An item analysis of Nason phonics test in grades one and two

Thesis (Ed.M.)--Boston Universit

Drivers of exceptionally cold North Atlantic Ocean temperatures and their link to the 2015 European heat wave

The North Atlantic and Europe experienced two extreme climate events in 2015: exceptionally cold ocean surface temperatures and a summer heat wave ranked in the top ten over the past 65 years. Here, we show that the cold ocean temperatures were the most extreme in the modern record over much of the mid-high latitude North-East Atlantic. Further, by considering surface heat loss, ocean heat content and wind driven upwelling we explain for the first time the genesis of this cold ocean anomaly. We find that it is primarily due to extreme ocean heat loss driven by atmospheric circulation changes in the preceding two winters combined with the re-emergence of cold ocean water masses. Furthermore, we reveal that a similar cold Atlantic anomaly was also present prior to the most extreme European heat waves since the 1980s indicating that it is a common factor in the development of these events. For the specific case of 2015, we show that the ocean anomaly is linked to a stationary position of the Jet Stream that favours the development of high surface temperatures over Central Europe during the heat wave. Our study calls for an urgent assessment of the impact of ocean drivers on major European summer temperature extremes in order to provide better advance warning measures of these high societal impact events

The North Atlantic Ocean is in a state of reduced overturning

The Atlantic Meridional Overturning Circulation (AMOC) is responsible for a variable and climatically important northward transport of heat. Using data from an array of instruments that span the Atlantic at 26°N, we show that the AMOC has been in a state of reduced overturning since 2008 as compared to 2004-2008. This change of AMOC state is concurrent with other changes in the North Atlantic such as a northward shift and broadening of the Gulf Stream, and altered patterns of heat content and sea-surface temperature. These changes resemble the response to a declining AMOC predicted by coupled climate models. Concurrent changes in air-sea fluxes close to the western boundary reveal that the changes in ocean heat transport and SST have altered the pattern of ocean-atmosphere heat exchange over the North Atlantic. These results provide strong observational evidence that the AMOC is a major factor in decadal scale variability of North Atlantic climate

The North Atlantic Ocean is in a state of reduced overturning

The Atlantic Meridional Overturning Circulation (AMOC) is responsible for a variable and climatically important northward transport of heat. Using data from an array of instruments that span the Atlantic at 26°N, we show that the AMOC has been in a state of reduced overturning since 2008 as compared to 2004-2008. This change of AMOC state is concurrent with other changes in the North Atlantic such as a northward shift and broadening of the Gulf Stream, and altered patterns of heat content and sea-surface temperature. These changes resemble the response to a declining AMOC predicted by coupled climate models. Concurrent changes in air-sea fluxes close to the western boundary reveal that the changes in ocean heat transport and SST have altered the pattern of ocean-atmosphere heat exchange over the North Atlantic. These results provide strong observational evidence that the AMOC is a major factor in decadal scale variability of North Atlantic climate

Shiga toxin-producing Escherichia coli clonal complex 32, including serotype O145:H28, in the UK and Ireland

Introduction. Shiga toxin-producing Escherichia coli (STEC) O157:H7 has been the most clinically significant STEC serotype in the UK for over four decades. Over the last 10 years we have observed a decrease in STEC O157:H7 and an increase in non-O157 STEC serotypes, such as O145:H28. Gap Statement. Little is known about the microbiology and epidemiology of STEC belonging to CC32 (including O145:H28) in the UK. The aim of this study was to integrate genomic data with patient information to gain a better understanding of the virulence, disease severity, epidemic risk assessment and population structure of this clinically significant clonal complex. Methodology. Isolates of E. coli belonging to CC32 (n=309) in the archives of public health agencies in the UK and Ireland were whole-genome-sequenced, virulence-profiled and integrated with enhanced surveillance questionnaire (ESQ) data, including exposures and disease severity. Results. Overall, diagnoses of STEC belonging to CC32 (290/309, 94 %) in the UK have increased every year since 2014. Most cases were female (61 %), and the highest proportion of cases belonged to the 0–4 age group (53/211,25 %). The frequency of symptoms of diarrhoea (92 %), abdominal pain (84 %), blood in stool (71 %) and nausea (51 %) was similar to that reported in cases of STEC O157:H7, although cases of STEC CC32 were more frequently admitted to hospital (STEC CC32 48 % vs O157:H7  34 %) and/or developed haemolytic uraemic syndrome (HUS) (STEC CC32 9 % vs O157:H7 4 %). The majority of STEC isolates (268/290, 92 %) had the stx2a/eae virulence gene combination, most commonly associated with progression to STEC HUS. There was evidence of person-to-person transmission and small, temporally related, geographically dispersed outbreaks, characteristic of foodborne outbreaks linked to nationally distributed products. Conclusion. We recommend more widespread use of polymerase chain reaction (PCR) for the detection of all STEC serogroups, the development of consistent strategies for the follow-up testing of PCR-positive faecal specimens, the implementation of more comprehensive and standardized collection of epidemiological data, and routine sharing of sequencing data between public health agencies worldwide

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions.

The development of a highly effective vaccine remains a key strategic goal to aid the control and eventual eradication of Plasmodium falciparum malaria. In recent years, the reticulocyte-binding protein homolog 5 (RH5) has emerged as the most promising blood-stage P. falciparum candidate antigen to date, capable of conferring protection against stringent challenge in Aotus monkeys. We report on the first clinical trial to our knowledge to assess the RH5 antigen - a dose-escalation phase Ia study in 24 healthy, malaria-naive adult volunteers. We utilized established viral vectors, the replication-deficient chimpanzee adenovirus serotype 63 (ChAd63), and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA), encoding RH5 from the 3D7 clone of P. falciparum. Vaccines were administered i.m. in a heterologous prime-boost regimen using an 8-week interval and were well tolerated. Vaccine-induced anti-RH5 serum antibodies exhibited cross-strain functional growth inhibition activity (GIA) in vitro, targeted linear and conformational epitopes within RH5, and inhibited key interactions within the RH5 invasion complex. This is the first time to our knowledge that substantial RH5-specific responses have been induced by immunization in humans, with levels greatly exceeding the serum antibody responses observed in African adults following years of natural malaria exposure. These data support the progression of RH5-based vaccines to human efficacy testing

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.

Gene-Lifestyle Interaction and Type 2 Diabetes: The EPIC InterAct Case-Cohort Study

Background: Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention. Methods and Findings: The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction = 1.20x10(-4)). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction = 1.50x10(-3)) and waist circumference (p for interaction = 7.49x10(-9)). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score. Conclusions: The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this subgroup is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention

Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.

Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.This study was funded by the UK Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1. This work was supported by the MRC Metabolic Diseases Unit (MC_UU_12012/5) and the Cambridge NIHR Biomedical Research Centre and EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant 115372). Funding for the InterAct project was provided by the EU FP6 program (grant LSHM_CT_2006_037197). This work was funded, in part, through an EFSD Rising Star award to R.A.S. supported by Novo Nordisk. D.B.S. is supported by Wellcome Trust grant 107064. M.I.M. is a Wellcome Trust Senior Investigator and is supported by the following grants from the Wellcome Trust: 090532 and 098381. M.v.d.B. is supported by a Novo Nordisk postdoctoral fellowship run in partnership with the University of Oxford. I.B. is supported by Wellcome Trust grant WT098051. S.O'R. acknowledges funding from the Wellcome Trust (Wellcome Trust Senior Investigator Award 095515/Z/11/Z and Wellcome Trust Strategic Award 100574/Z/12/Z)