Identification of Functional Single Nucleotide Polymorphisms Associated with Breast Cancer Based on Chromatin Modifications

Breast cancer affects 1 in 8 women and can be deadly; yet when detected early enough it is often treatable. Thus, early detection of breast cancer is imperative to save lives. The success of early detection depends, in part, on being able to stratify risk. A new approach to determining risk involves identifying genetic variants that alter an individual’s risk for developing breast cancer. This thesis identified key functional candidates involved in breast cancer development, some of which have been verified by other studies. For a few of the functional candidates, further research needs to be done in order to determine the biological significance they play in the development of breast cancer. The functional candidates were identified by comparing SNPs in Linkage Disequilibrium with high risk SNPS—determined by GWAS—using histone modification markers to identify functional genomic elements in breast cell lines. The results yielded three top tier candidates and multiple second tier candidates. Further research should be done in order to assess the risk involved with these variants and the underlying biological mechanism. As genetic testing becomes more accessible to the public, the identification and understanding of these high risk variants will be an essential tool in preventing and treating breast cancer

The Digital Reading Experiences of Middle School Readers: A Phenomenological Study

Reading digitally is part of the 21st century New Literacies, residing in the curriculum as a comprehension skill developed with print reading skills. Differences exist between purpose of digital reading and print reading, manifested in the association of digital reading as a mostly non-fiction genre, the immediacy to digital information and its relevance to a reader’s decision about the usefulness of the information. Contrastingly, print reading can be fiction or non-fiction with access to all the text. The differences suggest that learning focused on immediate evaluation, synthesis, and application of information while reading digitally should be taught in the context of digital reading. This hermeneutic phenonmenological study examined digital reading experiences of eight middle school students. Using indepth interviewing to describe and understand the experiences, findings are presented as themes. The findings contribute to the ongoing discourse of digital reading, teacher preparation and development, curriculum, new literacies, pedagogy, and turning research into practice

Evidence for Past Subduction Earthquakes at a Plate Boundary with Widespread Upper Plate Faulting: Southern Hikurangi Margin, New Zealand

At the southern Hikurangi margin, New Zealand, we use salt marsh stratigraphy, sedimentology, micropaleontology, and radiocarbon dating to document evidence of two earthquakes producing coseismic subsidence and (in one case) a tsunami over the past 1000 yrs. The earthquake at 520-470 yrs before present (B.P.) produced 0.25 +/- 0.1 m of subsidence at Big Lagoon. The earthquake at 880-800 yrs B.P. produced 0.45 +/- 0.1 m of subsidence at Big Lagoon and was accompanied by a tsunami that inundated >= 360 m inland with a probable height of >= 3.3 m. Distinguishing the effects of upper plate faulting from plate interface earthquakes is a significant challenge at this margin. We use correlation with regional upper plate paleoearthquake chronologies and elastic dislocation modeling to determine that the most likely cause of the subsidence and tsunami events is subduction interface rupture, although the older event may have been a synchronous subduction interface and upper plate fault rupture. The southern Hikurangi margin has had no significant (M > 6.5) documented subduction interface earthquakes in historic times, and previous assumptions that this margin segment is prone to rupture in large to great earthquakes were based on seismic and geodetic evidence of strong contemporary plate coupling. This is the first geologic evidence to confirm that the southern Hikurangi margin ruptures in large earthquakes. The relatively short-time interval between the two subduction earthquakes (similar to 350 yrs) is shorter than in current seismic-hazard models.GNSEQC Biennial ProjectNew Zealand Natural Hazards Research Platform and Foundation for Research Science and TechnologyInstitute for Geophysic

Polygenic adaptation after a sudden change in environment

Polygenic adaptation in response to selection on quantitative traits is thought to be ubiquitous in humans and other species, yet this mode of adaptation remains poorly understood. We investigate the dynamics of this process, assuming that a sudden change in environment shifts the optimal value of a highly polygenic quantitative trait. We find that when the shift is not too large relative to the genetic variance in the trait and this variance arises from segregating loci with small to moderate effect sizes (defined in terms of the selection acting on them before the shift), the mean phenotype's approach to the new optimum is well approximated by a rapid exponential process first described by Lande (1976). In contrast, when the shift is larger or large effect loci contribute substantially to genetic variance, the initially rapid approach is succeeded by a much slower one. In either case, the underlying changes to allele frequencies exhibit different behaviors short and long-term. Over the short term, strong directional selection on the trait introduces small differences between the frequencies of minor alleles whose effects are aligned with the shift in optimum versus those with effects in the opposite direction. The phenotypic effects of these differences are dominated by contributions from alleles with moderate and large effects, and cumulatively, these effects push the mean phenotype close to the new optimum. Over the longer term, weak directional selection on the trait can amplify the expected frequency differences between opposite alleles; however, since the mean phenotype is close to the new optimum, alleles are mainly affected by stabilizing selection on the trait. Consequently, the frequency differences between opposite alleles translate into small differences in their probabilities of fixation, and the short-term phenotypic contributions of large effect alleles are largely supplanted by contributions of fixed, moderate ones

Mindfulness-based exposure and response prevention for obsessive compulsive disorder: study protocol for a pilot randomised controlled trial

Background Obsessive Compulsive Disorder (OCD) is a distressing and debilitating condition affecting 1-2% of the population. Exposure and response prevention (ERP) is a behaviour therapy for OCD with the strongest evidence for effectiveness of any psychological therapy for the condition. Even so, only about half of people offered ERP show recovery after the therapy. An important reason for ERP failure is that about 25% of people drop out early, and even for those who continue with the therapy, many do not regularly engage in ERP tasks, an essential element of ERP. A mindfulness-based approach has the potential to reduce drop-out from ERP and to improve ERP task engagement with an emphasis on accepting difficult thoughts, feelings and bodily sessions and on becoming more aware of urges, rather than automatically acting on them. Methods/Design This is a pilot randomised controlled trial of mindfulness-based ERP (MB-ERP) with the aim of establishing parameters for a definitive trial. Forty participants diagnosed with OCD will be allocated at random to a 10-session ERP group or to a 10-session MB-ERP group. Primary outcomes are OCD symptom severity and therapy engagement. Secondary outcomes are depressive symptom severity, wellbeing and obsessive-compulsive beliefs. A semi-structured interview with participants will guide understanding of change processes. Discussion Findings from this pilot study will inform future research in this area, and if effect sizes on primary outcomes are in favour of MB-ERP in comparison to ERP, funding for a definitive trial will be sought

Synthetic Galaxy Images and Spectra from the Illustris Simulation

We present our methods for generating a catalog of 7,000 synthetic images and 40,000 integrated spectra of redshift z = 0 galaxies from the Illustris Simulation. The mock data products are produced by using stellar population synthesis models to assign spectral energy distributions (SED) to each star particle in the galaxies. The resulting synthetic images and integrated SEDs therefore properly reflect the spatial distribution, stellar metallicity distribution, and star formation history of the galaxies. From the synthetic data products it is possible to produce monochromatic or color-composite images, perform SED fitting, classify morphology, determine galaxy structural properties, and evaluate the impacts of galaxy viewing angle. The main contribution of this paper is to describe the production, format, and composition of the image catalog that makes up the Illustris Simulation Obsevatory. As a demonstration of this resource, we derive galactic stellar mass estimates by applying the SED fitting code FAST to the synthetic galaxy products, and compare the derived stellar masses against the true stellar masses from the simulation. We find from this idealized experiment that systematic biases exist in the photometrically derived stellar mass values that can be reduced by using a fixed metallicity in conjunction with a minimum galaxy age restriction.Comment: 21 pages, 17 figures, submitted to MNRAS. Comments welcom

COVID-19 related mortality and hospital admissions in the VIVALDI study cohort: October 2020-March 2023

Background: Long-term care facilities (LTCFs) were heavily affected by COVID-19 early in the pandemic, but the impact of the virus has reduced over time with vaccination campaigns and build-up of immunity from prior infection. // Objectives: To evaluate the mortality and hospital admissions associated with SARS-CoV-2 in LTCFs in England over the course of the VIVALDI study, from October 2020 to March 2023. // Methods: We included residents aged ≥65 years of participating LTCFs who had available follow-up time within the analysis period. We calculated incidence rates (IR) of COVID-19 linked mortality and hospital admissions per calendar quarter, along with infection fatality ratios (IFR, within 28d) and infection hospitalisation ratios (IHR, within 14d) following positive SARS-CoV-2 test. // Results: A total of 26286 residents were included, with at least one positive test for SARS-CoV-2 in 8513 (32.4%). The IR of COVID-19 related mortality peaked in the first quarter (Q1) 2021 at 0.47 per 1000 person-days (1kpd) (around a third of all deaths), in comparison to 0.10 per 1kpd for Q1 2023 which had a similar IR of SARS-CoV-2 infections. There was a fall in observed IFR for SARS-CoV-2 infections from 24.9% to 6.7% between these periods, with a fall in IHR from 12.1% to 8.8%. The population had high overall IRs for mortality for each quarter evaluated, corresponding to annual mortality probability of 28.8-41.3%. // Conclusions: Standardised real-time monitoring of hospitalisation and mortality following infection in LTCFs could inform policy on the need for non-pharmaceutical interventions to prevent transmission

Guillain-Barré Syndrome and Preceding Infection with Campylobacter, Influenza and Epstein-Barr Virus in the General Practice Research Database

BACKGROUND: A number of infectious agents have previously been suggested as risk factors for the development of Guillain-Barré syndrome (GBS), but robust epidemiologic evidence for these associations is lacking. METHODS AND FINDINGS: We conducted a nested case-control study using data from the United Kingdom General Practice Research Database between 1991 and 2001. Controls were matched to cases on general practice clinic, sex, year of birth and date of outcome diagnosis in their matched case. We found positive associations between GBS and infection with Campylobacter, Epstein-Barr virus and influenza-like illness in the previous two months, as well as evidence of a protective effect of influenza vaccination. After correction for under-ascertainment of Campylobacter infection, the excess risk of GBS following Campylobacter enteritis was 60-fold and 20% of GBS cases were attributable to this pathogen. CONCLUSIONS: Our findings indicate a far greater excess risk of GBS among Campylobacter enteritis patients than previously reported by retrospective serological studies. In addition, they confirm previously suggested associations between infection due to Epstein-Barr virus infection and influenza-like illness and GBS. Finally, we report evidence of a protective effect of influenza vaccination on GBS risk, which may be mediated through protection against influenza disease, or result from a lower likelihood of vaccination among those with recent infection. Cohort studies of GBS incidence in this population would help to clarify the burden of GBS due to influenza, and any potential protective effect of influenza vaccination

Hospital admission after primary care consultation for community-onset lower urinary tract infection: a cohort study of risks and predictors using linked data

BACKGROUND: Urinary tract infections (UTIs) are a common indication for antibiotic prescriptions, reductions in which would reduce antimicrobial resistance (AMR). Risk stratification of patients allows reductions to be made safely. AIM: To identify risk factors for hospital admission following UTI, to inform targeted antibiotic stewardship. DESIGN AND SETTING: Retrospective cohort study of East London primary care patients. METHOD: Hospital admission outcomes following primary care consultation for UTI were analysed using linked data from primary care, secondary care, and microbiology, from 1 April 2012 to 31 March 2017. The outcomes analysed were urinary infection-related hospital admission (UHA) and all-cause hospital admission (AHA) within 30 days of UTI in primary care. Odds ratios between specific variables (demographic characteristics, prior antibiotic exposure, and comorbidities) and the outcomes were predicted using generalised estimating equations, and fitted to a final multivariable model including all variables with a P-value <0.1 on univariable analysis. RESULTS: Of the 169 524 episodes of UTI, UHA occurred in 1336 cases (0.8%, 95% confidence interval [CI] = 0.7 to 0.8) and AHA in 6516 cases (3.8%, 95% CI = 3.8 to 3.9). On multivariable analysis, increased odds of UHA were seen in patients aged 55-74 years (adjusted odds ratio [AOR] 1.49) and ≥75 years (AOR 3.24), relative to adults aged 16-34 years. Increased odds of UHA were also associated with chronic kidney disease (CKD; AOR 1.55), urinary catheters (AOR 2.01), prior antibiotics (AOR 1.38 for ≥3 courses), recurrent UTI (AOR 1.33), faecal incontinence (FI; AOR 1.47), and diabetes mellitus (DM; AOR 1.37). CONCLUSION: Urinary infection-related hospital admission after primary care consultation for community-onset lower UTI was rare; however, increased odds for UHA were observed for some patient groups. Efforts to reduce antibiotic prescribing for suspected UTI should focus on patients aged <55 years without risk factors for complicated UTI, recurrent UTI, DM, or FI

Effectiveness of successive booster vaccine doses against SARS-CoV-2 related mortality in residents of long-term care facilities in the VIVALDI study

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused severe disease in unvaccinated long-term care facility (LTCF) residents. Initial booster vaccination following primary vaccination is known to provide strong short-term protection, but data are limited on duration of protection and the protective effect of further booster vaccinations. OBJECTIVE: To evaluate the effectiveness of third, fourth and fifth dose booster vaccination against SARS-CoV-2 related mortality amongst older residents of LTCFs. DESIGN: Prospective cohort study. SETTING: LTCFs for older people in England participating in the VIVALDI study. METHODS: Residents aged >65 years at participating LTCFs were eligible for inclusion if they had at least one polymerase chain reaction or lateral flow device result within the analysis period 1 January 2022 to 31 December 2022. We excluded individuals who had not received at least two vaccine doses before the analysis period. Cox regression was used to estimate relative hazards of SARS-CoV-2 related mortality following 1-3 booster vaccinations compared with primary vaccination, stratified by previous SARS-CoV-2 infection and adjusting for age, sex and LTCF size (total beds). RESULTS: A total of 13,407 residents were included. Our results indicate that third, fourth and fifth dose booster vaccination provide additional short-term protection against SARS-CoV-2 related mortality relative to primary vaccination, with consistent stabilisation beyond 112 days to 45-75% reduction in risk relative to primary vaccination. CONCLUSIONS: Successive booster vaccination doses provide additional short-term protection against SARS-CoV-2 related mortality amongst older LTCF residents. However, we did not find evidence of a longer-term reduction in risk beyond that provided by initial booster vaccination