Abstract
ASASSN-14ko is a recently discovered periodically flaring transient at the center of the active galactic nucleus (AGN) ESO 253−G003 with a slowly decreasing period. Here, we show that the ...flares originate from the northern, brighter nucleus in this dual-AGN, post-merger system. The light curves for the two flares that occurred in 2020 May and September are nearly identical over all wavelengths. For both events, Swift observations showed that the UV and optical wavelengths brightened in unison. The effective temperature of the UV/optical emission rises and falls with the increase and subsequent decline in the luminosity. The X-ray flux, by contrast, first rapidly drops over ∼2.6 days, rises for ∼5.8 days, drops again over ∼4.3 days, and then recovers. The X-ray spectral evolution of the two flares differ, however. During the 2020 May peak the spectrum softened with increases in the X-ray luminosity, while we observed the reverse for the 2020 September peak. We found a small change in the period derivative, which seems to indicate that the system does not have a static period derivative and there is some stochasticity in its evolution.
Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that ...incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services.
A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider).
Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included
and mismatch repair genes, with broader testing, such as
, for clinical trial eligibility.
was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for
carriers, with consideration in
, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches.
This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.
The spin states of single electrons in gate-defined quantum dots satisfy crucial requirements for a practical quantum computer. These include extremely long coherence times, high-fidelity quantum ...operation, and the ability to shuttle electrons as a mechanism for on-chip flying qubits. To increase the number of qubits to the thousands or millions of qubits needed for practical quantum information, we present an architecture based on shared control and a scalable number of lines. Crucially, the control lines define the qubit grid, such that no local components are required. Our design enables qubit coupling beyond nearest neighbors, providing prospects for nonplanar quantum error correction protocols. Fabrication is based on a three-layer design to define qubit and tunnel barrier gates. We show that a double stripline on top of the structure can drive high-fidelity single-qubit rotations. Self-aligned inhomogeneous magnetic fields induced by direct currents through superconducting gates enable qubit addressability and readout. Qubit coupling is based on the exchange interaction, and we show that parallel two-qubit gates can be performed at the detuning-noise insensitive point. While the architecture requires a high level of uniformity in the materials and critical dimensions to enable shared control, it stands out for its simplicity and provides prospects for large-scale quantum computation in the near future.
Cold brown dwarfs are excellent analogs of widely separated, gas giant exoplanets, and provide insight into the potential atmospheric chemistry and physics we may encounter in objects to be ...discovered by future direct imaging surveys. We present a low-resolution, R ∼ 300, M-band spectroscopic sequence of seven brown dwarfs with effective temperatures between 750 and 250 K along with Jupiter. These spectra reveal disequilibrium abundances of carbon monoxide (CO) produced by atmospheric quenching. We use the eddy diffusion coefficient (Kzz) to estimate the strength of vertical mixing in each object. The Kzz values of cooler gaseous objects are close to their theoretical maximum, and warmer objects show weaker mixing, likely due to less efficient convective mixing in primarily radiative layers. The CO-derived Kzz values imply that disequilibrium phosphine (PH3) should be easily observable in all of the brown dwarfs, but none as yet show any evidence for PH3 absorption. We find that ammonia is relatively insensitive to atmospheric quenching at these effective temperatures. We are able to improve the fit to WISE 0855's M-band spectrum by including both CO and water clouds in the atmospheric model.
Those designing autonomous systems that interact with humans will invariably face questions about how humans think and make decisions. Fortunately, computational cognitive science offers insight into ...human decision-making using tools that will be familiar to those with backgrounds in optimization and control (e.g., probability theory, statistical machine learning, and reinforcement learning). Here, we review some of this work, focusing on how cognitive science can provide forward models of human decision-making and inverse models of how humans think about others' decision-making. We highlight relevant recent developments, including approaches that synthesize blackbox and theory-driven modeling, accounts that recast heuristics and biases as forms of bounded optimality, and models that characterize human theory of mind and communication in decision-theoretic terms. In doing so, we aim to provide readers with a glimpse of the range of frameworks, methodologies, and actionable insights that lie at the intersection of cognitive science and control research.
Summary Background Concurrent testing for human papillomavirus (HPV) and cervical cytology (co-testing) is an approved alternative to cytology alone in women aged 30 years and older. We aimed to ...assess the safety in routine clinical practice of 3-year screening intervals for women testing negative for HPV with normal cytology and to assess if co-testing can identify women at high risk of cervical cancer or cervical intraepithelial neoplasia grade 3 (CIN3) or worse over 5 years. Methods We assessed the 5-year cumulative incidence, starting in 2003–05, of cervical cancer and CIN3 or worse for 331 818 women aged 30 years and older who enrolled in co-testing at Kaiser Permanente Northern California (Berkeley, CA, USA) and had adequate enrolment co-test results. Follow-up continued until Dec 31, 2009. We defined cumulative incidence to include prevalence at enrolment and incidence after enrolment. Prevalence at enrolment was defined as the ratio of women diagnosed with each outcome on the biopsy visit immediately after their enrolment screening visit to the total enrolled women. At screening visits only HPV test and Pap smear samples were collected, and at biopsy visits colposcopically directed biopsies were taken. To estimate post-enrolment incidence, we used Weibull survival models. Findings In 315 061 women negative by HPV testing, the 5-year cumulative incidence of cancer was 3·8 per 100 000 women per year, slightly higher than for the 306 969 who were both negative by HPV and Pap testing (3·2 per 100 000), and half the cancer risk of the 319 177 who were negative by Pap testing (7·5 per 100 000). 313 465 (99·5%) women negative by HPV testing had either normal cytology or equivocal abnormalities. Abnormal cytology greatly increased cumulative incidence of CIN3 or worse over 5 years for the 16 757 positive by HPV testing (12·1% vs 5·9%; p<0·0001). By contrast, although statistically significant, abnormal cytology did not increase 5-year risk of CIN3 or worse for women negative by HPV testing to a substantial level (0·86% vs 0·16%; p=0·004). 12 208 (73%) of the women positive by HPV testing had no cytological abnormality, and these women had 258 (35%) of 747 CIN3 or adenocarcinoma in situ, 25 (29%) of 87 cancers, and 17 (63%) of 27 adenocarcinomas. Interpretation For women aged 30 years and older in routine clinical practice who are negative by co-testing (both HPV and cytology), 3-year screening intervals were safe because a single negative test for HPV was sufficient to reassure against cervical cancer over 5 years. Incorporating HPV testing with cytology also resulted in earlier identification of women at high risk of cervical cancer, especially adenocarcinoma. Testing for HPV without adjunctive cytology might be sufficiently sensitive for primary screening for cervical cancer. Funding Intramural Research Program of the US National Cancer Institute/NIH/DHHS, and the American Cancer Society.
The Onclarity cervical cancer screening trial was designed to establish the clinical validity of the Onclarity HPV assay for extended genotyping (xGT) during detection of high-grade cervical ...neoplasia grades 2 or 3 (≥CIN2 or ≥CIN3). Here, three-year follow up data is presented to evaluate the overall efficacy of these screening strategies, compared to the baseline data.
At baseline 29,513 women, ≥25 years, had evaluable cytology and valid high-risk HPV results. Women with atypical squamous cells-undetermined significance or worse cytology or a positive HPV test were referred for colposcopy/biopsy. Participants that did not reach the study end point (treatment for ≥CIN2) continued into the longitudinal phase that included the same protocol as baseline.
The three-year cumulative incident risk (CIR) for ≥CIN3 in HPV-negative women was 0.15% 95%CI: 0.06, 0.26 and for HPV- and cytology-negative women was 0.12% 95% CI: 0.03,0.23. HPV16 carried the highest baseline and three-year ≥CIN3 CIR, followed by HPV31 and HPV18. At least one year of genotype-specific persistence increased ≥CIN3 risk for xGT results compared to genotype non-persistence, HPV clearance, or new infection over the same time period. Risk-based screening with immediate colposcopy for HPV16/18/31 and further xGT triage resulted in better ≥CIN3 sensitivity (79.2% versus 72.3%; relative difference of 6.9 95%CI: 3.3, 10.4) and a lower colposcopy/≥CIN3 ratio (9.2 versus 11.2; relative difference of −1.9 95%CI: −2.6, −1.3) when compared to primary HPV16/18-based screening.
An HPV-negative result offers the same assurance of no disease over three years of follow up as that offered by a negative co-testing result. xGT facilitates risk-based screening and persistence tracking and can help optimize disease detection during screening without excessive colposcopic procedures.
•29,513 subjects had evaluable cytology and valid HPV test results at baseline and 4985 were followed for three years.•Three-year risk of ≥CIN3 in HPV-negative women was statistically indistinguishable from that for co-testing negative women.•HPV16 and HPV31 carried the highest ≥CIN3 baseline and cumulative incident (three-year) risk values regardless of cytology.•Extended genotyping resulted in a good balance of disease detection and risk stratification.•Genotype-specific persistence led to greater ≥CIN3 risk stratification than genotype switch or new infections.
Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitors, but drug resistance invariably emerges. To elucidate mechanisms of acquired ...drug resistance, we performed systematic genetic and histological analyses of tumor biopsies from 37 patients with drug-resistant non-small cell lung cancers (NSCLCs) carrying EGFR mutations. All drug-resistant tumors retained their original activating EGFR mutations, and some acquired known mechanisms of resistance including the EGFR T790M mutation or MET gene amplification. Some resistant cancers showed unexpected genetic changes including EGFR amplification and mutations in the PIK3CA gene, whereas others underwent a pronounced epithelial-to-mesenchymal transition. Surprisingly, five resistant tumors (14%) transformed from NSCLC into small cell lung cancer (SCLC) and were sensitive to standard SCLC treatments. In three patients, serial biopsies revealed that genetic mechanisms of resistance were lost in the absence of the continued selective pressure of EGFR inhibitor treatment, and such cancers were sensitive to a second round of treatment with EGFR inhibitors. Collectively, these results deepen our understanding of resistance to EGFR inhibitors and underscore the importance of repeatedly assessing cancers throughout the course of the disease.
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