Lewis Acid Chemistry of Some Sulphur-Nitrogen Compounds

The compound S₄N₄ has been shown to react with the Lewis acids SbCl₅, SbF₅ and AsF₅ to produce the previously unreported cyclotetra-thiazyl dication, S₄N₄²⁺, in the form of the salts S₄N₄(SbCl₆)₂, S₄N₄(SbF₆)₂, S₄N₄(AsF₆)₂.xSO₂ and S₄N₄(Sb₃F₁₄)(SbF₆). A reaction sequence for the preparation of S₄N₄(SbCl₆)₂ has been suggested and the infrared and Raman spectra for each of the salts is reported as well as the crystal structures of the S₄N₄(SbCl₆)₂ and S₄N₄(Sb₃F₁₄)(SbF₆) salts. A brief investigation of the reaction of S₄N₄ with the Lewis acids PF₅ and PCl₅ produced in the S₄N₄/PF₅ system the new molecular adduct, S₄N₄PF₅, whereas the reaction of S₄N₄ with PCl₅ yielded a complex mixture of products, composed of phosphonitrilic chlorides. The chemistry of trichlorocyclotrithiazene with SbCl₅ has been studied. It has been determined for the first time that S₃H₃Cl₃ when oxidized by SbCl₅ produces the S₄N₄(SbCl₆)₂ salt with the compounds S₄N₄ SbCl₅ and S₅N₅ (SbCl₆) isolated as intermediates formed during the production of the S₄N₄²⁺ dication. The crystal structures of both Si₄N₄ SbCl₅ and S₅N₅(SbCl₆) are reported in this thesis. In contrast, the fluoride, trifluorocyclotrithiazene, S₃N₃F₃, when combined with the Lewis acids SbF₅, AsF₅ and SO₃ was not oxidized but rather simple fluoride ion abstraction occurred to yield the thiazyl salts SN(Sb₂F₁₁), SN(AsF₆) and SN(SO₃F). For the first time, the chemistry of the sulphur imides with Lewis acids of oxidative capability has been studied. Cyclotetrasulphurtetraimide, S₄N₄H₄, reacted readily with SbCl₅ to yield the S₄N₄²⁺ salt, S₄N₄(SbCl₆)₂. The compound S₄N₄ SbCl₅ has been shown to be an intermediate formed during the oxidation of S₄N₄H₄ with SbCl₅. Cycloheptasulphurimide, S₇NH, and 1,4-cyclohexasulphurdiimide, 1,4-S₆N₂H₂, produced the previously unknown dithionitronium ion, S₂N⁺, when treated with SbCl₅. Infrared and Raman spectra for the S₂N(SbCl₆) are reported as well as the crystal structure. In a limited investigation, the compound Cl₃PNPCl₃(PCl₆), has been isolated from the reaction of S₇NH with PCl₅. The crystal structure of the trichlorp[(trichlorophosphoranylidene)amino] phosphorus (V) hexachlorophosphate is reported in this work.Doctor of Philosophy (PhD

Protocol investigating the clinical outcomes and cost-effectiveness of cognitive–behavioural therapy delivered remotely for unscheduled care users with health anxiety: randomised controlled trial

Background Health anxiety and medically unexplained symptoms cost the National Health Service (NHS) an estimated £3 billion per year in unnecessary costs with little evidence of patient benefit. Effective treatment is rarely taken up due to issues such as stigma or previous negative experiences with mental health services. An approach to overcome this might be to offer remotely delivered psychological therapy, which can be just as effective as face-to-face therapy and may be more accessible and suitable. Aims To investigate the clinical outcomes and cost-effectiveness of remotely delivered cognitive–behavioural therapy (CBT) to people with high health anxiety repeatedly accessing unscheduled care (trial registration: NCT02298036). Method A multicentre randomised controlled trial (RCT) will be undertaken in primary and secondary care providers of unscheduled care across the East Midlands. One hundred and forty-four eligible participants will be equally randomised to receive either remote CBT (6–12 sessions) or treatment as usual (TAU). Two doctoral research studies will investigate the barriers and facilitators to delivering the intervention and the factors contributing to the optimisation of therapeutic outcome. Results This trial will be the first to test the clinical outcomes and costeffectiveness of remotely delivered CBT for the treatment of high health anxiety. Conclusions The findings will enable an understanding as to how this intervention might fit into a wider care pathway to enhance patient experience of care

Minocycline as a re-purposed anti-Wolbachia macrofilaricide: superiority compared with doxycycline regimens in a murine infection model of human lymphatic filariasis

Lymphatic filariasis and onchocerciasis are parasitic helminth diseases, which cause severe morbidities such as elephantiasis, skin disease and blindness, presenting a major public health burden in endemic communities. The anti-Wolbachia consortium (A·WOL: http://www.a-wol.com/) has identified a number of registered antibiotics that target the endosymbiotic bacterium, Wolbachia, delivering macrofilaricidal activity. Here we use pharmacokinetics/pharmacodynamics (PK/PD) analysis to rationally develop an anti-Wolbachia chemotherapy by linking drug exposure to pharmacological effect. We compare the pharmacokinetics and anti-Wolbachia efficacy in a murine Brugia malayi model of minocycline versus doxycycline. Doxycycline exhibits superior PK in comparison to minocycline resulting in a 3-fold greater exposure in SCID mice. Monte-Carlo simulations confirmed that a bi-daily 25–40 mg/Kg regimen is bioequivalent to a clinically effective 100–200 mg/day dose for these tetracyclines. Pharmacodynamic studies showed that minocycline depletes Wolbachia more effectively than doxycycline (99.51% vs. 90.35%) after 28 day 25 mg/Kg bid regimens with a more potent block in microfilarial production. PK/PD analysis predicts that minocycline would be expected to be 1.7 fold more effective than doxycycline in man despite lower exposure in our infection models. Our findings warrant onward clinical investigations to examine the clinical efficacy of minocycline treatment regimens against lymphatic filariasis and onchocerciasis

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Pornography addiction in adults: a systematic review of definitions and reported impact

Self-perceived pornography addiction (SPPA) has increasingly emerged as a concept in research and popular culture, and commentators warn of the reported negative impact that it can have. Despite this, “pornography addiction” is not a formally recognized disorder and there is disagreement among researchers regarding its definition or even its existence. Therefore, how SPPA is operationalized often varies, and this can significantly influence the conclusions made about its impact. This paper aimed to examine how SPPA is commonly operationalised, and its supposed impact, through a systematic review of quantitative and qualitative peer-reviewed literature. We found that SPPA is most frequently operationalized as excessive pornography use, and that reported negative consequences of SPPA included social isolation and relationship breakdowns. However, limitations within the primary studies reviewed (including lack of representative samples and inadequate measurements of SPPA) significantly limit the strength of the conclusions that can be drawn regarding the nature, phenomenology, or impact of self-perceived pornography addiction

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

A systematic environmental intervention, nidotherapy, given to whole communities: protocol for a randomised stepped-wedge trial

Environmental changes can be positive in mental illness. Systematic, planned and guided environmental change in all its aspects is called nidotherapy. It has shown some benefit but has not been extended to whole communities. A cluster-randomised step-wedge trial is planned in six village communities in Nottinghamshire, England, covering an adult population of 400. Adults in six villages will be offered a full personal environmental assessment followed by agreed change in different 3-month periods over the course of 1 year. All six villages have populations between 51 and 100 residents and are similar demographically. Assessments of mental health, personality status, social function, quality of life and environment satisfaction will be made. After the initial baseline period of 3 months, two villages will be randomised to nidotherapy for 3 months, a further two at 6 months and the last two at 9 months. The primary outcome will be change in social function; secondary outcomes include health-related quality of life, anxiety and depressive symptoms, personality status, costs of nidotherapy and life satisfaction. Adverse events will also be recorded. The analysis will be carried out using a multimodal statistical approach examining (a) the change in scores of the primary outcome (social function); (b) change in scores of all secondary outcomes, including costs; and (c) changes in environmental satisfaction. The findings of this study should help to determine whether nidotherapy has a place in the early detection and treatment of mental pathology.N/