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Cuvier's beaked whales (Ziphius cavirostris) are known as extreme divers, though behavioral data from this difficult-to-study species have been limited. They are also the species most often stranded in association with Mid-Frequency Active (MFA) sonar use, a relationship that remains poorly understood. We used satellite-linked tags to record the diving behavior and locations of eight Ziphius off the Southern California coast for periods up to three months. The effort resulted in 3732 hr of dive data with associated regional movements--the first dataset of its kind for any beaked whale--and included dives to 2992 m depth and lasting 137.5 min, both new mammalian dive records. Deep dives had a group mean depth of 1401 m (s.d. = 137.8, n = 1142) and duration of 67.4 min (s.d. = 6.9). The group mean time between deep dives was 102.3 min (s.d. = 30.8, n = 783). While the previously described stereotypic pattern of deep and shallow dives was apparent, there was considerable inter- and intra-individual variability in most parameters. There was significant diel behavioral variation, including increased time near the surface and decreased shallow diving at night. However, maximum depth and the proportion of time spent on deep dives (presumed foraging), varied little from day to night. Surprisingly, tagged whales were present within an MFA sonar training range for 38% of days locations were received, and though comprehensive records of sonar use during tag deployments were not available, we discuss the effects frequent acoustic disturbance may have had on the observed behaviors. These data better characterize the true behavioral range of this species, and suggest caution should be exercised when drawing conclusions about behavior using short-term datasets.

Objective Implement and demonstrate feasibility of in situ simulations to identify latent safety threats (LSTs) at a higher rate than lab-based training, and reinforce teamwork training in a paediatric emergency department (ED). Methods Multidisciplinary healthcare providers responded to critical simulated patients in an urban ED during all shifts. Unannounced in situ simulations were limited to 10 min of simulation and 10 min of debriefing, and were video recorded. A standardised debriefing template was used to assess LSTs. The primary outcome measure was the number and type of LSTs identified during the simulations. Secondary measures included: participants’ assessment of impact on patient care and value to participants. Blinded video review using a modified Anaesthetists Non-Technical Skills scale was used to assess team behaviours. Results 218 healthcare providers responded to 90 in situ simulations conducted over 1 year. A total of 73 LSTs were identified; a rate of one every 1.2 simulations performed. In situ simulations were cancelled at a rate of 28% initially, but the cancellation rate decreased as training matured. Examples of threats identified include malfunctioning equipment and knowledge gaps concerning role responsibilities. 78% of participants rated the simulations as extremely valuable or valuable, while only 5% rated the simulation as having little or no value. Of those responding to a postsimulation survey, 77% reported little or no clinical impact. Video recordings did not indicate changes in non-technical skills during this time. Conclusions In situ simulation is a practical method for the detection of LSTs and to reinforce team training behaviours. Embedding in situ simulation as a routine expectation positively affected operations and the safety climate in a high risk clinical setting.

The ICARUS T600 detector is the largest liquid argon time projection chamber (LArTPC) to be built and operated [1]. This detector was in operation in the INFN Gran Sasso underground laboratory until 2012, exposed to the CERN Neutrino to Gran Sasso (CNGS) νµ beam, performing neutrino oscillation studies. The ICARUS T600 is presently under refurbishment in order to make it suitable for surface level operation, as it will serve as the far detector for the Short-Baseline Neutrino (SBN) Program at Fermilab [2]. A major upgrade of the ICARUS detector in order to allow it to cope with a high cosmic background is the upgrade of the light collection system. The study presented here shows a simulation to optimize the PMT layout to allow for the localization and identification of interaction within the T600. An excellent performance can be obtained, with an error on the localization smaller than 20 cm and of the order of a few percent in the identification of cosmic rays.

Background: Despite major advances in the management of metastatic colorectal cancer (mCRC) with liver-only involvement, relapse rates are high and reliable prognostic markers are needed. Methods: To assess the prognostic impact of BRAF and RAS mutations in a large series of liver-resected patients, medical records of 3024 mCRC patients were reviewed. Eligible cases undergoing potentially curative liver resection were selected. BRAF and RAS mutational status was tested on primary and/or metastases by means of pyrosequencing and mass spectrometry genotyping assay. Primary endpoint was relapse-free survival (RFS). Results: In the final study population ( N =309) BRAF mutant, RAS mutant and all wild-type (wt) patients were 12(4%), 160(52%) and 137(44%), respectively. Median RFS was 5.7, 11.0 and 14.4 months respectively and differed significantly (Log-rank, P =0.043). At multivariate analyses, BRAF mutant had a higher risk of relapse in comparison to all wt (multivariate hazard ratio (HR)=2.31; 95% CI, 1.09–4.87; P =0.029) and to RAS mutant (multivariate HR=2.06; 95% CI, 1.02–4.14; P =0.044). Similar results were obtained in terms of overall survival. Compared with all wt patients, RAS mutant showed a higher risk of death (HR=1.47; 95% CI, 1.05–2.07; P =0.025), but such effect was lost at multivariate analyses. Conclusions: BRAF mutation is associated with an extremely poor median RFS after liver resection and with higher probability of relapse and death. Knowledge of BRAF mutational status may optimise clinical decision making in mCRC patients potentially candidate to hepatic surgery. RAS status as useful marker in this setting might require further studies.

Birth of a black-hole relativistic jet Two groups report observations of the X-ray source Swift J164449.3+573451, which was discovered when it triggered the Swift Burst Alert Telescope on 28 March 2011. Burrows et al . report that the source has increased in brightness in the X-ray band more than 10,000-fold since 1990, and by more than 100-fold since early 2010. They conclude that we are observing the onset of relativistic jet activity from a supermassive black hole. Zauderer et al . arrive at a similar conclusion based on their observation of a radio transient associated with the source, and extensive monitoring at centimetre to millimetre wavelengths during the first month of its evolution. They estimate the mass of the black hole at around 10 6 solar masses. Supermassive black holes have powerful gravitational fields with strong gradients that can destroy stars that get too close 1 , 2 , producing a bright flare in ultraviolet and X-ray spectral regions from stellar debris that forms an accretion disk around the black hole 3 , 4 , 5 , 6 , 7 . The aftermath of this process may have been seen several times over the past two decades in the form of sparsely sampled, slowly fading emission from distant galaxies 8 , 9 , 10 , 11 , 12 , 13 , 14 , but the onset of the stellar disruption event has not hitherto been observed. Here we report observations of a bright X-ray flare from the extragalactic transient Swift J164449.3+573451. This source increased in brightness in the X-ray band by a factor of at least 10,000 since 1990 and by a factor of at least 100 since early 2010. We conclude that we have captured the onset of relativistic jet activity from a supermassive black hole. A companion paper 15 comes to similar conclusions on the basis of radio observations. This event is probably due to the tidal disruption of a star falling into a supermassive black hole, but the detailed behaviour differs from current theoretical models of such events.

Polymerase chain reaction (PCR)-based minimal residual disease (MRD) analysis is a useful prognostic tool in multiple myeloma (MM), although its long-term impact still needs to be addressed. This report presents the updated results of the GIMEMA-VEL-03-096 trial. Thirty-nine MM patients receiving bortezomib–thalidomide–dexamethasone after autologous transplantation were monitored for MRD by both nested and real-time quantitative-PCR until relapse. Our data confirm the strong impact of MRD on survival: overall survival was 72% at 8 years median follow-up for patients in major MRD response versus 48% for those experiencing MRD persistence ( P =0.041). In addition, MRD kinetics resulted predictive for relapse: indeed median remission duration was not reached for patients in major MRD response, 38 months for those experiencing MRD reappearance and 9 months for patients with MRD persistence ( P <0.001). Moreover: (1) 26 patients achieving major MRD response (67%) benefit of excellent disease control (median TNT: 42 months); (2) MRD reappearance heralds relapse, with a TNT comparable to that of MRD persistence (9 versus 10 months, P =0.706); (3) the median lag between MRD reappearance and need for salvage treatment is 9 months. These results suggest the usefulness of a long-term MRD monitoring in MM patients and the need for maintenance or pre-emptive treatments ensuring durable responses.

Background: KRAS codons 12 and 13 mutations predict resistance to anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer. Also, BRAF V600E mutation has been associated with resistance. Additional KRAS mutations are described in CRC. Methods: We investigated the role of KRAS codons 61 and 146 and BRAF V600E mutations in predicting resistance to cetuximab plus irinotecan in a cohort of KRAS codons 12 and 13 wild-type patients. Results: Among 87 KRAS codons 12 and 13 wild-type patients, KRAS codons 61 and 146 were mutated in 7 and 1 case, respectively. None of mutated patients responded vs 22 of 68 wild type ( P =0.096). Eleven patients were not evaluable. KRAS mutations were associated with shorter progression-free survival (PFS, HR: 0.46, P =0.028). None of 13 BRAF -mutated patients responded vs 24 of 74 BRAF wild type ( P =0.016). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P =0.073). In the subgroup of BRAF wild-type patients, KRAS codons 61/146 mutations determined a lower response rate (0 vs 37%, P =0.047) and worse PFS (HR: 0.45, P =0.023). Patients bearing KRAS or BRAF mutations had poorer response rate (0 vs 37%, P =0.0005) and PFS (HR: 0.51, P =0.006) compared with KRAS and BRAF wild-type patients. Conclusion: Assessing KRAS codons 61/146 and BRAF V600E mutations might help optimising the selection of the candidate patients to receive anti-EGFR moAbs.

Mid-frequency military (1–10 kHz) sonars have been associated with lethal mass strandings of deep-diving toothed whales, but the effects on endangered baleen whale species are virtually unknown. Here, we used controlled exposure experiments with simulated military sonar and other mid-frequency sounds to measure behavioural responses of tagged blue whales (Balaenoptera musculus) in feeding areas within the Southern California Bight. Despite using source levels orders of magnitude below some operational military systems, our results demonstrate that mid-frequency sound can significantly affect blue whale behaviour, especially during deep feeding modes. When a response occurred, behavioural changes varied widely from cessation of deep feeding to increased swimming speed and directed travel away from the sound source. The variability of these behavioural responses was largely influenced by a complex interaction of behavioural state, the type of mid-frequency sound and received sound level. Sonar-induced disruption of feeding and displacement from high-quality prey patches could have significant and previously undocumented impacts on baleen whale foraging ecology, individual fitness and population health.

1. Marine mammals may be negatively affected by anthropogenic noise. Behavioural response studies (BRS) aim to establish a relationship between noise exposure conditions (dose) from a potential Stressor and associated behavioural responses of animals. A recent series of BRS have focused on the effects of naval sonar sounds on cetaceans. Here, we review the current state of understanding of naval sonar impact on marine mammals and highlight knowledge gaps and future research priorities. 2. Many marine mammal species exhibit responses to naval sonar sounds. However, responses vary between and within individuals and populations, highlighting the importance of exposure context in modulating dose-response relationships. 3. There is increasing support from both terrestrial and marine systems for the risk-disturbance hypothesis as an explanation for underlying response processes. This proposes that sonar sounds may be perceived by animals as a threat, evoking a response shaped by the underlying species-specific risk of predation and antipredator strategy. An understanding of responses within both the dose-response and risk-disturbance frameworks may enhance our ability to predict responsiveness for unstudied species and populations. 4. Many observed behavioural responses are energetically costly, but the way that these responses may lead to long-term individual and population-level impacts is poorly understood. 5. Synthesis and applications. Behavioural response studies have greatly improved our understanding of the potential effects of naval sonar on marine mammals. Despite data gaps, we believe a dose-response approach within a risk-disturbance framework will enhance our ability to predict responsiveness for unstudied species and populations. W e advocate for (1) regulatory frameworks to utilize peer-reviewed research findings when making predictions of impact, (2) regulatory frameworks to account for the inherent uncertainty in predictions of impact and (3) investment in monitoring programmes that are both directed by recent research and offer opportunities for validation of predictions at the individual and population level.

Depth distributions were analyzed from a study of 19 Cuvier’s beaked whales Ziphius cavirostris that were tagged with satellite transmitting instruments off southern California, USA. Over 113 000 depth measurements were made over the equivalent of ∼200 sampling days. The mean foraging depth was 1182 m (SD = 305 m), and the mean of the maximum depth of all foraging dives was 1427 m (SD = 298 m). Mean foraging depths increased with seafloor depths up to a maximum of ∼1300 m at a seafloor depth of 1900 m, but decreased slightly to a mean of ∼1200 m at seafloor depths of 2000–4000 m. Near-bottom habitat appears to be important for foraging; whales spent ∼30% of their foraging time within 200 m of the bottom at seafloor depths of 1000–2000 m. However, little foraging time was spent near the bottom at seafloor depths greater than 2000 m. The percentage of time spent at near-surface depths (< 50 m) was more than twice as high at night (25%) than during the day (12%). Lunar light also appears to affect diving, with 28% of dark nights and only 17% of brightly moonlit nights spent at these near-surface depths. The apparent avoidance of surface waters during daytime and on brightly moonlit nights is consistent with avoidance of visual predators. A considerably greater fraction of time was spent foraging at night (24.8%) than during the day (15.7%), possibly due to energetic constraints imposed by predator avoidance during the day.