Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood appr

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p(interaction) values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.Peer reviewe

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Liikunnallisen joulukalenterin kehittäminen ja hyödyntäminen kolmevuotiaiden lasten motoristen perustaitojen harjoittamisessa päiväkoti Horisontissa

Tämä opinnäytetyö on varhaiskasvatukseen suuntautunut toiminnallinen opinnäytetyö, jonka tavoitteena oli kehittää liikunnallinen joulukalenteri ja tätä kautta luoda lapsille päivittäinen mahdollisuus harjoittaa motorisia perustaitojaan. Joulukalenteri pyrittiin tekemään muokattavaksi, jotta sitä voisi käyttää tuleviinkin joulunodotuksiin. Liikunnallinen joulukalenteri suunniteltiin yksilöllisesti porvoolaiselle päiväkoti Horisontille heidän toiveitaan ja tarpeitaan vastaavaksi. Toteutus sijoittui joulukuuhun 2015 ja pääkohderyhmänä olivat päiväkodin kolmevuotiaat lapset. Toteutukseen kuului sekä tarina- että toimintaosio. Olennainen osa opinnäytetyötä oli liikunnallisen joulukalenterin kehittäminen ja sen muokkaaminen tarvetta vastaavaksi prosessinomaisesti toiminnan edetessä. Työmenetelminä käytettiin toimintatutkimuksen spiraalimallia, lasten motoristen taitojen arviointilomaketta ja havainnointia sekä palautteenkeruuta. Tietoperustassa kerrotaan varhaisvuosien liikunnasta, kolmevuotiaan lapsen kehityksestä fyysisestä ja motorisesta sekä psyykkisestä ja sosiaalisesta näkökulmasta. Toiminnan ja tuloksien analysoinnissa hyödynnettiin arviointilomakkeita, kuten myös lasten ja päiväkodin henkilökunnan palautetta. Palautteesta ilmenee, että liikunnallisen joulukalenterin luominen ja kehittäminen onnistui hyvin. Päiväkodin henkilökunta oli tyytyväinen joulukalenterin tarinaan ja liikunnallisiin tehtäviin. Tulosten perusteella lapset saivat toistojen kautta mahdollisuuden harjoittaa perusmotorisia taitojaan ja eräiden taitojen osa-aluessa näkyikin kehitystä. Tämän opinnäytetyön tuloksia voidaan hyödyntää joulukalenterin, motoristen harjoitusten ja lasten arviointilomakkeen osalta laajemminkin muissa varhaiskasvatuksen yksiköissä. Kuitenkaan opinnäytetyön kohderyhmän tuloksia taitojen harjaantumisesta ei voida suoraan sellaisenaan siirtää tai hyödyntää muualla, sillä kyse on enemmän yksilöistä kuin yleistettävästä ryhmästä.This Bachelor’s thesis is a functional thesis focusing on early childhood education. The purpose was to create an advent calendar based on physical education and thus provide children an opportunity to practise their fundamental motor skills on every day basis. The idea was to create a calendar that could be used also next christmas. The calendar was designed for daycare centre Horisontti, in Porvoo. It was tailored to fit the daycare centre’s wishes and needs. The implementation took place in December 2015 and the target group were the daycare centre’s three-year-old children. The implementation included a story section and a functional section. A relevant part of this thesis was to develop, shape and improve it during the implementation of the project. The working methods were the spiral model of operational research, the evaluation form of children’s motor skills, observation and feedback. The theoretical frame focuses on physical education in early childhood and the development of a three-year-old child from a physical, motor, psychic and social point of view. Observation and evaluation forms as well as feedback from the employees of the daycare centre and children were utilized to analyze the implementation and the results of this thesis. The feedback shows that the advent calendar was a success. The employees were pleased with the storyline and also the motor skills exercises. The results show that the children recieved an opportunity to practice their fundamental motor skills through repetition and that there was some progress in a few motor skills sections. The advent calendar, motor skills exercises and the observation form developed in this thesis can also be utilized in other early childhood education units. The results of the progress in motor skills of these particular and individual children cannot be transffered or applied in any other place

Rysk roulette eller kontrollerad spridning? : En kritisk diskursanalys av begreppet flockimmunitet

Under våren 2020, då coronaviruset började spridas världen över, blev flockimmunitet ett omdebatterat begrepp i media. Sverige och Storbritannien följde inledningsvis liknande strategier för att hantera pandemins framfart, som liknades med att uppnå flockimmunitet i samhället, för att därefter gå skilda vägar. Denna studie undersöker hur begreppet flockimmunitet fick sin betydelse i totalt 30 artiklar, i svenska Dagens Nyheter och brittiska The Guardian, under tidsperioden 11 mars – 31 maj 2020. I form av en kritisk diskursanalys undersöker studien vad det finns för likheter och skillnader i hur svensk och brittisk media skriver om flockimmunitet, om respektive lands coronastrategi återspeglas i den mediala diskursen och huruvida det används diskursiva strategier för att skapa en dominerande betydelse av begreppet flockimmunitet. Det teoretiska ramverk som ligger till grund för studien består av gestaltningsteorin och Norman Faircloughs diskursteori. I utformningen av vårt analysschema har vi även inspirerats av Peter Berglez samt Chantal Mouffe & Ernesto Laclau, från vilka begrepp som tecken, ekvivalenskedja, aktörer och överlexikalisering har hämtats. Resultatet visar att tidningarna använder sig av tydliga diskursiva strategier för att ge betydelse åt flockimmunitet. En stor skillnad som återfinns i materialet är hur The Guardian består av en dominerande diskurs, där flockimmunitet har en bestämd betydelse, medan Dagens Nyheter präglas av en diskursiv kamp mellan två diskurser som kämpar om att få ge betydelse åt begreppet. Både den brittiska strategin med en nedstängning av samhället, liksom den svenska, att hålla samhället öppet, återspeglas i hur respektive tidning skriver om flockimmunitet

Prognostic implications of renal dysfunction in patients with aortic stenosis

Aortic stenosis (AS) and renal dysfunction share risk factors and often occur simultaneously. The influence of renal dysfunction on the prognosis of patients with various grades of AS has not been extensively described. The present study aimed to assess the prognostic implications of renal dysfunction in a large cohort of patients with aortic sclerosis and patients with various grades of AS. Patients diagnosed with various grades of AS by transthoracic echocardiography were assessed and divided according to renal function by estimated glomerular filtration rate (eGFR). The occurrence of all-cause mortality (primary end point) and aortic valve replacement (AVR) was noted. Of 1,178 patients (mean age 70 ± 13 years, 60% male), 327 (28%) had aortic sclerosis, 86 (7%) had mild AS, 285 (24%) had moderate AS, and 480 (41%) had severe AS. Renal dysfunction (eGF