Synoptic Sky Surveys and the Diffuse Supernova Neutrino Background: Removing Astrophysical Uncertainties and Revealing Invisible Supernovae

The cumulative (anti)neutrino production from all core-collapse supernovae within our cosmic horizon gives rise to the diffuse supernova neutrino background (DSNB), which is on the verge of detectability. The observed flux depends on supernova physics, but also on the cosmic history of supernova explosions; currently, the cosmic supernova rate introduces a substantial (+/-40%) uncertainty, largely through its absolute normalization. However, a new class of wide-field, repeated-scan (synoptic) optical sky surveys is coming online, and will map the sky in the time domain with unprecedented depth, completeness, and dynamic range. We show that these surveys will obtain the cosmic supernova rate by direct counting, in an unbiased way and with high statistics, and thus will allow for precise predictions of the DSNB. Upcoming sky surveys will substantially reduce the uncertainties in the DSNB source history to an anticipated +/-5% that is dominated by systematics, so that the observed high-energy flux thus will test supernova neutrino physics. The portion of the universe (z < 1) accessible to upcoming sky surveys includes the progenitors of a large fraction (~ 87%) of the expected 10-26 MeV DSNB event rate. We show that precision determination of the (optically detected) cosmic supernova history will also make the DSNB into a strong probe of an extra flux of neutrinos from optically invisible supernovae, which may be unseen either due to unexpected large dust obscuration in host galaxies, or because some core-collapse events proceed directly to black hole formation and fail to give an optical outburst.Comment: 11 pages, 6 figure

CRISPRi-based radiation modifier screen identifies long non-coding RNA therapeutic targets in glioma.

BackgroundLong non-coding RNAs (lncRNAs) exhibit highly cell type-specific expression and function, making this class of transcript attractive for targeted cancer therapy. However, the vast majority of lncRNAs have not been tested as potential therapeutic targets, particularly in the context of currently used cancer treatments. Malignant glioma is rapidly fatal, and ionizing radiation is part of the current standard-of-care used to slow tumor growth in both adult and pediatric patients.ResultsWe use CRISPR interference (CRISPRi) to screen 5689 lncRNA loci in human glioblastoma (GBM) cells, identifying 467 hits that modify cell growth in the presence of clinically relevant doses of fractionated radiation. Thirty-three of these lncRNA hits sensitize cells to radiation, and based on their expression in adult and pediatric gliomas, nine of these hits are prioritized as lncRNA Glioma Radiation Sensitizers (lncGRS). Knockdown of lncGRS-1, a primate-conserved, nuclear-enriched lncRNA, inhibits the growth and proliferation of primary adult and pediatric glioma cells, but not the viability of normal brain cells. Using human brain organoids comprised of mature neural cell types as a three-dimensional tissue substrate to model the invasive growth of glioma, we find that antisense oligonucleotides targeting lncGRS-1 selectively decrease tumor growth and sensitize glioma cells to radiation therapy.ConclusionsThese studies identify lncGRS-1 as a glioma-specific therapeutic target and establish a generalizable approach to rapidly identify novel therapeutic targets in the vast non-coding genome to enhance radiation therapy

The role of frailty in geriatric cranial neurosurgery for primary central nervous system neoplasms

OBJECTIVE. Frailty is a clinical state of increased vulnerability due to age-associated decline and has been well established as a perioperative risk factor. Geriatric patients have a higher risk of frailty, higher incidence of brain cancer, and increased postoperative complication rates compared to nongeriatric patients. Yet, literature describing the effects of frailty on short- and long-term complications in geriatric patients is limited. In this study, the authors evaluate the effects of frailty in geriatric patients receiving cranial neurosurgery for a primary CNS neoplasm. METHODS. The authors conducted a retrospective cohort study of geriatric patients receiving cranial neurosurgery for a primary CNS neoplasm between 2010 and 2017 by using the Nationwide Readmission Database. Demographics and frailty were queried at primary admission, and readmissions were analyzed at 30-, 90-, and 180-day intervals. Complications of interest included infection, anemia, infarction, kidney injury, CSF leak, urinary tract infection, and mortality. Nearest-neighbor propensity score matching for demographics was implemented to identify nonfrail control patients with similar diagnoses and procedures. The analysis used Welch two-sample t-tests for continuous variables and chi-square test with odds ratios. RESULTS. A total of 6713 frail patients and 6629 nonfrail patients were identified at primary admission. At primary admission, frail geriatric patients undergoing cranial neurosurgery had increased odds of developing acute posthemorrhagic anemia (OR 1.56, 95% CI 1.23–1.98; p = 0.00020); acute infection (OR 3.16, 95% CI 1.70–6.36; p = 0.00022); acute kidney injury (OR 1.32, 95% CI 1.07–1.62; p = 0.0088); urinary tract infection prior to discharge (OR 1.97, 95% CI 1.71–2.29; p < 0.0001); acute postoperative cerebral infarction (OR 1.57, 95% CI 1.17–2.11; p = 0.0026); and mortality (OR 1.64, 95% CI 1.22–2.24; p = 0.0012) compared to nonfrail geriatric patients receiving the same procedure. In addition, frail patients had a significantly increased inpatient length of stay (p < 0.0001) and all-payer hospital cost (p < 0.0001) compared to nonfrail patients at the time of primary admission. However, no significant difference was found between frail and nonfrail patients with regard to rates of infection, thromboembolism, CSF leak, dural tear, cerebral infarction, acute kidney injury, and mortality at all readmission time points. CONCLUSIONS. Frailty may significantly increase the risks of short-term acute complications in geriatric patients receiving cranial neurosurgery for a primary CNS neoplasm. Long-term analysis revealed no significant difference in complications between frail and nonfrail patients. Further research is warranted to understand the effects and timeline of frailty in geriatric patients

Predictors of Patient Satisfaction in Spine Surgery: A Systematic Review

Background: Recently, there has been increased interest in patient satisfaction measures such as Press Ganey and Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) surveys. In this systematic review, the spine surgery literature is analyzed to evaluate factors predictive of patient satisfaction as measured by these surveys. Methods: A thorough literature search was performed in PubMed/MEDLINE, Google Scholar, and Cochrane databases. All English-language articles from database inception to July 2020 were screened for study inclusion according to PRISMA guidelines. Results: Twenty-four of the 1899 published studies were included for qualitative analysis. There has been a statistically significant increase in the number of publications across years (P = 0.04). Overall, the studies evaluated the relationship between patient satisfaction and patient demographics (71%), preoperative and intraoperative clinical factors (21%), and postoperative factors (33%). Top positive predictors of patient satisfaction were patient and nursing/medical staff relationship (n = 4; 17%), physician–patient relationship (n = 4; 17%), managerial oversight of received care (n = 3; 13%), same sex/ethnicity between patient and physician (n = 2; 8%), and older age (n = 2; 8%). Top negative predictors of patient satisfaction were high Charlson Comorbidity Index/high disability/worse overall health functioning (n = 7; 29%), increased length of hospital stay (n = 4; 17%), high rating for pain/complications/readmissions (n = 4; 17%), and psychosocial factors (n = 3; 13%). Conclusions: There is heterogeneity in terms of different factors, both clinical and nonclinically related, that affect patient satisfaction ratings. More research is warranted to investigate the role of hospital consumer surveys in the spine surgical patient population

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

Learned Value Magnifies Salience-Based Attentional Capture

Visual attention is captured by physically salient stimuli (termed salience-based attentional capture), and by otherwise task-irrelevant stimuli that contain goal-related features (termed contingent attentional capture). Recently, we reported that physically nonsalient stimuli associated with value through reward learning also capture attention involuntarily (Anderson, Laurent, & Yantis, PNAS, 2011). Although it is known that physical salience and goal-relatedness both influence attentional priority, it is unknown whether or how attentional capture by a salient stimulus is modulated by its associated value. Here we show that a physically salient, task-irrelevant distractor previously associated with a large reward slows visual search more than an equally salient distractor previously associated with a smaller reward. This magnification of salience-based attentional capture by learned value extinguishes over several hundred trials. These findings reveal a broad influence of learned value on involuntary attentional capture

All-sky Medium Energy Gamma-ray Observatory: Exploring the Extreme Multimessenger Universe

The All-sky Medium Energy Gamma-ray Observatory (AMEGO) is a probe class mission concept that will provide essential contributions to multimessenger astrophysics in the late 2020s and beyond. AMEGO combines high sensitivity in the 200 keV to 10 GeV energy range with a wide field of view, good spectral resolution, and polarization sensitivity. Therefore, AMEGO is key in the study of multimessenger astrophysical objects that have unique signatures in the gamma-ray regime, such as neutron star mergers, supernovae, and flaring active galactic nuclei. The order-of-magnitude improvement compared to previous MeV missions also enables discoveries of a wide range of phenomena whose energy output peaks in the relatively unexplored medium-energy gamma-ray band

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie