Time-Integrated Neutrino Source Searches with 10 Years of IceCube Data.

This Letter presents the results from pointlike neutrino source searches using ten years of IceCube data collected between April 6, 2008 and July 10, 2018. We evaluate the significance of an astrophysical signal from a pointlike source looking for an excess of clustered neutrino events with energies typically above ∼1 TeV among the background of atmospheric muons and neutrinos. We perform a full-sky scan, a search within a selected source catalog, a catalog population study, and three stacked Galactic catalog searches. The most significant point in the northern hemisphere from scanning the sky is coincident with the Seyfert II galaxy NGC 1068, which was included in the source catalog search. The excess at the coordinates of NGC 1068 is inconsistent with background expectations at the level of 2.9σ after accounting for statistical trials from the entire catalog. The combination of this result along with excesses observed at the coordinates of three other sources, including TXS 0506+056, suggests that, collectively, correlations with sources in the northern catalog are inconsistent with background at 3.3σ significance. The southern catalog is consistent with background. These results, all based on searches for a cumulative neutrino signal integrated over the 10 years of available data, motivate further study of these and similar sources, including time-dependent analyses, multimessenger correlations, and the possibility of stronger evidence with coming upgrades to the detector.

Constraints on Minute-Scale Transient Astrophysical Neutrino Sources.

High-energy neutrino emission has been predicted for several short-lived astrophysical transients including gamma-ray bursts (GRBs), core-collapse supernovae with choked jets, and neutron star mergers. IceCube's optical and x-ray follow-up program searches for such transient sources by looking for two or more muon neutrino candidates in directional coincidence and arriving within 100 s. The measured rate of neutrino alerts is consistent with the expected rate of chance coincidences of atmospheric background events and no likely electromagnetic counterparts have been identified in Swift follow-up observations. Here, we calculate generic bounds on the neutrino flux of short-lived transient sources. Assuming an E^{-2.5} neutrino spectrum, we find that the neutrino flux of rare sources, like long gamma-ray bursts, is constrained to <5% of the detected astrophysical flux and the energy released in neutrinos (100 GeV to 10 PeV) by a median bright GRB-like source is <10^{52.5} erg. For a harder E^{-2.13} neutrino spectrum up to 30% of the flux could be produced by GRBs and the allowed median source energy is <10^{52} erg. A hypothetical population of transient sources has to be more common than 10^{-5} Mpc^{-3} yr^{-1} (5×10^{-8} Mpc^{-3} yr^{-1} for the E^{-2.13} spectrum) to account for the complete astrophysical neutrino flux.

Measurement of Atmospheric Neutrino Oscillations at 6-56 GeV with IceCube DeepCore.

We present a measurement of the atmospheric neutrino oscillation parameters using three years of data from the IceCube Neutrino Observatory. The DeepCore infill array in the center of IceCube enables the detection and reconstruction of neutrinos produced by the interaction of cosmic rays in Earth's atmosphere at energies as low as ∼5 GeV. That energy threshold permits measurements of muon neutrino disappearance, over a range of baselines up to the diameter of the Earth, probing the same range of L/E_{ν} as long-baseline experiments but with substantially higher-energy neutrinos. This analysis uses neutrinos from the full sky with reconstructed energies from 5.6 to 56 GeV. We measure Δm_{32}^{2}=2.31_{-0.13}^{+0.11}×10^{-3} eV^{2} and sin^{2}θ_{23}=0.51_{-0.09}^{+0.07}, assuming normal neutrino mass ordering. These results are consistent with, and of similar precision to, those from accelerator- and reactor-based experiments.

Search for neutrinos from decaying dark matter with IceCube: IceCube Collaboration.

With the observation of high-energy astrophysical neutrinos by the IceCube Neutrino Observatory, interest has risen in models of PeV-mass decaying dark matter particles to explain the observed flux. We present two dedicated experimental analyses to test this hypothesis. One analysis uses 6 years of IceCube data focusing on muon neutrino 'track' events from the Northern Hemisphere, while the second analysis uses 2 years of 'cascade' events from the full sky. Known background components and the hypothetical flux from unstable dark matter are fitted to the experimental data. Since no significant excess is observed in either analysis, lower limits on the lifetime of dark matter particles are derived: we obtain the strongest constraint to date, excluding lifetimes shorter than 10 28 s at 90% CL for dark matter masses above 10 TeV .

Measurement of the ν µ energy spectrum with IceCube-79: IceCube Collaboration.

IceCube is a neutrino observatory deployed in the glacial ice at the geographic South Pole. The ν µ energy unfolding described in this paper is based on data taken with IceCube in its 79-string configuration. A sample of muon neutrino charged-current interactions with a purity of 99.5% was selected by means of a multivariate classification process based on machine learning. The subsequent unfolding was performed using the software Truee. The resulting spectrum covers an E ν -range of more than four orders of magnitude from 125 GeV to 3.2 PeV. Compared to the Honda atmospheric neutrino flux model, the energy spectrum shows an excess of more than 1.9 σ in four adjacent bins for neutrino energies E ν ≥ 177.8 TeV . The obtained spectrum is fully compatible with previous measurements of the atmospheric neutrino flux and recent IceCube measurements of a flux of high-energy astrophysical neutrinos.

Constraints on Ultrahigh-Energy Cosmic-Ray Sources from a Search for Neutrinos above 10 PeV with IceCube.

We report constraints on the sources of ultrahigh-energy cosmic rays (UHECRs) above 10^{9} GeV, based on an analysis of seven years of IceCube data. This analysis efficiently selects very high- energy neutrino-induced events which have deposited energies from 5×10^{5} GeV to above 10^{11} GeV. Two neutrino-induced events with an estimated deposited energy of (2.6±0.3)×10^{6} GeV, the highest neutrino energy observed so far, and (7.7±2.0)×10^{5} GeV were detected. The atmospheric background-only hypothesis of detecting these events is rejected at 3.6σ. The hypothesis that the observed events are of cosmogenic origin is also rejected at >99% CL because of the limited deposited energy and the nonobservation of events at higher energy, while their observation is consistent with an astrophysical origin. Our limits on cosmogenic neutrino fluxes disfavor the UHECR sources having a cosmological evolution stronger than the star formation rate, e.g., active galactic nuclei and γ-ray bursts, assuming proton-dominated UHECRs. Constraints on UHECR sources including mixed and heavy UHECR compositions are obtained for models of neutrino production within UHECR sources. Our limit disfavors a significant part of parameter space for active galactic nuclei and new-born pulsar models. These limits on the ultrahigh-energy neutrino flux models are the most stringent to date.

Searches for Sterile Neutrinos with the IceCube Detector.

The IceCube neutrino telescope at the South Pole has measured the atmospheric muon neutrino spectrum as a function of zenith angle and energy in the approximate 320 GeV to 20 TeV range, to search for the oscillation signatures of light sterile neutrinos. No evidence for anomalous ν_{µ} or ν[over ¯]_{µ} disappearance is observed in either of two independently developed analyses, each using one year of atmospheric neutrino data. New exclusion limits are placed on the parameter space of the 3+1 model, in which muon antineutrinos experience a strong Mikheyev-Smirnov-Wolfenstein-resonant oscillation. The exclusion limits extend to sin^{2}2θ_{24}≤0.02 at Δm^{2}∼0.3 eV^{2} at the 90% confidence level. The allowed region from global analysis of appearance experiments, including LSND and MiniBooNE, is excluded at approximately the 99% confidence level for the global best-fit value of |U_{e4}|^{2}.

Evidence for Astrophysical Muon Neutrinos from the Northern Sky with IceCube.

Results from the IceCube Neutrino Observatory have recently provided compelling evidence for the existence of a high energy astrophysical neutrino flux utilizing a dominantly Southern Hemisphere data set consisting primarily of ν(e) and ν(τ) charged-current and neutral-current (cascade) neutrino interactions. In the analysis presented here, a data sample of approximately 35,000 muon neutrinos from the Northern sky is extracted from data taken during 659.5 days of live time recorded between May 2010 and May 2012. While this sample is composed primarily of neutrinos produced by cosmic ray interactions in Earth's atmosphere, the highest energy events are inconsistent with a hypothesis of solely terrestrial origin at 3.7σ significance. These neutrinos can, however, be explained by an astrophysical flux per neutrino flavor at a level of Φ(E(ν))=9.9(-3.4)(+3.9)×10(-19) GeV(-1) cm(-2) sr(-1) s(-1)(E(ν)/100 TeV(-2), consistent with IceCube's Southern-Hemisphere-dominated result. Additionally, a fit for an astrophysical flux with an arbitrary spectral index is performed. We find a spectral index of 2.2(-0.2)(+0.2), which is also in good agreement with the Southern Hemisphere result.

Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06).

BACKGROUND: Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. PATIENTS AND METHODS: In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. RESULTS: The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30,000 USD per patient. CONCLUSIONS: Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00544700.

Ecology and conservation: contributions to One Health.

Although One Health is widely promoted as a more effective approach towards human, animal and ecosystem health, the momentum is still driven largely by health professionals, predominantly from the veterinary sector. While few can doubt the merits of interdisciplinary One Health approaches to tackle complex health problems, operating across the disciplines still presents many challenges. This paper focuses on the contributions of partners from ecology and conservation to One Health approaches, and identifies four broad areas which could act as a focus for practical engagement and bring ecological and conservation objectives more to the forefront of the One Health agenda: i) developing initiatives with shared conservation and health objectives, particularly in and around protected areas and including programmes addressing human reproductive health and mental health; ii) broadening concepts of health to extend beyond indicators of disease to include the assessment of ecological impacts; iii) the integration of ecological and epidemiological monitoring systems within protected areas to support conservation management and wildlife disease surveillance; iv) building partnerships to bring conservation, health, development and animal welfare agencies together to combat threats to global biodiversity and health from the international trade in wildlife and wildlife products.

Intratumoural budding (ITB) in preoperative biopsies predicts the presence of lymph node and distant metastases in colon and rectal cancer patients.

BACKGROUND: In colorectal cancer (CRC), tumour budding at the invasion front is associated with lymph node (LN) and distant metastasis. Interestingly, tumour budding can also be detected in biopsies (intratumoural budding; ITB) and may have similar clinical importance. Here we investigate whether ITB in preoperative CRC biopsies can be translated into daily diagnostic practice. METHODS: Preoperative biopsies from 133 CRC patients (no neoadjuvant therapy) underwent immunohistochemistry for pan-cytokeratin marker AE1/AE3. Across all biopsies for each patient, the densest region of buds at × 40 (high-power field; HPF) was identified and buds were counted. RESULTS: A greater number of tumour buds in the biopsy was associated with pT stage (P=0.0143), LN metastasis (P=0.0007), lymphatic (P=0.0065) and venous vessel invasion (P=0.0318) and distant metastasis (cM1) (P=0.0013). Using logistic regression, a 'scale' was developed to estimate the probability of LN and distant metastasis using the number of tumour buds (e.g. 10 buds per HPF: 64% chance of LN metastasis; 30 buds per HPF: 86% chance). Inter-observer agreement for ITB was excellent (intraclass correlation coefficient: 0.813). CONCLUSION: Tumour budding can be assessed in the preoperative biopsy of CRC patients. It is practical, reproducible and predictive of LN and distant metastasis. Intratumoural budding qualifies for further investigation in the prospective setting.

Conserving large populations of lions - the argument for fences has holes.

Packer et al. reported that fenced lion populations attain densities closer to carrying capacity than unfenced populations. However, fenced populations are often maintained above carrying capacity, and most are small. Many more lions are conserved per dollar invested in unfenced ecosystems, which avoid the ecological and economic costs of fencing.

Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07.

BACKGROUND: We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). RESULTS: Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). CONCLUSIONS: The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.

Energy loss and charge transfer of argon in a laser-generated carbon plasma.

This Letter reports on the measurement of the energy loss and the projectile charge states of argon ions at an energy of 4 MeV/u penetrating a fully ionized carbon plasma. The plasma of n(e)≈10(20) cm(-3) and T(e)≈180 eV is created by two laser beams at λ(Las)=532 nm incident from opposite sides on a thin carbon foil. The resulting plasma is spatially homogenous and allows us to record precise experimental data. The data show an increase of a factor of 2 in the stopping power which is in very good agreement with a specifically developed Monte Carlo code, that allows the calculation of the heavy ion beam's charge state distribution and its energy loss in the plasma.

Development of a Nomarski-type multi-frame interferometer as a time and space resolving diagnostics for the free electron density of laser-generated plasma.

This article reports on the development and set-up of a Nomarski-type multi-frame interferometer as a time and space resolving diagnostics of the free electron density in laser-generated plasma. The interferometer allows the recording of a series of 4 images within 6 ns of a single laser-plasma interaction. For the setup presented here, the minimal accessible free electron density is 5 × 10(18) cm(-3), the maximal one is 2 × 10(20) cm(-3). Furthermore, it provides a resolution of the electron density in space of 50 µm and in time of 0.5 ns for one image with a customizable magnification in space for each of the 4 images. The electron density was evaluated from the interferograms using an Abel inversion algorithm. The functionality of the system was proven during first experiments and the experimental results are presented and discussed. A ray tracing procedure was realized to verify the interferometry pictures taken. In particular, the experimental results are compared to simulations and show excellent agreement, providing a conclusive picture of the evolution of the electron density distribution.

Multicenter phase II trial of preoperative induction chemotherapy followed by chemoradiation with docetaxel and cisplatin for locally advanced esophageal carcinoma (SAKK 75/02).

BACKGROUND: This multicenter phase II study investigated the efficacy and feasibility of preoperative induction chemotherapy followed by chemoradiation and surgery in patients with esophageal carcinoma. PATIENTS AND METHODS: Patients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the esophagus received induction chemotherapy with cisplatin 75 mg/m(2) and docetaxel (Taxotere) 75 mg/m(2) on days 1 and 22, followed by radiotherapy of 45 Gy (25 x 1.8 Gy) and concurrent chemotherapy comprising cisplatin 25 mg/m(2) and docetaxel 20 mg/m(2) weekly for 5 weeks, followed by surgery. RESULTS: Sixty-six patients were enrolled at eleven centers and 57 underwent surgery. R0 resection was achieved in 52 patients. Fifteen patients showed complete, 16 patients nearly complete and 26 patients poor pathological remission. Median overall survival was 36.5 months and median event-free survival was 22.8 months. Squamous cell carcinoma and good pathologically documented response were associated with longer survival. Eighty-two percent of all included patients completed neoadjuvant therapy and survived for 30 days after surgery. Dysphagia and mucositis grade 3/4 were infrequent (<9%) during chemoradiation. Five patients (9%) died due to surgical complications. CONCLUSIONS: This neoadjuvant, taxane-containing regimen was efficacious and feasible in patients with locally advanced esophageal cancer in a multicenter, community-based setting and represents a suitable backbone for further investigation.

Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK.

BACKGROUND: To determine the activity and tolerability of adding cetuximab to the oxaliplatin and capecitabine (XELOX) combination in first-line treatment of metastatic colorectal cancer (MCC). PATIENTS AND METHODS: In a multicenter two-arm phase II trial, patients were randomized to receive oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks alone or in combination with standard dose cetuximab. Treatment was limited to a maximum of six cycles. RESULTS: Seventy-four patients with good performance status entered the trial. Objective partial response rates after external review and radiological confirmation were 14% and 41% in the XELOX and in the XELOX + Cetuximab arm, respectively. Stable disease has been observed in 62% and 35% of the patients, with 76% disease control in both arms. Cetuximab led to skin rash in 65% of the patients. The median overall survival was 16.5 months for arm A and 20.5 months for arm B. The median time to progression was 5.8 months for arm A and 7.2 months for arm B. CONCLUSION: Differences in response rates between the treatment arms indicate that cetuximab may improve outcome with XELOX. The correct place of the cetuximab, oxaliplatin and fluoropyrimidine combinations in first-line treatment of MCC has to be assessed in phase III trials.

[A 56-year-old patient with Gaucher's disease sustaining a pathologic subcapital fracture of the humerus]. / 56-jährige Patientin mit pathologischer subkapitaler Humerusfraktur bei Morbus Gaucher.

We present a case of a pathologic humerus fracture in a patient with the initial diagnosis of Gaucher's disease, which is the most frequent form of lipidosis transmitted as an autosomal recessive trait. It often results in orthopaedic complications with pain, osteonecrosis, fractures and joint infractions. If there is cause for suspicion, beta-glucocerebrosidase in white blood cells should be measured because of the important consequences for treatment. Therapy with a modified enzyme is effective in managing the disease.

[Intra-articular ketamine after arthroscopic knee surgery. Optimisation of postoperative analgesia]. / Intraartikuläre Ketamingabe bei arthroskopischen Knieoperationen. Optimierung der postoperativen Analgesie.

BACKGROUND: Surgery of the knee can be very painful and sufficient postoperative pain treatment is often problematic. To optimize postoperative analgesia, application of local analgesics has been suggested. In the present study it was investigated whether intra-articular administration of ketamine reduces the level of pain after arthroscopic knee surgery. MATERIAL AND METHODS: A total of 68 patients undergoing arthroscopic knee surgery were randomized into 4 groups. At the end of surgery the following pharmaceuticals were administered: 10 ml 0.25% bupivacaine intra-articular (i.a.), 0.25 mg S-(+)-ketamine/kg body weight to 10 ml in 0.9% NaCl i.a., 0.25 mg S-(+)-ketamine/kg body weight intravenous (i.v.), and 10 ml 0.9% NaCl i.a. as placebo. Postoperative pain therapy was performed as i.v. patient controlled analgesia (PCA) with piritramide. Postoperative opioid consumption and pain intensity were assessed as the main criteria in the postoperative course. RESULTS: All 4 groups were comparable with respect to biometrical data. The scores of the visual analogue scale (VAS) showed a significantly (p<0.05) lower pain intensity in patients treated with ketamine i.a. or i.v. compared to the other groups. Shortly after surgery the highest reduction of pain was detected in the i.a. ketamine group compared to i.a. bupivacaine or placebo administration. The postoperative opioid consumption was always lowest in the i.a. ketamine group. A significant difference in piritramide consumption (p<0.05) was demonstrated in the first 20 min after operation in the i.a. ketamine group compared to the i.a. administration of placebo and bupivacaine. CONCLUSIONS: The i.a. application of ketamine after arthroscopic knee surgery leads to a significant decrease of postoperative analgesic demand and decreases patients' subjective level of pain compared to i.a. application of bupivacaine or placebo. Likewise, the i.v. application of ketamine is similarly effective but the effect is of shorter duration.