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Easily constructed by investigators with no electronics knowledge, we present an inexpensive and open-source electroporation apparatus for Dictyostelium discoideum with all functional modules and peripherals from Cauchy et al., 2022, "A Low-cost Electroporator for Genetically Modifying Social Amoeba Dictyostelium discoideum" submitted to Journal of Open Hardware. Description: Electroporation to introduce DNA into cells is a common technique in genetic engineering. Dictyostelium discoideum is a well-established eukaryotic model organism that is frequently genetically modified (transformed). We present here an electroporator capable of high efficiency transformation. Our electroporator consists of a high voltage power supply, pulse generator circuit and cell sample cuvette chamber. The power supply is programmed to deliver desired voltage, which when activated by a double-pole, double-throw switch (DPDT) charges a capacitor. Further switching allows the charged capacitor to deliver a precise, consistent exponential decay wave of the proper duration to the cuvette containing a D. discoideum cell and DNA mixture. The high-voltage circuit is housed in an electrically insulated enclosure - we chose a plastic electrical junction box with appropriate holes for switch mounting and cables to pass. A 3D printable cuvette holder was designed and is available in .stl, .dwg and .iges formats. An inexpensive 1,000-volt digital multimeter was integrated into the design to aid in development and testing. To provide hands-free monitoring of the real-time capacitor voltage, we connected multimeter test leads to the capacitor poles. In addition to the standard build, we present here an alternative design for the pulse generator, which we will refer to as "modular". The standard pulse generator was designed to be durable for repeated use in multiple D. discoideum electroporation experiments. This design includes a soldered padboard with high power rated components. The modular pulse generator is designed for ease of build, is easily modified by swapping components for alternative waveforms, and is intended for a small number of electroporations and not routine or repeated use.

Effective decision making from randomised controlled clinical trials relies on robust interpretation of the numerical results. However, the language we use to describe clinical trials can cause confusion both in trial design and in comparing results across trials. ACceptability Curve Estimation using Probability Above Threshold (ACCEPT) aids comparison between trials (even where of different designs) by harmonising reporting of results, acknowledging different interpretations of the results may be valid in different situations, and moving the focus from comparison to a pre-specified value to interpretation of the trial data. ACCEPT can be applied to historical trials or incorporated into statistical analysis plans for future analyses. An online tool enables ACCEPT on up to three trials simultaneously.

Though psychogenic non-epileptic seizures (PNES) are seen commonly during evaluation of children and adolescents with epilepsy, the literature regarding developmental changes in PNES is limited. Literature search was conducted in PubMed. Key search terms included: Pseudoseizure* OR PNES OR [(non-epileptic or nonepileptic or psychogenic or non-epileptic attack disorder) AND (seizure*)], resulting in 3,236 articles. Filters included human, ages 1–18 years, English language and last 15 years (2004–2019), resulting in 533 articles. We reviewed 33 articles, which included 19 articles that involved children (1–18 years), with 10 or more children with PNES in their study group. 21 articles obtained in cross references that were outside the filter setting (including time frame and age range) were also reviewed, for a total of 54 articles. Majority of the studies were retrospective. We detail clinical features, predisposing factors and appropriate workup for children and adolescents with possible PNES. There is no consensus regarding frequency of psychiatric comorbidities in children with PNES. No controlled trials of treatment of PNES in children are available, but cognitive behavioral therapy is the consensus for adult PNES. Outcome appears to be better in children with PNES. There is a need for be long-term prospective studies to document various clinical features and outcome of pediatric and adolescent PNES, and also the comorbid conditions.

Abacavir hypersensitivity syndrome (ABC HSS) is strongly associated with carriage of human leukocyte antigen (HLA)-B*57:01, which has a 100% negative predictive value for the development of ABC HSS. However, 45% of individuals who carry HLA-B*57:01 can tolerate ABC. We investigated immune and non-immune related genes in ABC HSS (n = 95) and ABC tolerant (n = 43) HLA-B*57:01 + patients to determine other factors required for the development of ABC HSS. Assignment of phenotype showed that ABC HSS subjects were significantly less likely than tolerants to carry only ERAP1 hypoactive trimming allotypes (p = 0.02). An altered self-peptide repertoire model by which abacavir activates T cells is in keeping with observation that endoplasmic reticulum aminopeptidase 1 (ERAP1) allotypes that favour efficient peptide trimming are more common in ABC HSS patients compared to patients who tolerate ABC. Independently, non-specific immune activation via soluble cluster of differentiation antigen 14 (sCD14) may also influence susceptibility to ABC HSS.

Objectives The aim of this study was to investigate associations between baseline characteristics and CD4 cell count response on first-line antiretroviral therapy and risk of virological failure (VF) with or without drug resistance. Methods We conducted an analysis of UK Collaborative HIV Cohort data linked to the UK HIV Drug Resistance Database. Inclusion criteria were viral sequence showing no resistance prior to initiation of first-line efavirenz + tenofovir disoproxil fumarate + emtricitabine and virological suppression within 6 months. Outcomes of VF (≥200 copies/mL) with or without drug resistance were assessed using a competing risks approach fitted jointly with a model for CD4 cell count recovery. Hazard ratios for each VF outcome were estimated for baseline CD4 cell count and viral load and characteristics of CD4 cell count response using latent variables on a standard normal scale. Results A total of 3640 people were included with 338 VF events; corresponding viral sequences were available in 134 with ≥1 resistance mutation in 36. VF with resistance was associated with lower baseline CD4 (0.30, 0.09–0.62), lower CD4 recovery (0.04, 0.00–0.17) and higher CD4 variability (4.40, 1.22–12.68). A different pattern of associations was observed for VF without resistance, but the strength of these results was less consistent across sensitivity analyses. Cumulative incidence of VF with resistance was estimated to be >2% at 3 years for baseline CD4 ≥350 cells/μL. Conclusion Lower baseline CD4 cell count and suboptimal CD4 recovery are associated with VF with drug resistance. People with low CD4 cell count before ART or with suboptimal CD4 recovery on treatment should be a priority for regimens with high genetic barrier to resistance.

Child neurologists should provide initial care for the mental health problems of children and adolescents with epilepsy. Attention deficit hyperactivity disorder (ADHD), autism spectrum disorders are common comorbidities of childhood epilepsy. The psychotropic drugs used to treat mental health disorders can be safely employed in children with seizures. Child neurologists can diagnose common behavioral problems, should be comfortable with first-line agents to treat common psychiatric illnesses, and should recognize when support from psychologists or child and adolescent psychiatrists is needed. This article is part of the Special Issue "Obstacles of Treatment of Psychiatric Comorbidities in Epilepsy".

Background\ud Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations.\ud Methods\ud Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required.\ud Results\ud Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals.\ud Conclusions\ud Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.

Progress in animal modeling of polymorphisms and mutations in mitochondrial DNA (mtDNA) is not as developed as nuclear transgenesis due to a host of cellular and physiological distinctions. mtDNA mutation modeling is of critical importance as mutations in the mitochondrial genome give rise to a variety of pathological conditions and play a contributing role in many others. Nuclear localization and transcription of mtDNA genes followed by cytoplasmic translation and transport into mitochondria (allotopic expression, AE) provide an opportunity to create in vivo modeling of a targeted mutation in mitochondrial genes. Accordingly, such technology has been suggested as a strategy for gene replacement therapy in patients harboring mitochondrial DNA mutations. Here, we use our AE approach to transgenic mouse modeling of the pathogenic human T8993G mutation in mtATP6 as a case study for designing AE animal models.

Farmers may be reluctant to adopt variable rate nitrogen (VRN) management because of uncertain profits. This study assessed field landscape, soil, and weather effects on optical sensing (OS)-based VRN on cotton (Gossypium hirsutum L.) N rates, yields, and net returns (NRs). Field data were collected from 21 locations in Louisiana, Mississippi, Missouri, and Tennessee, USA, between 2011 and 2014. Data included yields, N rates, and NRs for the farmer practice (FP), OS-based VRN, and OS-based VRN supplemented with other information. Production data were augmented with landscape, soils, and weather data, and ANOVA and logistic regressions were used to identify field conditions where VRN was profitable, provided risk management benefits, and improved N efficiency. Key findings indicate that NRs were improved with VRN by applying additional N on more erodible soils. Higher organic matter soils also benefited from VRN through enhanced yields and NRs. VRN may also have provided risk management benefits by providing a lower probability of NRs below NRs for the FP on soils associated with greater water-holding capacity, higher organic matter levels, or deeper profiles. Results from this study may help identify farm fields with similar characteristics for adoption of VRN management.

In the current study we investigated the interaction of hypothalamic paraventricular nucleus (PVN) glucagon-like peptide-1 (GLP-1) and ghrelin signaling in the control of metabolic function. We first demonstrated that acylated ghrelin injected directly into the PVN reliably altered the respiratory exchange ratio (RER) of adult male Sprague Dawley rats. All testing was carried out during the initial 2 h of the nocturnal cycle using an indirect open circuit calorimeter. Results indicated that acylated ghrelin induced a robust increase in RER representing a shift toward enhanced carbohydrate oxidation and reduced lipid utilization. In contrast, treatment with comparable dosing of des-acyl ghrelin failed to significantly impact metabolic activity. In separate groups of rats we subsequently investigated the ability of exendin-4 (Ex-4), a GLP-1 analogue, to alter acylated ghrelin’s metabolic effects. Rodents were treated with either systemic or direct PVN Ex-4 followed by acyl ghrelin microinjection. While our results showed that both systemic and PVN administration of Ex-4 significantly reduced RER, importantly, Ex-4 pretreatment itself reliably inhibited the impact of ghrelin on RER. Overall, these findings provide increasingly compelling evidence that GLP-1 and ghrelin signaling interact in the neural control of metabolic function within the PVN.

We present multi-wavelength VLA observations in the microwave of Saturn's rings. The data were obtained over two observational windows and cover a range from the Q to S bands (0.7–13 cm). Key ring particle properties are determined in the C and B rings such as particle porosity and non-icy material fraction in order to compare them directly with previously derived results using the 2-cm Cassini RADAR radiometry data (Zhang et al., 2017a, b). We confirm that these new data are consistent with the particles in the C ring being quite porous with porosity values of roughly 75–90% depending on different scattering phase functions, as well as the presence of a “hot band” in the middle C ring which is associated with both an anomalously high non-icy material fraction and low opacity relative to the rest of the C ring. Furthermore, with our multi-wavelength study we find that the amount of intrinsic thermal emission is almost constant with wavelength, which is unexpected since particles tend to become more absorbing at higher frequencies. If we assume that the non-icy material in the rings is intramixed within the ring particles, this result suggests a corresponding decrease in the imaginary part of the non-icy material dielectric constant at higher frequencies, which is most noticeable in the middle C ring. We do not see evidence for such decrease in the B ring particles. If true, this supports the idea that the non-icy material in the middle C ring has a different origin, and that the larger particles in the middle C ring may be composed of a rocky core covered by a porous, icy mantle. If the non-icy materials in the middle C ring are embedded as large chunks, a core-mantle model for the ring particles there naturally explains this almost constant intrinsic thermal emission. Furthermore, because the VLA has more complete azimuthal angle coverage than the Cassini radiometry observations, we are able to investigate the ring brightness in more detail. In particular, we notice a flatter scattering profile than that predicted by using a pure Mie phase function at higher frequencies (Q and K bands; 0.7–1.3 cm) for azimuthal angles between |40|o and |60|o. We can match the observed scattering profile better by introducing a semi-empirical phase function for large particles to account for nonsphericity effects. Finally, the non-icy material fraction in the B ring is less than 1%, which is in agreement with that derived from Cassini observations. The frequency-dependence of the B ring thermal emission sets the lower limit of B ring particle porosity. We confirm that the B ring particles are likely over 80% porous, which at the same time explains the high opacity in the B ring as measured from density waves. Because we are limited by the signal-to-noise ratio, the optical depth of the middle B ring could be higher than the currently accepted values. However, we found that even if the middle B ring is six times more optically thick than the value measured from UVIS occultations, the surface mass density is still likely to be less than 300 g/cm^2, while the exposure time to non-icy pollutants due to micrometeoroid bombardment is less than 200 Myr.

This article addresses the question of what the Taliban think about drones. Western literature on this question is predominately anti-war, anti-drone, or critical of the lack of transparency, which...

Anxiety is a common comorbidity in children with epilepsy, though often overlooked and undertreated. Fear and worry are common reactions of children with epilepsy and their parents. Risk factors are multiple and include demographical, epilepsy-related, genetic, and family variables. Anxiety negatively affects health-related quality of life (QOL) and may contribute to poor seizure control. Appropriate treatment of anxiety in children with epilepsy should follow practice guidelines developed for treatment of anxiety in children without epilepsy and consist of education, counseling, and potentially psychopharmacology.

Background Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by benign tumors in multiple organs, including non-cancerous kidney lesions known as renal angiomyolipomas. This study’s objective is to describe the age-stratified morbidity, treatment patterns, and health-related quality of life of TSC patients with renal angiomyolipomas in the United States. A cross-sectional, anonymous web-based survey was conducted with a convenience sample of TSC patients and caregivers identified through a patient advocacy organization. Results Out of the total sample of 676, 182 respondents reported having kidney complications with 33% of the pediatric group and 25% of the adult group with TSC reporting them. Of those with kidney complications, 110 (60%) reported a diagnosis of renal angiomyolipomas, of which 79 (72%) were adult patients and 31 (28%) were pediatric age patients. Eighty-four percent of the pediatric group and 76% of the adult group reported lesions on both kidneys. Of the patients experiencing involvement of only one kidney, 60% of the pediatric group and 21% of the adult group reported having multiple tumors within the affected kidney. Almost all of the sample (99%) reported seeing a physician and having a procedure or test for TSC in the past year. Less than half the respondents (44%) reported being hospitalized in the past year. Thirty-nine percent reported an emergency room visit as well. Compared to scores for patients with kidney disease, the angiomyolipoma adult patients reported significantly lower Mental Component Summary scores on the SF-12. Conclusions Renal angiomyolipomas burden leads to frequent healthcare resource use including hospitalization, invasive treatments, and surgical procedures, which result in an impaired mental health related quality of life.

Background Minimisation of the delay to diagnosis is critical to achieving optimal outcomes for HIV patients and to limiting the potential for further onward infections. However, investigation of diagnosis delay is hampered by the fact that in most newly diagnosed patients the exact timing of infection cannot be determined and so inferences must be drawn from biomarker data. Methods We develop a Bayesian statistical model to evaluate delay-to-diagnosis distributions in HIV patients without known infection date, based on viral sequence genetic diversity and longitudinal viral load and CD4 count data. The delay to diagnosis is treated as a random variable for each patient and their biomarker data are modelled relative to the true time elapsed since infection, with this dependence used to obtain a posterior distribution for the delay to diagnosis. Data from a national seroconverter cohort with infection date known to within ± 6 months, linked to a database of viral sequences, are used to calibrate the model parameters. An exponential survival model is implemented that allows general inferences regarding diagnosis delay and pooling of information across groups of patients. If diagnoses are only observed within a given window period, then it is necessary to also model incidence as a function of time; we suggest a pragmatic approach to this problem when dealing with data from an established epidemic. The model developed is used to investigate delay-to-diagnosis distributions in men who have sex with men diagnosed with HIV in London in the period 2009–2013 with unknown date of infection. Results Cross-validation and simulation analyses indicate that the models developed provide more accurate information regarding the timing of infection than does CD4 count-based estimation. Delay-to-diagnosis distributions were estimated in the London cohort, and substantial differences were observed according to ethnicity. Conclusion The combination of all available biomarker data with pooled estimation of the distribution of diagnosis-delays allows for more precise prediction of the true timing of infection in individual patients, and the models developed also provide useful population-level information.

Evaluate long-term rates of virological failure and treatment interruption for people living with HIV (PLWHIV) with viral suppression on first-line efavirenz+tenofovir disoproxil fumarate+emtricitabine/lamivudine (EFV+TDF+FTC/3TC), and compare these according to patient characteristics.Methods:PLWHIV enrolled in the Collaboration of Observational HIV Epidemiological Research Europe cohort collaboration, who started first-line EFV+TDF+FTC/3TC at age at least 16 years and had viral suppression (

WOS: 000428055300023, 29357082, Our aim was to transplant blue catfish germ line stem cells into blastulae of triploid channel catfish embryos to produce interspecific xenogenic catfish. The morphological structure of the gonads of blue catfish (Ictalurus furcatus) in similar to 90- to 100-day-old juveniles, two-year-old juveniles, and mature adults was studied histologically. Both oogonia (12-15 mu m, diameter with distinct nucleus 7-8 mu m diameter) and spermatogonia (12-15 mu m, with distinct nucleus 6-7.5 mu m diameter) were found in all ages of fish. The percentage of germ line stem cells was higher in younger blue catfish of both sexes. After the testicular tissue was trypsinized, a discontinuous density gradient centrifugation was performed using 70, 45, and 35% Percoll to enrich the percentage of spermatogonial stem cells (SSCs). Four distinct cell bands were generated after the centrifugation. It was estimated that 50% of the total cells in the top band were type A spermatogonia (diameter 12-15 mu m) and type B spermatogonia (diameter 10-11 mu m). Germ cells were confirmed with expression of vasa. Blastula-stage embryos of channel catfish (I. punctatus) were injected with freshly dissociated blue catfish testicular germ cells as donor cells for transplantation. Seventeen days after the transplantation, 33.3% of the triploid channel catfish fry were determined to be xenogenic catfish. This transplantation technique was efficient, and these xenogenic channel catfish need to be grown to maturity to verify their reproductive capacity and to verify that for the first time SSCs injected into blastulae were able to migrate to the genital ridge and colonize. These results open the possibility of artificially producing xenogenic channel catfish males that can produce blue catfish sperm and mate with normal channel catfish females naturally. The progeny would be all C x B hybrid catfish, and the efficiency of hybrid catfish production could be improved tremendously in the catfish industry., USDA-Biotechnology Risk Assessment Program [2009-33522-05774]; Alabama Agricultural Experiment Station [80-009]; Office of the Vice President for Research, Auburn University (OVPR-AU-IGP), This work was partially funded by the USDA-Biotechnology Risk Assessment Program (grant no.: 2009-33522-05774), the Alabama Agricultural Experiment Station (80-009), and the Office of the Vice President for Research, Auburn University (OVPR-AU-IGP).

This chapter discusses the structure and biochemistry of endotoxin, with an emphasis upon the portions of the molecule that confer antigenicity and toxicity. It presents an overview of the physiologic and biologic effects of endotoxin at both the systemic and cellular levels. The chapter also discusses the development and testing of antiendotoxin Abs, and also presents a meta-analysis of the protective capacity of antiendotoxin Abs with an attempt to define characteristics that produce protective capacity. A large body of data has accumulated, providing evidence that the mechanisms which underlie the lethality of lethal disease are derived from the complex interactions of the host with both the intact organism and Gram-negative bacterial endotoxins. Endotoxins are a heterogeneous group of macromolecules with an approximate molecular weight of 200,000 that reside in the outer membrane of the cell wall of Gram-negative bacteria.

The present study examined the ability of ghrelin administration into either the ventral tegmental area (VTA) or nucleus accumbens (NAc) to potentiate cocaine-induced conditioned place preference (CPP). Additionally, we examined the impact of co-injection of the ghrelin 1a antagonist JMV 2959 with ghrelin in order to evaluate the potential attenuation of ghrelin’s effects on cocaine-induced CPP. Adult male Sprague-Dawley rats were allowed simultaneous access to either side of the CPP apparatus to establish baseline chamber preferences. The rats were then restricted to either their non-preferred or preferred side over the course of conditioning which lasted for a total of 8 consecutive days. On days in which rats were restricted to their non-preferred side, systemic cocaine (0.5–5.0 mg/kg IP) followed by central ghrelin (300 pmol), or co-administration of ghrelin (300 pmol) with JMV 2959 (10 μg), was administered either into the VTA or NAc immediately prior to the conditioning period. On alternate days rats were treated with vehicle then placed into what was initially determined to be their preferred side. CPP was calculated as the difference in the percentage of total time spent in the treatment-paired compartment during the post-conditioning session and the pre-conditioning session. Our results indicated that ghrelin potentiated cocaine-induced CPP and that this effect was attenuated by JMV 2959. Overall, these findings provide further evidence that mesolimbic ghrelin signaling is indeed critically involved in mediating the rewarding effects of cocaine.

Putative spermatogonia A from a fresh-cell isolate or a density-gradient-centrifuged isolate from the testes of Blue Catfish Ictalurus furcatus were transplanted into the gonads of triploid Channel Catfish I. punctatus. The cells were introduced into gonads of the host via catheterization (2 × 104–1.43 × 106 cells) or by surgically inserting the cells directly into the gonad (7 × 104–1.25 × 105 cells). Ten months after implantation, DNA was analyzed from biopsies of the gonads and seven of eight males were found to be xenogenic, having Blue Catfish cells in their gonads. The xenogenic males successfully courted normal Channel Catfish that had been induced with hormones to ovulate, but none of the eggs hatched, indicating inadequate sperm production, an inability to ejaculate, and/or low sperm quality. Male xenogenic catfish treated with luteinizing hormone releasing hormone analog had well-developed testes, and sperm production was detected in three of seven xenogenic males examined 2 years after transplantation. Sperm were removed from a male that had been surgically transplanted with Blue Catfish cells and used to fertilize eggs from a hand-stripped Channel Catfish female. One percent of these eggs hatched. All seven surviving 6-month-old progeny of this male had the external morphology, swim bladder shape, nuclear DNA profile, and mitochondrial DNA profile of female Channel Catfish × male Blue Catfish F1 hybrids, indicating that this triploid Channel Catfish male produced Blue Catfish sperm. This is the first report of successful production of xenogenic catfish and the first report of producing 100% hybrid progeny using xenogenesis in fish. Received March 23, 2016; accepted July 23, 2016 Published online November 18, 2016

The result of the UK referendum on membership of the EU has occasioned considerable debate on Britain’s international standing. An important (but so far largely overlooked) aspect of this debate is how the possibility of Brexit impacts upon NATO and, specifically, the UK’s position within the Atlantic alliance. In this connection, the initial signs are worrying. London may wish to focus on NATO as a way of compensating for a troubled exit from the EU, but its ability to do so is weakened by uncertainties over the UK defence budget (and standing as a nuclear power), a loss of credibility as a global player and the blame that will attach to it for undermining NATO cohesion. The likely upshot of Brexit will be a loss of British influence and a blow to the integrity of the alliance.

Acoustic signals are used for intraspecific communication in bark beetles and a variety of stridulatory mechanisms have evolved within the subfamily Scolytinae (Coleoptera: Curculionidae). Bark beetles use stridulatory signals for communication at the tree surface and within tunnels inside tree tissues. Bark beetles produce a variety of call types that are broadband with frequencies ranging from 1 to 80 kHz. Not only are airborne and substrate-borne vibrations available, but every stridulation event produces both airborne and substrate-borne vibrations via the same action of the animal. Vibrations appear to be used during species recognition, premating interactions, pair formation, mate selection, intraspecies aggression, territoriality, and predator deterrence. No sound receptors have been located for bark beetles; however, we propose potential locations in this chapter. We provide an overview of acoustic communication and its use by adult bark beetles, describe their stridulatory structures, interpret how vibrations move within tree materials and how this affects the beetles’ ecology and behavior, and present technical and applied applications of acoustic tools for bark beetle management.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common and widely researched disorders of childhood. US prevalence estimates of attention-deficit/hyperactivity disorder in youth ages 4–17 range from 5% to 11%, with the childhood male to female ratio estimated to be 3–4:1 in epidemiological samples. The economic and psychosocial costs of ADHD are significant for patients, their families, and the society, and ADHD is associated with a higher risk for substance use disorders and other comorbid psychiatric disorders, increased mortality due to accidents, unwanted pregnancies, lower academic achievement and occupational performance, adult antisocial behavior, and poor social functioning, including higher divorce rates. ADHD is a heterogeneous disorder with a variety of core symptom presentations, degree of severity, and psychiatric comorbidities. Therefore, treatment involves a stepwise, systematic approach targeting the predominant clinical symptoms with the goal of minimizing the negative impact on social and academic functioning. Pharmacological treatment for ADHD, although highly effective, is associated with marked variabilities in clinical response, optimal dosage needed, and tolerability. In this chapter, the authors discuss both established and novel pharmacological treatment and neuromodulation in treatment-resistant ADHD.

Neuropsychiatric symptoms, including mania and psychosis, have been reported with new or recent pediatric brain tumor diagnoses. However, such symptoms have rarely been described in the setting of stable postoperative posterior fossa lesions. The cerebellar cognitive affective syndrome, described more commonly in adults than children, suggests an association between the posterior fossa and affective dysregulation and cognition.

Attention‐deficit/hyperactivity disorder (ADHD) is a common and challenging comorbidity affecting many children with epilepsy. A working group under the International League Against Epilepsy (ILAE) Pediatric Commission identified key questions on the identification and management of ADHD in children with epilepsy. Systematic reviews of the evidence to support approaches to these questions were collated and graded using criteria from the American Academy of Neurology Practice Parameter. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) requirements were followed, with PROSPERO registration (CRD42018094617). No increased risk of ADHD in boys with epilepsy compared to girls with epilepsy was found (Level A). Valproate use in pregnancy is associated with inattentiveness and hyperactivity in offspring (1 class I study), and children with intellectual and developmental disabilities are at increased risk of ADHD (Level A). Impact of early seizure onset on development of ADHD was unclear (Level U), but more evident with poor seizure control (Level B). ADHD screening should be performed from 6 years of age, or at diagnosis, and repeated annually (Level U) and reevaluated after change of antiepileptic drug (AED) (Level U). Diagnosis should involve health practitioners with expert training in ADHD (Level U). Use of the Strength and Difficulties Questionnaire screening tool is supported (Level B). Formal cognitive testing is strongly recommended in children with epilepsy who are struggling at school (Level U). Behavioral problems are more likely with polytherapy than monotherapy (Level C). Valproate can exacerbate attentional issues in children with childhood absence epilepsy (Level A). Methylphenidate is tolerated and effective in children with epilepsy (Level B). Limited evidence supports that atomoxetine is tolerated (Level C). Multidisciplinary involvement in transition and adult ADHD clinics is essential (Level U). In conclusion, although recommendations could be proposed for some of the study questions, this systematic review highlighted the need for more comprehensive and targeted large‐population prospective studies.

Tuberous sclerosis complex (TSC) is a multi-organ autosomal-dominant, genetic disorder with incomplete penetrance. The multiple manifestations of TSC and impacts to numerous organ systems represent significant disease, healthcare, and treatment burden. The economic and employment burden of the disease on individuals and their families is poorly understood. This study assessed the cost of illness and work and school productivity burden associated with TSC in a cross-sectional web-survey sample.Eligible TSC individuals and caregivers were invited through the Tuberous Sclerosis Alliance advocacy group to complete a web-based survey about illness characteristics, treatment, disease burden, direct and indirect healthcare costs, work and school impairment.Data from 609 TSC adults or caregiver respondents with no cognitive impairments were analyzed. TSC adults (18 years of age) had significantly higher direct out-of-pocket costs for ER visits, expenses for medical tests and procedures, alternative treatments, medications and lifetime cost of surgeries compared to TSC pediatric individuals. Both TSC adults and TSC caregivers reported work and school absenteeism and presenteeism; however, adults reported significantly higher absenteeism and presenteeism and overall activity impairment due to TSC, as might be expected, compared to TSC caregivers. TSC adults had significantly higher absenteeism and presenteeism rates compared to adults with moderate-to-severe plaque psoriasis and muscular sclerosis.TSC results in considerable direct out-of-pocket medical costs and impairment to work productivity, especially for adults. Future studies should include the comparator group and examine direct cost burden in the US using electronic medical records and insurance databases.

Commencing from an observation by Freedman that Donald Rumsfeld’s legacy as US Secretary for Defense was comparable with that of Robert McNamara, and that where the latter begat the ‘Vietnam syndrome’ , the former would leave behind the ‘Iraq syndrome’. Analysis of discourse under President Obama reveals that the effects of Iraq are more profound than Freedman indicated. In the Obama era the use of force itself was ever more in doubt. In limiting US commitment to fighting for core interests and formal allies, the Obama administration broke with the main post-war tradition of US foreign policy. This made the use or threat of force more difficult, as the appetite for risk was blunted by its experience in Iraq. Obama’s position was unhelpful in embracing the implications of the limitations of American power. US ‘risk aversion’ risked failing both the US and the world.

Objective Parent variables (stigma, mood, unmet needs for information and support, and worry) are associated with behavioral difficulties in children with seizures; however, it is not known how this relationship is influenced by additional seizures. This study followed children (ages 4–14 years) and their parents over a 24-month period (with data collected at baseline and 6, 12, and 24 months) and investigated the effect of an additional seizure on the relationship between parenting variables and child behavior difficulties. Methods The sample was parents of 196 children (104 girls and 92 boys) with a first seizure within the past 6 weeks. Child mean age at baseline was 8 years, 3 months (SD 3 years). Data were analyzed using t-tests, chi-square tests, and repeated measures analyses of covariance. Results Relationships between parent variables, additional seizures, and child behavior problems were consistent across time. Several associations between parent variables and child behavior problems were stronger in the additional seizure group than in the no additional seizure group. Conclusions Findings suggest that interventions that assist families to respond constructively to the reactions of others regarding their child's seizure condition and to address their needs for information and support could help families of children with continuing seizures to have an improved quality of life.

Summary Background Standard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options. Methods In this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (

This is the first report on human leukocyte antigen (HLA) allele and haplotype frequencies at three class I loci and two class II loci in unrelated healthy individuals from two ethnic groups, 170 Burmese and 200 Karen, originally from Burma (Myanmar), but sampled while residing in Thailand. Overall, the HLA allele and haplotype frequencies detected by polymerase chain reaction sequence-specific primer (PCR-SSP) at five loci (A, B, C, DRB1 and DRQB1) at low resolution showed distinct differences between the Burmese and Karen. In Burmese, five HLA-B*15 haplotypes with different HLA-A and HLA-DR/DQ combinations were detected with three of these not previously reported in other Asian populations. The data are important in the fields of anthropology, transplantation and disease-association studies.

ObjectiveIndividuals with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of seizures, but there is uncertainty about whether ADHD medication treatment increases risk among patients with and without preexisting seizures.MethodsWe followed a sample of 801,838 patients with ADHD who had prescribed drug claims from the Truven Health MarketScan Commercial Claims and Encounters databases to examine whether ADHD medication increases the likelihood of seizures among ADHD patients with and without a history of seizures. First, we assessed overall risk of seizures among patients with ADHD. Second, within-individual concurrent analyses assessed odds of seizure events during months when a patient with ADHD received ADHD medication compared with when the same individual did not, while adjusting for antiepileptic medications. Third, within-individual long-term analyses examined odds of seizure events in relation to the duration of months over the previous 2 years patients received medication.ResultsPatients with ADHD were at higher odds for any seizure compared with non-ADHD controls (odds ratio [OR] = 2.33, 95% confidence interval [CI] = 2.24–2.42 males; OR = 2.31, 95% CI = 2.22–2.42 females). In adjusted within-individual comparisons, ADHD medication was associated with lower odds of seizures among patients with (OR = 0.71, 95% CI = 0.60–0.85) and without (OR = 0.71, 95% CI = 0.62–0.82) prior seizures. Long-term within-individual comparisons suggested no evidence of an association between medication use and seizures among individuals with (OR = 0.87, 95% CI = 0.59–1.30) and without (OR = 1.01, 95% CI = 0.80–1.28) a seizure history.ConclusionsResults reaffirm that patients with ADHD are at higher risk of seizures. However, ADHD medication was associated with lower risk of seizures within individuals while they were dispensed medication, which is not consistent with the hypothesis that ADHD medication increases risk of seizures.