia.Clinical Trial Registry: ClinicalTrials.gov: NCT00191048 The 2 most common developmental disabilities of school-aged children are attention-deficit/hyperactivity disorder (ADHD) and learning disabilities, with prevalence rates of 3%-7% and 5%-10%, respectively ,5. WhileBoth ADHD and dyslexia are also associated with deficits in working memory, the ability to hold information in mind for brief periods of time in the course of ongoing cognitive activities. Low working memory performance has recently been shown to be linked specifically to the severity of inattentive symptoms in ADHD  and is aAtomoxetine hydrochloride (hereafter referred to as atomoxetine) is a nonstimulant, selective norepinephrine transporter inhibitor. Atomoxetine has demonstrated efficacy across age, gender, and ADHD subtypes  -14. SpecProtocol B4Z-US-LYCE(a) was an open-label, multi-center outpatient, parallel-design, fixed-dose pilot study investigating the efficacy of atomoxetine in reducing symptoms of ADHD in individuals aged 10 to 16 years meeting DSM-IV diagnostic criteria for ADHD and dyslexia. As part of this investigation, a smaller group of individuals meeting DSM-IV criteria for ADHD only were assessed to determine to what extent symptomatic change in the comorbid ADHD and dyslexia group was conferred independently by the effect of atomoxetine on ADHD alone. The primary hypothesis of this study was that atomoxetine would provide therapeutic benefit for the symptoms of ADHD in individuals with ADHD and comorbid dyslexia. Secondarily, the study investigated to what extent any medication-specific change in reading performance may correlate to change in ADHD symptoms and in working memory function, and to what extent the effect of atomoxetine on certain component skills related to reading may correlate with changes in overall reading performance.®, Eli Lilly and Company, Indianapolis, IN, USA) for approximately 16 weeks. The maximum dose prescribed was 1.4 mg/kg or 100 mg, whichever dose was less. After initiating treatment, patients were assessed every 2 weeks for 8 weeks and then once a month for the remaining 8 weeks of the study.This open-label, non-randomized, parallel-design pilot study was conducted from October 2003 to March 2006 at 12 centers in the United States. The study protocol was approved and conducted in accordance with the principles of the Declaration of Helsinki, and all parents or legal guardian(s) of the patients provided written informed consent (and patients provided assent where applicable) after the procedure(s) and possible side effects were fully explained. All patients meeting criteria received open-label treatment with atomoxetine at doses ranging from 1.0-1.4 mg/kg once daily given orally as capsules  were enrolled. In addition to meeting DSM-IV diagnosis criteria for ADHD, patients in the ADHD-only and ADHD+D treatment groups were required to meet Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime, Behavioral Disorders Supplement  module cPatients were excluded for any of the following reasons: weight less than 25 kg or greater than 70 kg at study entry; any current or previous diagnosis of bipolar I or II disorder or psychosis; autism, Asperger's syndrome, or pervasive developmental disorder; serious suicidal risk; serious medical illness or clinically significant laboratory abnormalities, hospitalization, or an excluded medication during the course of the study; a history of substance abuse or dependence within the past 3 months (excluding nicotine and caffeine); a positive urine drug screen for any substances of abuse; and treatment with a monoamine oxidase inhibitor within 14 days prior to baseline.Concomitant medications with primarily central nervous system activity were not allowed. Medications that are strong CYP2D6 inhibitors or substrates were not permitted. Chronic use of cough and cold medications containing pseudoephedrine or the sedating antihistamine diphenhydramine were not allowed. Narcotic use was not permitted unless special circumstances arose  and approval of the Lilly physician or designee was granted. Patients on methylphenidate or another prescribed stimulant for the treatment of ADHD were required to be stimulant-free 24 hours prior to obtaining baseline measures and to subsequently discontinue medication 1 day prior to the last screening visit before dispensation of study medication.The primary objective was to assess the effect of atomoxetine on patients with ADHD+D as measured by the mean change from baseline on the ADHDRS-IV. Secondary measures included comparison between the ADHD and ADHD+D groups on mean change in the ADHDRS-IV total and subscale scores; K-TEA measures  ; the Worcrystallized thinking) by assessing a person's word knowledge and verbal concept formation. Matrices measure non-verbal skills and the ability to solve new problems (fluid thinking) by assessing an individual's ability to perceive relationships and complete analogies [The K-BIT is a brief, individually administered measure of verbal and non-verbal intelligence. The test is composed of 2 subtests: Vocabulary and Matrices. Vocabulary measures verbal, school-related skills  make up the Reading Composite score, which is transformed to a standard score that indicates age equivalency .The WMTB-C consists of 9 subtests designed to reflect 3 main components of working memory: central executive, phonological loop, and visuo-spatial sketchpad. The frontal regions of both hemispheres of the brain are associated with the central executive functions of coordinating, processing and storage, controlling flow of information through working memory, and attentional control. The 3 central executive (CE) subtests include: Backward Digit Recall, Listening Recall, and Counting Recall. The phonological loop, located in the temporal lobes of left hemisphere, is associated with functions of temporary storage of material in a phonological (sound-based) form, which includes spoken language and both written language and pictures. The 4 subtests designed to measure phonological loop function are: Digit Recall, Word List Matching, Word List Recall, and Non-word List Recall. The visuo-spatial sketchpad, located in the right hemisphere, is associated with functions of storage of materials in terms of visual or spatial features . Two subtests tap visuo-spatial sketchpad function: Block Recall and Mazes Memory .Safety measures recorded at every visit included spontaneously reported treatment-emergent adverse events (TEAEs) and vital signs. Blood for chemistry and hematology laboratories were collected at baseline, after 4, 6, and 10 weeks of treatment, and at the end of the 16-week treatment period. Electrocardiograms were collected at baseline, after 4 weeks of treatment, and at discontinuation of the study.The primary measure, the determination of significant improvement from baseline on the ADHDRS-IV total score for patients with ADHD+D, was analyzed using a Student's t-test applied to the least squares mean change from baseline score. Change scores were computed for each patient as the difference between the last observation carried forward (LOCF) score and baseline score. The least squares mean change and associated standard error used in the Student's t-test were derived from an analysis of covariance (ANCOVA) model, with terms for diagnostic group, investigator, gender, age, baseline score, and baseline score-by-diagnostic group interaction. All patients with comorbid ADHD+D and at least 1 baseline and 1 post-baseline score were included in the primary analysis.Between-group changes from baseline to endpoint in efficacy measure variables were analyzed using a fixed-effects ANCOVA model, with terms for diagnostic group, investigator, gender, baseline score, age, and baseline score-by-diagnostic group interaction. Type III sums of squares were used for between-group tests. Changes within diagnostic group were assessed using Student's t-test applied to the least squares mean for the diagnostic group from the ANCOVA model. There were no adjustments made for the number of tests conducted.Between-group changes in efficacy measure variables over time were analyzed using the relevant contrast from a restricted maximum likelihood repeated measures model, with terms for diagnostic group, investigator, visit, baseline score, diagnostic group-by-visit interaction, and baseline score-by-diagnostic group interaction. This model used the covariance structure that maximizes Schwartz's Bayesian Criterion and the Kenward-Roger method for estimating denominator degrees of freedom. Student's t-test was applied to the least squares mean and standard error to estimate within-group change to endpoint based on the relevant contrast from the diagnostic group-by-visit interaction from this model.Incidence of categorical response variables were compared across diagnostic groups using Fisher's exact test. Correlations between change and baseline (Visit 1) scores for LPS-C Investigator- and Parent-rated scales were computed to assess the consistency of responses using alternate sources for rating the patient's behavior. Pearson correlation coefficients were calculated to examine the relationships between the changes of selected efficacy measures. Tests were two-tailed.A total of 134 patients were screened, and 56 patients met criteria for ADHD (n = 20) and ADHD+D (n = 36). A total of 47 patients, 16 in the ADHD group and 31 in the ADHD+D group, completed the study. Figure The primary efficacy measure was the ADHDRS-IV total score. Similar statistically significant mean change improvement was demonstrated in both the ADHD and ADHD+D groups on ADHDRS-IV total score  and the subscores for inattention  and hyperactive/impulsivity . There was no differentiation of response between the 2 groups on total score and the inattentive and hyperactive/impulsivity subscores . Figure The secondary efficacy outcome measure of the LPS-C showed statistically significant adaptive function improvement and agreement between the investigator-rated and parent-rated versions of the scale. Mean change from baseline to endpoint was statistically significant for both groups, though there were no differences between groups.One of the key secondary objectives in this study was to assess the effects of atomoxetine on K-TEA measures in patients with ADHD or ADHD+D after 16 weeks of treatment. Patients with ADHD and ADHD+D demonstrated statistically significant improvements in mean standard scores and age equivalencies in all K-TEA reading decoding, reading comprehension, reading composite, and spelling measures , with the following exception: The ADHD reading decoding standard score (p = .08) and the ADHD+D spelling standard scores (p = .14) were not statistically significantly improved Table . BaselinAnother key secondary objective evaluated performance on the WMTB-C. For the ADHD group, the mean component and standard scores for central executive function (CE) were statistically significantly improved from baseline to endpoint  mean changes for the WMTB-C revealed a statistically significantly greater improvement at the last week for patients with ADHD over the ADHD+D group on the CE standard p = .003) and component scores . There were no statistically significant correlations between the ADHDRS-IV total score or subscores and any other K-TEA measures or to any WMTB-C components.There were no serious adverse events reported. A total of 4 (7.1%) patients of the 56 randomized to the trial discontinued due to adverse events, which included nausea, mood swings, and abdominal pain. Adverse events occurring in at least 5% of all patients in the study were somnolence (n = 19), nausea (n = 17), decreased appetite (n = 12), headache (n = 11), nasopharyngitis (n = 7), upper abdominal pain (n = 11), vomiting (n = 9), cough (n = 4), upper respiratory tract infection (n = 3), constipation (n = 3), irritability (n = 5), psychomotor hyperactivity (n = 3), fatigue (n = 6), and abdominal pain (n = 3). There were no differences between groups in the occurrence of any reported adverse event. Likewise, ECGs, laboratory analytes, vital signs, height, and weight evaluations revealed no clinically significant changes from baseline to endpoint.These preliminary data demonstrated that atomoxetine was effective in treating ADHD symptoms in patients with ADHD and ADHD+D, and support the primary objective of this study. The presence of dyslexia did not appear to change the response to atomoxetine in reduction of ADHD symptoms. Baseline scores for the academic reading measures for patients in the ADHD+D group were numerically lower, but improvement gains by the end of study were comparable to the ADHD group. Notably, the ADHD+D age equivalent gains of 23.5 months were numerically greater than gains achieved in the ADHD group (17.2 months). Although the K-TEA and WMTB-C were administered 4 times throughout the 16-week study period and therefore could have posed a limitation to the study, the repeated administration of these measures was well within the test/re-test reliabilities described in the test manuals ,20. The On measures of neurocognitive function, the baseline values in 3 domains of interest assessed by the WMTB-C were comparable between the 2 groups. The ADHD group showed more marked improvement in the component scores related to central executive function, and the ADHD+D group showed more marked improvement in component scores related to the phonological loop. The phonological, visual-spatial, and central executive tests assess neurocognitive function served by different neural systems. These data could suggest that the brain systems related to the therapeutic benefit of atomoxetine in reducing ADHD symptoms may be different in individuals with ADHD+D and ADHD without dyslexia. The data suggesting that selective areas of working memory can be enhanced by atomoxetine is important, as poor working memory function appears to be a cognitive constraint on academic learning .The findings of this study must be considered in light of design limitations, which include small sample size that was not distributed to groups by randomization and the lack of a placebo comparator group. Although this was an open-label study, the reduction of ADHD symptoms as measured by the ADHDRS was similar to previously conducted placebo-controlled atomoxetine trials ,13. FurtAtomoxetine was equally effective in the reduction of ADHD symptoms for both the ADHD and ADHD+D groups, and both groups saw improvement in reading scores. In contrast, for patients with ADHD and ADHD+D, atomoxetine appeared to provide different patterns and magnitude of improvement in working memory component scores between groups. The data suggests that atomoxetine was well tolerated. Commonly reported adverse events were similar to those reported in previous studies of atomoxetine in children and adolescents ,24. AgaiCS was a minor stock shareholder and full-time employee of Lilly USA, LLC at the time this manuscript was written. He is currently employed by Biobehavioral Diagnostics Company. DW and LW are minor stock shareholders and full-time employees of Lilly USA, LLC. MH is a former employee of Lilly USA, LLC. SG has no financial conflicts of interest to report. MG has served as a clinical investigator for Eli Lilly and Company and/or one of its subsidiaries, Shire, McNeil/Johnson & Johnson, AstraZeneca, Sanofi-Avenis, Wyeth, Labopharm, Novartis, Abbott, and Pfizer; and has served on speaker's bureaus for Novartis, McNeil, Shire, and Eli Lilly and Company and/or one of its subsidiaries. RR has received research grants from Abbott, Cephalon, Eli Lilly and Company and/or one of its subsidiaries, New River, and Shire; and has served on advisory boards and provided consulting for Addrenex, Cephalon, Eli Lilly and Company and/or one of its subsidiaries, and Shire; and has served on speaker's bureaus for Cephalon, Eli Lilly and Company and/or one of its subsidiaries, and Shire.CS and LW developed the clinical trial. MG and RR were study investigators. DW was the study statistical expert. All authors contributed to the analysis and interpretation of data. MH drafted the manuscript. All authors critically revised the manuscript for important intellectual content and approved the final version.


How often will elections end in landslides? What is the probability for a head-to-head race? Analyzing ballot results from several large countries rather anomalous and yet unexplained distributions have been observed. We identify tactical voting as the driving ingredient for the anomalies and introduce a model to study its effect on plurality elections, characterized by the relative strength of the feedback from polls and the pairwise interaction between individuals in the society. With this model it becomes possible to explain the polarization of votes between two candidates, understand the small margin of victories frequently observed for different elections, and analyze the polls' impact in American, Canadian, and Brazilian ballots. Moreover, the model reproduces, quantitatively, the distribution of votes obtained in the Brazilian mayor elections with two, three, and four candidates. Sometimes one candidate wins in a landslide victory and many times two candidates compete head-to-head leaving much suspense. What is the probability of finding a certain situation? This question can be assessed through the distribution of the percentages that each candidate obtains and has in fact been monitored in several large countries with reasonably good statistics. Instead of being Gaussian as one would expect in a simple-minded application of the central limit theorem, an anomalous distribution has been observed. Different mechanisms can affect the electors' opinion formation during an electoral process For plurality elections tactical voting as a response to information from polls is a dominant effect. Specifically, since only the most voted candidate will win, electors can change their vote to an “unwanted” candidate just to decrease the margin of victory . Maurice Duverger, a French sociologist, recognized this effect as responsible for the emergence of two-party systems in a statement known, today, as Duverger's law et al.head-to-head and landslide voting. In the former, the margin between the first and second candidate is so tight that individuals tend to stick their vote to their favorite candidate. In the latter, the leading candidate has a large margin with respect to all the others, which increases the tendency towards tactical voting. To study the effect of the “useful vote” on the ballots, we propose a model where a vote results from the competition between two mechanisms: the tendency to align with peers (herding) and the “useful vote” Recently, Restrepo To verify the model, let us first consider Brazilian mayor elections since, for such elections detailed data is available Let us consider now the limit of large Since both the degree of subcriticality and tactical voting impact characterize the society, they should be independent on the number of candidates. In As referred before a square lattice is not very realistic due to the lack of long-range connections. In real systems, individuals can contact each other beyond their neighborhood . To account for such a type of connections we also consider a small-world network Let us now consider the results from mayor elections in the United States (2008) To understand how the right-hand side tail is affected by the ratio Summarizing, to understand plurality elections, we put forward a model where the relevant parameter corresponds to the ratio between the strength of polls impact and society's degree of subcriticality. With the model we have been able to compare the distributions from three large countries, namely, United States, Canada, and Brazil. The analysis reveals a similar impact of the polls on the elections in United States and Canada and an even stronger one in Brazil. Using available results for mayor elections with two candidates in Brazil, we have been able to parametrize the set of electors. With the obtained parameters we reproduce the distribution of the fraction of votes in elections with three and four candidates. The model has been implemented on a square lattice and a small-world network and, despite the differences discussed previously, the main features of the model do not depend on these topologies, e.g., for both systems, the small margins of victories as well as the polarization between the first two candidates (Duverger's law) are quantitatively reproduced. At this stage, our model does not account for blank or null votes, notwithstanding, that such votes shall not affect the candidates' relative fraction of votes. Our approach opens up the possibility to make statistical predictions about the outcome of elections by determining the new characteristic parameter We have performed Monte Carlo simulations on the square lattice, for three different system sizes, namely,


Echinococcus multilocularis, the sibling vole, has restricted spatial distribution. A survey of feces from the main host, the arctic fox, showed that only the area occupied by the intermediate host is associated with increased risk for human infection.In Svalbard, Norway, the only intermediate host for  Echinococcus multilocularis is the causative agent of alveolar echinococcosis, a rare but potentially lethal human disease. In the Arctic, E. multilocularis depends on the arctic fox  or domestic dog (Canis lupus familiaris) as its definitive hosts, and human infections are caused by ingestion of infective eggs distributed with the feces of these hosts. A wide variety of small rodents, especially voles and lemmings of the subfamily Arvicolinae, can function as intermediate hosts . The distribution of sibling voles on the island seems to be limited by availability of plants for food and is at present restricted to the heavily fertilized bird cliffs along the coastline in the Grumant area : A) Grumant, the core sibling vole range, Grumant to Lille Bjørndalen; B) Bjørndalen, the neighboring valley 2–6 km from Grumant; C) Nordenskiöld Land, the more distant areas surveyed on the Nordenskiöld Land peninsula, 6–40 km from Grumant; and D) Distant, the Hornsund area 130 km south of Grumant and the Ny-Ålesund area 110 km north of Grumant. The main Norwegian settlement, Longyearbyen,  is located 12 km east of Grumant; the Russian settlement, Barentsburg, (population ≈500), is located 24 km southwest of Grumant.E. multilocularis coproantigen detection was performed as described by Deplazes et al. , and 10 transects of 20 m each  were placed in Adventdalen, next to Longyearbyen and 15 km east of Grumant. The distance from the line to detected feces was noted; all feces detected up to 1.6 m on each side of the transect lines were included in the density estimation. The data were analyzed by using Distance 5.0  in 2004 were E. multilocularis positive. These may be false-positive results, or the feces may have come from arctic foxes that were infected in the Grumant area before a long-distance dispersal event or perhaps from even more distant locations, e.g., Northern Russia, which has been speculated to be the initial source of infection to Svalbard . No fox feces were detected along the 10 transects in Adventdalen, but the estimated confidence intervals suggest a density of 0–0.4 feces per 100 m2. The density of fox feces is therefore likely to be at least 11 times higher in Grumant than in Adventdalen (4.5/0.4 = 11.25). This difference can be explained by differences in fox densities as a result of lower resource availability in the inland valley of Adventdalen compared with the high resource availability at large seabird cliffs in the Grumant area (The density of fox feces in Grumant was estimated to be 4.5 feces per 100 mE. multilocularis–positive feces and a high density of arctic fox feces in the Grumant area suggests that this is an area of high risk for human infection. Infected foxes have the potential to spread infective E. multilocularis eggs far from this area; however, our data suggest that the risk for human infection drops to low levels at a very short distance from the Grumant area. A simple approach for reducing the risk for human infection on Spitsbergen is therefore to limit human exposure to this area, e.g., minimize the use of the Grumant area for recreational and tourist purposes. Further monitoring should focus on the possible vole colonization of new areas with high fox densities, i.e., areas under large seabird cliffs, which might increase the endemic range of infection. In summary, human alveolar echinococcosis risk in Svalbard is associated with the spatially restricted sibling vole population, and efficient risk management could be achieved by limiting recreational use of the vole habitat.The combination of a high proportion of


Pharmacological and genetic studies suggest the importance of the dopaminergic, serotonergic, and noradrenergic systems in the pathogenesis of Attention Deficit Hyperactivity Disorder (ADHD) and Disruptive Behavior Disorder (DBD). We have, in a population-based sample, studied associations between dimensions of the ADHD/DBD phenotype and Monoamine Oxidase B (MAO-B) activity in platelets and polymorphisms in two serotonergic genes: the Monoamine Oxidase A Variable Number of Tandem Repeats (MAO-A VNTR) and the 5-Hydroxytryptamine Transporter gene-Linked Polymorphic Region (5-HTT LPR).A population-based sample of twins, with an average age of 16 years, was assessed for ADHD/DBD with a clinical interview; Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL). Blood was drawn from 247 subjects and analyzed for platelet MAO-B activity and polymorphisms in the MAO-A and 5-HTT genes.We found an association in girls between low platelet MAO-B activity and symptoms of Oppositional Defiant Disorder (ODD). In girls, there was also an association between the heterozygote long/short 5-HTT LPR genotype and symptoms of conduct disorder. Furthermore the heterozygote 5-HTT LPR genotype in boys was found to be associated with symptoms of Conduct Disorder (CD). In boys, hemizygosity for the short MAO-A VNTR allele was associated with disruptive behavior.Our study suggests that the serotonin system, in addition to the dopamine system, should be further investigated when studying genetic influences on the development of Disruptive Behavior Disorders. Attention Deficit Hyperactivity Disorder (ADHD) and Disruptive Behavior Disorders (DBD), including Conduct Disorder (CD) and Oppositional Defiant Disorder (ODD), are common child and adolescent psychiatric diagnoses. They are disabling and associated with high costs, both for society and in terms of individual suffering. Research regarding these disorders in children and adolescents from the general population is important in order to identify risk factors related to the etiology and prognosis . ADHD afThe symptoms included in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), categorical diagnoses of ADHD and DBD can also be studied as dimensions and conceptualized as quantitative variations of behaviors that most individuals show to a greater or lesser degree. There is support for an internal validity of the inattention, hyperactivity/impulsivity, oppositional defiant, and conduct disorder dimensions respectively . DimensiMolecular, genetic and pharmacological studies have indicated that the dopaminergic and serotonergic systems play important roles in the development of ADHD . At presPlatelet monoamine oxidase (MAO) activity is highly genetically regulated and has repeatedly been associated with temperament . Low plaIn the present study, we have tested the hypothesis that a selection of biological markers, related to central serotonergic functioning, are associated with dimensions of the ADHD and DBD phenotype. In a population-based series of adolescent boys and girls, we investigated platelet MAO-B activity and the candidate genes: MAO-A (VNTR) and 5-HTT (LPR).The subjects were recruited from the population-based TCHAD-study , and comThe twin pairs and parents were invited to an assessment including a structured clinical interview with Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL). The K-SADS-PL is a widely used semi structured diagnostic interview designed to assess current and past episodes of psychopathology in children and adolescent according to Diagnostic and Statistical Manual of Mental Disorders, 3rd revised edition (DSM-III-R) and DSM-IV criteria. K-SADS-PL has been shown to be a reliable and valid diagnostic instrument for child and adolescent psychiatric diagnoses .In this study, the present version of the Swedish K-SADS-PL was used to assess the symptoms according to DSM-IV. In the K-SADS-PL interview procedure, the interview was first performed with the child alone and thereafter with at least one parent. The clinical interviewer then summarized the information from the parent (about the child) with the information from the child and classified the symptoms as "not present" (0), "possible" (1) or "certain" (2).For the purpose of this study, the symptoms included in the criteria for ADHD subtypes, ODD and CD were assessed according to K-SADS-PL and compiled in three ways:1. Dimensional scales of the symptoms, that is, the summary scores of symptoms included in the criteria for the following diagnoses  were calculated: ADHD inattentive type, ADHD hyperactive type, ADHD combined type, ODD, CD and a combined scale for CD and ODD.2. DSM-IV diagnostic criteria where applied using the information from K-SADS-PL. Each symptom was counted if the item was assessed as "certain" by the interviewer giving the following diagnoses: ADHD inattentive type, ADHD hyperactive type, ADHD combined type, ODD, CD and the combination (CD or ODD) Table .3. The symptoms of the diagnoses described in 1 and 2 were also dichotomized. DSM-IV diagnostic criteria were applied according to the following; the individual child was regarded as having "high score of the ADHD phenotype" if the symptom was assessed as "possible" or "certain" using the same diagnostic criteria as in 2. In order to avoid confusion with clinical diagnoses, we have chosen to use "high/low scores of phenotype" instead of the term "sub threshold" or "probable" diagnosis  which is a scale for children very similar with the Global Assessment of Functioning in DSM-IV .Blood samples were obtained from 247 individuals , 106 boys and 141 girls, and genomic DNA was isolated by standard methods. For MAO-B activity measurement, platelet rich plasma was prepared by low-speed centrifugation, 200 × g for 10 minutes. Platelet concentration of the plasma samples were estimated electronically and the plasma was stored at -80°C.PCR-based genotyping was performed as described in   as substrate. Before analysis, the samples of platelet rich plasma were thawed and sonicated at 0°C during 5 × 10 seconds with intervals of 5 seconds for lysis of the platelets. 50 μl of the plasma was added to 50 μl of 0.1 mM 14C-β-PEA (0.5 μCi/ml) in 0.1 M sodium phosphate buffer. The reaction mixture was incubated at 37°C for 4 minutes, and the reaction terminated by the addition of 30 μl 1 M HCL. Thereafter, the radioactive aldehyde product formed was extracted by shaking for 30 seconds into 750 μl toluene: ethylacetate (1:1). The samples were then centrifuged at room temperature for 5 minutes at 1000 × g. The organic phase (500 μl), containing the aldehyde product, was pipetted into vials with 8 ml scintillation fluid and the amount of radioactive aldehyde product subsequently quantified by scintillation analysis. Enzyme activity is expressed as nmol of substrate oxidized per 1010 platelets per minute. All samples were analyzed blindly and in duplicate.Catalytic activity of platelet MAO-B was analyzed with CThere are compounds in cigarette smoke that exert inhibitory effect on MAO activity, however only in quantities exceeding 300 cigarettes per month . InformaEach of the main behavioral symptoms ADHD, ODD and CD, included either as categorical variables (high/low scores of ADHD phenotype) or dimensional scales, were analyzed with respect to their association with MAO-B activity in platelets and genotype of the MAO-A VNTR and the 5-HTT LPR. Separate analyses were performed for boys and girls. For these analyses the general linear model (GLM) in Stata statistical software package was used . StandarThe dimensional measures of ADHD, ODD and CD problems had skewed distributions. Therefore, for the dimensional measures, non-parametric bootstrap tests were performed using the GLM model in Stata. In the GLM analyses, when calculating the relationships between behavioral problems and 5-HTT genotype, the nominal scales included three variants . This nominal scale was transformed into three index variables and used in the GLM analyses using the long-long variant as the reference variable (omitting this variable). In each of the GLM analyses of platelet MAO-B activity, the information about cigarette smoking, at the time for the blood sampling, whether they had smoked in the past 24 hours, and the smoking information from K-SADS-PL were included as a covariate; smoking (yes/no). For the dimensional ADHD/disruptive behavior scales interactions between sex and polymorphisms in the 5-HTT genotypes were analyzed using GLM. In the same way interactions between sex and platelet MAO-B activity were studied.Children with missing values for two or more symptoms included in the criteria for each of the diagnoses in this study , were excluded from the analyses. If there were missing values for only one of the symptoms in each of the diagnoses this missing value was recorded as "no symptom."The study was approved by the ethical committee at Karolinska Hospital, Stockholm, Sweden. For all subjects the participating parent and the teenagers gave written informed consent.The observed frequencies of the ADHD phenotype, both for diagnoses and high/low dimensions of phenotype are shown in Table The CGAS scores were significantly lower  in the children with each subtype of the high dimensions of ADHD phenotype  and DBD  compared to children with low dimensions of the phenotype, supporting the validity of the dichotomization.10 platelets in boys and 6.3–23.7 nmol/min/1010 platelets in girls. Boys had significantly lower mean MAO-B activity than girls (p < 0.001). Low platelet MAO-B activity was associated with higher levels of ODD symptoms and disruptive behavior symptoms in girls but not in boys. This was true for both the DSM-IV dichotomization and for the dimensional analysis  than boys with the long allele , ODD or CD (p = 0.018)  and the long/short genotype (Additional file In our population-based sample of adolescent twins, we observed significant associations between dimensions of the DBD phenotype and polymorphisms in the candidate genes 5-HTT and MAO-A, as well as with platelet MAO-B activity.The gender ratio in the present study is somewhat lower than what is usually reported. One explanation for this could be that our sample consists of adolescents that are between childhood and adulthood whereas in other studies subjects are usually children or adults: Meta-analyses of childhood ADHD have shown a male:female ratio of 3:1 in non referred populations . In our Our hypothesis that low platelet MAO-B activity is associated with high dimensions of the ADHD and DBD phenotype was verified only for DBD-symptoms in girls. Acting out anti-social related behaviors is more common and more socially acceptable for boys than for girls and behavioral deviances are thought to be under-diagnosed in girls ,33. It iCompounds in tobacco smoke inhibit the MAO-B enzyme , hence sMAO-A VNTR genotype frequencies were in good agreement with those reported by Caspi et al . The 5-HTraditionally, genes of importance for the serotonergic system, in particular the 5-HTT and MAO-A genes, have been associated with certain traits and behavioral disorders . The MAOAlso with regard to the 5-HTT polymorphism, there are conflicting results with studies showing associations between an ADHD phenotype and both the long and the short allele as well as no association at all ,43. We fWe did not genotype the A/G SNP within the 5-HTT LPR  which maWe found a relationship between low platelet MAO-B activity and ODD, however only in girls. There was, in girls, also an association between the long/short 5-HTT genotype and conduct symptoms. Furthermore, the heterozygote 5-HTT genotype in boys was found to be associated with CD. In boys, homozygosity for the short MAO-A allele was associated with disruptive behavior. Our study suggests that the serotonin system, in addition to the dopamine system should be further investigated when studying genetic influences on the development of Disruptive Behavior Disorders.ADHD: Attention Deficit Hyperactivity Disorder; CD: Conduct Disorder; DAT: Dopamine Transporter; CGAS: Children Global Assessment Scale; DBD: Disruptive Behavior Disorders; DRD4: Dopamine Receptor 4; DRD5: Dopamine Receptor 5; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th edition; DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders, 3rd revised edition; K-SADS-PL: Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version; ODD: Oppositional Defiant Disorder; 5-HTT: 5-hydroxytryptamine transporter; MAO-A: Monoamine Oxidase A; VNTR: Variable Number of Tandem Repeats; LPR: gene-Linked Polymorphic Region.The authors declare that they have no competing interests.KM collected clinical data and blood samples, and drafted the manuscript. HW carried out the enzyme measurements and the genotyping, and drafted the manuscript. PL and LO were involved in the conception of the study and in the writing of the manuscript. JOL participated in the design of this study and carried out the statistical analyses and helped draft the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:Dichotomized symptom scale of ADHD/disruptive behavior and activity of MAO-B in platelets in boys.Click here for fileDichotomized symptom scale of ADHD/disruptive behavior and MAO-A VNTR genotype in boys.Click here for fileDichotomized symptom scale of ADHD/disruptive behavior related to 5-HTT LPR genotype in boys.Click here for fileDimensional symptom scales of ADHD and disruptive behavior related to genetic markers for 5-HTT LPR genotype in girls.Click here for file


Eleven previous reports have shown potential benefit of a 36-ingredient micronutrient formula (known as EMPowerplus) for the treatment of psychiatric symptoms. The current study asked whether children (7-18 years) with pediatric bipolar disorder (PBD) benefited from this same micronutrient formula; the impact of Attention-Deficit/Hyperactivity Disorder (ADHD) on their response was also evaluated.Data were available from an existing database for 120 children whose parents reported a diagnosis of PBD; 79% were taking psychiatric medications that are used to treat mood disorders; 24% were also reported as ADHD. Using Last Observation Carried Forward (LOCF), data were analyzed from 3 to 6 months of micronutrient use.p < 0.001). In terms of responder status, 46% experienced >50% improvement at LOCF, with 38% still taking psychiatric medication (52% drop from baseline) but at much lower levels (74% reduction in number of medications being used from baseline). The results were similar for those with both ADHD and PBD: a 43% decline in PBD symptoms (ES = 0.72) and 40% in ADHD symptoms (ES = 0.62). An alternative sample of children with just ADHD symptoms (n = 41) showed a 47% reduction in symptoms from baseline to LOCF (ES = 1.04). The duration of reductions in symptom severity suggests that benefits were not attributable to placebo/expectancy effects. Similar findings were found for younger and older children and for both sexes.At LOCF, mean symptom severity of bipolar symptoms was 46% lower than baseline (effect size (ES) = 0.78) (The data are limited by the open label nature of the study, the lack of a control group, and the inherent self-selection bias. While these data cannot establish efficacy, the results are consistent with a growing body of research suggesting that micronutrients appear to have therapeutic benefit for children with PBD with or without ADHD in the absence of significant side effects and may allow for a reduction in psychiatric medications while improving symptoms. The consistent reporting of positive changes across multiple sites and countries are substantial enough to warrant a call for randomized clinical trials using micronutrients. The diagnosis of pediatric bipolar disorder (PBD) is one of the most controversial in modern child psychiatry . DisagreAlthough there has been a significant increase in the number of studies describing the treatment of PBD over the last decade, there are surprisingly few controlled studies of pharmacotherapy for mania in children and adolescents . Mood stAtypical antipsychotics  have been increasingly reported to be used as frontline agents for the treatment of PBD and they may be more effective than mood stabilizers in the treatment of acute mania in youth. A recent comparative analysis of acute randomized placebo controlled trials for the treatment of mania in pediatric populations found five trials that had used antipsychotics and estimated a pooled effect size for the YMRS at .65  with allOne group of children who have proved to be particularly difficult to manage is those who are diagnosed with both Attention-Deficit/Hyperactivity Disorder (ADHD) and PBD. The rate of ADHD comorbidity in pediatric bipolar populations ranges from 57% to 93% -18. TherIn contrast, medications typically used to treat ADHD have been used with this population with better success, at least in controlling the ADHD symptoms in PBD children and adolescents. Hah and Chang  reportedAlthough there are a range of psychopharmacological options available to try to treat emerging mood symptoms in children and adolescents, the results to date indicate that many are not responding to these treatments , especiaThe literature on nonpharmacological biological treatments for PBD is sparse. The trials on omega-3 fatty acids have been mixed, with as many showing no effect as showing an effect  of the 36 micronutrients used in the current study ..in combiThere are many limitations associated with a database analysis such as this one. Foremost, all of the data were based on parent report, and there was no corroborating clinician or teacher report. However, by its very nature, clinician report is based on patient-based information. Further, parents have been found to be as sensitive to monitoring change as teachers . What woThe clients were clinical patients and, as in any naturalistic study, were not assessed using structured interviews to confirm diagnosis. Even in research settings that use structured interviews, differentiating bipolar from ADHD is fraught with controversy in the pediatric literature and the diagnosis of PBD can be unreliable , with soOn a related note, the self-report questionnaire used to assess change in ADHD symptoms was not ideal. There were only three questions we could confidently analyse to monitor change in ADHD symptoms which makes it difficult to compare these results to those of other treatment studies for ADHD carried out in research environments. However, those three questions are the cardinal questions related to the ADHD diagnosis - assessing the three main problems associated with ADHD. Other research has confirmed that those three questions are reliable and valid indicators of the disorder .Given the sample size, we could not address the impact that co-occurring conditions had on the response to the micronutrients. We are aware that many of the children reported other problems, such as anxiety, behavioural problems, and pervasive development disorders, likely making them more impaired than individuals typically recruited for pharmacological trials; however, we did not have enough information to independently assess the impact of co-occurring diagnoses on treatment response. Further, given that it was a database analysis, there are many other variables we cannot control for such as use of other nonpharmacological treatments such as psychotherapy, change in diet and nutritional status, and use of other nutritional products, such as omega-3 s or amino acid supplements, that may have been used in conjunction with these micronutrients. Compliance could only be assessed via client report (which is inherently problematic) and could not be confirmed via blood work or other more careful monitoring systems. Further, the large number of pills that the children are required to consume could be viewed as a disadvantage for many and may have contributed to the early drop outs. However, the formula is now available in a powder form, which may reduce the problems associated with consuming a large number of pills.There are three types of self-selection bias inherent to this type of study: participation, reporting, and dropping out. With respect to participation bias, people searching for nutritional methods to manage their mood symptoms are likely to have been ineffectively treated by pharmaceuticals, and are not necessarily representative of everyone with bipolar disorder. In other words, many of the participants in this database could be considered treatment resistant, making these positive findings even more important clinically. Reporting bias relates to the fact that many people who purchase this product choose not to monitor their symptoms due to the time and effort involved in doing so as well as the impact of the illness itself; the possible extent of this bias cannot be analyzed with the available data, but most clients who purchased this product chose not to monitor symptoms consistently enough to be included in the analysis. Reporting bias could also result in more favorable reports, given that the clients chose the treatment that they received. Research shows that when participants choose their therapy, they are more likely to rate it as effective , therebyIt is also possible that rather than choosing not to report on symptoms while consuming the formula, that these clients represent treatment failures; i.e., their lack of reporting was due to early discontinuation of the treatment, because they either found it ineffective, did not like the side effects or could not comply with the regimen, similar to reasons for drop-outs in RCT studies. Indeed, 709 children were found in the database but only 120 met our inclusion criteria for continued reporting, so we do not know what happened to the remaining 83% of the clients and to what extent their response rate mirrored those in this sample of 120. While it is tempting to draw parallels to well controlled designs and conclude that the treatment was not effective for these other clients, we simply cannot establish why reporting did not continue, in contrast to RCTs, where researchers know that a participant who stops reporting has also stopped taking the treatment because the investigators control the distribution of pills. As most of the children who were excluded from the Primary Sample ceased reporting within the first two weeks, any lack of change at that point would not have been due to lack of effectiveness given that it typically takes at least that amount of time before any effect is noted. Nevertheless, given that many who start taking this formula choose not to report on symptoms, we cannot establish with any certainly whether the response rate noted in the Primary Sample can generalize to the wider clinical population.The third type of self-selection bias occurs as a result of non-responders ceasing to continue to report symptoms due to lack of improvement. About 50% of the Primary Sample stopped reporting before 6 months. Analysis of these "drop-outs" indicated that they did experience significant reduction in their symptoms, suggesting that they likely stopped reporting, not because of a lack of response, but because they found it tiresome to continue to monitor and report symptoms. A similar finding was reported in the adult sample .The fact that we continued to see benefit through 6 months of reporting is a strength in that it reduces the likelihood that placebo, natural cycles of PBD, or positive expectancy effects were contributing to the positive changes observed. Having a control group would have given greater confidence that the changes observed were due to the consumption of the formula and not natural remission of the symptoms over time.It is important to note that none of the authors was involved in any way with the data collection. Further, none of the authors and none of their Universities are commercially affiliated with the developer/manufacturer. Unlike drug trials, these clients were not being paid to complete questionnaires; indeed, they were paying to purchase the product.There are many methodological problems inherent in a database study, the most pertinent ones being its open label nature which naturally inflates the effectiveness of the treatment, and the low number of clients who opted to monitor their symptoms for any length of time. However, the results reported here, in combination with the other publications to date, illustrate a consistent pattern of improvements in psychiatric symptoms, providing a powerful case for further research on micronutrient treatment, in particular investment in RCTs. Although the current study cannot be generalized to population response rates and as such we urge caution to not over-interpret these results, a more carefully diagnosed sample of children exhibited similar reductions in psychiatric symptoms . FundingThe authors declare that they have no competing interests.All authors: 1) have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; 2) have been involved in drafting the manuscript or revising it critically for important intellectual content; and 3) have given final approval of the version to be published.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/10/74/prepubTable S1. EMPowerplus Capsule Ingredient ListClick here for fileTable S2. Symptom Rating Scale for Bipolar and ADHD symptomsClick here for file