We report the discovery and constrain the physical conditions of the interstellar medium of the highest-redshift millimeter-selected dusty star-forming galaxy to date, SPT-S J031132−5823.4 (hereafter ...SPT0311−58), at . SPT0311−58 was discovered via its 1.4 mm thermal dust continuum emission in the South Pole Telescope (SPT)-SZ survey. The spectroscopic redshift was determined through an Atacama Large Millimeter/submillimeter Array 3 mm frequency scan that detected CO(6-5), CO(7-6), and (2-1), and subsequently was confirmed by detections of CO(3-2) with the Australia Telescope Compact Array and with APEX. We constrain the properties of the ISM in SPT0311−58 with a radiative transfer analysis of the dust continuum photometry and the CO and line emission. This allows us to determine the gas content without ad hoc assumptions about gas mass scaling factors. SPT0311−58 is extremely massive, with an intrinsic gas mass of . Its large mass and intense star formation is very rare for a source well into the epoch of reionization.
According to the current understanding of cosmic structure formation, the precursors of the most massive structures in the Universe began to form shortly after the Big Bang, in regions corresponding ...to the largest fluctuations in the cosmic density field. Observing these structures during their period of active growth and assembly-the first few hundred million years of the Universe-is challenging because it requires surveys that are sensitive enough to detect the distant galaxies that act as signposts for these structures and wide enough to capture the rarest objects. As a result, very few such objects have been detected so far. Here we report observations of a far-infrared-luminous object at redshift 6.900 (less than 800 million years after the Big Bang) that was discovered in a wide-field survey. High-resolution imaging shows it to be a pair of extremely massive star-forming galaxies. The larger is forming stars at a rate of 2,900 solar masses per year, contains 270 billion solar masses of gas and 2.5 billion solar masses of dust, and is more massive than any other known object at a redshift of more than 6. Its rapid star formation is probably triggered by its companion galaxy at a projected separation of 8 kiloparsecs. This merging companion hosts 35 billion solar masses of stars and has a star-formation rate of 540 solar masses per year, but has an order of magnitude less gas and dust than its neighbour and physical conditions akin to those observed in lower-metallicity galaxies in the nearby Universe. These objects suggest the presence of a dark-matter halo with a mass of more than 100 billion solar masses, making it among the rarest dark-matter haloes that should exist in the Universe at this epoch.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Discovery of magnetic Weyl fermions: Dirac fermions split into pairs of Weyl fermions by slow magnetic fluctuations.
Weyl fermions as emergent quasiparticles can arise in Weyl semimetals (WSMs) in ...which the energy bands are nondegenerate, resulting from inversion or time-reversal symmetry breaking. Nevertheless, experimental evidence for magnetically induced WSMs is scarce. Here, using photoemission spectroscopy, we observe that the degeneracy of Bloch bands is already lifted in the paramagnetic phase of EuCd
2
As
2
. We attribute this effect to the itinerant electrons experiencing quasi-static and quasi–long-range ferromagnetic fluctuations. Moreover, the spin-nondegenerate band structure harbors a pair of ideal Weyl nodes near the Fermi level. Hence, we show that long-range magnetic order and the spontaneous breaking of time-reversal symmetry are not essential requirements for WSM states in centrosymmetric systems and that WSM states can emerge in a wider range of condensed matter systems than previously thought.
Summary Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment ...can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary
Background
Strict avoidance is the only accepted management for cow's milk (CM) allergy. CM oral immunotherapy (CM‐OIT) is under investigation.
Objectives
To evaluate long‐term safety of ...CM‐OIT. To identify clinical/immunological predictors of adverse events.
Methods
Prospective longitudinal epidemiological intervention study. CM‐allergic children aged 5–18 underwent a Spanish‐approved CM‐OIT protocol without premedication. Clinical data, skin prick test (SPT) and specific IgE (sIgE) at baseline and 1 year after OIT were registered. All dose‐related reactions, treatments needed and cofactors involved were recorded. Through survival analysis, we studied the cumulative probability of reactions resolution over time and clinical/immunological risk factors of reactions persistence.
Results
81 children were recruited. Mean follow‐up was 25 months. 95% of children suffered reactions, 91% of which affected a single organ. Reactions were heterogeneously distributed: (a) 60 children (75%) had occasional symptoms which ceased over time. 86% of them reached complete desensitization (200 mL). (b) 20 children (25%) suffered frequent (78% of total reactions), more severe and unpredictable reactions, which persisted during follow‐up or led to withdrawal (6 cases). Reactions persistence was associated with a higher frequency and severity. Kaplan–Meier estimate revealed a cumulative probability of reactions resolution of 25% at 3 months (95% CI: 1.9–4.1) and 50% (95% CI: 6.1–9.9) at 8 months based on all patients. Cox proportional hazards multivariate regression model identified 3 variables (CM‐sIgE ≥ 50 KU L−1, CM‐SPT ≥ 9 mm and Sampson's severity grades 2, 3 and 4 at baseline food challenge) as independent risk factors of reactions persistence. The combination of 2 or 3 of these factors involved hazard ratios to develop persistent reactions of 2.26 (95% CI: 1.14–4.46; P = 0.019) and 6.06 (95% CI: 2.7–13.7; P < 0.001), respectively.
Clinical implications
CM‐OIT was insufficiently safe in 25% of children. The above‐mentioned clinical and immunological parameters would help clinicians to identify highly reactive patients before CM‐OIT. In them, individualized schedules and premedication should be considered.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Hexagonal boron nitride (h-BN) is a natural hyperbolic material, in which the dielectric constants are the same in the basal plane (ε(t) ≡ ε(x) = ε(y)) but have opposite signs (ε(t)ε(z) < 0) in the ...normal plane (ε(z)). Owing to this property, finite-thickness slabs of h-BN act as multimode waveguides for the propagation of hyperbolic phonon polaritons--collective modes that originate from the coupling between photons and electric dipoles in phonons. However, control of these hyperbolic phonon polaritons modes has remained challenging, mostly because their electrodynamic properties are dictated by the crystal lattice of h-BN. Here we show, by direct nano-infrared imaging, that these hyperbolic polaritons can be effectively modulated in a van der Waals heterostructure composed of monolayer graphene on h-BN. Tunability originates from the hybridization of surface plasmon polaritons in graphene with hyperbolic phonon polaritons in h-BN, so that the eigenmodes of the graphene/h-BN heterostructure are hyperbolic plasmon-phonon polaritons. The hyperbolic plasmon-phonon polaritons in graphene/h-BN suffer little from ohmic losses, making their propagation length 1.5-2.0 times greater than that of hyperbolic phonon polaritons in h-BN. The hyperbolic plasmon-phonon polaritons possess the combined virtues of surface plasmon polaritons in graphene and hyperbolic phonon polaritons in h-BN. Therefore, graphene/h-BN can be classified as an electromagnetic metamaterial as the resulting properties of these devices are not present in its constituent elements alone.
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IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UL, UM, UPUK
Summary Background Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss ...of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor. Methods ARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA. In ARIEL2 Part 1, patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma were classified into one of three predefined homologous recombination deficiency subgroups on the basis of tumour mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). We prespecified a cutoff of 14% or more genomic LOH for LOH high. Patients began treatment with oral rucaparib at 600 mg twice per day for continuous 28 day cycles until disease progression or any other reason for discontinuation. The primary endpoint was progression-free survival. All patients treated with at least one dose of rucaparib were included in the safety analyses and all treated patients who were classified were included in the primary endpoint analysis. This trial is registered with ClinicalTrials.gov , number NCT01891344 . Enrolment into ARIEL2 Part 1 is complete, although an extension (Part 2) is ongoing. Findings 256 patients were screened and 206 were enrolled between Oct 30, 2013, and Dec 19, 2014. At the data cutoff date (Jan 18, 2016), 204 patients had received rucaparib, with 28 patients remaining in the study. 192 patients could be classified into one of the three predefined homologous recombination deficiency subgroups: BRCA mutant (n=40), LOH high (n=82), or LOH low (n=70). Tumours from 12 patients were established as BRCA wild-type, but could not be classified for LOH, because of insufficient neoplastic nuclei in the sample. The median duration of treatment for the 204 patients was 5·7 months (IQR 2·8–10·1). 24 patients in the BRCA mutant subgroup, 56 patients in the LOH high subgroup, and 59 patients in the LOH low subgroup had disease progression or died. Median progression-free survival after rucaparib treatment was 12·8 months (95% CI 9·0–14·7) in the BRCA mutant subgroup, 5·7 months (5·3–7·6) in the LOH high subgroup, and 5·2 months (3·6–5·5) in the LOH low subgroup. Progression-free survival was significantly longer in the BRCA mutant (hazard ratio 0·27, 95% CI 0·16–0·44, p<0·0001) and LOH high (0·62, 0·42–0·90, p=0·011) subgroups compared with the LOH low subgroup. The most common grade 3 or worse treatment-emergent adverse events were anaemia or decreased haemoglobin (45 22% patients), and elevations in alanine aminotransferase or aspartate aminotransferase (25 12%). Common serious adverse events included small intestinal obstruction (10 5% of 204 patients), malignant neoplasm progression (10 5%), and anaemia (nine 4%). Three patients died during the study (two because of disease progression and one because of sepsis and disease progression). No treatment-related deaths occurred. Interpretation In patients with BRCA mutant or BRCA wild-type and LOH high platinum-sensitive ovarian carcinomas treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type LOH low carcinomas. Our results suggest that assessment of tumour LOH can be used to identify patients with BRCA wild-type platinum-sensitive ovarian cancers who might benefit from rucaparib. These results extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours. Funding Clovis Oncology, US Department of Defense Ovarian Cancer Research Program, Stand Up To Cancer—Ovarian Cancer Research Fund Alliance—National Ovarian Cancer Coalition Dream Team Translational Research Grant, and V Foundation Translational Award.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Most malaria deaths occur in rural areas. Rapid progression from illness to death can be interrupted by prompt, effective medication. Antimalarial treatment cannot rescue ...terminally ill patients but could be effective if given earlier. If patients who cannot be treated orally are several hours from facilities for injections, rectal artesunate can be given before referral and acts rapidly on parasites. We investigated whether this intervention reduced mortality and permanent disability. Methods In Bangladesh, Ghana, and Tanzania, patients with suspected severe malaria who could not be treated orally were allocated randomly to a single artesunate (n=8954) or placebo (n=8872) suppository by taking the next numbered box, then referred to clinics at which injections could be given. Those with antimalarial injections or negative blood smears before randomisation were excluded, leaving 12 068 patients (6072 artesunate, 5996 placebo) for analysis. Primary endpoints were mortality, assessed 7–30 days later, and permanent disability, reassessed periodically. All investigators were masked to group assignment. Analysis was by intention to treat. This study is registered in all three countries, numbers ISRCTN83979018, 46343627, and 76987662. Results Mortality was 154 of 6072 artesunate versus 177 of 5996 placebo (2·5% vs 3·0%, p=0·1). Two versus 13 (0·03% vs 0·22%, p=0·0020) were permanently disabled; total dead or disabled: 156 versus 190 (2·6% vs 3·2%, p=0·0484). There was no reduction in early mortality (56 vs 51 deaths within 6 h; median 2 h). In patients reaching clinic within 6 h (median 3 h), pre-referral artesunate had no significant effect on death after 6 h or permanent disability (71/4450 1·6% vs 82/4426 1·9%, risk ratio 0·86 95% CI 0·63–1·18, p=0·35). In patients still not in clinic after more than 6 h, however, half were still not there after more than 15 h, and pre-referral rectal artesunate significantly reduced death or permanent disability (29/1566 1·9% vs 57/1519 3·8%, risk ratio 0·49 95% CI 0·32–0·77, p=0·0013). Interpretation If patients with severe malaria cannot be treated orally and access to injections will take several hours, a single inexpensive artesunate suppository at the time of referral substantially reduces the risk of death or permanent disability. Funding UNICEF/UNDP/World Bank Special Programme for Research and Training in Tropical Diseases (WHO/TDR); WHO Global Malaria Programme (WHO/GMP); Sall Family Foundation; the European Union (QLRT-2000-01430); the UK Medical Research Council; USAID; Irish Aid; the Karolinska Institute; and the University of Oxford Clinical Trial Service Unit (CTSU).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. ...The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.
ABSTRACT We use the Atacama Large Millimeter/submillimeter Array (ALMA) in Cycle 1 to determine spectroscopic redshifts of high-redshift dusty star-forming galaxies (DSFGs) selected by their 1.4 mm ...continuum emission in the South Pole Telescope (SPT) survey. We present ALMA 3 mm spectral scans between 84 and 114 GHz for 15 galaxies and targeted ALMA 1 mm observations for an additional eight sources. Our observations yield 30 new line detections from CO, C i, N ii, H2O and NH3. We further present Atacama Pathfinder Experiment C ii and CO mid-J observations for seven sources for which only a single line was detected in spectral-scan data from ALMA Cycle 0 or Cycle 1. We combine the new observations with previously published and new millimeter/submillimeter line and photometric data of the SPT-selected DSFGs to study their redshift distribution. The combined data yield 39 spectroscopic redshifts from molecular lines, a success rate of >85%. Our sample represents the largest data set of its kind today and has the highest spectroscopic completeness among all redshift surveys of high-z DSFGs. The median of the redshift distribution is z = 3.9 0.4, and the highest-redshift source in our sample is at z = 5.8. We discuss how the selection of our sources affects the redshift distribution, focusing on source brightness, selection wavelength, and strong gravitational lensing. We correct for the effect of gravitational lensing and find the redshift distribution for 1.4 mm selected sources with a median redshift of z = 3.1 0.3. Comparing to redshift distributions selected at shorter wavelengths from the literature, we show that selection wavelength affects the shape of the redshift distribution.
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