This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature ...is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype‐guided warfarin dosing to achieve a target international normalized ratio of 2–3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.
Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one ...has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients.
Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified.
One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N=52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren’s syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N=6) or neurological disorders (N=5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N=67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3–4) and 8 (12%) discontinued treatment. There were no treatment-related deaths.
In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.
Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%–30% of patients recur within 1 year. This ...study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy.
Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately.
Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3–35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors.
Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.
•Melanoma recurrence occurred in 147 (17%) of 850 patients, after a median 4.6 months after starting adjuvant PD1.•At initial recurrence, 57% had distant metastases, mostly detected on imaging while asymptomatic.•Some 38% of patients with initial local recurrence then recurred distantly within short follow-up (median 8.3 months).•PD1 monotherapy was not active in those who recurred ON adjuvant PD1, but had activity in those who recurred OFF adjuvant PD1.•BRAF/MEK inhibitors and ipilimumab (alone or in combination with PD1) had the highest activity in this setting.
The Boston University-Five College Radio Astronomy Observatory Galactic Ring Survey is a new survey of Galactic super(13)CO J = 1 1 0 emission. The survey used the SEQUOIA multipixel array on the ...Five College Radio Astronomy Observatory 14m telescope to cover a longitude range of l = 18-55.7 and a latitude range of |b| < 1, a total of 75.4 deg super(2). Using both position-switching and On-The-Fly mapping modes, we achieved an angular sampling of 22, better than half of the telescope's 46 angular resolution. The survey's velocity coverage is -5 to 135 km s super(-1) for Galactic longitudes l, 40 and -5 to 85 km s super(-1) for Galactic longitudes l > 40. At the velocity resolution of 0.21 km s super(-1), the typical rms sensitivity is s(T super(*)A) 6 0.13 K. The survey comprises a total of 1,993,522 spectra. We show integrated intensity images (zeroth moment maps), channel maps, position-velocity diagrams, and an average spectrum of the completed survey data set. We also discuss the telescope and instrumental parameters, the observing modes, the data reduction processes, and the emission and noise characteristics of the data set. The Galactic Ring Survey data are available to the community online or in DVD form by request.
The magnetic‐field‐dependent spin ordering of strained BiFeO3 films is determined using nuclear resonant scattering and Raman spectroscopy. The critical field required to destroy the cycloidal ...modulation of the Fe spins is found to be significantly lower than in the bulk, with appealing implications for field‐controlled spintronic and magnonic devices.
Abstract
We analyse the velocity dispersion properties of 472 z ∼ 0.9 star-forming galaxies observed as part of the KMOS Redshift One Spectroscopic Survey (KROSS). The majority of this sample is ...rotationally dominated (83 ± 5 per cent with vC/σ0 > 1) but also dynamically hot and highly turbulent. After correcting for beam smearing effects, the median intrinsic velocity dispersion for the final sample is σ0 = 43.2 ± 0.8 km s−1 with a rotational velocity to dispersion ratio of vC/σ0 = 2.6 ± 0.1. To explore the relationship between velocity dispersion, stellar mass, star formation rate, and redshift, we combine KROSS with data from the SAMI survey (z ∼ 0.05) and an intermediate redshift MUSE sample (z ∼ 0.5). Whilst there is, at most, a weak trend between velocity dispersion and stellar mass, at fixed mass there is a strong increase with redshift. At all redshifts, galaxies appear to follow the same weak trend of increasing velocity dispersion with star formation rate. Our results are consistent with an evolution of galaxy dynamics driven by discs that are more gas rich, and increasingly gravitationally unstable, as a function of increasing redshift. Finally, we test two analytic models that predict turbulence is driven by either gravitational instabilities or stellar feedback. Both provide an adequate description of the data, and further observations are required to rule out either model.
Abstract
Investigations of the origin and evolution of the Milky Way disc have long relied on chemical and kinematic identifications of its components to reconstruct our Galactic past. Difficulties ...in determining precise stellar ages have restricted most studies to small samples, normally confined to the solar neighbourhood. Here, we break this impasse with the help of asteroseismic inference and perform a chronology of the evolution of the disc throughout the age of the Galaxy. We chemically dissect the Milky Way disc population using a sample of red giant stars spanning out to 2 kpc in the solar annulus observed by the Kepler satellite, with the added dimension of asteroseismic ages. Our results reveal a clear difference in age between the low- and high-α populations, which also show distinct velocity dispersions in the V and W components. We find no tight correlation between age and metallicity nor α/Fe for the high-α disc stars. Our results indicate that this component formed over a period of more than 2 Gyr with a wide range of M/H and α/Fe independent of time. Our findings show that the kinematic properties of young α-rich stars are consistent with the rest of the high-α population and different from the low-α stars of similar age, rendering support to their origin being old stars that went through a mass transfer or stellar merger event, making them appear younger, instead of migration of truly young stars formed close to the Galactic bar.
Developing interpretive breakpoints for any given organism-drug combination requires integration of the MIC distribution, pharmacokinetic and pharmacodynamic parameters, and the relationship between ...the in vitro activity and outcome from both in vivo and clinical studies. Using data generated by standardized broth microdilution and disk diffusion test methods, the Antifungal Susceptibility Subcommittee of the Clinical and Laboratory Standards Institute has now proposed interpretive breakpoints for voriconazole and Candida species. The MIC distribution for voriconazole was determined using a collection of 8,702 clinical isolates. The overall MIC₉₀ was 0.25 microg/ml and 99% of the isolates were inhibited at </=1 microg/ml of voriconazole. Similar results were obtained for 1,681 Candida isolates (16 species) from the phase III clinical trials. Analysis of the available data for 249 patients from six phase III voriconazole clinical trials demonstrated a statistically significant correlation (P = 0.021) between MIC and investigator end-of-treatment assessment of outcome. Consistent with parallel pharmacodynamic analyses, these data support the following MIC breakpoints for voriconazole and Candida species: susceptible (S), </=1 microg/ml; susceptible dose dependent (SDD), 2 microg/ml; and resistant (R), >/=4 microg/ml. The corresponding disk test breakpoints are as follows: S, >/=17 mm; SDD, 14 to 16 mm; and R, </=13 mm.
Abstract
We present dynamical measurements for 586 Hα-detected star-forming galaxies from the KMOS (K-band Multi-Object Spectrograph) Redshift One Spectroscopic Survey (KROSS). The sample represents ...typical star-forming galaxies at this redshift (z = 0.6–1.0), with a median star formation rate of ≈7 M⊙ yr−1 and a stellar mass range of log (M⋆M⊙) ≈ 9–11. We find that the rotation velocity–stellar mass relationship (the inverse of the Tully–Fisher relationship) for our rotationally dominated sources (vC/σ0 > 1) has a consistent slope and normalization as that observed for z = 0 discs. In contrast, the specific angular momentum (j⋆; angular momentum divided by stellar mass) is ≈0.2–0.3 dex lower on average compared to z = 0 discs. The specific angular momentum scales as $j_{\rm s}\propto M_{\star }^{0.6\pm 0.2}$, consistent with that expected for dark matter (i.e. $j_{\rm DM}\propto M_{\rm DM}^{2/3}$). We find that z ≈ 0.9 star-forming galaxies have decreasing specific angular momentum with increasing Sérsic index. Visually, the sources with the highest specific angular momentum, for a given mass, have the most disc-dominated morphologies. This implies that an angular momentum–mass–morphology relationship, similar to that observed in local massive galaxies, is already in place by z ≈ 1.
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