Radiocarbon ages, grain sizes, paleomagentic properties and XRF data of Lake Nam Co sediments, Tibetan Plateau

In September 2008 several cores (68 cm-115 cm length) (water depth: 93 m) were retrieved from Lake Nam Co (southern-central Tibetan Plateau; 4718 m a.s.l.). This study focuses on the interpretation of high-resolution (partly 0.2 cm) data from three gravity cores and the upper part of a 10.4 m long piston core, i.e., the past 4000 cal BP in terms of lake level changes, hydrological variations in the catchment area and consequently variations in monsoon strength. A wide spectrum of sedimentological, geochemical and mineralogical investigations was carried out. Results are presented for XRF core-scans, grain size distribution, XRD-measurements and SEM-image analyses. These data are complemented by an age-depth model using 210Pb and 137Cs analyses as well as eleven AMS-14C-ages. This model is supported by excellent agreement between secular variations determined on one of the gravity cores to geomagnetic field models. This is a significant improvement of the chronology as most catchments of lacustrine systems on the Tibetan Plateau contain carbonates resulting in an unknown reservoir effect for radiocarbon dates. The good correlation of our record to the geomagnetic field models confirms our age-depth model and indicates only insignificant changes in the reservoir effect throughout the last 4 ka. High (summer-) monsoonal activity, i.e. moist environmental conditions, was detected in our record between approximately 4000 and 1950 cal BP as well as between 1480 and 1200 cal BP. Accordingly, lower monsoon activity prevails in periods between the two intervals and thereafter. This pattern shows a good correlation to the variability of the Indian Ocean Summer Monsoon (IOSM) as recorded in a peat bog ~1000 km in NE direction from Lake Nam Co. This is the first time that such a supra regional homogenous monsoon activity is shown on the Tibetan Plateau and beyond. Finally our data show a significant lake level rise after the Little Ice Age (LIA) in Lake Nam Co which is suggested to be linked to glacier melting in consequence of rising temperatures occurring on the whole Tibetan Plateau during this time.

Eating habits of a population undergoing a rapid dietary transition: portion sizes of traditional and non-traditional foods and beverages consumed by Inuit adults in Nunavut, Canada

Background: To determine the portion sizes of traditional and non-traditional foods being consumed by Inuit adults in three remote communities in Nunavut, Canada. Methods. A cross-sectional study was carried out between June and October, 2008. Trained field workers collected dietary data using a culturally appropriate, validated quantitative food frequency questionnaire (QFFQ) developed specifically for the study population. Results: Caribou, muktuk (whale blubber and skin) and Arctic char (salmon family), were the most commonly consumed traditional foods; mean portion sizes for traditional foods ranged from 10 g for fermented seal fat to 424 g for fried caribou. Fried bannock and white bread were consumed by >85% of participants; mean portion sizes for these foods were 189 g and 70 g, respectively. Sugar-sweetened beverages and energy-dense, nutrient-poor foods were also widely consumed. Mean portion sizes for regular pop and sweetened juices with added sugar were 663 g and 572 g, respectively. Mean portion sizes for potato chips, pilot biscuits, cakes, chocolate and cookies were 59 g, 59 g, 106 g, 59 g, and 46 g, respectively. Conclusions: The present study provides further evidence of the nutrition transition that is occurring among Inuit in the Canadian Arctic. It also highlights a number of foods and beverages that could be targeted in future nutritional intervention programs aimed at obesity and diet-related chronic disease prevention in these and other Inuit communities.

Test sizes of planktic foraminifera from the South Atlantic

Geographical size distribution within entire Holocene foraminiferal assemblages is related to global environmental gradients such as temperature, primary productivity, and environmental variability. This study demonstrates that these correlations are also recognizable in late Quaternary assemblages from three locations in the South Atlantic on temporal and latitudinal scales. The size response to temporal paleoenvironmental changes during glacial-interglacial cycles mimics the geographic Holocene size variability. The amplitude of size variability is directly related to the amplitude of the climatic fluctuations as shown by the stable size-temperature relationship over time. The documented changes in the assemblage size are caused by species replacement and intraspecific size variability. The relative importance of these processes depends on the environmental setting. Species have been shown to reach their maximum size and abundance under certain optimum conditions and decrease in size if environmental conditions differ from these optima. We confirm that late Quaternary species sizes were largest at paleotemperatures identical to Holocene ones.

(Table 1) Bulk Fe isotope values and pyrite framboids sizes of Cenomanian-Turonian samples

Organic carbon-rich shales from localities in England, Italy, and Morocco, which formed during the Cenomanian-Turonian oceanic anoxic event (OAE), have been examined for their total organic carbon (TOC) values together with their carbon, nitrogen, and iron isotope ratios. Carbon isotope stratigraphy (d13Corg and d13Ccarb) allows accurate recognition of the strata that record the oceanic anoxic event, in some cases allowing characterization of isotopic species before, during, and after the OAE. Within the black shales formed during the OAE, relatively heavy nitrogen isotope ratios, which correlate positively with TOC, suggest nitrate reduction (leading ultimately to denitrification and/or anaerobic ammonium oxidation). Black shales deposited before the onset of the OAE in Italy have unusually low bulk d57Fe values, unlike those found in the black shale (Livello Bonarelli) deposited during the oceanic anoxic event itself: These latter conform to the Phanerozoic norm for organic-rich sediments. Pyrite formation in the pre-OAE black shales has apparently taken place via dissimilatory iron reduction (DIR), within the sediment, a suboxic process that causes an approximately -2 per mil fractionation between a lithogenic Fe(III)oxide source and Fe(II)aq. In contrast, bacterial sulfate reduction (BSR), at least partly in the water column, characterized the OAE itself and was accompanied by only minor iron isotope fractionation. This change in the manner of pyrite formation is reflected in a decrease in the average pyrite framboid diameter from ~10 to ~7 µm. The gradual, albeit irregular increase in Fe isotope values during the OAE, as recorded in the Italian section, is taken to demonstrate limited isotopic evolution of the dissolved iron pool, consequent upon ongoing water column precipitation of pyrite under euxinic conditions. Given that evidence exists for both nitrate and sulfate reduction during the OAE, it is evident that redox conditions in the water column were highly variable, in both time and space.

Nonparametric Evaluation of Quantitative Traits in Population-Based Association Studies when the Genetic Model is Unknown

Statistical association between a single nucleotide polymorphism (SNP) genotype and a quantitative trait in genome-wide association studies is usually assessed using a linear regression model, or, in the case of non-normally distributed trait values, using the Kruskal-Wallis test. While linear regression models assume an additive mode of inheritance via equi-distant genotype scores, Kruskal-Wallis test merely tests global differences in trait values associated with the three genotype groups. Both approaches thus exhibit suboptimal power when the underlying inheritance mode is dominant or recessive. Furthermore, these tests do not perform well in the common situations when only a few trait values are available in a rare genotype category (disbalance), or when the values associated with the three genotype categories exhibit unequal variance (variance heterogeneity). We propose a maximum test based on Marcus-type multiple contrast test for relative effect sizes. This test allows model-specific testing of either dominant, additive or recessive mode of inheritance, and it is robust against variance heterogeneity. We show how to obtain mode-specific simultaneous confidence intervals for the relative effect sizes to aid in interpreting the biological relevance of the results. Further, we discuss the use of a related all-pairwise comparisons contrast test with range preserving confidence intervals as an alternative to Kruskal-Wallis heterogeneity test. We applied the proposed maximum test to the Bogalusa Heart Study dataset, and gained a remarkable increase in the power to detect association, particularly for rare genotypes. Our simulation study also demonstrated that the proposed non-parametric tests control family-wise error rate in the presence of non-normality and variance heterogeneity contrary to the standard parametric approaches. We provide a publicly available R library nparcomp that can be used to estimate simultaneous confidence intervals or compatible multiplicity-adjusted p-values associated with the proposed maximum test.

An alternative benchmarking approach for electricity utility regulation using maximum entropy

The main purpose of this study is to present an alternative benchmarking approach that can be used by national regulators of utilities. It is widely known that the lack of sizeable data sets limits the choice of the benchmarking method and the specification of the model to set price controls within incentive-based regulation. Ill-posed frontier models are the problem that some national regulators have been facing. Maximum entropy estimators are useful in the estimation of such ill-posed models, in particular in models exhibiting small sample sizes, collinearity and non-normal errors, as well as in models where the number of parameters to be estimated exceeds the number of observations available. The empirical study involves a sample data used by the Portuguese regulator of the electricity sector to set the parameters for the electricity distribution companies in the regulatory period of 2012-2014. DEA and maximum entropy methods are applied and the efficiency results are compared.

Epidemiology and genetic architecture of blood pressure: a family based study of Generation Scotland

Hypertension is a major risk factor for cardiovascular disease and mortality, and a growing global public health concern, with up to one-third of the world’s population affected. Despite the vast amount of evidence for the benefits of blood pressure (BP) lowering accumulated to date, elevated BP is still the leading risk factor for disease and disability worldwide. It is well established that hypertension and BP are common complex traits, where multiple genetic and environmental factors contribute to BP variation. Furthermore, family and twin studies confirmed the genetic component of BP, with a heritability estimate in the range of 30-50%. Contemporary genomic tools enabling the genotyping of millions of genetic variants across the human genome in an efficient, reliable, and cost-effective manner, has transformed hypertension genetics research. This is accompanied by the presence of international consortia that have offered unprecedentedly large sample sizes for genome-wide association studies (GWASs). While GWAS for hypertension and BP have identified more than 60 loci, variants in these loci are associated with modest effects on BP and in aggregate can explain less than 3% of the variance in BP. The aims of this thesis are to study the genetic and environmental factors that influence BP and hypertension traits in the Scottish population, by performing several genetic epidemiological analyses. In the first part of this thesis, it aims to study the burden of hypertension in the Scottish population, along with assessing the familial aggregation and heritialbity of BP and hypertension traits. In the second part, it aims to validate the association of common SNPs reported in the large GWAS and to estimate the variance explained by these variants. In this thesis, comprehensive genetic epidemiology analyses were performed on Generation Scotland: Scottish Family Health Study (GS:SFHS), one of the largest population-based family design studies. The availability of clinical, biological samples, self-reported information, and medical records for study participants has allowed several assessments to be performed to evaluate factors that influence BP variation in the Scottish population. Of the 20,753 subjects genotyped in the study, a total of 18,470 individuals (grouped into 7,025 extended families) passed the stringent quality control (QC) criteria and were available for all subsequent analysis. Based on the BP-lowering treatment exposure sources, subjects were further classified into two groups. First, subjects with both a self-reported medications (SRMs) history and electronic-prescription records (EPRs; n =12,347); second, all the subjects with at least one medication history source (n =18,470). In the first group, the analysis showed a good concordance between SRMs and EPRs (kappa =71%), indicating that SRMs can be used as a surrogate to assess the exposure to BP-lowering medication in GS:SFHS participants. Although both sources suffer from some limitations, SRMs can be considered the best available source to estimate the drug exposure history in those without EPRs. The prevalence of hypertension was 40.8% with higher prevalence in men (46.3%) compared to women (35.8%). The prevalence of awareness, treatment and controlled hypertension as defined by the study definition were 25.3%, 31.2%, and 54.3%, respectively. These findings are lower than similar reported studies in other populations, with the exception of controlled hypertension prevalence, which can be considered better than other populations. Odds of hypertension were higher in men, obese or overweight individuals, people with a parental history of hypertension, and those living in the most deprived area of Scotland. On the other hand, deprivation was associated with higher odds of treatment, awareness and controlled hypertension, suggesting that people living in the most deprived area may have been receiving better quality of care, or have higher comorbidity levels requiring greater engagement with doctors. These findings highlight the need for further work to improve hypertension management in Scotland. The family design of GS:SFHS has allowed family-based analysis to be performed to assess the familial aggregation and heritability of BP and hypertension traits. The familial correlation of BP traits ranged from 0.07 to 0.20, and from 0.18 to 0.34 for parent-offspring pairs and sibling pairs, respectively. A higher correlation of BP traits was observed among first-degree relatives than other types of relative pairs. A variance-component model that was adjusted for sex, body mass index (BMI), age, and age-squared was used to estimate heritability of BP traits, which ranged from 24% to 32% with pulse pressure (PP) having the lowest estimates. The genetic correlation between BP traits showed a high correlation between systolic (SBP), diastolic (DBP) and mean arterial pressure (MAP) (G: 81% to 94%), but lower correlations with PP (G: 22% to 78%). The sibling recurrence risk ratio (λS) for hypertension and treatment were calculated as 1.60 and 2.04 respectively. These findings confirm the genetic components of BP traits in GS:SFHS, and justify further work to investigate genetic determinants of BP. Genetic variants reported in the recent large GWAS of BP traits were selected for genotyping in GS:SFHS using a custom designed TaqMan® OpenArray®. The genotyping plate included 44 single nucleotide polymorphisms (SNPs) that have been previously reported to be associated with BP or hypertension at genome-wide significance level. A linear mixed model that is adjusted for age, age-squared, sex, and BMI was used to test for the association between the genetic variants and BP traits. Of the 43 variants that passed the QC, 11 variants showed statistically significant association with at least one BP trait. The phenotypic variance explained by these variant for the four BP traits were 1.4%, 1.5%, 1.6%, and 0.8% for SBP, DBP, MAP, and PP, respectively. The association of genetic risk score (GRS) that were constructed from selected variants has showed a positive association with BP level and hypertension prevalence, with an average effect of one mmHg increase with each 0.80 unit increases in the GRS across the different BP traits. The impact of BP-lowering medication on the genetic association study for BP traits has been established, with typical practice of adding a fixed value (i.e. 15/10 mmHg) to the measured BP values to adjust for BP treatment. Using the subset of participants with the two treatment exposure sources (i.e. SRMs and EPRs), the influence of using either source to justify the addition of fixed values in SNP association signal was analysed. BP phenotypes derived from EPRs were considered the true phenotypes, and those derived from SRMs were considered less accurate, with some phenotypic noise. Comparing SNPs association signals between the four BP traits in the two model derived from the different adjustments showed that MAP was the least impacted by the phenotypic noise. This was suggested by identifying the same overlapped significant SNPs for the two models in the case of MAP, while other BP traits had some discrepancy between the two sources

Knowledge and use of asthma control measurement tools in the management of asthma: a survey of doctors working in family and internal medicine practice in Nigeria.

Objective: To investigate the knowledge and use of asthma control measurement (ACM) tools in the management of asthma among doctors working in family and internal medicine practice in Nigeria. Method: A questionnaire based on the global initiative on asthma (GINA) guideline was self-administered by 194 doctors. It contains 12 test items on knowledge of ACM tools and its application. The knowledge score was obtained by adding the correct answers and classified as good if the score ≥ 9, satisfactory if score was 6-8 and poor if < 6. Results: The overall doctors knowledge score of ACM tools was 4.49±2.14 (maximum of 12). Pulmonologists recorded the highest knowledge score of 10.75±1.85. The majority (69.6%) had poor knowledge score of ACM tools. Fifty (25.8%) assessed their patients’ level of asthma control and 34(17.5%) at every visit. Thirty-nine (20.1%) used ACM tools in their consultation, 29 (15.0%) of them used GINA defined control while 10 (5.2 %) used asthma control test (ACT). The use of the tools was associated with pulmonologists, having attended CME within six months and graduated within five years prior to the survey. Conclusion: The results highlight the poor knowledge and use of ACM tools and the need to address the knowledge gap.

BIAS-CORRECTED MAXIMUM LIKELIHOOD ESTIMATION OF THE PARAMETERS OF THE WEIGHTED LINDLEY DISTRIBUTION

This report discusses the calculation of analytic second-order bias techniques for the maximum likelihood estimates (for short, MLEs) of the unknown parameters of the distribution in quality and reliability analysis. It is well-known that the MLEs are widely used to estimate the unknown parameters of the probability distributions due to their various desirable properties; for example, the MLEs are asymptotically unbiased, consistent, and asymptotically normal. However, many of these properties depend on an extremely large sample sizes. Those properties, such as unbiasedness, may not be valid for small or even moderate sample sizes, which are more practical in real data applications. Therefore, some bias-corrected techniques for the MLEs are desired in practice, especially when the sample size is small. Two commonly used popular techniques to reduce the bias of the MLEs, are ‘preventive’ and ‘corrective’ approaches. They both can reduce the bias of the MLEs to order O(n−2), whereas the ‘preventive’ approach does not have an explicit closed form expression. Consequently, we mainly focus on the ‘corrective’ approach in this report. To illustrate the importance of the bias-correction in practice, we apply the bias-corrected method to two popular lifetime distributions: the inverse Lindley distribution and the weighted Lindley distribution. Numerical studies based on the two distributions show that the considered bias-corrected technique is highly recommended over other commonly used estimators without bias-correction. Therefore, special attention should be paid when we estimate the unknown parameters of the probability distributions under the scenario in which the sample size is small or moderate.

The role of cancer related inflammation, Src family kinases and matrix metalloproteinase 9 in colorectal cancer

Colorectal cancer (CRC) is the third most common cancer in the UK with 41,000 new cases diagnosed in 2011. Despite undergoing potentially curative resection, a significant amount of patients develop recurrence. Biomarkers that aid prognostication or identify patients who are suitable for adjuvant treatments are needed. The TNM staging system does a reasonably good job at offering prognostic information to the treating clinician, but it could be better and identifying methods of improving its accuracy are needed. Tumour progression is based on a complex relationship between tumour behaviour and the hosts’ inflammatory responses. Sustained tumour cell proliferation, evading growth suppressors, resisting apoptosis, replicative immortality, sustained angiogenesis, invasion & metastasis, avoiding immune destruction, deregulated cellular energetics, tumour promoting inflammation and genomic instability & mutation have been identified as hallmarks. These hallmarks are malignant behaviors are what makes the cell cancerous and the more extreme the behaviour the more aggressive the cancer the more likely the risk of a poor outcome. There are two primary genomic instability pathways: Microsatellite Instability (MSI) and Chromosomal Instability (CI) also referred to as Microsatellite Stability (MSS). Tumours arising by these pathways have a predilection for specific anatomical, histological and molecular biological features. It is possible that aberrant molecular expression of genes/proteins that promote malignant behaviors may also act as prognostic and predictive biomarkers, which may offer superior prognostic information to classical prognostic features. Cancer related inflammation has been described as a 7th hallmark of cancer. Despite the systemic inflammatory response (SIR) being associated with more aggressive malignant disease, infiltration by immune cells, particularly CD8+ lymphocytes, at the advancing edge of the tumour have been associated with improved outcome and tumour MSI. It remains unknown if the SIR is associated with tumour MSI and this requires further study. The mechanisms by which colorectal cancer cells locally invade through the bowel remain uncertain, but connective tissue degradation by matrix metalloproteinases (MMPs) such as MMP-9 have been implicated. MMP-9 has been found in the cancer cells, stromal cells and patient circulation. Although tumoural MMP-9 has been associated with poor survival, reports are conflicting and contain relatively small sample sizes. Furthermore, the influence of high serum MMP-9 on survival remains unknown. Src family kinases (SFKs) have been implicated in many adverse cancer cell behaviors. SFKs comprise 9 family members BLK, C-SRC, FGR, FYN, HCK, LCK, LYN, YES, YRK. C-SRC has been the most investigated of all SFKs, but the role of other SFKs in cellular behaviors and their prognostic value remains largely unknown. The development of Src inhibitors, such as Dasatinib, has identified SFKs as a potential therapeutic target for patients at higher risk of poor survival. Unfortunately, clinical trials so far have not been promising but this may reflect inadequate patient selection and SFKs may act as useful prognostic and predictive biomarkers. In chapter 3, the association between cancer related inflammation, tumour MSI, clinicopathological factors and survival was tested in two independent cohorts. A training cohort consisting of n=182 patients and a validation cohort of n=677 patients. MSI tumours were associated with a raised CRP (p=0.003). Hypoalbuminaemia was independently associated with poor overall survival in TNM stage II cancer (HR 3.04 (95% CI 1.44 – 6.43);p=0.004), poor recurrence free survival in TNM stage III cancer (HR 1.86 (95% 1.03 – 3.36);p=0.040) and poor overall survival in CI colorectal cancer (HR 1.49 (95% CI 1.06 – 2.10);p=0.022). Interestingly, MSI tumours were associated with poor overall survival in TNM stage III cancer (HR 2.20 (95% CI 1.10 – 4.37);p=0.025). In chapter 4, the role of MMP-9 in colorectal cancer progression and survival was examined. MMP-9 in the tissue was assessed using IHC and serum expression quantified using ELISA. Serum MMP-9 was associated with cancer cell expression (Spearman’s Correlation Coefficient (SCC) 0.393, p<0.001)) and stromal expression (SCC 0.319, p=0.002). Serum MMP-9 was associated with poor recurrence-free (HR 3.37 (95% CI 1.20 – 9.48);p=0.021) and overall survival (HR 3.16 (95% CI 1.22 – 8.15);p=0.018), but tumour MMP-9 was not survival or MSI status. In chapter 5, the role of SFK expression and activation in colorectal cancer progression and survival was studied. On PCR analysis, although LYN, C-SRC and YES were the most highly expressed, FGR and HCK had higher expression profiles as tumours progressed. Using IHC, raised cytoplasmic FAK (tyr 861) was independently associated with poor recurrence free survival in all cancers (HR 1.48 (95% CI 1.02 – 2.16);p=0.040) and CI cancers (HR 1.50 (95% CI 1.02 – 2.21);p=0.040). However, raised cytoplasmic HCK (HR 2.04 (95% CI 1.11 – 3.76);p=0.022) was independently associated with poor recurrence-free survival in TNM stage II cancers. T84 and HT29 cell lines were used to examine the cellular effects of Dasatinib. Cell viability was assessed using WST-1 assay and apoptosis assessed using an ELISA cell death detection assay. Dasatinib increased T84 tumour cell apoptosis in a dose dependent manner and resulted in reduced expression of nuclear (p=0.008) and cytoplasmic (p=0.016) FAK (tyr 861) expression and increased nuclear FGR expression (p=0.004). The results of this thesis confirm that colorectal cancer is a complex disease that represents several subtypes of cancer based on molecular biological behaviors. This thesis concentrated on features of the disease related to inflammation in terms of genetic and molecular characterisation. MSI cancers are closely associated with systemic inflammation but despite this observation, they retain their relatively improved survival. MMP-9 is a feature of tissue remodeling during inflammation and is also associated with degradation of connective tissue, advanced T-stage and poor outcome when measured in the serum. The lack of stromal quantification due to TMA use rather than full sections makes the value of tumoural MMP-9 immunoreactivity in the prognostication and its association with MSI unknown and requires further study. Finally, SFK activation was also associated with SIR, however, only cytoplasmic HCK was independently associated with poor survival in patients with TNM stage II disease, the group of patients where identifying a novel biomarker is most needed. There is still some way to go before these biomarkers are translated into clinical practice and future work needs to focus on obtaining a reliable and robust scientific technique with validation in an adequately powered independent cohort.