Context.
Characterising the large-scale structure in the Universe from present times to the high redshift epoch of reionisation is essential to constraining the cosmology, the history of star ...formation, and reionisation, to measuring the gas content of the Universe, and to obtaining a better understanding of the physical processes that drive galaxy formation and evolution. Using the integrated emission from unresolved galaxies or gas clouds, line intensity mapping (LIM) provides a new observational window to measure the larger properties of structures. This very promising technique motivates the community to plan for LIM experiments.
Aims.
We describe the development of a large field-of-view instrument, named CONCERTO (for CarbON CII line in post-rEionisation and ReionisaTiOn epoch), operating in the range 130–310 GHz from the APEX 12-m telescope (5100 m above sea level). CONCERTO is a low-resolution spectrometer based on the lumped element kinetic inductance detectors (LEKID) technology. Spectra are obtained using a fast Fourier transform spectrometer (FTS), coupled to a dilution cryostat with a base temperature of 0.1 K. Two two kilo-pixel arrays of LEKID are mounted inside the cryostat that also contains the cold optics and the front-end electronics.
Methods.
We present, in detail, the technological choices leading to the instrumental concept, together with the design and fabrication of the instrument and preliminary laboratory tests on the detectors. We also give our best estimates for CONCERTO sensitivity and give predictions for two of the main scientific goals of CONCERTO, that is, a CII-intensity mapping survey and observations of galaxy clusters.
Results.
We provide a detailed description of the instrument design. Based on realistic comparisons with existing instruments developed by our group (NIKA, NIKA2, and KISS), and on the laboratory characterisation of our detectors, we provide an estimate for CONCERTO sensitivity on the sky. Finally, we describe, in detail, two of the main scientific goals offered by CONCERTO at APEX.
Efficacy of endocrine therapy in HR+/HER2- metastatic breast cancer could differ depending on the presence of BRCA1/2 germline mutation.
The ESME metastatic breast cancer platform (NCT03275311) is a ...French real world database. Multivariable models including a time-varying approach and landmark analyses assessed the association between time-dependent gBRCA status (categorised as gBRCAm, gBRCAwt (wild type), and untested), overall survival (OS), and first-line progression-free survival (PFS1).
A total of 170 patients were gBRCAm carriers, 676 gBRCAwt, and 12,930 were untested at baseline. In the multivariable analysis, gBRCAm carriers overall had a lower OS compared to gBRCAwt (adjusted HR 95% CI 1.26 1.03-1.55). gBRCAm patients treated with front-line endocrine therapy had lower adjusted OS (adjusted HR 95% CI = 1.54 1.03-2.32) and PFS1 (adjusted HR 95% CI 1.58 1.17-2.12) compared to gBRCAwt patients. However, for patients who received frontline chemotherapy, neither OS nor PFS1 differed between gBRCAm carriers and the other groups (HR versus gBRCAwt for OS: 1.12 0.88-1.41, p = 0.350; PFS1: 1.09 0.90-1.31, p = 0.379).
In this large cohort of HR+/HER2- MBC patients treated in a pre-CDK4/6 inhibitors era, gBRCAm status was associated with a lower OS and lower PFS following first-line endocrine therapy, but not following first-line chemotherapy.
Atmospheric warming is projected to increase global mean surface temperatures by 0.3 to 4.8 degrees Celsius above pre-industrial values by the end of this century. If anthropogenic emissions continue ...unchecked, the warming increase may reach 8-10 degrees Celsius by 2300 (ref. 2). The contribution that large ice sheets will make to sea-level rise under such warming scenarios is difficult to quantify because the equilibrium-response timescale of ice sheets is longer than those of the atmosphere or ocean. Here we use a coupled ice-sheet/ice-shelf model to show that if atmospheric warming exceeds 1.5 to 2 degrees Celsius above present, collapse of the major Antarctic ice shelves triggers a centennial- to millennial-scale response of the Antarctic ice sheet in which enhanced viscous flow produces a long-term commitment (an unstoppable contribution) to sea-level rise. Our simulations represent the response of the present-day Antarctic ice-sheet system to the oceanic and climatic changes of four representative concentration pathways (RCPs) from the Fifth Assessment Report of the Intergovernmental Panel on Climate Change. We find that substantial Antarctic ice loss can be prevented only by limiting greenhouse gas emissions to RCP 2.6 levels. Higher-emissions scenarios lead to ice loss from Antarctic that will raise sea level by 0.6-3 metres by the year 2300. Our results imply that greenhouse gas emissions in the next few decades will strongly influence the long-term contribution of the Antarctic ice sheet to global sea level.
Everolimus is an agent frequently associated with specific toxicities. Predictive markers of efficacy are needed to help define which patients could benefit from it. The goal of this exploratory ...study was to identify potential predictive biomarkers in the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activation pathway using primary tumor samples collected during the phase II tamoxifen plus everolimus (TAMRAD) trial.
Tumor tissues were collected retrospectively from the TAMRAD trial. Immunohistochemistry was carried out using specific antibodies directed toward proteins that result in mTORC1 activation canonical phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR or alternative pathways. DNA was extracted from the tumor tissue; mutation screening in the PIK3CA gene (exons 9 and 20) and the KRAS gene (exons 2 and 3) was first carried out using Sanger direct sequencing, and then completed by next-generation sequencing for PIK3CA. An exploratory analysis of everolimus efficacy in terms of a time-to-progression (TTP) increase was carried out in each biomarker subgroup (high versus low expression referring to the median percentage of marked cells).
A total of 55 primary tumor samples from the TAMRAD trial—25 from the tamoxifen-alone group and 30 from the tamoxifen/everolimus group—were evaluated for biomarkers. The subgroups most likely to have an improvement in TTP with tamoxifen/everolimus therapy, compared with tamoxifen alone, were patients with high p4EBP1, low 4EBP1, low liver kinase B1, low pAkt, and low PI3K. Among the 45 samples screened for mutation status, nine samples (20%; 95% CI 9.6–34.6) had a PIK3CA mutation. KRAS mutation was observed in one patient.
A positive correlation between late effectors of mTORC1 activation, a positive correlation between Akt-independent mTORC1 activation, and an inverse correlation between canonical PI3K/Akt/mTOR pathway and everolimus efficacy were observed in this exploratory analysis. However, these correlations need to be validated in larger studies before applying the findings to routine clinical practice.
Noninvasive ventilation has become increasingly available to spinal muscular atrophy (SMA) patients since the early 1990 s. This is expected to have improved survival for SMA type 1 patients.
To ...assess whether there has been a change in survival in patients with SMA type 1 between 1980 and 2006.
We used deidentified, family-reported data from participants in the International Spinal Muscular Atrophy Patient Registry and obtained additional clinical information through a mail-in questionnaire. One hundred forty-three patients with SMA type 1 were included in the analysis. Survival of patients born in 1995-2006 (n = 78) was compared with that of patients born in 1980-1994 (n = 65), using the Kaplan-Meier method and Cox proportional hazards models with age at death as the outcome.
Patients born in 1995 though 2006 had significantly increased survival compared with those born in 1980-1994 (log-rank test, p < 0.001). In a Cox model, patients born in 1995-2006 had a 70% reduction in the risk of death compared with those born in 1980-1994 (hazard ratio HR 0.3, 95% CI 0.2-0.5, p < 0.001) over a mean follow-up of 49.9 months (SD 61.1, median 22.0). However, when controlling for demographic and clinical care variables, year of birth was no longer significantly associated with age at death (HR 1.0, 95% CI 0.6-1.8, p = 0.9), whereas ventilation for more than 16 h/d, use of a mechanical insufflation-exsufflation device, and gastrostomy tube feeding showed a significant effect in reducing the risk of death.
Survival in spinal muscular atrophy type 1 patients has increased in recent years, in relation to the growing trend toward more proactive clinical care.
Permanent pacemaker (PPM) requirement is a recognized complication of transcatheter aortic valve implantation. We assessed the UK incidence of permanent pacing within 30 days of CoreValve ...implantation and formulated an anatomic and electrophysiological model.
Data from 270 patients at 10 centers in the United Kingdom were examined. Twenty-five patients (8%) had preexisting PPMs; 2 patients had incomplete data. The remaining 243 were 81.3±6.7 years of age; 50.6% were male. QRS duration increased from 105±23 to 135±29 milliseconds (P<0.01). Left bundle-branch block incidence was 13% at baseline and 61% after the procedure (P<0.001). Eighty-one patients (33.3%) required a PPM within 30 days. Rates of pacing according to preexisting ECG abnormalities were as follows: right bundle-branch block, 65.2%; left bundle-branch block, 43.75%; normal QRS, 27.6%. Among patients who required PPM implantation, the median time to insertion was 4.0 days (interquartile range, 2.0 to 7.75 days). Multivariable analysis revealed that periprocedural atrioventricular block (odds ratio, 6.29; 95% confidence interval, 3.55 to 11.15), balloon predilatation (odds ratio, 2.68; 95% confidence interval, 2.00 to 3.47), use of the larger (29 mm) CoreValve prosthesis (odds ratio, 2.50; 95% confidence interval, 1.22 to 5.11), interventricular septum diameter (odds ratio, 1.18; 95% confidence interval, 1.10 to 3.06), and prolonged QRS duration (odds ratio, 3.45; 95% confidence interval, 1.61 to 7.40) were independently associated with the need for PPM.
One third of patients undergoing a CoreValve transcatheter aortic valve implantation procedure require a PPM within 30 days. Periprocedural atrioventricular block, balloon predilatation, use of the larger CoreValve prosthesis, increased interventricular septum diameter and prolonged QRS duration were associated with the need for PPM.
During the last glacial termination, the upwelling strength of the southern polar limb of the Atlantic Meridional Overturning Circulation varied, changing the ventilation and stratification of the ...high-latitude Southern Ocean. During the same period, at least two phases of abrupt global sea-level rise--meltwater pulses--took place. Although the timing and magnitude of these events have become better constrained, a causal link between ocean stratification, the meltwater pulses and accelerated ice loss from Antarctica has not been proven. Here we simulate Antarctic ice sheet evolution over the last 25 kyr using a data-constrained ice-sheet model forced by changes in Southern Ocean temperature from an Earth system model. Results reveal several episodes of accelerated ice-sheet recession, the largest being coincident with meltwater pulse 1A. This resulted from reduced Southern Ocean overturning following Heinrich Event 1, when warmer subsurface water thermally eroded grounded marine-based ice and instigated a positive feedback that further accelerated ice-sheet retreat.
Summary Objective To evaluate the retail sales of pressurised metered-dose inhalers (pMDIs), dry-powder inhalers (DPIs) and liquids for nebulisation in 16 European countries. Methods Retail sales ...data relating to pMDIs, DPIs and liquids for nebulisation delivering short- and long-acting bronchodilators, corticosteroids and combinations between 2002 and 2008 were obtained from the IMS sales database. The IMS database ensured that wholesalers’ stock sales accurately matched that of retail pharmacies and included purchases by panel pharmacies directly from pharmaceutical manufacturers, specialist wholesalers and distribution cooperatives. Results Mean inhaler retail sales (expressed as percentages of total sales) were 47.5% for pMDIs, 39.5% for DPIs and 13% for nebulisers. The distribution of inhaler sales differed significantly between the countries with pMDI sales greatest in the United Kingdom and Hungary compared to other countries, where DPI sales prevailed. Sales of nebulisation liquids were high in Italy. The pMDI was the most frequently prescribed inhaler for bronchodilators. In contrast, retail sales of DPIs were similar to those of pMDIs for inhaled corticosteroids, and higher in the case of inhalers with combined long-acting β2 -agonist and corticosteroid. Conclusion We found a high degree of variability in inhaler prescription between European countries. Differing health policies, costs, health insurance issues, pharmaceutical/commercial aspects and prescribers’ and patients’ preferences may explain this variation. We suggest a need for more uniform, outcome-led inhaler prescribing practice across Europe to improve the efficacy and cost effectiveness of the treatment of obstructive airways diseases.
Fertility rates in Europe are among the lowest in the world, which may be attributed to both biological and lifestyle factors. Cost and reimbursement of fertility treatments vary across Europe, ...although its citizens enjoy wide access to fertility care. Since few regional studies evaluating public support for fertility treatment exist, we conducted the Listening IVF and Fertility in Europe (LIFE) survey to ascertain public perception of in vitro fertilization (IVF) and gamete donation as a treatment for infertility among European men and women.
This survey was distributed via an online questionnaire to 8,682 individuals who were voluntary participants in an online research panel residing in France, Germany, Italy, Spain, Sweden, or the UK. The survey covered items to determine respondents' beliefs regarding IVF and its success, the need for public funding, the use of IVF among modern families with different lifestyles, and the support for gamete donation. Results were analyzed by age, country of origin, sex, and sexual orientation. A total of 6,110 (70% of total) men and women responded. Among all respondents, 10% had undergone IVF treatment and 48% had considered or would consider IVF in case of infertility. Respondents estimated IVF mean success rate to be 47% and over half of respondents believed that availability of IVF would encourage people to delay conception. Although 93% of respondents believed that IVF treatment should be publicly funded to some extent, a majority believed that secondary infertility or use of fertility treatments allowing to delay parenthood should be financed privately. Survey respondents believed that the mean number of stimulated IVF cycles funded publicly should be limited 2 to 3 (average 2.4). 79% of respondents were willing to pay for IVF if needed with a mean amount of 5,400 € for a child brought to life through IVF. According to respondents, mean minimum and maximum ages for IVF should be 29 and 42 years old, respectively. The current survey showed support for egg and sperm donation (78%), for IVF in single women (61%) and for same-sex female couples (64%). When analyzing the results per group (i.e., sex, age, sexual orientation, and countries), youngest age groups, homosexuals, bisexuals, German respondents, and men had similar overall positive attitudes and beliefs toward IVF and opinions on public funding. Perceived limits to availability were stronger in women.
Overall, the survey results demonstrate a positive attitude among respondents in an online panel toward IVF, gamete donation, and support for public funding for fertility treatment. These findings could potentially drive discussions between patients and prescribers to explore IVF treatment and among legislators and payers to support public funding for these procedures.
We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory ...breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab.
Nonmetastatic T4d patients were enrolled in two phase II multicentre trials, evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy of four cycles of FEC followed by four cycles of docetaxel in HER2-negative tumour (BEVERLY-1) or docetaxel and trastuzumab in HER2-positive tumour (BEVERLY-2). CTC and CEC were detected in 7.5 and 4ml of blood, respectively, with the CellSearch System.
From October 2008 to September 2010, 152 patients were included and 137 were evaluable for CTC and CEC. At baseline, 55 patients had detectable CTC (39%). After four cycles of chemotherapy, a dramatic drop in CTC to a rate of 9% was observed (P<0.01). Pathological complete response (pCR) rate was 40%. No correlation was found between CTC or CEC levels and pCR rate. Median follow-up was 43 months. CTC detection (≥1 CTC/7.5ml) at baseline was associated with shorter 3-year disease-free survival (39% versus 70% for patients without CTC, P<0.01, HR 2.80) and shorter 3-year overall survival (OS) (P<0.01). In multivariate analysis, independent prognostic parameters for shorter survival were absence of hormonal receptors, no pCR and CTC detection at baseline. CEC level at baseline or variations during treatment had no prognostic value.
In this pooled analysis of two prospective trials in nonmetastatic IBC, detection rate of CTC was 39% with a strong and independent prognostic value for survival. Combination of pCR after neoadjuvant treatment with no CTC detection at baseline isolated a subgroup of IBC with excellent OS (94% 3-year OS), suggesting that CTC count could be part of IBC stratification in prospective trials.
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