21 cm epoch of reionization (EoR) observations promise to transform our understanding of galaxy formation, but these observations are impossible without unprecedented levels of instrument ...calibration. We present end-to-end simulations of a full EoR power spectrum (PS) analysis including all of the major components of a real data processing pipeline: models of astrophysical foregrounds and EoR signal, frequency-dependent instrument effects, sky-based antenna calibration, and the full PS analysis. This study reveals that traditional sky-based per-frequency antenna calibration can only be implemented in EoR measurement analyses if the calibration model is unrealistically accurate. For reasonable levels of catalogue completeness, the calibration introduces contamination in otherwise foreground-free PS modes, precluding a PS measurement. We explore the origin of this contamination and potential mitigation techniques. We show that there is a strong joint constraint on the precision of the calibration catalogue and the inherent spectral smoothness of antennas, and that this has significant implications for the instrumental design of the SKA (Square Kilometre Array) and other future EoR observatories.
Non-small-cell lung cancer (NSCLC) harbouring HER2 alterations is now considered a distinct molecular subtype. The activation of HER2 in NSCLC occurs via three mechanisms, i.e. gene mutation (1%-4% ...of cases), gene amplification (2%-5%) and protein overexpression (2%-30%), with different prognostic and predictive outcomes. So far, non-selective tyrosine kinase inhibitors (TKIs) have shown a minor benefit in HER2-mutant NSCLC patients with objective response rates (ORRs) ranging from 0% to 19%. Trastuzumab-based chemotherapy was not found to be superior to chemotherapy alone median progression-free survival (PFS) 6.1 versus 7 months, respectively and dual HER2 antibody blockade with trastuzumab and pertuzumab had limited efficacy (ORR 13%-21%). In contrast, novel more selective HER2 TKIs such as poziotinib and pyrotinib have shown a promising activity in HER2-mutant pre-treated NSCLC patients, with response rates up to 38% and 44%, respectively. The most encouraging data come from phase II studies that evaluated the antibody–drug conjugates (ADCs) ado-trastuzumab–emtansine and trastuzumab–deruxtecan in patients with HER2-mutant NSCLC, with response rates of 50% and 62%, respectively. These agents are bringing hope to the management of HER2-altered NSCLC. Moreover, a paradigm shift from monotherapies towards combinations of agents with distinct mechanisms of action, such as ADCs with irreversible TKIs or immune checkpoint inhibitors, is already taking place and will change the therapeutic landscape of HER2-driven NSCLC. This paper provides a practical, concise and updated review on the therapeutic strategies in NSCLC with HER2 molecular alterations.
•Activation of Her2 in NSCLC occurs via gene mutation, amplification or protein overexpression.•Selective Her2 TKIs like poziotinib and pyrotinib induced responses in up to 44% of pre-treated Her2-mutant NSCLC patients.•ADCs trastuzumab–emtansine and trastuzumab–deruxtecan showed impressive response rates in 62% of Her2-mutant NSCLC patients.•Ongoing studies evaluating combination strategies may help improve the therapeutic landscape in Her2-dependent NSCLC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Measurements of 21 cm Epoch of Reionization (EoR) structure are subject to systematics originating from both the analysis and the observation conditions. Using 2013 data from the Murchison Widefield ...Array (MWA), we show the importance of mitigating both sources of contamination. A direct comparison between results from Beardsley et al. and our updated analysis demonstrates new precision techniques, lowering analysis systematics by a factor of 2.8 in power. We then further lower systematics by excising observations contaminated by ultra-faint RFI, reducing by an additional factor of 3.8 in power for the zenith pointing. With this enhanced analysis precision and newly developed RFI mitigation, we calculate a noise-dominated upper limit on the EoR structure of Δ2 ≤ 3.9 × 103 mK2 at k = 0.20 h Mpc−1 and z = 7 using 21 hr of data, improving previous MWA limits by almost an order of magnitude.
Summary
The use of cell salvage during caesarean section has been increasing steadily, although there are concerns relating to cost, a perceived risk of amniotic fluid embolism, and fetal red cell ...sensitisation. We present observational data from almost a decade of use of intra‐operative cell salvage in obstetrics. By the end of this period, we set up cell salvage collection for > 98% of all caesarean sections. From 2008 to 2017, 1170 women have had a re‐infusion of cell salvaged blood with no clinical safety concerns; the median (IQR range) volume was 231 (154–306 80–1690) ml. During this time there has been a marked reduction in the number of women who were transfused allogeneic blood, as well as the amount of blood transfused. In total, 647 (55%) women have had alloimmunisation testing, with two positive cases. Quality control data indicate that the quality of blood processed from partial first bowls is no worse than that from full bowls. We discuss the costs of providing this service with regard to: staffing costs; single suction; leucodepletion filters; selectivity in the processing of collected blood; and the use of partial first bowls.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Experiments that pursue detection of signals from the Epoch of Reionization (EoR) are relying on spectral smoothness of source spectra at low frequencies. This article empirically explores the effect ...of foreground spectra on EoR experiments by measuring high-resolution full-polarization spectra for the 586 brightest unresolved sources in one of the Murchison Widefield Array (MWA) EoR fields using 45 h of observation. A novel peeling scheme is used to subtract 2500 sources from the visibilities with ionospheric and beam corrections, resulting in the deepest, confusion-limited MWA image so far. The resulting spectra are found to be affected by instrumental effects, which limit the constraints that can be set on source-intrinsic spectral structure. The sensitivity and power-spectrum of the spectra are analysed, and it is found that the spectra of residuals are dominated by point spread function sidelobes from nearby undeconvolved sources. We release a catalogue describing the spectral parameters for each measured source.
Prior antibiotic therapy (pATB) is known to impair efficacy of single-agent immune checkpoint inhibitors (ICIs), potentially through the induction of gut dysbiosis. Whether ATB also affects outcomes ...to chemo-immunotherapy combinations is still unknown.
In this international multicentre study, we evaluated the association between pATB, concurrent ATB (cATB) and overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in patients with non-small-cell lung cancer (NSCLC) treated with first-line chemo-immunotherapy at eight referral institutions.
Among 302 patients with stage IV NSCLC, 216 (71.5%) and 61 (20.2%) patients were former and current smokers, respectively. Programmed death-ligand 1 tumour expression in assessable patients (274, 90.7%) was ≥50% in 76 (25.2%), 1%-49% in 84 (27.9%) and <1% in 113 (37.5%). Multivariable analysis showed pATB-exposed patients to have similar OS {hazard ratio (HR) = 1.42 95% confidence interval (CI): 0.91-2.22; P = 0.1207} and PFS HR = 1.12 (95% CI: 0.76-1.63); P = 0.5552, compared to unexposed patients, regardless of performance status. Similarly, no difference with respect to ORR was found across pATB exposure groups (42.6% versus 57.4%, P = 0.1794). No differential effect was found depending on pATB exposure duration (≥7 versus <7 days) and route of administration (intravenous versus oral). Similarly, cATB was not associated with OS HR = 1.29 (95% CI: 0.91-1.84); P = 0.149 and PFS HR = 1.20 (95% CI: 0.89-1.63); P = 0.222 when evaluated as time-varying covariate in multivariable analysis.
In contrast to what has been reported in patients receiving single-agent ICIs, pATB does not impair clinical outcomes to first-line chemo-immunotherapy of patients with NSCLC. pATB status should integrate currently available clinico-pathologic factors for guiding first-line treatment decisions, whilst there should be no concern in offering cATB during chemo-immunotherapy when needed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The telomere sequence, TTAGGG, is conserved across all vertebrates and plays an essential role in suppressing the DNA damage response by binding a set of proteins termed shelterin. Changes in the ...telomere sequence impair shelterin binding, initiate a DNA damage response, and are toxic to cells. Here we identify a family with a variant in the telomere template sequence of telomerase, the enzyme responsible for telomere elongation, that led to a non-canonical telomere sequence. The variant is inherited across at least one generation and one family member reports no significant medical concerns despite ~9% of their telomeres converting to the novel sequence. The variant template disrupts telomerase repeat addition processivity and decreased the binding of the telomere-binding protein POT1. Despite these disruptions, the sequence is readily incorporated into cellular chromosomes. Incorporation of a variant sequence prevents POT1-mediated inhibition of telomerase suggesting that incorporation of a variant sequence may influence telomere addition. These findings demonstrate that telomeres can tolerate substantial degeneracy while remaining functional and provide insights as to how incorporation of a non-canonical telomere sequence might alter telomere length dynamics.
ABSTRACT We present the 21 cm power spectrum analysis approach of the Murchison Widefield Array Epoch of Reionization project. In this paper, we compare the outputs of multiple pipelines for the ...purpose of validating statistical limits cosmological hydrogen at redshifts between 6 and 12. Multiple independent data calibration and reduction pipelines are used to make power spectrum limits on a fiducial night of data. Comparing the outputs of imaging and power spectrum stages highlights differences in calibration, foreground subtraction, and power spectrum calculation. The power spectra found using these different methods span a space defined by the various tradeoffs between speed, accuracy, and systematic control. Lessons learned from comparing the pipelines range from the algorithmic to the prosaically mundane; all demonstrate the many pitfalls of neglecting reproducibility. We briefly discuss the way these different methods attempt to handle the question of evaluating a significant detection in the presence of foregrounds.
SUMMARY
Background
The significance of fetal red blood cell (RBC) contamination in obstetric intra‐operative cell salvage is not fully known. It is unclear if we re‐infuse a larger volume of fetal ...RBCs into the maternal circulation than the amount that occurs secondary to transplacental haemorrhages is unclear. We also do not know if there is a critical volume required to cause alloimmunisation or if larger volumes increase the risk.
Objectives
The aim of this study is to provide data on the level of fetal RBC contamination in the maternal circulation prior to delivery and immediately post‐partum and to compare these levels to those found in processed cell‐salvaged blood.
Methods
In the first part of this study, we quantified the levels of fetal RBCs circulating in women immediately prior to delivery. This was then repeated with a separate group measuring the levels of fetal RBCs pre‐ and post‐delivery.
Results
We found that 37% of women had fetal cells detected in their circulation, median 0·00 mL (IQR 0–0·24; average 0·3 mL, maximum 4·56 mL). Fetal RBCs were present pre‐delivery (maximum 0·66 mL) in 16% of women, increasing to 53% post‐delivery (median 0·66 mL; IQR 0·22–2·20, maximum 21·20 mL).
Conclusions
We have shown that fetal RBCs are present in the maternal circulation throughout pregnancy and that the volumes are comparable to that obtained from intra‐operative salvage, with contamination amounts of up to 19 mL. At the Royal Cornwall Hospital, our experience and evidence supports offering intra‐operative salvage to all women, and we have not noted an increase in antibody formation, compared to allogeneic transfusion.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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