The Association of Genetic and Dietary Exposures with Gestational Diabetes Mellitus Risk

Background: Although lifestyle modification is the cornerstone of GDM management, the evidence base on which dietary recommendations to prevent GDM is diverse and has not been synthesized in a consistent fashion. Objectives: The overall objective of this thesis is to assess the relationship of diet patterns, foods, and nutrients with GDM risk. Specifically, we seek to: 1) Quantify the relationship between dietary factors and GDM and metabolic disorders of pregnancy; 2) Compare the effects of dietary factors on markers of glycemic control, such as fasting glucose, fasting insulin, HbA1c, and the homeostatic model assessment for insulin resistance (HOMA-IR); 3) Assess the association and interaction between carbohydrate quality, and genetic load on the risk of developing GDM using data from 2 prospective birth cohort studies. Methods: We follow the approach set by the Cochrane Group’s Handbook for Systematic Review of Interventions to conduct meta-analyses and assess the quality of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. We analyze prospective cohort data of 2,504 women from the CHILD and START studies, which enrolled women of White-Caucasian and South Asian ethnicity. We quantify carbohydrate quality by deriving the glycemic index and load (GL), and total and added sugar intake. We construct a gene score using 102 loci that were previously associated with type 2 diabetes in genome-wide association studies. Results: 1) The meta-analysis identified high-quality evidence that red meat increases GDM risk; however, most associations of foods and nutrients with GDM and other metabolic disorders of pregnancy are of low-quality; 2) The network meta-analysis identified that most dietary interventions given with gestational weight gain advice will lower fasting glucose; 3) In South Asians, a high GL coupled with a high genetic load increased GDM risk six fold, but a high total sugar intake in the presence of a high genetic load reduced GDM risk. This paradoxical finding may be explained by a high correlation between total sugars and other healthy foods. Conclusions: Few valid associations between dietary factors and GDM risk exist. GL and total sugars may modify the genetic risk of GDM in South Asians but not in White-Caucasians. Further research is needed to determine effective interventions that can assist women in adopting healthier eating habits during pregnancy.ThesisDoctor of Philosophy (PhD)Gestational diabetes mellitus (GDM) is glucose intolerance that first appears during pregnancy. Although lifestyle modification is the cornerstone of GDM management, dietary recommendations for GDM prevention are sparse. The overarching objective of this thesis is to describe the relationships between diets, foods, and nutrients and GDM and metabolic disorders of pregnancy and to understand whether carbohydrate quality can modify a genetic predisposition to diabetes. In the systematic literature reviews, high-quality evidence showed that red meat increases GDM risk. Moderate-quality evidence showed that several dietary factors also influence the risk of GDM and metabolic disorders of pregnancy, but most of the existing evidence is of low-quality. More high-quality studies are needed before dietary interventions can be implemented In our genetic study, we observed that carbohydrate quality may modify the genetic risk of diabetes in South Asians but not in White-Caucasians and conclude that carbohydrate quality may provide only a limited assessment of overall diet quality

Stability and error analysis for a diffuse interface approach to an advection-diffusion equation on a moving surface

In this paper we analyze a fully discrete numerical scheme for solving a parabolic PDE on a moving surface. The method is based on a diffuse interface approach that involves a level set description of the moving surface. Under suitable conditions on the spatial grid size, the time step and the interface width we obtain stability and error bounds with respect to natural norms. Furthermore, we present test calculations that confirm our analysis

A novel ciprofloxacin-resistant subclade of H58 Salmonella Typhi is associated with fluoroquinolone treatment failure.

The interplay between bacterial antimicrobial susceptibility, phylogenetics and patient outcome is poorly understood. During a typhoid clinical treatment trial in Nepal, we observed several treatment failures and isolated highly fluoroquinolone-resistant Salmonella Typhi (S. Typhi). Seventy-eight S. Typhi isolates were genome sequenced and clinical observations, treatment failures and fever clearance times (FCTs) were stratified by lineage. Most fluoroquinolone-resistant S. Typhi belonged to a specific H58 subclade. Treatment failure with S. Typhi-H58 was significantly less frequent with ceftriaxone (3/31; 9.7%) than gatifloxacin (15/34; 44.1%)(Hazard Ratio 0.19, p=0.002). Further, for gatifloxacin-treated patients, those infected with fluoroquinolone-resistant organisms had significantly higher median FCTs (8.2 days) than those infected with susceptible (2.96) or intermediately resistant organisms (4.01)(pS. Typhi clade internationally, but there are no data regarding disease outcome with this organism. We report an emergent new subclade of S. Typhi-H58 that is associated with fluoroquinolone treatment failure

A new primary dental care service compared with standard care for child and family to reduce the re-occurrence of childhood dental caries (Dental RECUR): study protocol for a randomised controlled trial

Background: In England and Scotland, dental extraction is the single highest cause of planned admission to the hospital for children under 11 years. Traditional dental services have had limited success in reducing this disease burden. Interventions based on motivational interviewing have been shown to impact positively dental health behaviours and could facilitate the prevention of re-occurrence of dental caries in this high-risk population. The objective of the study is to evaluate whether a new, dental nurse-led service, delivered using a brief negotiated interview based on motivational interviewing, is a more cost-effective service than treatment as usual, in reducing the re-occurrence of dental decay in young children with previous dental extractions. Methods/Design: This 2-year, two-arm, multicentre, randomised controlled trial will include 224 child participants, initially aged 5 to 7 years, who are scheduled to have one or more primary teeth extracted for dental caries under general anaesthesia (GA), relative analgesia (RA: inhalation sedation) or local anaesthesia (LA). The trial will be conducted in University Dental Hospitals, Secondary Care Centres or other providers of dental extraction services across the United Kingdom. The intervention will include a brief negotiated interview (based on the principles of motivational interviewing) delivered between enrolment and 6 weeks post-extraction, followed by directed prevention in primary dental care. Participants will be followed up for 2 years. The main outcome measure will be the dental caries experienced by 2 years post-enrolment at the level of dentine involvement on any tooth in either dentition, which had been caries-free at the baseline assessment. Discussion: The participants are a hard-to-reach group in which secondary prevention is a challenge. Lack of engagement with dental care makes the children and their families scheduled for extraction particularly difficult to recruit to an RCT. Variations in service delivery between sites have also added to the challenges in implementing the Dental RECUR protocol during the recruitment phase. Trial registration: ISRCTN24958829 (date of registration: 27 September 2013), Current protocol version: 5.0

Methyl-donor depletion of head and neck cancer cells in vitro establishes a less aggressive tumour cell phenotype

PURPOSE: DNA methylation plays a fundamental role in the epigenetic control of carcinogenesis and is, in part, influenced by the availability of methyl donors obtained from the diet. In this study, we developed an in-vitro model to investigate whether methyl donor depletion affects the phenotype and gene expression in head and neck squamous cell carcinoma (HNSCC) cells. METHODS: HNSCC cell lines (UD-SCC2 and UPCI-SCC72) were cultured in medium deficient in methionine, folate, and choline or methyl donor complete medium. Cell doubling-time, proliferation, migration, and apoptosis were analysed. The effects of methyl donor depletion on enzymes controlling DNA methylation and the pro-apoptotic factors death-associated protein kinase-1 (DAPK1) and p53 upregulated modulator of apoptosis (PUMA) were examined by quantitative-PCR or immunoblotting. RESULTS: HNSCC cells cultured in methyl donor deplete conditions showed significantly increased cell doubling times, reduced cell proliferation, impaired cell migration, and a dose-dependent increase in apoptosis when compared to cells cultured in complete medium. Methyl donor depletion significantly increased the gene expression of DNMT3a and TET-1, an effect that was reversed upon methyl donor repletion in UD-SCC2 cells. In addition, expression of DAPK1 and PUMA was increased in UD-SCC2 cells cultured in methyl donor deplete compared to complete medium, possibly explaining the observed increase in apoptosis in these cells. CONCLUSION: Taken together, these data show that depleting HNSCC cells of methyl donors reduces the growth and mobility of HNSCC cells, while increasing rates of apoptosis, suggesting that a methyl donor depleted diet may significantly affect the growth of established HNSCC

Efficacy and Safety of Abacavir/Lamivudine/Zidovudine Plus Tenofovir in HBV/HIV-1 Coinfected Adults: 48-Week Data

In HBV/HIV-coinfected patients, the risk of end-stage liver disease and death is increased. This open-label, prospective, pilot study evaluated abacavir/lamivudine/zidovudine twice daily plus tenofovir once daily in HBV/HIV-coinfected antiretroviral-naïve subjects. Nine adults (8 males) enrolled, with baseline mean HIV-1 RNA = 4.5 log10 copies/mL, HBV DNA = 9.0 log10 copies/mL, and median CD4 count =158 cells/mm3. No subject had baseline ALT >5x ULN

Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons

Metformin is a widely prescribed drug used to treat type-2 diabetes, although recent studies show it has wide ranging effects to treat other diseases. Animal and retrospective human studies indicate that Metformin treatment is neuroprotective in Parkinson’s Disease (PD), although the neuroprotective mechanism is unknown, numerous studies suggest the beneficial effects on glucose homeostasis may be through AMPK activation. In this study we tested whether or not AMPK activation in dopamine neurons was required for the neuroprotective effects of Metformin in PD. We generated transgenic mice in which AMPK activity in dopamine neurons was ablated by removing AMPK beta 1 and beta 2 subunits from dopamine transporter expressing neurons. These AMPK WT and KO mice were then chronically exposed to Metformin in the drinking water then exposed to MPTP, the mouse model of PD. Chronic Metformin treatment significantly attenuated the MPTP-induced loss of Tyrosine Hydroxylase (TH) neuronal number and volume and TH protein concentration in the nigrostriatal pathway. Additionally, Metformin treatment prevented the MPTP-induced elevation of the DOPAC:DA ratio regardless of genotype. Metformin also prevented MPTP induced gliosis in the Substantia Nigra. These neuroprotective actions were independent of genotype and occurred in both AMPK WT and AMPK KO mice. Overall, our studies suggest that Metformin’s neuroprotective effects are not due to AMPK activation in dopaminergic neurons and that more research is required to determine how metformin acts to restrict the development of PD

CPPN2GAN: Combining Compositional Pattern Producing Networks and GANs for Large-Scale Pattern Generation

Generative Adversarial Networks (GANs) are proving to be a powerful indirect genotype-to-phenotype mapping for evolutionary search, but they have limitations. In particular, GAN output does not scale to arbitrary dimensions, and there is no obvious way of combining multiple GAN outputs into a cohesive whole, which would be useful in many areas, such as the generation of video game levels. Game levels often consist of several segments, sometimes repeated directly or with variation, organized into an engaging pattern. Such patterns can be produced with Compositional Pattern Producing Networks (CPPNs). Specifically, a CPPN can define latent vector GAN inputs as a function of geometry, which provides a way to organize level segments output by a GAN into a complete level. This new CPPN2GAN approach is validated in both Super Mario Bros. and The Legend of Zelda. Specifically, divergent search via MAP-Elites demonstrates that CPPN2GAN can better cover the space of possible levels. The layouts of the resulting levels are also more cohesive and aesthetically consistent.Comment: GECCO 2020. arXiv admin note: text overlap with arXiv:2004.0015

A INTERPELAÇÃO DAS MULHERES INDÍGENAS SOBRE A CONSERVAÇÃO DE SEUS TERRITÓRIOS

The increase of socioenvironmental crises worldwide claims the understanding of indigenous peoples and their knowledge to deal with it. The indigenous women have focused in present their body-territories as a crucial part of the conservation of nature since the relationship between body and territory from their perspective is different. Ideas and initiatives of the women’s indigenous movement to protect their territories, body-territories-spirits, and nature are presented. The results of these initiatives are expressed in collective engagements inside and outside their lands, resisting to guarantee their lifestyle and well-being, reporting a lack of rights, and episodes of violence. Therefore, disclosure and maximizing local and global initiatives of the indigenous movement to protect their body-territory and nature from environmental crises through collective engagement is essential worldwide. In summary, indigenous women are organized and promote ideas based on their understanding of the human-nature relationship and the importance of immediate actions.El aumento de las crisis socioambientales en el mundo requiere la comprensión de los pueblos indígenas y sus conocimientos para combatirlas. Las mujeres indígenas han presentado sus cuerpos-territorios como parte crucial de la conservación de la naturaleza, ya que la relación entre cuerpo y territorio desde su perspectiva es diferente. Así, se presentan ideas e iniciativas del movimiento de mujeres indígenas para proteger sus territorios, cuerpos-territorios-espíritus y la naturaleza. Los resultados de estas iniciativas se expresan en compromisos colectivos dentro y fuera de sus tierras, resistiendo para garantizar su estilo de vida y bienestar, denunciando la falta de derechos y episodios de violencia. Difundir y aprovechar las iniciativas locales y globales del movimiento indígena para proteger su cuerpo-territorio y la naturaleza de las crisis ambientales a través del compromiso colectivo es esencial en todo el mundo. Las mujeres indígenas se organizan y promueven ideas basadas en su comprensión de la relación hombre-naturaleza y la importancia de la acción inmediata.O aumento das crises socioambientais no mundo exige a compreensão dos povos indígenas e de seu conhecimento para combatê-los. As mulheres indígenas têm apresentado seus corpos-territórios como parte crucial para conservação da natureza, pois a relação entre corpo e território sob sua perspectiva é diferente. Assim, ideias e iniciativas do movimento de mulheres indígenas para proteger seus territórios, corpos-territórios-espíritos e a natureza são apresentadas. Resultados dessas iniciativas se expressam em engajamentos coletivos dentro e fora de suas terras, resistindo para garantir seu estilo de vida e bem-estar, denunciando a falta de direitos e os episódios de violência. Divulgar e potencializar as iniciativas locais e globais do movimento indígena para proteger seu corpo-território e natureza das crises ambientais por meio do engajamento coletivo é essencial em todo o mundo. Mulheres indígenas organizam-se e promovem ideias a partir de sua compreensão sobre a relação ser humano-natureza e da importância de ações imediatas