Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

ВЛИЯНИЕ АПРАМИЦИНА НА СТРУКТУРНО-ФУНКЦИОНАЛЬНЫЕ СВОЙСТВА ЭРИТРОЦИТОВ ПЕРИФЕРИЧЕСКОЙ КРОВИ КРЫС ПО ПАРАМЕТРАМ ОСМОТИЧЕСКИХ И КИСЛОТНЫХ ЭРИТРОГРАММ

Using automatic registration of erythrograms, the hypoosmotic and acid resistance of rat peripheral blood erythrocytes, modified with the antibiotic apramycin, were studied. It was found that a preliminary 30-minute incubation of a suspension of erythrocytes in physiological solution together with the antibiotic apramycin at a concentration of 0.2 mg/ml reduced the resistance of blood cells to hypoosmotic and acid conditions compared with intact erythrocytes. In a 0.45 % NaCl solution, erythrocytes modified with apramycin were more actively involved in the hemolytic process and 90 % of the cells were subjected to osmotic hemolysis for 90 s. In physiological saline with pH of 3.5-4.0, the latent period of acid hemolysis of erythrocytes modified with apramycin was 130 s. The number of erythrocytes hemolyzed in an acidic environment did not exceed 29 %. It was stated that the aminoglycoside antibiotic apramycin at a concentration of 0.2 mg/ml can interact with rat blood erythrocytes and cause latent changes in membrane structures and other organic components of cells in them, thereby reducing their resistance properties in hypoosmotic and acidic conditions.С помощью автоматической регистрации эритрограмм изучены гипоосмотическая и кислотная резистентность эритроцитов периферической крови крыс, модифицированных антибиотиком апрамицином. Установлено, что предварительная 30 минутная инкубация взвеси эритроцитов в физиологическом растворе вместе антибиотиком апрамицином в концентрации 0.2 мг/мл снижает резистентость клеток крови к гипоосмотическим и кислотным условиям по сравнению с интактными эритроцитами. В 0.45 % растворе NaCl эритроциты, модифицированные апрамицином, активнее вовлекались в гемолитический процесс и в течение 90 с осмотическому гемолизу подвергалось 90 % клеток. В физиологическом растворе с рН 3.5-4.0 латентный период кислотного гемолиза эритроцитов, модифицированных апрамицином, составил 130 с. Количество эритроцитов, гемолизированных в кислой среде, не превышало 29 %. Установлено, что аминогликозидный антибиотик апрамицин в концентрации 0.2 мг/мл может взаимодействовать с эритроцитами крови крыс и, вызывать в них скрытые изменения мембранных структур и других органических компонентов клеток, снижая тем самым их резистентные свойства в условиях гипоосмотической и кислой среды

TAGS measurements of 100Nb ground and isomeric states and 140Cs for neutrino physics with the new DTAS detector

In this work we report on total absorption γ -ray spectroscopy measurements of the β decay of fission products that are important contributors to the antineutrino spectrum. The experiment was performed at IGISOL as a part of a campaign of measurements with the new DTAS spectrometer. Preliminary results of the analysis of the β decay of 100Nb,100mNb and 140Cs are presented.peerReviewe

First experiment with the NUSTAR/FAIR Decay Total Absorption γ-Ray Spectrometer (DTAS) at the IGISOL IV facility

The new Decay Total Absorption Spectrometer (DTAS) has been commissioned with low energy radioactive beams at the upgraded IGISOL IV facility. The DTAS is a segmented detector composed of up to 18 NaI(Tl) crystals and it will be a key instrument in the DESPEC experiment at FAIR. In this document we report on the experimental setup and the first measurements performed with DTAS at IGISOL. The detector was characterized by means of MC simulations, and this allowed us to calculate the response function of the spectrometer and analyse the first cases of interest.peerReviewe

Total Absorption Spectroscopy of Fission Fragments Relevant for Reactor Antineutrino Spectra and Decay Heat Calculations

Beta decay of fission products is at the origin of decay heat and antineutrino emission in nuclear reactors. Decay heat represents about 7% of the reactor power during operation and strongly impacts reactor safety. Reactor antineutrino detection is used in several fundamental neutrino physics experiments and it can also be used for reactor monitoring and non-proliferation purposes. 92,93Rb are two fission products of importance in reactor antineutrino spectra and decay heat, but their β-decay properties are not well known. New measurements of 92,93Rb β-decay properties have been performed at the IGISOL facility (Jyväskylä, Finland) using Total Absorption Spectroscopy (TAS). TAS is complementary to techniques based on Germanium detectors. It implies the use of a calorimeter to measure the total gamma intensity de-exciting each level in the daughter nucleus providing a direct measurement of the beta feeding. In these proceedings we present preliminary results for 93Rb, our measured beta feedings for 92Rb and we show the impact of these results on reactor antineutrino spectra and decay heat calculations.peerReviewe

Total absorption studies of high priority decays for reactor applications: 86Br and 91Rb

Preliminary results from beta decay studies of nuclei that are important for reactor applications are presented. The beta decays have been studied using the total absorption technique (TAS) and the pure beams provided by the JYFLTRAP system at the IGISOL facility of the University of Jyväskylä.peerReviewe