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Sodium valproate and related preparations have recently undergone regulatory review following concern about effects on the unborn child and doctors' failure to communicate risk. The issues are wider. Valproate is overused in psychiatry based on the false perception that ‘ease’ of use equates to better safety than alternatives. Valproic acid can disrupt fundamental physiological processes, the consequences of which are poorly understood and little discussed in the psychiatric literature. Valproate may be useful in a small number of patients with bipolar disorder but current prescribing patterns are unjustified. Perception needs to change.
Declaration of interest
D.C.O. is psychiatric commissioner on the Commission on Human Medicines and a member of the European Medicines Agency's Scientific Advisory Group on Psychiatry. He chaired the European Medicines Agency's review of the psychiatric use of valproate in pregnancy and women of childbearing potential.
The development of rational treatments for tardive dyskinesia has been held back by limitations to our understanding of its aetiology, which even now does not extend far beyond its association with centrally acting dopamine-blocking drugs. This article reviews briefly the major aetiological theories and addresses general management and specific treatment options. Primary prevention and early recognition remain the crucial management issues because, once the condition is established, there are no satisfactory treatments. The article considers two newly developed drugs, valbenazine and deutetrabenazine, in some detail as, although they are not yet licensed in Europe, they have largely been responsible for an upsurge in interest in tardive dyskinesia in the North American literature and are likely to be widely promoted in the future. Although possessed of undoubted benefits, the evidence suggests that these represent small steps rather than large leaps forward in treatment.
•Be able to discuss the major aetiological theories on the causation of a common, and sometimes serious, adverse action of antidopaminergic drugs
•Understand general management and specific treatment options
•Understand the pharmacology and efficacy of two drugs recently approved by the FDA for the treatment of tardive dyskinesia
DECLARATION OF INTEREST
D.C.O. is psychiatric commissioner on the Commission on Human Medicines, the UK drug regulator, and chair of its expert advisory group on CNS drugs. He is also a member of the psychiatry Scientific Advisory Group of the European Medicines Agency.
Tardive dyskinesia is a common iatrogenic neurological and neurobehavioural syndrome associated with the use of antidopaminergic medication, especially antipsychotics. Prior to the introduction of the newer antipsychotics in the 1990s, it was one of the major areas of psychiatric research but interest waned as the new drugs were reputed to have a reduced liability to extrapyramidal adverse effects in general, a claim now discredited by numerous pragmatic research studies. Early small-scale short-term prevalence studies were presented as evidence to support the assumption that patients on the newer drugs did indeed have a lower prevalence of tardive dyskinesia but recent large-scale review of studies with patients exposed for longer suggest that things have not changed. This article presents a clinical overview of a complex and varied syndrome in terms of its phenomenology, epidemiology and risk factors; a companion article will consider treatment. This overview aims to highlight tardive dyskinesia once again, especially to practitioners who have trained in an environment where this was considered mainly in historical terms.
•Understand the complex phenomenology comprising the syndrome of tardive dyskinesia
•Appreciate recent data on prevalence and incidence with the newer antipsychotics
•Be aware of risk factors when recommending antipsychotic (and other antidopaminergic) drugs
The aim of this study was to investigate how innovation is defined with respect to new medicines.
MEDLINE, Embase, and EconLit databases were searched for articles published between January 1, 2010 and May 25, 2016 that described a relevant definition of innovation. Identified definitions were analyzed by mapping the concepts described onto a set of ten dimensions of innovation.
In total, thirty-six articles were included, and described a total of twenty-five different definitions of innovation. The most commonly occurring dimension was therapeutic benefit, with novelty and the availability of existing treatments the second and third most common dimensions. Overall, there was little agreement in the published literature on what characteristics of new medicines constitute rewardable innovation.
Alignment across countries and among regulators, health technology assessment bodies and payers would help manufacturers define research policies that can drive innovation, but may be challenging, as judgements about what aspects of innovation should be rewarded vary among stakeholders, and depend on political and societal factors.
22q11.2 deletion syndrome (22q11.2DS) is associated with high rates of neurodevelopmental disorder, however, the links between developmental coordination disorder (DCD), intellectual function and psychiatric disorder remain unexplored.
To establish the prevalence of indicative DCD in children with 22q11.2DS and examine associations with IQ, neurocognition and psychopathology.
Neurocognitive assessments and psychiatric interviews of 70 children with 22q11.2DS (mean age 11.2, s.d. = 2.2) and 32 control siblings (mean age 11.5, s.d. = 2.1) were carried out in their homes. Nine children with 22q11.2DS and indicative DCD were subsequently assessed in an occupational therapy clinic.
Indicative DCD was found in 57 (81.4%) children with 22q11.2DS compared with 2 (6.3%) control siblings (odds ratio (OR) = 36.7, P < 0.001). Eight of nine (89%) children with indicative DCD met DSM-5 criteria for DCD. Poorer coordination was associated with increased numbers of anxiety, (P < 0.001), attention-deficit hyperactivity disorder (ADHD) (P < 0.001) and autism-spectrum disorder (ASD) symptoms (P < 0.001) in children with 22q11.2DS. Furthermore, 100% of children with 22q11.2DS and ADHD had indicative DCD (20 of 20), as did 90% of children with anxiety disorder (17 of 19) and 96% of children who screened positive for ASD (22 of 23). The Developmental Coordination Disorder Questionnaire score was related to sustained attention (P = 0.006), even after history of epileptic fits (P = 0.006) and heart problems (P = 0.009) was taken into account.
Clinicians should be aware of the high risk of coordination difficulties in children with 22q11.2DS and its association with risk of mental disorder and specific neurocognitive deficits.
This paper focuses on the ways in which past racial contention shapes possibilities for contemporary civic action focused on youth education. Drawing on the recently legislated Civil Rights/Human Rights Education curriculum in Mississippi—a state with an exceptionally charged history of racial contention—we identify barriers to curricular implementation in Mississippi public schools and draw on case studies of initiatives in two communities that have successfully overcome these barriers. Results emphasize how the legacies of civil rights era struggles interact with contemporary demographic and educational dynamics to enable two distinct forms of robust civic action. School-centered civic practice is enabled by communities characterized by strong civil rights organizing infrastructures, high levels of contention with White authorities throughout the civil rights era, and low participation in public schools by White families. Conversely, youth civic practice in communities marked by high levels of civil rights-era contention but significant contemporary White participation in public schools occurs through out-of-school initiatives. In both cases, however, participation in and exposure to civil rights and human rights education has occurred in racially-bifurcated ways that reflect the state’s legacy of institutionalized racism.
The study of complex organic molecules, and more specifically those of prebiotic interest, is important to understand the chemical richness of star-forming regions. The chemistry of nitrogen bearing molecules such as formamide or methyl isocyanate is poorly constrained. We study different chemical pathways to form and destroy these molecules from both the gas phase and grain surface chemistry. From comparison with observations of four different relevant astrophysical regions, we show that both the gas phase and grain surface chemistry are required to explain the observed abundances of these species.
The eastern bettong Bettongia gaimardi, a potoroid marsupial, has been extinct on the Australian mainland since the 1920s. Sixty adult bettongs were reintroduced from the island of Tasmania to two predator-free fenced reserves on mainland Australia. We examined baseline health parameters (body weight, haematology and biochemistry, parasites and infectious disease exposure) in a subset of 30 (13 male, 17 female) individuals at translocation and again at 12–24 months post-reintroduction. The mean body weight increased significantly post-reintroduction but there were no significant differences in body weight between the two reintroduction sites or between the sexes in response to reintroduction. Differences were evident in multiple haematological and biochemical variables post-reintroduction but there were few differences between the two reintroduced populations or between the sexes in response to reintroduction. Ectoparasite assemblages differed, with five of 13 species failing to persist, and an additional four species were identified post-reintroduction. None of the bettongs had detectable antibodies to the alphaherpesviruses Macropodid herpesvirus 1 and 2 post-reintroduction, including one individual that was seropositive at translocation. Similarly, the novel gammaherpesvirus potoroid herpesvirus 1 was not detected by polymerase chain reaction (PCR) in any of the bettongs post-reintroduction, including one individual that was PCR-positive at translocation. None of the bettongs had detectable antibodies to Toxoplasma gondii either at translocation or post-reintroduction. Our data demonstrate changing baseline health parameters in eastern bettongs following reintroduction to the Australian mainland are suggestive of improved health in the reintroduced populations, and provide additional metrics for assessing the response of macropodoids to reintroduction.
Civil wars occur in some countries at some times and not in other countries at other times. This articleexamines how the potential for large-scale external intervention can prevent civil wars. The authorargues that intervention by external states in civil war can be so overwhelming that it reduces one side’s probability of victory to essentially zero. When dissidents expect this type of intervention on the side of government, they anticipate no chance of achieving success through violence and do not initiate civil wars. When governments anticipate this type of intervention on their behalf, they feel protected from internal threat and are less constrained in their dealings with their populations. This repression increases grievances, leading dissidents to engage in strategies of dissent other than civil war. The authortests three implications of this argument-that states in more hierarchical relationships will experience civil war at lower rates, be more repressive, and experience other forms of dissent at higher rates-and finds strong support for it.
Between 1956 and 1971, the Federal Bureau of Investigation (FBI) operated five counterintelligence programs (COINTELPROs) designed to repress a range of threats to the status quo. This article examines more than twelve thousand pages of memos related to FBI programs against white hate groups (mostly the Ku Klux Klan) and the New Left in an effort to gain insight into the Bureau's repression of left- and right- wing targets. The article's goals are both general and historically specific: First, to introduce a two-dimensional typology to organize and categorize repressive acts generally and then to use this typology to examine the patterning of repressive acts across the COINTELPROs. This approach allows for the uncovering of distinct overarching strategies applied to left- versus right-wing targets. These strategies are emergent in the sense that they are not apparent from a textual analysis of Bureau memos or through a comparison of the outcomes of each COINTELPRO. Recognition of these emergent strategies provides insight into the complex, ambiguous relationship that the FBI had with both the civil rights movement and the Klan.
We consider the rigid monoidal category of character sheaves on a smooth commutative group scheme
over a finite field
, and expand the scope of the function-sheaf dictionary from connected commutative algebraic groups to this setting. We find the group of isomorphism classes of character sheaves on
, and show that it is an extension of the group of characters of
by a cohomology group determined by the component group scheme of
. We also classify all morphisms in the category character sheaves on
. As an application, we study character sheaves on Greenberg transforms of locally finite type Néron models of algebraic tori over local fields. This provides a geometrization of quasicharacters of
A large literature has demonstrated that international action can promote the resolution of civil wars. However, international actors do not wait until violence starts to seek to manage conflicts. This article considers the ways in which the United Nations Security Council (UNSC) reduces the propensity for self-determination movements to escalate to civil war, through actions that directly pertain to the disputing actors or that indirectly shape actor incentives. It examines the relationship between the content of UNSC resolutions in all self-determination disputes from 1960 to 2005 and the onset of armed conflict in the disputes. The study finds that diplomatic actions that directly address disputes reduce the likelihood of armed conflict, and that military force and sanctions have more indirect preventive effects.
Quantitative studies of conflict analyze either civil or interstate war. While there may be observable differences between civil and interstate wars, theories of conflict focus on phenomena—such as information asymmetries, commitment problems, and issue divisibility—that should explain both conflicts within and between states. In analyses of conflict onset, duration, and outcome combining civil and interstate wars, we find most variables have similar effects on both “types” of war. We thus question whether there is any justification for separate study of war types.
To categorise records according to primary cardiac diagnosis in the United Kingdom Central Cardiac Audit Database in order to add this information to a risk adjustment model for paediatric cardiac surgery.
Codes from the International Paediatric Congenital Cardiac Code were mapped to recognisable primary cardiac diagnosis groupings, allocated using a hierarchy and less refined diagnosis groups, based on the number of functional ventricles and presence of aortic obstruction.
A National Clinical Audit Database.
Children undergoing cardiac interventions: the proportions for each diagnosis scheme are presented for 13,551 first patient surgical episodes since 2004.
In Scheme 1, the most prevalent diagnoses nationally were ventricular septal defect (13%), patent ductus arteriosus (10.4%), and tetralogy of Fallot (9.5%). In Scheme 2, the prevalence of a biventricular heart without aortic obstruction was 64.2% and with aortic obstruction was 14.1%; the prevalence of a functionally univentricular heart without aortic obstruction was 4.3% and with aortic obstruction was 4.7%; the prevalence of unknown (ambiguous) number of ventricles was 8.4%; and the prevalence of acquired heart disease only was 2.2%. Diagnostic groups added to procedural information: of the 17% of all operations classed as “not a specific procedure”, 97.1% had a diagnosis identified in Scheme 1 and 97.2% in Scheme 2.
Diagnostic information adds to surgical procedural data when the complexity of case mix is analysed in a national database. These diagnostic categorisation schemes may be used for future investigation of the frequency of conditions and evaluation of long-term outcome over a series of procedures.
A number of pragmatic trials have cast doubt on the concept of ‘atypicality’ in relation to antipsychotic drugs, and some commentators have argued that the dichotomy between ‘typical’ (‘first-generation’) and ‘atypical’ ('second-generation’) compounds is artificial and should be abandoned, leaving the entire class of antipsychotics available for consideration in more individualised treatment planning. However, younger psychiatrists now gain little or no experience in the use of older antipsychotics. This is the first of two articles addressing practical issues for consideration in prescribing the older antipsychotics available in the UK. It covers background, including the fundamental clinical action of antipsychotics, the nature of drug licensing and identification of pharmacological parameters that may be of value in prescribing decisions, and discusses the phenothiazines: chlorpromazine, promazine, levomepromazine, pericyazine, perphenazine, trifluoperazine and prochlorperazine.