Master of Science

thesisMarine boundary layer clouds are an important component of Earth's climate system due to their vast spatial and temporal coverage. Representation of these clouds in climate models remains challenging and continues to result in the largest feedback uncertainties. It is essential to increase understanding of cloud physical processes in order to improve climate models. In this study, we investigate possible conditions influencing albedo and precipitation susceptibility of marine boundary layer clouds, which gauge the clouds' sensitivity to perturbations in aerosol concentration. To do so, we employ a recently developed retrieval algorithm that uses A-Train satellite data to infer cloud properties. This unique algorithm assumes a bimodal particle size distribution, and then uses information from CloudSat and MODIS to simultaneously retrieve cloud mode and precipitation mode properties. Additionally, a new parameterization for the single scattering properties of clouds is developed to account for the bimodal size distribution, and is used to help provide constraints for the cloud retrieval. An equivalent retrieval has been developed to use ground-based ARM data. To study marine boundary layer cloud susceptibility, we focus our attention on the region spanning the stratocumulus cloud regime near California and the trade cumulus cloud regime near Hawaii. We compare albedo and precipitation susceptibility between winter and summer months and also between high and low surface wind conditions. It is found that cloud droplet number concentrations vary between seasons and surface wind conditions. Albedo susceptibility tends to increase monotonically with liquid water path (LWP). Precipitation susceptibility, on the other hand, shows non-monotonic behavior characterized by an autoconversion regime at low LWP and a transition to an accretion regime at higher LWP

BRCA2 inhibition enhances cisplatin-mediated alterations in tumor cell proliferation, metabolism, and metastasis

Tumor cells have unstable genomes relative to non-tumor cells. Decreased DNA integrity resulting from tumor cell instability is important in generating favorable therapeutic indices, and intact DNA repair mediates resistance to therapy. Targeting DNA repair to promote the action of anti-cancer agents is therefore an attractive therapeutic strategy. BRCA2 is involved in homologous recombination repair. BRCA2 defects increase cancer risk but, paradoxically, cancer patients with BRCA2 mutations have better survival rates. We queried TCGA data and found that BRCA2 alterations led to increased survival in patients with ovarian and endometrial cancer. We developed a BRCA2-targeting second-generation antisense oligonucleotide (ASO), which sensitized human lung, ovarian, and breast cancer cells to cisplatin by as much as 60%. BRCA2 ASO treatment overcame acquired cisplatin resistance in head and neck cancer cells, but induced minimal cisplatin sensitivity in non-tumor cells. BRCA2 ASO plus cisplatin reduced respiration as an early event preceding cell death, concurrent with increased glucose uptake without a difference in glycolysis. BRCA2 ASO and cisplatin decreased metastatic frequency invivo by 77%. These results implicate BRCA2 as a regulator of metastatic frequency and cellular metabolic response following cisplatin treatment. BRCA2 ASO, in combination with cisplatin, is a potential therapeutic anti-cancer agent

The Jamaica Salt Consumption Study Protocol: Sodium Intake; Sodium Content in Restaurant Foods; Knowledge, Attitudes, and Practices; Spot Urine Sodium Validation [version 2; peer review: 1 approved, 2 approved with reservations]

Background Excess dietary salt consumption is a major contributor to hypertension and cardiovascular disease. Public education programs on the dangers of high salt intake, and population level interventions to reduce the salt content in foods are possible strategies to address this problem. In Jamaica, there are limited data on the levels of salt consumption and the population’s knowledge and practices with regards to salt consumption. This study therefore aims to obtain baseline data on salt consumption, salt content in foods sold in restaurants, and evaluate knowledge, attitudes, and practices of Jamaicans regarding salt consumption. Methods The study is divided into four components. Component 1 will be a secondary analysis of data on urinary sodium from spot urine samples collected as part of a national survey, the Jamaica Health and Lifestyle Survey 2016-2017. Component 2 will be a survey of chain and non-chain restaurants in Jamaica, to estimate the sodium content of foods sold in restaurants. Component 3 is another national survey, this time on a sample 1,200 individuals to obtain data on knowledge, attitudes and practices regarding salt consumption and estimation of urinary sodium excretion. Component 4 is a validation study to assess the level of agreement between spot urine sodium estimates and 24-hour urinary sodium from 120 individuals from Component 3. Discussion This study will provide important baseline data on salt consumption in Jamaica and will fulfil the first components of the World Health Organization SHAKE Technical Package for Salt Reduction. The findings will serve as a guide to Jamaica’s Ministry of Health and Wellness in the development of a national salt reduction program. Findings will also inform interventions to promote individual and population level sodium reduction strategies as the country seeks to achieve the national target of a 30% reduction in salt consumption by 2025

Absence of Adolescent Obesity in Grenada: Is This a Generational Effect?

Background: Low- and middle-income countries are affected disproportionately by the ongoing global obesity pandemic. Representing a middle income country, the high prevalence of obesity among Grenadian adults as compared to US adults is expected as part of global obesity trends. The objective of this study was to determine if Grenadian adolescents have a higher prevalence of overweight compared to their US counterparts, and if a disparity exists between urban and rural adolescents.Methods: Using a subcohort of participants in the Grenadian Nutrition Student Survey, diet quality and anthropometric measures were collected from 55% of the classrooms of first year secondary students in Grenada (n = 639). Rural or urban designations were given to each school. Body Mass Index (BMI) was calculated and categorized as overweight or obese for each student following CDC classification cutoffs. A standardized BMI (BMIz) was calculated for each school. Sex-specific BMI and overall BMIz were compared to a 1980s US cohort. Multilevel models, overall and stratified by sex, of students nested within schools were conducted to determine if BMIz differed by rural or urban locality, gender, and diet quality.Results: The mean age of this cohort was 12.7 (SD = 0.8) years with 83.8% of the cohort identifying as Afro-Caribbean. Females had nearly twice the prevalence of overweight when compared to males (22.7 vs. 12.2%) but a similar prevalence of obesity (8.2 vs. 6.8%). Grenadian adolescents had lower prevalence of overweight (females: 22.7 vs. 44.7%; males: 12.2 vs. 38.8%, respectively) as compared to US counterparts. Eating a traditional diet was negatively associated with BMIz score among females (β^ = −0.395; SE = 0.123) in a stratified, multilevel analysis. BMIz scores did not differ significantly by rural or urban school designation.Conclusions: Among Grenadian adolescents, this study identified a lower overweight prevalence compared to US counterparts and no difference in overweight prevalence by urban or rural location. We hypothesize that the late introduction of processed foods to Grenada protected this cohort from obesogenic promoters due to a lack of fetal overnutrition. However, further research in subsequent birth cohorts is needed to determine if adolescent obesity will increase due to a generational effect

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

Laboratory-based and office-based risk scores and charts to predict 10-year risk of cardiovascular disease in 182 countries: a pooled analysis of prospective cohorts and health surveys

Background: Worldwide implementation of risk-based cardiovascular disease (CVD) prevention requires risk prediction tools that are contemporarily recalibrated for the target country and can be used where laboratory measurements are unavailable. We present two cardiovascular risk scores, with and without laboratory-based measurements, and the corresponding risk charts for 182 countries to predict 10-year risk of fatal and non-fatal CVD in adults aged 40–74 years. Methods: Based on our previous laboratory-based prediction model (Globorisk), we used data from eight prospective studies to estimate coefficients of the risk equations using proportional hazard regressions. The laboratory-based risk score included age, sex, smoking, blood pressure, diabetes, and total cholesterol; in the non-laboratory (office-based) risk score, we replaced diabetes and total cholesterol with BMI. We recalibrated risk scores for each sex and age group in each country using country-specific mean risk factor levels and CVD rates. We used recalibrated risk scores and data from national surveys (using data from adults aged 40–64 years) to estimate the proportion of the population at different levels of CVD risk for ten countries from different world regions as examples of the information the risk scores provide; we applied a risk threshold for high risk of at least 10% for high-income countries (HICs) and at least 20% for low-income and middle-income countries (LMICs) on the basis of national and international guidelines for CVD prevention. We estimated the proportion of men and women who were similarly categorised as high risk or low risk by the two risk scores. Findings: Predicted risks for the same risk factor profile were generally lower in HICs than in LMICs, with the highest risks in countries in central and southeast Asia and eastern Europe, including China and Russia. In HICs, the proportion of people aged 40–64 years at high risk of CVD ranged from 1% for South Korean women to 42% for Czech men (using a ≥10% risk threshold), and in low-income countries ranged from 2% in Uganda (men and women) to 13% in Iranian men (using a ≥20% risk threshold). More than 80% of adults were similarly classified as low or high risk by the laboratory-based and office-based risk scores. However, the office-based model substantially underestimated the risk among patients with diabetes. Interpretation: Our risk charts provide risk assessment tools that are recalibrated for each country and make the estimation of CVD risk possible without using laboratory-based measurements

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Language endangerment and language documentation in Africa

Non peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead