Attention deficit/hyperactivity disorder (ADHD) is an under-recognized comorbid disorder among patients with mood disorders. ADHD is an independent risk factor for suicidal ideation and behavior and contributes to many aspects of impaired function in adults. Diagnosis of ADHD in Major Depressive Disorder (MDD) patients is challenging due to the overlap in cognitive symptoms between the two disorders. The ADHD Self-Report Scale, version 1.1 (ASRS-v1.1) is a widely used screening instrument for ADHD in adults but its accuracy has not been evaluated previously in treatment-seeking MDD patients. We administered the ASRS-v1.1 to 55 healthy controls and 40 adults with a primary psychiatric diagnosis of MDD who were participating in clinical research studies. ADHD diagnosis was assessed via structured interview with the adult ADHD module of the Mini International Neuropsychiatric Interview Plus version 6.0.0 (MINI) along with a psychiatrist’s assessment. Overall, full-syndrome ADHD was diagnosed in 12.5% of the MDD patients. MDD patients endorsed all 18 items of the ASRS-v1.1 more frequently than the healthy controls and the number of ASRS-v1.1 items endorsed correlated with levels of anxiety in the MDD patients. The ASRS-v1.1 demonstrated fair performance for identifying full syndrome DSM-IV ADHD diagnosis, with sensitivity 60%, specificity: 68.6%, positive predictive value 21.4%, negative predictive value 92.3% and total classification accuracy of 67.5%. Positive predictive value improved substantially when the ADHD criterion requiring symptom onset before age 7 was omitted. In adult MDD patients, a negative ASRS-v1.1 screen strongly suggests the absence of ADHD but positive screen results require careful evaluation to determine whether self-reported ADHD symptoms simply emerge from depression or whether comorbid ADHD is present. Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by hyperactivity, inattentiveness and impulsivity that onsets during childhood . AlthougAdults with ADHD have substantially 2–3 fold) higher rates of having mood, anxiety, or substance use disorders, as established by both epidemiological  fold hig and clinThe limited data about ADHD among patients with depressive disorders represents a particularly important knowledge gap. The clinical significance of identifying ADHD comorbidity among patients with depression is evident in the greater levels of functional impairment, longer depressive episodes and the increased suicidal ideation and behavior among comorbid patients than those with MDD without ADHD ,12. DespA widely used screening instrument for identifying adult ADHD is the Adult ADHD Self-Report Scale, version 1.1 (ASRS-v1.1). Using a total score of ≥4 on the six-item Part A section of the scale as the threshold to indicate a positive screening test, the developers of the ASRS-v1.1 reported moderate sensitivity (68.7%), along with excellent specificity (99.5%) and total classification accuracy (97.9%) when assessing symptoms among a community sample . DespiteRemarkably, there are no published studies on the accuracy of the ASRS-v1.1 among adults with MDD. Here we report an evaluation of the ASRS-v1.1 among a sample of adult outpatients with MDD participating in clinical research studies. We hypothesized that the ASRS-v1.1 would have high sensitivity and negative predictive value but low positive predictive value, due to the expectation that depressed patients would frequently endorse the inattentive and procrastination items on part A of the instrument.The data being analyzed for this paper was collected from two studies of MDD that enrolled adult healthy control subjects and MDD patients through the Mood and Anxiety Disorders Program at Emory University in Atlanta, Georgia, between August 2013 and September 2016. Both studies compared healthy control (HC) adults with those with MDD. One study examined a blood test for MDD (data not published); the other examined differences in decision-making between adults with and without MDD  . The insThe psychiatric assessment procedure for both studies was identical (described below) and both studies enrolled adult men and women, ages 18–65 using similar inclusion and exclusion criteria. Eligibility criteria for HC included absence in the past year of a DSM-IV mental illness diagnosis (including ADHD), no history of MDD or dysthymia, no history of psychotropic medication use and a score of ≤7 on the 17-item Hamilton Depression Rating Scale (HDRS) . Depresssymptom count criteria for ADHD were considered met. To achieve the formal diagnosis of DSM-IV adult ADHD, participants also had to be scored positively on both sections TA3 and TA4 and have the diagnosis confirmed by a study psychiatrist. To confirm the diagnoses of ADHD, the study psychiatrist assessed the temporal course of ADHD symptoms and established that the symptoms of ADHD had emerged prior to the first lifetime depressive episode and could not be better explained by another psychiatric diagnosis (DSM-IV Criterion E), including posttraumatic stress disorder arising from traumatic events experienced in childhood. The SCID was used to confirm the diagnosis of MDD among depressed participants and to identify comorbid psychiatric disorders.All participants were assessed with the Structured Interview for DSM-IV (SCID)  and the The ASRS-v1.1 is a self-report form used to assess symptoms of ADHD based on the 18 DSM-IV symptom criteria . The insTo assess depression severity, the HDRS was administered and a study physician scored the Clinical Global Impression-Severity (CGI-S) . The Hamformal ADHD diagnosis was meeting all DSM-IV diagnostic criteria for ADHD as assessed by module TA of the MINI, along with confirmation of the diagnosis by a study psychiatrist’s interview. There has been growing concern that the DSM-IV requirement that ADHD symptoms be present before the age of 7 excludes many afflicted individuals  andThe high NPV of the ASRS-v1.1 is consistent with other studies examining the performance of the ASRS-v1.1 in patients with primary substance use disorders  and primThe high potential for false positives using Part A of the ASRS-v1.1 to screen for ADHD is demonstrated in that of the five most frequently endorsed 18 ASRS-v1.1 items, four were from the six Part A items and all of them were inattention items (items 1–4). The other two Part A items that refer to hyperactivity, including “feeling driven by a motor”, which was the least frequently endorsed of the 18 items.Depressed patients screening positive on the ASRS-v1.1 reported significantly more anxiety and rumination than patients screening negative. Interestingly, neither anxiety nor rumination was associated with the ADHD symptoms as assessed by the structured MINI interview. Having any lifetime anxiety disorder was not associated with either ASRS-v1.1 or MINI ADHD symptom endorsement. These data suggest that anxious (compared to non-anxious) depression, defined as high levels of current anxiety symptoms is associated with greater subjective reports of inattention. One prior study found that anxious arousal but not anxious apprehension, was associated with greater cognitive impairments , which cImpairments in cognitive control, specifically impaired inhibition, contribute to both ruminative thinking and reduced emotion regulation ,36 and pA recent important development in ADHD has been the emergence of epidemiologic evidence suggesting the existence of an adult-onset form of ADHD. Three large studies from New Zealand , the UniLimitations to this analysis include the relatively small sample size of depressed patients. However, the 12.5% prevalence of full syndrome ADHD in our MDD sample is consistent with other prevalence data in MDD patients ,9,13. ThRecently, the World Health Organization published a new scale for detecting ADHD in adults applying the DSM-5 criteria, the Adult ADHD Self-Report Scale (ASRS) . This scIn adult MDD patients, detecting comorbid ADHD is challenging due to the overlap in cognitive symptoms between the disorders. Applying the ASRS-v1.1 as a screener in these patients can help rule out the presence of ADHD when the screening result is negative. However, positive ASRS-v1.1 screen results are more likely to be false positives rather than true positives. Consequently, treatment for ADHD among MDD patients who screen positive on the ASRS-v1.1 should only be initiated after careful clinician evaluation of the time course of the ADHD symptoms and their relationship to major depressive episodes.


To spot the frontal theta/beta ratio alterations during Tests of Variance of Attention (TOVA) in Egyptian attention deficit hyperactivity disorder (ADHD) children.This is a cross sectional study performed in Clinical Neurophysiology Unit, Cairo University, Egypt. It included 2 groups, each of 52 children . EEG was recorded for every subject during normal relaxing circumstance with eyes opened as well as during TOVA.Comparing both groups revealed statistically significant difference in the theta/beta ratio in both state , also we found that the theta/beta ratio decreased in normal group (during concentration) while in the ADHD group it increased with a specific pattern.The theta/beta ratio can be of value in helping for differential diagnosis in patients presenting with mild ADHD. Attention deficit hyperactivity disorder (ADHD) is the most commonly identified neurobehavioral complaint in childhood, its frequency is supposed to be 6-7%.The study took place between November 2013 and April 2014 in the Clinical Neurophysiology Unit, Cairo University, Egypt, where 52 children diagnosed with ADHD were prospectively enrolled. Patients were referred from Child Psychiatry Center in social and preventive medicine , Cairo University, Egypt and special needs clinic in National Research Centre, Cairo, Egypt. The methods were approved by the National research center Medical research Ethics Committee.Inclusion criteria were as follows 1) Age 8-12 years; (2) male; (3) clinical symptoms and signs of ADHD  according to diagnostic and statistical manual 4th edition- text revised (DSM-IV-TR) criteria.5Exclusion criteria were as follows 1) Children with ADHD on medication; (2) Children with hyperactive only subtype of ADHD; (3) Children with any neurologic, cardiac or any other state that may delay mental development.® video-EEG system with Profusion EEG 4® software. The high frequency filter was 70 Hz, time constant 0.3 and screen speed 30 mm/sec. The input signal referenced to the ears was filtered between 0.5-50 Hz, and digitized with 250 Hz sampling rate. Impedance was kept below 5 kOhm for all electrodes. The EEG was recorded for 10 minutes during relaxing state with eyes open. Subjects full relaxation was ensured by performing the recording in recombinant position, on a comfortable bed in a semi dark quite room. Furthermore, EEG was recorded for another 10 minutes while the patient was performing TOVA; in a sitting position, on a comfortable chair, at a fixed distance in front of a computer screen where the targets were presented.Fifty-two age and gender matched normal subjects were included as a control group. Those were enrolled from Gastroenterology Clinic, Abu El Reesh hospital, Cairo University, Egypt. All included individuals were subjected to detailed history taking and full general examination to exclude any medical state that might interfere with the process of the study. The EEG was recorded using a Compudmedics E-series  a PC-controlled 32-channel system. 21 scalp EEG electrodes were applied according to the International 10/20 system using Silver chloride electrodes. Video EEG was continuously monitored by a technologist utilizing a CompudmedicsFigure 1). The assignment is to push a button as fast as possible in response to all GO trials. During the assignment, patients are seated 1.5 m in front of a computer monitor. The stimuli are displayed on a 19-inch screen using Psytask . In addition to EEG recordings, behavioral data including omission errors, commission errors, and reaction time are also registered.The EEG was monitored by visual inspection for: artifacts (epochs containing artifacts were excluded from the record), presence of any abnormal activity  and symmetry between both hemispheres. Then Quantitative data of the frontal zone  were analyzed using WinEEG software. Before processing, epochs of the filtered EEG with large amplitude (>100µV) and/or very fast (>35µV in 20 to 35Hz band) and slow (>50µV in 0 to 1 Hz band) frequency activities were marked and removed from further analysis. The band ranges for theta and beta were set at 4-8 Hz (theta) and 13–21 Hz (beta) registered at Cz, in the eyes-opened (EO) state. Absolute power of these measures were used in the statistical analysis.The study was approved by the research committee at Cairo University. The parents or caregivers of all patients and controls involved in the study signed written informed consent.p-value<0.05 was considered statistically significant. All statistical calculations were carried out using the IBM SPSS Statistics for Windows version 22.0 .Descriptive results were presented as mean and standard deviation. Comparisons of quantitative variables between the studied groups were carried out using Mann Whitney test. Comparisons in between groups were carried out using Bonferroni multiple comparisons test. Correlation between variables was carried out using Pearson’s correlation. A The current study included 104 male subjects, 52 ADHD patients and 52 normal control, their ages ranged between 8-12 years. Where, the mean age of patients group was 9.5±1.11 and that of control group was 9.8±1.16. There was no statistically significant difference between them.Table 1 and Figure 2). In TOVA, the ADHD group showed statistically significant higher values compared to the control group, where the mean values for omission were: 10.7±2.74 and 6.25±2.69 with p<0.0001, for commission were 35.75±4.64 and 24.03±4.98 with p<0.0001, while they were 431.5±22.37 and 385.9±20.9 respectively with p<0.0001 for reaction time.The patients group showed significantly higher theta/beta ratio during both eyes open and TOVA states compared to the control group (Table 2).Theta/beta ratio ; mid frontal, right as well as left frontal brain areas; in ADHD group during TOVA showed significant increase compared to control group during eye open relaxed state as well as during TOVA, (p<0.0001), left r=-0.69 (p<0.0001) and mid frontal zones r=-0.711 (p<0.0001) in both eye open relaxing state and during TOVA among right where r=-0.707 (p<0.0001), left r=-0.726 (p<0.0001) and mid frontal zones r=-0.739 (p<0.0001). The same correlation trend was also detected between age and omission error in TOVA, where r=-0.579 (p<0.0001). There was a significant positive correlation between omission error and mean theta/beta ratio among right where r=0.331 (p=0.024), left r=0.338 (p=0.014) and mid frontal zones r=0.340 (p=0.014) in both eye open relaxing state, as well as during TOVA among right where r=0.4 (p=0.003), left r=0.43 (p=0.001) and mid frontal zones r=0.396 (p=0.004) .In patients group, there was a significant negative correlation between age and mean theta/beta ratio among right where r=-0.681  activity during relaxing state, a divergence demonstrating lessened cortical activity that may possibly be tracked to under arousal. Hz activ8A current meta-analysis of 9 research papers with a combined sample of 1,498 ADHD children found an average excess of 32% in theta band power relative to controls.During relaxing state, we detected an increase in theta power in the patients compared with control group. This may possibly point to hindered maturation. As reduced speed of the background activity throughout wakefulness is customary till age of 3 years, afterwards alpha waves ought to dominate, and this perseverance of theta waves beyond age of 8 is counted odd. This comes in line with maturational-lag model of ADHD, which clarified that ADHD is coupled with tardy maturity of the brain, presenting traits of younger ages. Also, since theta/beta level reflects brain attention and vigilance. This slowing and increase in theta power may point to under-arousal of ADHD children.During TOVA, the control group showed reduction in mean theta/beta ratio in all studied frontal zones which can be explained by increased attention and thus increased power of faster waves as beta and a decreased power of slow waves as theta power. While, mean theta/beta ratio increased in children with ADHD. This opposite pattern signifies different functional activation response, where, attention or brain stimulation implies development of more slowing in patients group.Figure 2). However, in relaxing state there was no difference between patients and control group in this respect i.e. the reversal of the pattern noticed in the ADHD group was only aggravated by the TOVA.Moreover, we observed that, during TOVA, the theta/beta ratio in mid frontal zone was lower than that in right and left frontal zones in patients group, whereas, it remained higher in control group (From this topographical differences between states we can deduce that specific central frontal brain structures are affected in ADHD and they are responsible for concentration and mission carrying out during TOVA.Theta and beta activities changed during eyes opened and TOVA states in both groups, comes in line with EEG topographies reported by Barry et al.Among patients group, there was a significant negative correlation between age on one side and mean theta/beta ratio among frontal zones during both states and omission error, on the other side. Which, can be explained by maturation of the brain by aging causing amelioration of ADHD signs, explaining the disappearance of ADHD symptoms around teens in the majority of patients. Furthermore the omission errors revealed a significantly positive linear correlation with mean theta/beta ratio. This reveals that the main pathology in ADHD children may possibly be tracked down to under-arousal and reduced level of brain attention causing cognitive function disarray. This result is in harmony with outcomes of other studies which observed a significant correlation between the left forehead theta power and the results of TOVA and that reported significantly higher power of theta and response delay error in ADHD patients compared to the control group.12Relative small sample size and sometimes lack of cooperation from the subjects lead to repetition and even cancellation in some cases. Analysis of only the frontal areas however the data for the rest of the brain areas is available for further analysis and might reflect other topographic patterns in the future.We conclude that mid frontal neuronal structures responsible for attention are the most affected brain area in ADHD. In addition, mean theta/beta ratio represent a credible objective diagnostic test that can be valuable in differential diagnosis of mild ADHD.


Attention-deficit hyperactivity disorder (ADHD) is associated with higher risk for fracture. Whether the medical treatment for ADHD would mitigate the risk remains unclear. In this study, we sought to investigate the effect of methylphenidate treatment on risk for fracture, as well the moderational role of treatment duration on the risk of fracture, in a large national sample. Cases less than 18 years old were identified from Taiwan’s National Health Insurance Research Database with a new primary diagnosis of ADHD (ICD-9:314) between 1996 and 2013. A total of 6201 cases with ADHD were included as the study cohort. The cases were divided into 3 groups according to the duration of methylphenidate treatment . All groups were followed until the end of 2013 for first diagnoses of fracture (ICD-9 codes 800 to 829). Cox proportional hazards models were applied. Compared to the group without methylphenidate treatment, the risk for fracture was lower among the group treated for more than 180 days. The adjusted hazard ratio was 0.77 . The groups treated for 180 days or fewer had no significant difference in the risk for fracture. In conclusion, methylphenidate treatment was associated with lower risk for fracture among ADHD patients. The association was evident only in the cohort treated for more than 180 days. Attention-deficit hyperactivity disorder (ADHD) is a neuropsychiatric condition characterized by hyperactivity, impulsivity, and cognitive dysfunction . The typThe impact of ADHD medication also received growing attention as well. The study by van den Ban et al revealed that the incidence rate for injuries during exposure to ADHD drugs was lower in the exposed period compared to the period prior to ADHD drug use . AnotherWithin the broad category of unintentional self-harm or injuries among children and adolescent, fracture is a well-defined diagnosis. The injuries from fracture are common and further add to the illness-associated morbidity in ADHD –21. Two Despite unequivocal evidence documenting efficacy across core symptoms of ADHD , insuffiHerein, we primarily aimed to determine, by using a nationwide population-based dataset in Taiwan, the effect of psychostimulant prescription for ADHD on mitigating the risk of fracture, and whether the mitigating effects are moderated by the duration of exposure among cases less than 18 years old.This retrospective cohort study utilized data from the Taiwan National Health Insurance Research Database (NHIRD) under the aegis of the National Health Research Institute (NHRI) which included outpatient, ambulatory, hospital inpatient care, as well as dental services. The National Health Insurance (NHI) program provides compulsory universal health insurance, implemented in March 1995, covering all delivery of health care in 99.5% of the national population. In cooperation with the Bureau of NHI, the NHRI extracted a randomly sampled representative database of 1,000,000 people from the registry of all NHI enrollees using a systematic sampling method for research purposes, forming the Longitudinal Health Insurance Database (LHID). There are no statistically significant differences in age, sex, or health care costs between this sample and all enrollees .ADHD cases were identified based on recorded International Classification of Disease, Ninth revision (ICD-9) codes of 314. All medical claims made under this diagnostic code between 1996 and 2013 were collected from NHIRD for further analysis. The definition of ADHD for this analysis required an inpatient diagnosis or two outpatient diagnoses during one year. Using the foregoing definition, 9826 ADHD cases between 1996 and 2013 were identified. Cases born before 1996 or after 2005, fracture before ADHD diagnosis, missing residential data, or ADHD diagnosis within one year prior to study period were excluded. Total 6201 cases of ADHD comprised the final study cohort.In Taiwan, methylphenidate was the only stimulant approved for ADHD treatment during 1996 to 2013, including short- and sustained-release preparations The two preparations of methylphenidate had similar effects on ADHD symptoms, but the sustained-release preparation was more convenient with lesser rebound side effects , 31. AtoThe treatment intervals chosen were 0, 1–180, and more than 180 days respectively. It was based on several epidemiological studies revealing that most ADHD cases received medical treatment for less than 180 days –34. The Covariates considered in this analysis were chosen a priori on the basis of hypothetical associations with the exposure and outcome of interest. These comprised several demographic factors such as sex, age and urbanized level of residence . ComorbiThe NHIRD consists of de-identified secondary data released to the public for research purposes. This study had been reviewed and approved by the Institutional Review Board of Chung Shan Medical University Hospital.The distribution of demographic factors and the proportions of comorbidities between the three groups with different treatment duration of methylphenidate were compared. Cox proportional hazards models were used to compute the hazard ratios (HRs) accompanying 95% confidence intervals (CIs) after adjustment for sex, age, urbanized level of residence, seizure, asthma, intellectual disability, autism, BZD/hypnotic use, and conduct disorder. Two-tailed P = 0.05 was considered significant. Patients with a death date in the admission file and those withdrawn from the registry for beneficiaries were censored. All of these analyses were conducted using SAS statistical software .The study cohort comprised 6201 cases with ADHD. The characteristics of the three groups with different treatment duration of methylphenidate are described and compared in The differences of demographic characters between three groups were sex, age, urbanized level of residence, and follow-up duration. The group with medication for more than 180 days had the highest male/female ratio (83.6%/16.4%). Most cases were between 6–11 years old and the mean age was lowest in the group without methylphenidate treatment (6.90± 2.69). Most cases were from the area of moderate to high level of urbanization and the group without methylphenidate treatment had the least cases from the least urbanized area (3.5%). The follow-up duration was longest in the group with methylphenidate treatment for more than 180 days (5.75 ± 2.79 years).Three groups have no significant difference in the rates of comorbid seizure, asthma, intellectual disability, autism, and BZD/hypnotic use. The group with methylphenidate treatment for more than 180 days had the highest rate of comorbid conduct disorder (3.8%). The incidence of fracture was significantly different among three groups: 9.5% (0 day), 11.3% (1–180 days), and 8.7% (more than 180 days) respectively.Analysis of methylphenidate treatment and the risk of fracture is shown in To our knowledge, this is the first study that has investigated the effect of medical treatment for ADHD, and the moderational role of treatment duration, on risk for fracture. The findings revealed that methylphenidate treatment exceeding 180 days or greater was linked to nearly 25% lower risk for fracture comparing to those never received methylphenidate. In addition, shorter duration of medical treatment did not mitigate risk for fracture.Relatively few studies have evaluated the effect of psychostimulants on bone health. The cohort study by Chou et al. reported that ADHD was associated a 1.32 times greater likelihood of fractures . They alAnother recent retrospective cohort study also reported that medication for ADHD was associated with lower risk of fracture . They coIn our study, we explored the role of the methylphenidate treatment duration on the risk for fracture. The group receiving methylphenidate for more than 180 days had significantly lower risk for fracture when compared to the group without methylphenidate treatment . A protective role of pharmacotherapy in the prevention of fracture was inferred. Moreover, the protective effect was observed only in cohort with exposure >180 days. Amongst individuals receiving methylphenidate for 1–180 days, the risk for fracture had no significant difference compared to those without methylphenidate treatment. That is, the treatment duration moderated the risk reduction.Our results replicate the risk mitigation effect reported by Chou or Perry et al. Our results, however, further extend knowledge by identifying duration of exposure as a critical moderational factor. The exact mechanism was unknown. We conjecture that the salutary effects of stimulants are possibly mediated by improved cognitive function (e.g. reduced impulsivity). In previous studies, the increased risk for fracture in ADHD patients had been accounted by the core symptoms including impulsivity, recklessness, hyperactivity, and distractibility in daily life . The chiThe main outcome in our study was fracture. Comparing with several recent studies on the association between ADHD, medication, and different types of injuries–16, our Other significant risks for fracture in our analysis were male sex, age, and asthma.Male sex was associated with higher risk for fracture in our multivariate analysis . In previous literature, boys were more likely to have all injuries than girls generally . Male seThe risk for fracture increased with ages among our study population. This finding was consistent with previous studies . Among AIn multivariate analysis, asthma was associated with higher risk for fracture . It was consistent with previous studies regarding the risk of fracture in asthma cases , 54, 55.The findings from our study have several important public health and therapeutic implications. From the aspect of public health, pharmacotherapy should be considered as an important strategy for preventing fracture-related dysfunction among young ADHD patient. In our study cohort, only 29.6% of ADHD cases received methylphenidate for more than 180 days. For clinicians, the need for sufficient treatment duration of pharmacotherapy should be addressed to the patients as well as their parents. Moreover, the interplay of ADHD, fracture, and pharmacotherapy merits further researches.To our knowledge, this is the first study using a nationally representative sample and longitudinal dataset to investigate the relationship between methylphenidate prescription and risk for fracture. Our use of a cross-national, highly inclusive, representative database would be less susceptible to selection and recall bias. The observation that duration of exposure is significantly influenced by risk mitigation is directly consistent with the hypothesis that methylphenidate treatment is the critical intervention influencing our dependent variable.There are several methodological limitations that affect inferences and interpretations of our data. First, the exact adherence of methylphenidate was unknown. Second, the severity of ADHD was not evaluated, quantified, and/or measured. The severity of symptoms between groups with different treatment duration could not be compared or adjusted in the following analysis. Furthermore, we are unable to ascertain whether fracture risk reduction correlates with a reduction in overall ADHD psychopathology severity. Last, several confounding factors were not available in NHIRD dataset including, but not limited to, lifestyle and body mass index. It is also unknown whether other medications or interventions had a similar impact, or moderational effects, on the fracture risk reduction seen with methylphenidate.Methylphenidate treatment decreased the risk for fracture amongst individuals with ADHD. The risk reduction is observed in individuals with longer treatment duration (i.e. >180 days). The high lifetime prevalence and persistence of ADHD, as well as the personal and economic costs associated with fracture and other unintentional injuries, underscores the public health significance of this topic. Moreover, adjudicating risk and benefits of psychostimulants in ADHD need to take into consideration both conventional measures (e.g. ADHD psychopathology), as well as the impact on real-world outcomes.


Bartonella species are emerging human pathogens. Bats are known to carry diverse Bartonella species, some of which are capable of infecting humans. However, as the second largest mammalian group by a number of species, the role of bats as the reservoirs of Bartonella species is not fully explored, in term of their species diversity and worldwide distribution. China, especially Northern China, harbors a number of endemic insectivorous bat species; however, to our knowledge, there are not yet studies about Bartonella in bats in China. The aim of the study was to investigate the prevalence and genetic diversity of Bartonella species in bats in Northern China. Bartonella species were detected by PCR amplification of gltA gene in 25.2% (27/107) bats in Mengyin County, Shandong Province of China, including 1/3 Rhinolophus ferrumequinum, 2/10 Rhinolophus pusillus, 9/16 Myotis fimbriatus, 1/5 Myotis ricketti, 14/58 Myotis pequinius. Phylogenetic analysis showed that Bartonella species detected in bats in this study clustered into ten groups, and some might be novel Bartonella species. An association between Bartonella species and bat species was demonstrated and co-infection with different Bartonella species in a single bat was also observed. Our findings expanded our knowledge on the genetic diversity of Bartonella in bats, and shed light on the ecology of bat-borne Bartonella species. Bartonella is the only genus in the family Bartonellaceae of order Rhizobiales. Bartonella are facultative intracellular bacteria that infect the erythrocytes and endothelial cells of a wide variety of mammals worldwide [Bartonella species are the causative agents of Peruvian bartonellosis, cat scratch disease, trench fever, and bacillary angiomatosis [Bartonella infection can also cause various cardiovascular, neurological, and rheumatologic diseases [Bartonella species are identified as human pathogens [Bartonella species are associated with human infections [orldwide ,2. In huomatosis , and Bardiseases ,5. An Inathogens ,7, and afections ,8.Bartonella species [Bartonella mayotimonensis [Bartonella species in bats have been investigated in America, Europe, Africa and Asia [Bartonella species in bats have only been reported in regions of South Asia [Bartonella have been conducted in mainland China, the Northern of which harbors a d number of endemic insectivorous bat species. To expand our understanding of Bartonella species in bats, we investigated the prevalence and genetic diversity of Bartonella species in bats in Mengyin County, Shandong Province of China.Numerous studies demonstrated that bats and their ectoparasites carried diverse  species . Bats wemonensis . Howeverand Asia –20, howeuth Asia ,22, and This study was carried out in accordance with the Guidelines of Regulations for the Administration of Laboratory Animals . The collection of bats for microbiological studies was approved by the Ethics Committee of Prevention Medicine of Shandong University (No.20150501), and all efforts were made to minimize discomfort to bats. Bats were sampled with the help of Mengyin County Center for Disease Control and Prevention. For sampling in karst cave and human houses, it was approved by the cave owner and house owners, respectively. While for sampling in cave and city sewer, no specific permission was needed for they were not private places. There are no endangered or protected species in the sampling habitats.Bats were collected from March to October, 2015, in Mengyin County , Shandong Province, which is located in the east of China .cytB) gene amplified from bat liver DNA as described previously [Bats were captured using mist nets settled near the entrance of karst caves or sewers at sunset when bats left roosts for night feeding and were collected from the mist nets in the next early morning. Bats were also captured by hand with butterfly nets within caves and residential houses. Captured bats were anesthetized by an intramuscular injection of chloral hydrate. Blood samples were obtained immediately after sedation by puncturing into the median artery. The amount of blood sampled varied from 0.2–0.5 mL according to the size of bats. Blood samples were stored at 4°C for a few hours before centrifuged for 5 minutes at 4000 rpm to separate the blood clots and the serum. Then the bats were euthanized by injection of overdose chloral hydrate. Selected internal organs were collected for further microbiological analysis. All specimens were transported in liquid nitrogen and were then stored frozen at –80°C until use. Bat species was identified by sequencing PCR product of the cytochrome B (eviously .rpoB) gene of Bartonella species with primers BArBF/BArBR [rpoB results were subsequently amplified for Bartonella citrate synthase gene (gltA), which was a reliable tool for distinguishing closely related Bartonella genotypes [gltA gene was performed with primers BhCS781.p/ BhCS1137.n or CS443f/ CS1210, targeting a 379-bp and 767-bp fragment of gltA gene, respectively [DNA was extracted from blood clots with QIAGEN DNA kit  according to the manufacturer’s instructions. All 107 blood samples were initially screened for the RNA polymerase B , respectively. Bartonella gltA sequences were aligned and trimmed with MEGA7.0 to a 327-bp fragment (positions 801–1127), which was commonly used for taxonomic classification of Bartonella species[Sequence chromatograms and sequence analysis were examined by using Chromas  and BLAST program (a species. The phyRhinolophus ferrumequinum (Greater horseshoe bat) and Rhinolophus pusillus(Least horseshoe bat) were collected from a karst cave, while Myotis fimbriatus (Fringed long-footed bat) and Myotis ricketti (Rickett's big-footed bat) were captured from a city sewer. Eptesicus serotinus (Common serotinus bat) were collected from two farmers’ houses and Myotis pequinius (Beijing mouse-eared bat) were collected from a cave. Blood samples were obtained from 107 living bats and were used in this study. Blood were not obtained from 38 bats which were died before collecting blood or were difficult to collect blood because of small body size.A total of 145 insectivorous bats were collected from Mengyin County, Shandong Province of China. Bats were captured from 4 different habitats and were molecularly identified into 6 species. Bartonella gltA gene was successfully amplified and sequenced from 27(25.2%) bats. Prevalence of Bartonella species by gltA in bats was as follows ; Rhinolophus pusillus, 2/10 (20.0%); Eptesicus serotinus, 0/15 (0.00%); Myotis fimbriatus, 9/16 (56.3%); Myotis ricketti, 1/5 (20.0%); and Myotis pequinius, 14/58 (24.1%).Of 107 bats tested,  follows : RhinologltA sequences of Bartonella species were obtained from 27 bats, with 1 sequence from each bat for 25 bats and 2 divergent sequences from each bat for 2 bats. Subsequent analyses of the 29 gltA sequences revealed that they clustered into 10 phylogroups (I–X) with 4.4%-19.9% divergence , indicating they might represent novel Bartonella species.Twenty-nine vergence . Five phgltA identity, our investigation showed an association between specific Bartonella genotypes and bat species, despite that some Bartonella species can infect several bat species  of bats. Phylogenetic analysis showed that Bartonella species detected in bats clustered into several genotypes, with diverse potentially novel Bartonella species. Some Bartonella species are specifically associated with special bat species, and co-infection with different Bartonella genotypes in a single bat was also observed. Our findings expanded our knowledge on the genetic diversity of Bartonella infection in bats, and shed light on the ecology of bat-borne Bartonella species.Our study provided the pioneer report of the genetic diversity of


Growing evidence suggests that maternal cholesterol levels are important in the offspring’s brain growth and development. Previous studies on cholesterols and brain functions were mostly in adults. We sought to examine the prospective association between maternal cholesterol levels and the risk of attention deficit hyperactivity disorder (ADHD) in the offspring. We analyzed data from the Boston Birth Cohort, enrolled at birth and followed from birth up to age 15 years. The final analyses included 1479 mother-infant pairs: 303 children with ADHD, and 1176 neurotypical children without clinician-diagnosed neurodevelopmental disorders. The median age of the first diagnosis of ADHD was seven years. The multiple logistic regression results showed that a low maternal high-density lipoprotein level (≤60 mg/dL) was associated with an increased risk of ADHD, compared to a higher maternal high-density lipoprotein level, after adjusting for pertinent covariables. A “J” shaped relationship was observed between triglycerides and ADHD risk. The associations with ADHD for maternal high-density lipoprotein and triglycerides were more pronounced among boys. The findings based on this predominantly urban low-income minority birth cohort raise a new mechanistic perspective for understanding the origins of ADHD and the gender differences and future targets in the prevention of ADHD. In the US, attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children; its prevalence has risen from 7.0% to 10.2% among children aged 4–17 years during the past two decades ,4,5, andAt present, our knowledge regarding the biological mechanisms of ADHD development and effective ways to prevent ADHD is insufficient. While research has identified several potential etiological mechanisms, such as gene variants, brain structural abnormalities, and neurotransmitter deficiency and dysregulation ,12, muchMaternal cholesterol levels are biologically plausible to influence neurodevelopment in the offspring ,38,39,40During normal pregnancy in humans, maternal blood cholesterol levels increase with gestational age to meet the increasing demands of fetal growth and development, especially with regards to the fetal brain ,43,44. CTo fill in the aforementioned knowledge gaps, in this study, we sought to examine the prospective association between maternal cholesterol levels 24–72 h after delivery and the development of ADHD in the offspring using a longitudinal birth cohort design. Findings from such a study have important clinical and public health implications. The current clinical guidelines for optimal cholesterol levels have been set for non-pregnant women based on cardio-metabolic outcomes, aiming to control cholesterol levels. However, the requirements for optimal nutrition, including cholesterols, are higher during pregnancy due to the increasing demands of the uterus, placenta, and fetal growth. Furthermore, no guidelines for cholesterol levels have been established for pregnant women in the context of fetal brain growth and long-term neurodevelopmental outcomes.The Boston Birth Cohort (BBC) has successfully recruited mother-infant pairs at birth; the participation rate has been >90% among eligible mothers approached by the research staff. Details of the recruitment of the BBC were published previously ,49. EligOf enrolled mother-infant pairs at birth in the BBC, 3098 who continued to receive pediatric primary care at BMC were enrolled in a postnatal follow-up study ,48,50. OMother-infant pairs were enrolled 24 to 72 h after birth. After obtaining informed consent, face-to-face interviews using a standardized questionnaire were conducted to collect mothers’ reports on family socio-demographics, substance use, and other prenatal exposure information. The maternal and newborn medical records were extracted using a standardized abstraction form. Since 2003, electronic medical records (EMRs) have become part of routine clinical data collection for the BBC, including both well-child and specialty medical visits at BMC. For each primary care visit, the EMRs contain the primary and secondary diagnoses from the International Classification of Diseases, Ninth Revision (ICD-9) (before 1 October 2015) and ICD-10 (after 1 October 2015).Maternal serum total cholesterol (TC), triglycerides (TG), and high-density lipoprotein (HDL) levels were measured using nonfasting blood samples obtained between 24 to 72 h after delivery. Serum low-density lipoprotein (LDL) levels were calculated using the Friedwald equation. The detailed measurement and calculation methods are described in our previous publication . Of noteThe “ADHD group” was defined as having any of the following clinician-diagnosed ICD-9 codes: , or any of the following ICD-10 codes: F90.0 , F90.1 , F90.2 , F90.8 , and F90.9 , as documented in the child’s EMRs.The “neurotypical (NT) group” was defined as not having any clinician diagnosis of autism spectrum disorder, ADHD, conduct disorders, developmental delays, intellectual disabilities, failure to thrive, or congenital anomalies. This definition was established by clinical experts and has been applied by multiple published papers ,53. The 2 test for categorical variables. TC, HDL, LDL, and TG were further analyzed as categorical variables based on clinically-established cut-off points [® version 14.0 software . The characteristics of the study sample between the “ADHD” and the “NT” groups were examined by t-test for continuous variables and χf points ,55, in af points . The quaThere were 303 children with a clinician diagnosis of ADHD. Of these, 214 were diagnosed by a developmental specialist and 89 by a general pediatrician. The median age at the first ADHD diagnosis was seven years. For TG, the risk of ADHD diagnosis for the children whose maternal TG levels were ≥200 mg/dL  was not statistically significantly different to those children whose mothers had <200 mg/dL TG levels ). Compared to mothers with second quartile TG levels, the mothers with first, third or fourth quartile TG levels had a 51% increased odds of having a child with any ADHD diagnosis ), suggesting a “J” shaped association. When LDL was analyzed as a continuous variable, the average odds of having a child with any ADHD diagnosis dropped 7% for every 20 mg/dL increase in maternal LDL levels ). The MLR results for maternal TC levels did not show any significant association with the child’s ADHD diagnosis. Despite the notion that cholesterol is essential for brain health, few prospective birth cohort studies have examined the effect of maternal cholesterol on offspring’s neurodevelopment. In the BBC, we found a significant association between maternal cholesterol levels, particularly HDL and TG measured 24–72 h after delivery , and ADHD risk in offspring. In contrast, this association is not significant for the risk of other neurodevelopmental disorders. Furthermore, our study sheds new light on the ADHD sex difference by demonstrating that boys are more vulnerable than girls to suboptimal maternal cholesterol levels. Our study findings were further strengthened by several aspects of our study design. We used clinician diagnosis extracted from the EMRs to define ADHD cases. More than half of the children in the ADHD group had over three ADHD clinician diagnoses in their EMRs. Additionally, over 80% of ADHD cases in the BBC were diagnosed by a neurodevelopmental specialist, thus, with a much higher specificity and lesser probability of case misclassification. The results of our sensitivity analyses, which restricted ADHD cases to those with a neurobehavioral specialist diagnosis and excluded those with a diagnosis at age younger than six years showed similar effect sizes and levels of significance as for our major findings.While we cannot make a causality inference, and although biological mechanisms underlying the maternal HDL and child ADHD association remain to be determined, our findings are biologically plausible and in alignment with previous research. The central nervous system (CNS) is insulated from the systemic circulation by the blood brain barrier (BBB). Cholesterol and its carrying lipoproteins in the CNS are mainly synthesized locally within the brain ,57 whileThe mechanism underlying the actions of maternal TG appears to be different from that underlying HDL. TG cannot cross the BBB but can influence multiple hormonal transportations across the BBB. For example, TG can effectively inhibit leptin transport across the BBB . BesidesIf further confirmed by future investigation, our findings may have important research, clinical and public health implications. First, our data suggest that pregnant women should maintain a relatively higher level of HDL to meet the need for rapid fetal brain development during pregnancy and to reduce ADHD risk; this is particularly important for male fetuses. Our data indicate that the current clinical cut-off point for HDL (>50 mg/dL) for nonpregnant women, as recommended by the American Heart Association for reducing the risk of heart disease ,55, may The long-observed and striking sex difference in ADHD risk continues to be poorly understood. Our study revealed that the maternal HDL and TG effects on ADHD are most pronounced among boys. This sex differences in response to suboptimal nutritional status are also found in other chronic diseases. For example, both human and animal studies showed that male fetuses are more likely to develop hypertension in response to the mother’s unfavorable nutrition and metabolism status during pregnancy ,68,69,70Our study had the following limitations. First, our study only included a single measurement of maternal cholesterol taken 24–72 h after delivery. Ideally, a serial collection of lipid levels throughout pregnancy would best inform our hypotheses. At best, our one-time measurement reflects maternal cholesterol levels during peripartum. Additionally, the change in lipid levels between 24 and 72 h after delivery might add another potential source of variability for lipid measurement. Second, our study used non-fasting blood samples. The values for TC and TG levels may have been inflated in non-fasting blood samples and thus may have biased our study results towards the null. Further studies using fasting blood samples should be conducted to provide a more precise assessment of optimal TG levels during pregnancy. Third, our study was conducted in a US urban, low-income, primarily minority setting; thus, this was a population at higher risk of exposure to other risk factors for ADHD. Our analyses adjusted for known risk factors of ADHD, but could not adjust for multiple parent-related factors identified in previous studies such as poor parenting ,14, maltIn this large, prospective, predominantly US urban, low income, minority birth cohort, we found that suboptimal maternal cholesterol levels, in particular low HDL, may increase the risk of ADHD in offspring. The male fetus appears to be particularly vulnerable to suboptimal maternal cholesterol levels. Our findings raise new hypotheses for understanding of origins of ADHD, gender differences and future targets in the prevention of ADHD, and warrant additional investigation.


This paper discusses the advantages of progress testing. A utopia is described where medical schools would work together to develop and administer progress testing. This would lead to a significant reduction of cost, an increase in the quality of measurement and phenomenal feedback to learner and school. Progress testing would also provide more freedom and resources for more creative in-school assessment. It would be an educationally attractive alternative for the creation of cognitive licensing exams. A utopia is always far away in the future, but by formulating a vision for that future we may engage in discussions on how to get there. An innovative way of assessing knowledge through progress testing was introduced in the late 1970 s , 3, but The second advantage is the information that it provides to learners and schools. The learner receives not only profile scores on every test, but also on their longitudinal knowledge growth . Schoolshttps://www.youtube.com/watch?v=Mc_-fVmEf1M). That means that individual schools can still have unique curricula and different learning methods. The tests are just the tools to see if the student is making progress within those unique curricula.In our utopia schools would work together to collaboratively develop and administer progress testing. It is a waste of resources for schools to reinvent the wheel and start an expensive process of item production and test administration. Progress testing is just that, using tests to measure progress . This allows a further reduction of the length of the test by about 50%, while the reliability is significantly higher (above 0.90). This is particularly advantageous for students in junior years, a period known to have lower reliabilities in its traditional, paper-based form [Progress testing with all of its educational benefits would be a low-cost assessment strategy. Schools would have to contribute yearly with a few but high quality items to a central bank. Some cost would be associated with the central administrative and psychometric expertise that is required, but when more schools buy in this would be a marginal cost. Schools would also need to agree on a blueprint for the test. The European Board of Medical Assessors offers progress testing in an online adaptive form (sed form . With anMany countries have national licensing exams, but also many countries have no licensing exams. Some countries are preparing or contemplating national exams. Big bang final exams may be useful as a licensing strategy to protect the public , 12, butFinally, an educational synergy should be sketched that might have a phenomenal impact on assessment in medical education. Once a system of progress testing is in place in a school’s assessment strategy, the big question is what it replaces. In some schools the progress test is the only form of knowledge testing . ImagineUtopia is a sketch of the ideal. Given that educational changes move slowly, we are aware we are far away from that ideal. Nevertheless, we might start small and team up with a few medical schools willing to pursue the vision we have shared here: implementing and optimizing a cost-effective assessment tool capable of fostering excellence in learning. It would already be fantastic if some of the current schools using progress testing were to collaborate and reach some of the above synergies. All the psychometric and technological tools necessary for our utopia to become a reality are already available. Together we could make a big difference in assessment in medical education. Let’s start tomorrow.


Multiple growth factors can be administered to mimic the natural process of bone healing in bone tissue engineering. We investigated the effects of sequential release of bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) from polylactide-poly (ethylene glycol)-polylactide (PELA) microcapsule-based scaffolds on bone regeneration. To improve the double emulsion/solvent evaporation technique, VEGF was encapsulated in PELA microcapsules, to which BMP-2 was attached. The scaffold (BMP-2/PELA/VEGF) was then fused to these microcapsules using the dichloromethane vapor method. The bioactivity of the released BMP-2 and VEGF was then quantified in rat mesenchymal stem cells (rMSCs). Immunoblotting analysis showed that BMP-2/PELA/VEG promoted the differentiation of rMSCs into osteoblasts via the MAPK and Wnt pathways. Osteoblast differentiation was assessed through alkaline phosphatase expression. When compared with simple BMP-2 plus VEGF group and pure PELA group, osteoblast differentiation in BMP-2/PELA/VEGF group significantly increased. An MTT assay indicated that BMP-2-loaded PELA scaffolds had no adverse effects on cell activity. BMP-2/PELA/VEG promoted the differentiation of rMSCs into osteoblast via the ERK1/2 and Wnt pathways. Our findings indicate that the sequential release of BMP-2 and VEGF from PELA microcapsule-based scaffolds is a promising approach for the treatment of bone defects. It has BMP-2 and VEGF were purchased from Sigma (USA). Antibodies to IgG, β-actin, alkaline phosphatase (ALP), EKR1/2, JNK, p38, p-ERK1/2, p-JNK, p-p38, Wnt andβ-catenin were purchased from Cell Signaling Technology (USA).Microcapsules containing BMP-2 and VEGF were prepared using the improved double emulsion/solvent evaporation technique as previously described . In brieMicrocapsules  were fused with scaffolds using the dichloromethane vapor method as previously described . In briein vitro swelling and degradation.Scaffold swelling and degradation tests were performed in PBS pH 7.4 at 37°C. Sixty milligrams of scaffolds were placed into 15-mL tubes containing 10 mL of PBS and incubated at 37°C. The PBS was replaced every third day. At each time , scaffolds were centrifuged and their wet weight (Ww) was recorded. Thereafter, scaffolds were lyophilized for 12 h and their dry weight (Wd) was recorded. The weight loss of each scaffold was calculated. The swelling ratio was calculated as the 4 cells. This experiment was carried out in triplicate.The release of BMP2 from BMP-2/PELA/VEGF scaffolds in PBS pH 7.4 was measured at 37°C. The concentrations of BMP-2 and VEGF at each time point  were measured using human BMP-2 and VEGF. ELISA kits were purchased from R&D Systems, Germany. VEGF and BMP-2 expression was evaluated in an ELISA plate reader at 450 nm with a correction at 570 nm. Results were normalized to picogram VEGF and BMP-2 per hour treatment per 102. The Inner Mongolia Medical University Experimental Animal Management Committee approved the animal protocol.rMSCs were obtained from a neonatal New Zealand white rabbit. The bone marrow was flushed with a 1-mL syringe containing low glucose Dulbecco's modified Eagle's medium (DMEM). Cells were harvested, transferred to a dish, and cultured in an incubator at 37°C with 5% COProteins derived from rMSCs were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis using 12% gels and transferred to nitrocellulose membranes for immunoblotting analysis. Membranes were blocked and incubated with primary antibodies overnight at 4°C. Membranes were subsequently washed three times with PBS and incubated with peroxidase-conjugated secondary antibodies. Immunoreactive bands were detected with Pierce ECL reagents (USA). The endogenous control was GAPHD.4 cell/cm2 and incubated with10 mg of scaffolds in every well. The cell culture medium  was refreshed once every 3 days. Cells were cultured at 37°C in a humidified atmosphere with 5% CO2. At days 3, 7, and 14, cells were obtained. Osteogenic differentiation was achieved following established in vitro protocols.rMSCs were seeded on 48-wellplates at 5×10www.graphpad.com/company/). Data are reported as means±SD.Statistical analyses were conducted by one-way analysis of variance (ANOVA) using the GraphPad Prism Software (version 5.0; GraphPad Software, USA, The swelling and degradation of scaffolds in PBS were assessed at 37°C for 28 days. The swelling ratio was significantly higher from days 1 to 14 than from days 15 to 28, reaching its peak on day 14. The swelling ratio then decreased, reaching its lowest level on day 28. Furthermore, there was no significant loss in scaffold weight from days 1 to 12 , consistThe concentrations of BMP-2 and VEGF released from BMP-2/PELA/VEGF scaffolds were measured by ELISA . The BMPThere was no difference in cell viability between PELA and control scaffolds at all time points . ViabiliTo identify the signaling pathway through which BMP-2/PELA/VEG promotes the differentiation of rMSCs into osteoblasts, cells were cultured for 3, 7, and 14 days in the presence of control, BMP-2/PELA/VEGF, BMP-2/PELA or PELA/VEGF scaffolds. The level of phosphorylated ERK1/2 was also examined  and 4. TThe Wnt and β-catenin were also detected . The expTo investigate the effects of BMP-2/PELA/VEGF scaffolds on rMSC-derived osteoblasts, we induced the differentiation of rMSCs into osteoblasts and cultured cells in the presence of control, BMP-2/PELA/VEGF, BMP-2/PELA or PELA/VEGF scaffolds. Thereafter, the ALP level was examined. There was a significant change in the ALP level in cells cultured in the presence of BMP-2/PELA/VEGF scaffolds than in those cultured in the presence of control scaffolds .Many factors, including porosity, temperature and medium, can affect the scaffold degradation rate . For exain vitro release profile of BMP-2/PELA/VEGF scaffolds, BMP-2 exhibited a classic initial burst release, followed by a sustained release for more than 28 days. This release profile has been reported to improve bone regeneration compared to a sustained release without a burst.In scaffolds, BMP-2 was attached to the surface of PELA microcapsules, which was responsible for its rapid burst release, whereas VEGF was encapsulated by PELA microcapsules, which was responsible for its sustained release. According to the To gain further insight into the mechanism by which BMP-2/PELA/VEGF scaffolds enhance rMSC proliferation, we investigated the involvement of the MAPK signaling pathway. The MAPK signaling pathway is comprised of ERK, JNK and p38 serine/threonine kinases that are primarily involved in the activation of nuclear transcription factors that control cell proliferation, differentiation and apoptosis . Extrace


Although low birthweight (LBW) babies represent only 15.5% of global births, it is the leading underlying cause of deaths among newborns in countries where neonatal mortality rates are high. In Uganda, like many other sub-Saharan African countries, the progress of reducing neonatal mortality has been slow and the contribution of low birthweight to neonatal deaths over time is unclear. The aim of this study is to investigate the association between low birthweight and neonatal mortality and to determine the trends of neonatal deaths attributable to low birthweight in Uganda between 1995 and 2011.Cross-sectional survey datasets from Uganda Demographic and Health Surveys between 1995 and 2011 were analyzed using binary logistic regression with 95% confidence interval (CI) and Kaplan-Meier survival analysis to examine associations and trends of neonatal mortalities with respect to LBW. A total of 5973 singleton last-born live births with measured birthweights were included in the study.The odds of mortality among low birthweight neonates relative to normal birthweight babies were; in 1995, 6.2 (95% CI 2.3 −17.0), in 2000–2001, 5.3 (95% CI 1.7 −16.1), in 2006, 4.3 (95% CI 1.3 − 14.2) and in 2011, 3.8 (95% CI 1.3 − 11.2). The proportion of neonatal deaths attributable to LBW in the entire population declined by more than half, from 33.6% in 1995 to 15.3% in 2011. Neonatal mortality among LBW newborns also declined from 83.8% to 73.7% during the same period.Low birthweight contributes to a substantial proportion of neonatal deaths in Uganda. Although significant progress has been made to reduce newborn deaths, about three-quarters of all LBW neonates died in the neonatal period by 2011. This implies that the health system has been inadequate in its efforts to save LBW babies. A holistic strategy of community level interventions such as improved nutrition for pregnant mothers, prevention of teenage pregnancies, use of mosquito nets during pregnancy, antenatal care for all, adequate skilled care during birth to prevent birth asphyxia among LBW babies, and enhanced quality of postnatal care among others could effectively reduce the mortality numbers. About 20 million low birthweight (LBW) babies are born every year, representing 15.5% of all births globally . HoweverIn sub-Saharan Africa (SSA), the general rate of decline in neonatal mortality (NM) has been slow compared to infant or under-five mortality  and moreIn Uganda, like in many SSA settings, apart from health system limitations such as inadequate resources, paucity of data in hospital registries makes it difficult to determine the prevalence of LBW and associated mortality trends , 21. TheWith an annual population growth rate of about 3.2 and an overall fertility rate of 5.6, Uganda’s population rose from about 17 million in the 1990s to about 34 million in 2011 . The sexWe obtained secondary data from repeated cross-sectional surveys by the Demographic and Health Survey (DHS) program. The datasets are independent and nationally representative. We used four datasets from the Uganda DHS birth recodes for the years 1995, 2000–2001, 2006, and 2011. A total of 5973 singleton last-born live births with birthweight measures were included in the study. This consisted of 1160 children in 1995 representing 25% of all the last-born live births in the data sample for that year and 1100 children for the year 2000–2001 representing 30% of all the last-born live births in the sample for that year. Similarly, 1514 (35%) children were included for the year 2006 and 2199 (50%) for the year 2011. We targeted and utilized the birth recode information for the last-born live births born within the 5-year period prior to each of the surveys. The Demographic and Health Survey (DHS) program employs standardized questionnaires and protocols that ensure that the participants remain anonymous . The DHSThis referred to death of newborn within 28 days after birth. It was dichotomized into yes (died) or no .The variable low birthweight (LBW) was the predictor variable. Birthweight records were obtained from the child’s health card or from the mother’s verbal report of measured weight at birth. Birthweight was dichotomized into LBW (< 2500 g) or normal birthweight (NBW) ≥ 2500 g. Macrosomia (> 4000 g)  was elimPreterm birth, LBW and birth asphyxia are highly correlated and it is difficult to determine their independent contributions towards neonatal deaths. These three, together with infections, contribute to 80% of neonatal mortality as the highest cause of neonatal mortality, with LBW being the underlying factor .In this study, independent variables that are known to be direct and indirect risk factors for neonatal mortality and LBW such as ‘young’ maternal age (7) and poor nutrition (resulting from poverty and low or no education (9) were investigated. Wealth status was determined as a composite cumulative living standard measured in terms of household asset inventory. These were investigated in the univariate analysis to determine their distribution and possible associations with birthweight and neonatal survival categories. Smoking was not examined due to lack of data. Figure Below Table  is a sumWe used analytical software IBM SPSS version 24 and MS excel for analyses. Pearson’s chi square test of independence and association was used to examine the distribution of variables according to birthweight and neonatal mortality for each survey. Survival plots of the birthweight categories were generated using Kaplan-Meier’s estimator. Binomial logistic regression analysis was used to determine the odds ratios for the association between LBW and neonatal mortality after adjusting for socio-demographic and maternal factors, cesarean births and check-ups for pregnancy complications. The analysis was conducted at 5% significant level. In order to improve the validity of the results, the national representativeness of the data and to adjust for non-response, the complexity of DHS sampling design was taken into account, and data sampling weights were applied to datasets for the years 2000−2001, 2006, and 2011. However, the 1995 dataset was not subjected to weighting due to the need to maintain the statistical power of the data for that year, the implication of which is a very minimal difference. A total of 5973 last-born live births with birthweights were included in the analyses.The LBW-attributable neonatal mortality risk fraction (AF) and population-attributable mortality risk fraction (PAF) were computed as proportion of prevalent deaths that could be avoided if LBW was prevented or the death of LBW babies was eliminated. These were calculated manually using eqs.  and 2)  2) belowThe population attributable mortality risk fraction PAF, expressed as a percentage (%) was computed using the eq. .2\documePe is the proportion of deaths that have the exposure.OR is the odds ratio generated from binary logistic regression analysis and p <  0.05).Table p <  0.05) of mothers with no formal education had LBW babies in almost all the years except 2011. Similarly, maternal age < 20 years of age was associated with having higher proportions of LBW babies as shown in the 1995 and 2006 findings (p < 0.01).Table In all surveys, LBW was significantly associated with neonatal mortality as shown in Table Figure The LBW-attributable neonatal mortality in Uganda declined by more than half, from 33.6% (%) in 1995 to 15.3% in 2011 as shown in Table Figure Overall, the odds of neonatal mortality among LBW babies as compared to normal birthweight were reduced by a third, from about 6 times higher in 1995 to 3.8 times higher in 2011. The LBW-attributable neonatal mortality in the population declined by more than half, from 33.6% in 1995 to 15% in 2011. This present study is the first of its kind in Uganda and perhaps the whole of east Africa that examines the trends of LBW-attributable mortality over the years. The study reinforces the very few LBW-related studies in Uganda and east Africa by providing new peer-reviewed findings on the contribution of LBW towards neonatal mortality countrywide over a period of over 15 years. The study findings might be useful for auditing the causes of neonatal deaths, and for evaluation, future health planning and policy making aimed at improving neonatal survival. The WHO emphasizes that auditing the causes of neonatal deaths is paramount for effective monitoring and improving mother and child health care .The 3.8 times higher odds of deaths among LBW neonates in 2011 in the present study is consistent with the findings of a related study conducted by Kananura et al. in eastern Uganda in 2012–2013 that indicated a 3.51 mortality odds ratio . Comparap < 0.05) for the year 2000–2001 in Table p >  0.05) indicated improvements in obstetric services that has enabled the survival of many cesarean birth babies.The results indicated a significantly higher proportion of deaths among LBW babies and this corroborates with findings of other studies , 3 that Figure According to a facility-based study by Hedstrom et al. in central Uganda that admitted neonates born between December 2005 and September 2008, 89% of neonatal deaths among LBW neonates weighing under 1000 g could be attributable to LBW . AnotherNeonatal mortality accounts for about 40% of global under-five mortality . In UganThe greatest national decline of LBW-attributable mortality estimated in 2011 in our study is a notable finding that could be attributed to the efforts of the inter-agency national Newborn Steering Committee (NSC) . The NSCAlso, the Uganda Newborn Study (UNEST) Project partly contributed to the decline in mortality of LBW and preterm newborns in parts of eastern Uganda and consequently contributed to the overall national decline during this period .The survival analysis indicated that the rate of decline in LBW-attributable mortality in the 5-year periods increased from 6.6% between 1995 and 2000–2001 to 8.7% between 2006 and 2011 in the population Table ) and neo(P >  0.05)  Table . Althoug(p < or > 0.05)  Table . HoweverThe random sampling of data across the entire country and the standardized nature of data collection method of the DHS strengthen the external validity of our study and enable global comparability among countries. Weighting the data for the years 2000, 2006 and 2011enabled us to adjust for disproportionate sampling and non-response. This improved the national representativeness and validity of the study estimates. The 1995 dataset was not weighted and the results for that year are slightly less representative. However, the results are still valid, due to the fact that there was only a small difference when weighted and unweighted results of all the other years were compared. The national representativeness of the 1995 data was only dependent on the random sampling across the entire country and the standardized nature of DHS data collection for its reliability.The repeated findings of significant associations between LBW and neonatal mortality across all surveys confirm the existing evidence of association and the internal validity of this present study. Nonetheless, our study could not confirm the causal association because the exact causes of newborn deaths were not ascertained medically. The in-depth use of the nationally representative DHS datasets in this study has revealed the need to improve data collection techniques and to include other similarly important variables such as diagnostic causes of death among individual children, for example, birth asphyxia.Another limitation of our study was that although hospital births recorded and/or communicated birthweights, over 65% were from mothers` recall and the rest from the health card, and we cannot therefore completely dismiss the possibility of recall bias. This also applies to the 1995 data that included both hospital and home births. Nevertheless, child birth is a significant event in a mother’s life and with our study selection of the most recent birth experience, there is a very high possibility that the mothers recalled correct birthweights. Moreover, for the years 2000 to 2011, birthweight data concerned solely information regarding hospital born babies because these were measured birthweights and not estimated weights as in-home births, where birthweights are mainly estimated based on the physical size of the body parts such as foot length, chest or head . A studyAlthough the 1995 data included both home and hospital births, which undermined the consistency of the study methodology across years, preliminary analysis indicated that among the selected sample of newborns with birthweight measures in 1995, only 3.5% of the births were home births . The 1995 data thus has a reasonable degree of consistency with other survey years. However, the selection of only hospital births in other survey years improved the quality and validity of the findings for those years.The recording of neonatal survival data from day 0 to 30 by the DHS allowed us to clearly categorize our outcome variable and investigate risk factors across all the survey years with consistency. Given the large number of home births (about 50%) in all the surveys, both the LBW and neonatal deaths were likely underreported.The birthweight data are prone to rounding-off or aggregation into 500 g-weight intervals which could have slightly compromised the accuracy of Kaplan-Meier’s survival analysis in this study. This aggregation of data was observed in a study by Channon et al. . HoweverLow birthweight is associated with neonatal mortality and contributes to a substantial proportion of neonatal deaths in Uganda. Although significant progress has been made to reduce newborn deaths attributed to LBW, by 2011, about 74% of all LBW neonates died in the neonatal period. This implies that the health system in place has been inadequate to meet the challenge of ensuring LBW survival. There is also profound need to strengthen both birth and neonatal death registration irrespective of whether the infants are born at home or at the health centers. The decentralized health system in Uganda can enable community health workers (CHW) and the village health teams (VHT) in liaison with the sub-counties and the districts to close the existing gaps concerning neonatal birth and death audits. This will enable robust and continuous research and monitoring of the progress of LBW neonatal survival. Our study presents national estimates of risks and mortality trends that provide national basis for continual evaluation and policy recommendations to prevent LBW and minimize risks of neonatal deaths. A holistic approach to reduce the incidence of preventable LBW babies could be fostered to reduce these mortality rates. Viable fronts that could be strengthened include sexual education in schools to prevent teenage pregnancies, complementing nutritional diet of pregnant mothers, HIV testing, ensuring that all pregnant mothers use mosquito nets, training of health workers, and promoting antenatal care visits and hospital births. Enhancing the quality of postnatal care could also reduce mortality incidence of LBW newborns.


BackgroundThere is growing risk from terrorism following radicalisation of young men. It is unclear whether psychopathology is associated.AimsTo investigate the population distribution of extremist views among UK men.MethodCross-sectional study of 3679 men, 18–34 years, in Great Britain. Multivariate analyses of attitudes, psychiatric morbidity, ethnicity and religion.ResultsP<0.001, adjusted OR = 1.33, 95% CI 1.13–1.58, P<0.001, respectively) and negatively with depression .Pro-British men were more likely to be White, UK born, not religious; anti-British were Muslim, religious, of Pakistani origin, from deprived areas. Pro- and anti-British views were linearly associated with violence (adjusted odds ratio (OR) = 1.51, 95% CI 1.38–1.64, ConclusionsMen at risk of depression may experience protection from strong cultural or religious identity. Antisocial behaviour increases with extremism. Religion is protective but may determine targets of violence following radicalisation. Migrants from countries without effective governance may not easily assimilate and may become radicalised, with extremist views. However, extremist views may also involve nationalism. In both contexts, war may be perceived as a ‘just cause’. There has been little research into factors maintaining loyalty and willingness to fight for a country, and pathways to terrorism remain complex and unclear. However, potential recruits for terrorist groups are more likely to feel angry, alienated or disenfranchised, believe political involvement cannot effect change, identify with perceived victims of social injustice and feel need to take action. They believe violence against the state is justified, have friends or family sympathetic to the cause, and benefit psychologically from sense of adventure, camaraderie and heightened identity.2 Poor mental health could be associated with some of these characteristics, increasing risk of engaging in terrorism or becoming radicalised. A common characteristic, however, is that terrorists, unless lone actors,3 have little evidence of psychopathology.7 Severe mental disorders are therefore not commonly associated with terrorism, but mental disorder may confer vulnerability to radicalising influences.8 Extremism could be a reaction to adversity, leading to empowerment, overcoming or averting symptoms such as depression. By 2010, UK media reported growing numbers of British-born Muslim men, mainly of Pakistani descent, recruited by Al-Qaeda, trained in Pakistan and fighting against the British army in Afghanistan. This represented open armed conflict against British political and cultural values. It is unclear whether these men were an isolated minority or came from communities with shared attitudes supporting terrorism. Support for terrorism within a population is thought to resemble a pyramidal structure running from the largest proportion at the bottom, consisting of neutral individuals, and moving up through levels of diminishing size, from sympathisers, to supporters, with finally terrorists at the apex.9Threats from international terrorism are increasingNo previous research has investigated the population distribution of extremist attitudes and support for armed conflict and corresponding associations with mental disorder. We therefore carried out a representative survey of the attitudes of men aged 18–34 years in England, Scotland and Wales towards the war in Afghanistan. Our aims were to investigate: (a) the population distribution of pro-British and anti-British views associated with the war; (b) linear associations between ethnicity/religion, violence/criminality and psychiatric morbidity; and (c) explanatory factors for observed associations.10 It was based on random location sampling, an advanced form of quota sampling shown to reduce biases introduced when interviewers are able to choose locations to sample from. Individual sampling units (census areas of 150 households each) were randomly selected within British regions in proportion to their population. The basic survey included a representative sample of young men (18–34 years) from England, Scotland and Wales. In addition, there were two boost surveys. First, young Black and minority ethnic (BME) men were selected from output areas with a minimum of 5% BME inhabitants. Second, young men from lower social grades  were selected from output areas in which there was a minimum of 30 men 18–34 years of age in these social grades. A self-administered questionnaire piloted in a previous survey was adapted for this study. Informed consent was obtained from all survey respondents, who then completed pencil and paper questionnaires in privacy. They were paid £5 for participation. Ethical approval to carry out the survey was granted by the Ethics Committee, Queen Mary University of London, UK.The survey was carried out in 2011 and has previously been described.11 screened participants for psychotic experiences; individuals were defined as screen-positive if they met three or more criteria. Questions from the Structured Clinical Interview for DSM-IV personality disorders screening questionnaire12 identified antisocial personality disorder. Anxiety disorder and depression were defined as a score of ⩾11 on the Hospital Anxiety and Depression Scale13 in the past week. Scores ⩾20 on the Alcohol Use Disorders Identification Test14 and ⩾25 on the Drug Use Disorders Identification Test15 indicated alcohol dependence and drug misuse disorder, respectively. Participants were questioned about violent behaviour as in previous surveys of violence.16 Information was sought about involvement in and attitudes towards violence.The Psychosis Screening QuestionnaireWe could not ask participants if they actively supported terrorism. We used proxy measures to investigate extremist attitudes, support for Britain and the war in Afghanistan. We asked which of the following applied: ‘I feel strongly British  if that means standing up for yourself or your country’; ‘I feel more like people with my own religious, cultural or political beliefs than people who are British’; ‘I support the war in Afghanistan’; ‘I oppose the war in Afghanistan’; ‘I could fight in the British army in Afghanistan’; ‘I could fight against the British army in Afghanistan’. The variable pairs were combined to reflect extremes in both directions. There were few differences between those who responded negatively to each pair of questions and those who endorsed ‘I don't know’. These two groups were therefore combined and constituted the reference group against which the extremes were contrasted.To study the distribution of degrees of extremism we created two exposure variables: ‘pro-British’ and ‘anti-British’ by combining the variables described above. Those who endorsed negative answers or ‘don't know’ to cultural identity, support of/opposition to the war, and fighting for/against the British army were coded ‘0’ and constituted the reference group for both variables. Study participants who reported British/dual identity or supported the war or own identity or opposed the war received a rating of ‘1’. Those who reported British/dual identity and supported the war or own identity and opposed the war received a rating of ‘2’. A rating of ‘3’ was assigned when the person reported support for, or opposition to, the war in Afghanistan. The higher the rating on these two variables, the stronger were the opinions towards the extreme. The survey participants were also asked about current religious affiliation, how often they attended religious services in the past month, and how often they prayed.For descriptive purposes, weighted absolute and relative frequencies were reported for binary/polytomous variables and weighted means and standard deviations for variables on interval/ratio level. We ran weighted survey commands for logistic regression models with binary outcomes. Analyses incorporated adjustment of standard errors for clustering of individuals within postcodes and important demographic characteristics (age and index of multiple deprivation).We first studied associations between the three exposure variables cultural identity, support for/opposition to the war, and fighting for/against the British army. We then investigated whether increasing extremist views in both directions were related to demography, ethnicity, religion, psychiatric morbidity and violence and criminal behaviour. The two variables (pro-British and anti-British) were treated as continuous exposure in the logistic regression model.In a final step we investigated psychiatric vulnerabilities and protective effects in ethnic minority and religious groups and associations with religiosity. If (a) a significant association between ethnic/religious group and psychiatric morbidity was found and (b) if the ethnic/religious group also demonstrated a significant relationship with extremism, and (c) if extremism was associated with psychiatric morbidity, we included the extremism variables in the statistical model. If the association between ethnic/religious group and psychiatric illness was no longer significant following adjustment, extremism was interpreted as an explanatory variable in this relationship.All statistical analyses were carried out using Stata 14. A significance level of <0.05 was adopted throughout.The weighted sample included 3679 men aged 18–34 years: 1983 (53.9%) from the main survey; 1075 (29.2%) from the minority ethnic sample; and 621 (16.9%) from the sample of men from lower social classes. Their mean age was 25.9 years (s.d. = 5.0), more than half were single  and more than a third were unemployed . The sample was ethnically diverse, with 38.5% (1413) participants of BME origin.P<0.001) and opposition to the war . This was also true of men identifying with their own culture, ethnicity or cultural group . The pattern was similar among those identifying with both cultures .When contrasted to those endorsing ‘no’ or ‘I don't know’, men reporting British identity demonstrated higher rates of support  but not against it. In contrast, men identifying uniquely with their own culture were more likely to report they would fight against the British army  but not in it. Among men with British identity, support for the war was significantly associated with willingness to fight in the British army . Among men who identified with their own culture, opposition to the war was associated with willingness to fight against the British army .Men with strong British identity and those identifying with both cultures were more likely to report that they would fight in the British army  is shown in Associations between these opposing trends and demographic characteristics are shown in online Table DS1 and those for psychiatric morbidity, violence and crime are shown in Trends towards anti-British extremism were positively associated with socioeconomic deprivation, other White, Indian, Pakistani, Bangladeshi, Black African, Chinese/other ethnicity, non-UK born, other Christian, Muslim, Jewish/Sikh/Buddhist/other religion, attendance at services and frequency of praying (online Table DS1). Increasing anti-British attitudes demonstrated positive relationships with antisocial personality disorder, violence and imprisonment and an inverse association with depression .We then investigated associations between ethnicity, religion and psychiatric morbidity (Table DS2). Ethnicity and religion/religiosity were not associated with psychosis or anxiety disorder, apart from an inverse association between Protestant religion and anxiety disorder. The prevalence of depression was significantly higher among Pakistani and Black minority groups than UK-born White men. Alcohol dependence was less prevalent among Pakistani men, all religious groups and among those endorsing measures of religiosity compared with those affirming no religion/atheism. Contrasted with White British men, there was less drug misuse among Indian, Pakistani, Bangladeshi and Chinese/other minority groups. Compared with men who were not religious, there was less drug misuse among all religious groups and degrees of religiosity, except Jewish/Sikh/Buddhist/other who showed no difference. Antisocial personality disorder was also less prevalent among Indian, Pakistani and Bangladeshi men, Protestant, Muslim and Hindu men and among those endorsing religiosity.In a final step, we investigated whether associations found between ethnic/religious groups and psychiatric morbidity were explained by extremist views, both pro- and anti-British. Ethnic and religious groups listed in 9 A large number of men held neutral views at the base of this structure, progressing through increasing levels of opposition to the war and non-British identity, with willingness to fight against the British army at the apex  could result in a protective sense of empowerment involving new meaning, belief systems and identity25 along a pathway ultimately leading to violent action. However, since we cannot determine the direction of association in this cross-sectional survey, respondents with depression may simply have been less likely to fight for or against their country or to hold extreme views because of their depression.The key finding was that men at the bottom of this structure, with neutral or undecided views,  were morThe other key finding observed towards opposite extremes in 30 Increasing anti-British extremist views were linearly associated with religion and religiosity, whereas increasing support for British intervention in Afghanistan was negatively associated. This polarisation of religious views may reflect ongoing processes of mutual rejection and an exclusionary circle in the British population, currently evident among many Muslim and non-Muslim communities.31 Within these communities, particularly those with multiple risk factors for radicalisation, extremism may result from perception of an aggressive, oppressive non-Muslim culture. A four-stage model of Al-Qaeda-influenced radicalisation proposes a pre-radicalisation stage of vulnerability followed by early exploration of Salafi Islam and gradual gravitation away from old identity, association with like-minded individuals and adoption of ideology.24 This is followed by progressive adoption of jihadi-salafi ideology and finally jihadisation.6 Further investigation is needed into whether depression is intensified among Muslims by this mutual exclusionary process and whether radicalisation, with new sense of belonging and identity,32 and willingness to take violent action are associated with protection and symptomatic improvement.As expected, religious affiliation and practice was protective against externalising disorders such as alcohol dependence, drug misuse and antisocial personality disorder, in line with religious teachings.33 We did not investigate support for suicidal attacks. Furthermore, these studies found inconsistencies across different countries and that these specific associations with religious practice were strongest among Palestinians and Israeli settlers. In the UK, needs for excitement through violent action, camaraderie and strong masculine identity may, for some men, be more important proximal factors than religion, politics or cultural identity. Nevertheless, the latter may legitimise and ultimately determine targets of violence.Experimental studies of support for suicide attacks have found that attendance at religious services corresponds as a function of collective religious activities, but differed from our findings in that frequency of praying does not.Our survey had several limitations, including our method of defining identity where we combined ethnicity, cultural, religious and political beliefs. Although we defined support for armed conflict as ‘extremism’ for the purpose of our study, it could not be ascertained whether men reporting willingness to fight against the British Army actually intended to do so. Violent behaviour within the past 5 years was self-reported, without objective information such as data on arrest or convictions. Use of self-report captures more violence than comes to the attention of the authorities but may still have underestimated true prevalence. Socially undesirable behaviours may be underreported because of religious beliefs and cultural expectations.Clinical presentations were derived from self-report questionnaires and not confirmed by clinical interview. However, clinician assessments compare favourably with self-report instruments. Given the cross-sectional nature of the data, we could not identify whether these measures were associated with changes in cultural, ethnic, religious and political views held by the respondent. Nonetheless, the community-based design and large sample size allowed examination of associations between different population subgroups holding different beliefs and mental disorder categories. Furthermore, sample size provided sufficient statistical power to test complex models and control for confounding.Random location sampling does not provide detailed information on number of young men who declined to participate. However, because the method is based on the national census, participants were identified and included according to representative strata and their actual frequency in the population. Because young adult men of lower social class are more likely to decline participation in household surveys, this method has considerable advantages when investigating antisocial behaviour. The alternative would be to rely on a method requiring statistical weighting to adjust for attrition, which may be particularly high among this subgroup.31The finding that anti-British extremist views were negatively associated with depression among Pakistani men but not Black African men may be as a result of heterogeneity among countries included in the latter combined category. The BME boost sample, although large and representative, was underpowered to examine men from specific African countries with large Muslim populations and ongoing insurgencies. It was of interest that men of Bangladeshi origin were no more likely to hold anti-British extremist views or to have depression than White UK-born men. However, it would be necessary to conduct further studies with larger BME samples to investigate the roles of differing experiences of racial discrimination, social mobility and ethnic density effects across certain BME subgroups. It would also be necessary to investigate the effects of right-wing and anti-immigrant views on exacerbation of mutual rejection and an exclusionary circle.34 Our findings indicated considerable heterogeneity across the population among those expressing extremist views, with deep divisions in personal attitudes and identity corresponding to processes of mutual rejection and exclusion. Depressive symptoms are more prevalent among minority populations in Europe.35 Separation with maintenance of ethnic culture but no participation in local culture is associated with mood and anxiety disorders.36 Further research is needed into interventions that reduce discrimination, exclusion and extremism in these communities and associated depression.Since withdrawal of coalition forces from Afghanistan, concern has grown over future support for terrorism within BME communities, particularly in Europe. Young men who travel to fight for Islamic State in Syria and Iraq, follow radical interpretations of Islam, and oppose political and economic interests of their host countries may return to threaten national security through insurgency. Religious identity may have become an increasingly important unifying and mobilising factor since 2011, when shared language, geographical and cultural origin, and blood ties additionally contributed to willingness to fight against the British army in southern Afghanistan among young men of Pakistani origin.37 Views and opinions initially considered extreme may become the norm.38 Simulated models suggest that when a large part of the population hold moderate views or are uncertain, extreme views tend to prevail. This leads to either convergence on a single extreme or to bipolarisation.39 Bipolarisation implies strongly opposing views with neither achieving dominance.Extremism can spread to those with moderate views through epidemic transmission when culture, religious and political values shift quickly.40 However, this process is thought to depend on whether members of a group share the same core characteristics and values. Individuals in the group are more likely to fight and die for family members, or those with whom they perceive close ties similar to those in families within small social groups than for their country. Promoting shared values and perceived similarity in personal identity may therefore be important in preventing processes that lead to bipolarisation. Our study may be a starting point for more sophisticated investigation into whether these processes are failing in European countries, whether bipolarisation has accelerated and intensified within vulnerable communities with high levels of depression, leading to convergence on a single extreme, and increasing numbers of radicalised young men prepared to engage in armed conflict.Endorsement of willingness to fight for one's country would not be interpreted by most UK people as ‘extremism’ but willingness, if necessary, to make an extreme sacrifice for the benefit of, and to defend, the majority. Fusion theory would suggest that the asymmetrical distribution in