Persuader: Mobilization of Support

Law reform can be achieved through precedent-setting case law and through legislation. Each is a time-consuming activity with its own stumbling blocks. To establish law through the case method, one must have a fact situation directly on point with the inequity which one is trying to remedy. In many situations the client must be willing to follow through a long process of trial and appeal, instead of settling for a more immediate but incomplete resolution of his problem. The costs of litigation may become an insurmountable problem. Another difficulty with the test case as a vehicle for law reform is the possibility that a decision is rendered for the client in such a way as to avoid decision on the issue to be tested. For example, a case may be decided as a matter of statutory construction so that any constitutional question is avoided

PREPARE manual for nurses : Building trust, promoting health and changing communities

One in every five people in the world is an adolescent and 85% live in low and middle-income countries. Nearly two thirds of premature death and one third of the total disease burden in adults are associated with conditions or behaviour that begin in youth. Among 15-19 year olds, suicide is the second leading cause of death, followed by violence in the community and family. Promoting nurturing relationships between parents and children early in life, good relationships between young people, training in life skills, and reducing access to alcohol and lethal items such as firearms and knives can help prevent violence. More effective and sensitive care for adolescents experiencing violence is needed. Many adolescent health challenges are closely interrelated and successful interventions in one area can lead to positive outcomes in other areas. The World Health Organization reports that among women aged 15-45 years, gender-based violence accounts for more deaths and disability than cancer, malaria and traffic injuries put together. This has become an important factor, which negatively affects girls and women’s reproductive health and wellbeing. This manual was written for the PREPARE school clinics to promote positive relationships through mentoring, role modelling, education, research and empathic service provision so that young people feel valued, respected and can enjoy positive self and peer relationships free from harm

Gut bacterial activity in a cohort of preterm infants in health and disease

Introduction: Randomised controlled trials administering probiotic supplements to preterm infants to prevent sepsis and necrotising enterocolitis are already underway, despite the lack of a robust evidence base of normative values for gut microbiota, bacterial metabolites, and markers of inflammation and immunity. There are increasing calls for observational studies to establish baseline data in these infants. Most of these studies to date have involved the measurement of these analytes individually. In the studies presented in this thesis, we measured a range of stool markers collectively in a cohort of preterm infants in health and disease. Design: 56 infants at <32 week gestation and less than 1500g birth weight were sequentially recruited from all three Glasgow Neonatal Units within week one of life after commencement of enteral feeds. Anthropometric, dietary and treatment data were collected. Stool samples were taken once weekly for the first four weeks, testing: short chain fatty acids; calprotectin, secretory immunoglobulin A; and microbial diversity by temporal temperature gel electrophoresis. Results: Out of 61 live births meeting the study criteria, 56 infants were enrolled in the study, 62.5% of whom were female. 19.6% were between 24-26 weeks gestation, 28% were 26-28 weeks, 30% were 28-30 weeks, and 21% were 30-32 weeks. 5.3% were between 490-600g in birth weight, 17.8% were 600-800g, 21.4% were 801-1000g, 39.2% 1001-1250g, and 16% were between 1251-1500g. Feed regimen was heterogeneous, comprising 5 combinations of maternal, donor and formula milks. The highest social deprivation level as measured by the Carlisle ‘Depcat’ scoring system of level 7 was significantly higher in the study group than Glasgow or Scotland-wide averages. Sepsis rates were low, with a group median of only 1 per infant. Overall mortality: 7%. 32 with any NEC (56%), 20 with Bells’ ≥2a NEC. 8 (14%) with surgically treated NEC, 5 (8%) underwent ileostomy. SCFAs: (n=56) there were no correlations between gestation, weekly totals, feed type, or NEC and SCFA concentration. Acetate and lactate dominated each sample. Few significant changes were noted with respect to NEC, and these were in the less dominant SCFAs: stage 2a NEC showed higher concentrations of propionate in week 4 than week 3, and lower valerate in week 4 than 2. Stage 3b levels of isobutyrate and heptanoate were significantly lower in week 4 than 3. FC: (n=56) there were no significant differences in FC levels between each week in infants with or without NEC, although the former illustrated a trend to lower levels by week 4. There were no significant differences in NEC before and after clinical signs were apparent, or in those before NEC and after stoma formation for stage 3b NEC. However, significantly lower FC levels were noted in stage 3b NEC requiring ileostomy compared to the immediate pre-operative sample. SIgA: (n=34) Levels rose significantly week on week, and were considerably higher in weeks three and four than week one. There were no significant differences in stool SIgA concentration between infants with and without NEC. A significant increase in mean stool SIgA concentration appeared from week 2 to week 3 in NEC infants, and from week 1 to week 2 for those without. For all breastfed preterm neonates (n=6), the level of milk SIgA was significant higher on week 1 (colostrum) than week 2 and week 3. TTGE: (n=22) There was large variability between number (1-17) and species diversity (25-36 different species). Bacterial composition varied largely between the 2 sample points. No difference in species richness or similarity within the 2 feeding groups was observed. 4 bands were identified in >50% of infants. Intra-individual similarity varied greatly and ranged from a similarity index (Cs) of 0% to 66.8%. There was no statistical difference between the similarity indices of the feeding groups or between those with and without NEC. There were no significant correlations between any of the analytes. Conclusions: Only extreme prematurity and extremely low birth weight were associated with NEC, which was at a strikingly high incidence. A limitation was therefore the unexpected onset of severe NEC resulting in prolonged paralytic ileus with low stool production. No correlations were found between analytes, indicating that each set of stool investigations may signify independent physiological, biochemical and immunological gut processes. Despite the severity of NEC, the levels of each analyte were remarkably consistent. High levels of deprivation within the study population may provide the constellation for an as of yet undefined genetic and epigenetic predisposition to NEC in this cohort, similar to that of other illnesses endemic to different geographical areas – notably Multiple Sclerosis in the North East of Scotland – and both follow up of these infants into childhood as well as further analysis of future inborn infants with NEC is planned

Classifying Variants of Undetermined Significance in BRCA2 with Protein Likelihood Ratios

Background: Missense (amino-acid changing) variants found in cancer predisposition genes often create difficulties when clinically interpreting genetic testing results. Although bioinformatics has developed approaches to predicting the impact of these variants, many of these approaches have not been readily applicable in the clinical setting. Bioinformatics approaches for predicting the impact of these variants have not yet found their footing in clinical practice because 1) interpreting the medical relevance of predictive scores is difficult; 2) the relationship between bioinformatics “predictors” (sequence conservation, protein structure) and cancer susceptibility is not understood.Methodology/Principal Findings: We present a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function. We apply the method to a tumor suppressor gene, BRCA2, whose loss of function is important to cancer susceptibility. Protein likelihood ratios are computed for 229 unclassified variants found in individuals from high-risk breast/ovarian cancer families. We map the variants onto a protein structure model, and suggest that a cluster of predicted deleterious variants in the BRCA2 OB1 domain may destabilize BRCA2 and a protein binding partner, the small acidic protein DSS1. We compare our predictions with variant “re-classifications” provided by Myriad Genetics, a biotechnology company that holds the patent on BRCA2 genetic testing in the U.S., and with classifications made by an established medical genetics model [1]. Our approach uses bioinformatics data that is independent of these genetics-based classifications and yet shows significant agreement with them. Preliminary results indicate that our method is less likely to make false positive errors than other bioinformatics methods, which were designed to predict the impact of missense mutations in general.Conclusions/Significance: Missense mutations are the most common disease-producing genetic variants. We present a fast, scalable bioinformatics method that integrates information about protein sequence, conservation, and structure in a likelihood ratio that can be integrated with medical genetics likelihood ratios. The protein likelihood ratio, together with medical genetics likelihood ratios, can be used by clinicians and counselors to communicate the relevance of a VUS to the individual who has that VUS. The approach described here is generalizable to regions of any tumor suppressor gene that have been structurally determined by X-ray crystallography or for which a protein homology model can be built

Unexpected Vulnerability of DPEphos to C-O Activation in the Presence of Nucleophilic Metal Hydrides

C−O bond activation of DPEphos occurs upon mild heating in the presence of [Ru(NHC)2(PPh3)2H2] (NHC=N-heterocyclic carbene) to form phosphinophenolate products. When NHC=IEt2Me2, C−O activation is accompanied by C−N activation of an NHC ligand to yield a coordinated N-phosphino-functionalised carbene. DFT calculations define a nucleophilic mechanism in which a hydride ligand attacks the aryl carbon of the DPEphos C−O bond. This is promoted by the strongly donating NHC ligands which render a trans dihydride intermediate featuring highly nucleophilic hydride ligands accessible. C−O bond activation also occurs upon heating cis-[Ru(DPEphos)2H2]. DFT calculations suggest this reaction is promoted by the steric encumbrance associated with two bulky DPEphos ligands. Our observations that facile degradation of the DPEphos ligand via C−O bond activation is possible under relatively mild reaction conditions has potential ramifications for the use of this ligand in high-temperature catalysis.</p

Pharmacogenetic testing affects choice of therapy among women considering tamoxifen treatment

Abstract Background Pharmacogenetic testing holds major promise in allowing physicians to tailor therapy to patients based on genotype. However, there is little data on the impact of pharmacogenetic test results on patient and clinician choice of therapy. CYP2D6 testing among tamoxifen users offers a potential test case of the use of pharmacogenetic testing in the clinic. We evaluated the effect of CYP2D6 testing in clinical practice to determine whether genotype results affected choice of hormone therapy in a prospective cohort study. Methods Women planning to take or currently taking tamoxifen were considered eligible. Participants were enrolled in an informational session that reviewed the results of studies of CYP2D6 genotype on breast cancer recurrence. CYP2D6 genotyping was offered to participants using the AmpliChip CYP450 Test. Women were classified as either poor, intermediate, extensive or ultra-rapid metabolizers. Results were provided to clinicians without specific treatment recommendations. Follow-up was performed with a structured phone interview 3 to 6 months after testing to evaluate changes in medication. Results A total of 245 women were tested and 235 completed the follow-up survey. Six of 13 (46%) women classified as poor metabolizers reported changing treatment compared with 11 of 218 (5%) classified as intermediate, extensive or ultra-rapid metabolizers (P &lt; 0.001). There was no difference in treatment choices between women classified as intermediate and extensive metabolizers. In multi-variate models that adjusted for age, race/ethnicity, educational status, method of referral into the study, prior knowledge of CYP2D6 testing, the patients' CYP2D6 genotype was the only significant factor that predicted a change in therapy (odds ratio 22.8; 95% confidence interval 5.2 to 98.8). Genetic testing did not affect use of co-medications that interact with CYP2D6. Conclusions CYP2D6 genotype testing led to changes in therapy among poor metabolizers, even in the absence of definitive data that an alternative medicine improved outcomes. Pharmacogenetic testing can affect choice of therapy, even in the absence of definitive data on clinical impact

A Lagerstätte from Australia provides insight into the nature of Miocene mesic ecosystems

Reduced precipitation in the Miocene triggered the geographic contraction of rainforest ecosystems around the world. In Australia, this change was particularly pronounced; mesic rainforest ecosystems that once dominated the landscape transformed into the shrublands, grasslands, and deserts of today. A lack of well-preserved fossils has made it difficult to understand the nature of Australian ecosystems before the aridification. Here, we report on an exceptionally well-preserved rainforest biota from New South Wales, Australia. This Konservat-Lagerstätte hosts a rich diversity of microfossils, plants, insects, spiders, and vertebrate remains preserved in goethite. We document evidence for several species interactions including predation, parasitism, and pollination. The fossils are indicative of an oxbow lake in a mesic rainforest and suggest that rainforest distributions have shifted since the Miocene. The variety of fossils preserved, together with high fidelity of preservation, allows for unprecedented insights into the mesic ecosystems that dominated Australia during the Miocene