Polymorphism in Sulfadimidine/4-Aminosalicylic Acid Cocrystals: Solid-State Characterization and Physicochemical Properties

Polymorphism of crystalline drugs is a common phenomenon. However, the number of reported polymorphic cocrystals is very limited. In this work, the synthesis and solid-state characterization of a polymorphic cocrystal composed of sulfadimidine (SD) and 4-aminosalicylic acid (4-ASA) is reported for the first time. By liquid-assisted milling, the SD:4-ASA 1:1 form I cocrystal, the structure of which has been previously reported, was formed. By spray drying, a new polymorphic form (form II) of the SD:4-ASA 1:1 cocrystal was discovered which could also be obtained by solvent evaporation from ethanol and acetone. Structure determination of the form II cocrystal was calculated using high-resolution X-ray powder diffraction. The solubility of the SD:4-ASA 1:1 cocrystal was dependent on the pH and predicted by a model established for a two amphoteric component cocrystal. The form I cocrystal was found to be thermodynamically more stable in aqueous solution than form II, which showed transformation to form I. Dissolution studies revealed that the dissolution rate of SD from both cocrystals was enhanced when compared with a physical equimolar mixture and pure SD.

Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Geographical differences in first acquisition of Pseudomonas aeruginosa in cystic fibrosis

RATIONALE: Risk of infection with Pseudomonas aeruginosa in cystic fibrosis (CF) may be associated with environmental factors.

OBJECTIVES: To determine whether residential location is associated with risk of first acquisition of P. aeruginosa.

METHODS: We performed bronchoalveolar lavage and upper airway cultures in children newly diagnosed with CF to identify infection with P. aeruginosa during infancy and early childhood. Children were assessed according to their residence in a regional or metropolitan area. Multilocus sequence typing was used to determine P. aeruginosa genotype. An environmental questionnaire was also administered.

MEASUREMENTS AND MAIN RESULTS: A total of 105 of 120 (87.5%) infants diagnosed with CF were included in this study. Diagnosis in 65 infants (61.9%) followed newborn screening at mean age of 4.6 weeks. Sixty subjects (57.1%) were homozygous ΔF508, and 47 (44.8%) were female. Fifty-five (52.3%) infants were regional, of whom 26 (47.3%), compared with 9 of 50 (18.0%) metropolitan children, acquired infection with P. aeruginosa (odds ratio, 4.084; 95% confidence interval, 1.55-11.30). Age at acquisition was similar (regional: median, 2.31 yr; range, 0.27-5.96 yr; metropolitan: median, 3.10 yr, range, 0.89-3.70 yr). Strain typing identified P. aeruginosa genotypes often encountered in different ecological settings and little evidence of cross-infection. Ninety questionnaires (85.7%) were completed. Those who acquired P. aeruginosa were more likely to be living in a household that used water sprinkler systems (P = 0.032), but no differences were identified to explain increased risk of acquisition of P. aeruginosa in regional children.

CONCLUSIONS: Geographical difference in residence of children with CF was associated with increased risk of first acquisition of P. aeruginosa, usually with strains associated with the environment rather than with cross-infection.

Risk, Regulation and the Reintegration of Sexual Offenders

Media reporting of and public concern about sexual offending, particularly relating to children, affects and reflects political, policy and organisational responses to those convicted of such crimes. The development of regulatory policies on sexual offending has taken place within a highly emotive and overtly politicized public and policy discourse. This chapter charts the various ways in which the risks imagined or posed by sexual offenders have been conceptualised within public discourses and regulated and managed under the legislative and organisational ‘risk paradigm.’ Ultimately, it argues that risk-based responses to sexual offending are at best uncertain in their effects and at worst counterproductive, in that they often reduce the potential for successful reintegration. In seeking to look ‘beyond risk’, the chapter also explores the usefulness of restorative and related practices in supporting sex offender reintegration aimed at the primary and secondary levels of harm prevention.

Restorative Justice and Sex Offending

This essay examines the origins and uses of restorative justice with sexual offending and the contemporary challenges and controversies surrounding this. It charts the range of ad hoc initiatives which have sought to apply a restorative form of intervention with violent or sexual offending from first time and ‘acquaintance’ rape as well as young sexual abusers to high risk sexual offenders in the form of circles of support and accountability. Such schemes are often presented as a counter to the failings of retributive forms of justice and are premised on Braithwaite’s (1989) notion of ‘reintegrative shaming’ that seek to reintegrate offenders into the community. Critics of restorative justice traditionally put forward a number of core objectives when restorative justice is applied to serious forms of offending such as sexual offending. The essay also sets out and seeks to counter these principal challenges and how they may be overcome. For the most part, however, restorative justice has failed to reach its potential as a fully fledged sentencing rationale in being applied as a mainstream response to a wide range of offending including that at the higher end of the spectrum. The essay also seeks to examine barriers to restorative justice within contemporary penal policy and to highlight some of the most controversial applications of the restorative paradigm including those related to clergy sexual abuse. It concludes by offering some thoughts on the future of restorative justice as a mainstream responses to serious forms of offending.

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Depicting Characters and danced Narratives: Handel, 'The Italian troupe', and Marie Sallé

Handel’s London career afforded opportunities for responding to dancers working in distinct styles of movement—most notably the Italian troupe resident at the King’s Theatre in 1726-27, and Marie Sallé at Covent Garden in 1734-35. By studying the dances from Admeto (1727) and Ariodante (1735), this paper will explore Handel's response to the serious and grotesque styles, as well as to the character and narrative modes.

Criminal Justice in Transition: The Northern Ireland Context

This book represents a critical examination of key aspects of crime and criminal justice in Northern Ireland which will have resonance elsewhere. It considers the core aspects of criminal justice policymaking in Northern Ireland which are central to the process of post-conflict transition, including reform of policing, judicial decision-making and correctional services such as probation and prisons. It examines contemporary trends in criminal justice in Northern Ireland as related to various dimensions of crime relating to female offenders, young offenders, sexual and violent offenders, race and criminal justice, community safety and restorative justice. The book also considers the extent to which crime and criminal justice issues in Northern Ireland are being affected by the broader processes of ‘policy transfer’, globalisation and transnationalism and the extent to which criminal justice in Northern Ireland is divergent from the other jurisdictions in the United Kingdom. Written by leading international authorities in the field, the book offers a snapshot of the cutting edge of critical thinking in criminal justice practice and transitional justice contexts.