Online and offline heuristics for inferring hierarchies of repetitions in sequences

Hierarchical dictionary-based compression schemes form a grammar for a text by replacing each repeated string with a production rule. While such schemes usually operate online, making a replacement as soon as repetition is detected, offline operation permits greater freedom in choosing the order of replacement. In this paper, we compare the online method with three offline heuristics for selecting the next substring to replace: longest string first, most common string first, and the string that minimized the size of the grammar locally. Surprisingly, two of the offline techniques, like the online method, run in time linear in the size of the input. We evaluate each technique on artificial and natural sequences. In general, the locally-most-compressive heuristic performs best, followed by most frequent, the online technique, and, lagging by some distance, the longest-first technique

Comparing open and minimally invasive surgical procedures for oesophagectomy in the treatment of cancer: the ROMIO (Randomised Oesophagectomy: Minimally Invasive or Open) feasibility study and pilot trial

Localised oesophageal cancer can be curatively treated with surgery (oesophagectomy) but the procedure is complex with a risk of complications, negative effects on quality of life and a recovery period of 6-9 months. Minimal-access surgery may accelerate recovery.The ROMIO (Randomised Oesophagectomy: Minimally Invasive or Open) study aimed to establish the feasibility of, and methodology for, a definitive trial comparing minimally invasive and open surgery for oesophagectomy. Objectives were to quantify the number of eligible patients in a pilot trial; develop surgical manuals as the basis for quality assurance; standardise pathological processing; establish a method to blind patients to their allocation in the first week post surgery; identify measures of postsurgical outcome of importance to patients and clinicians; and establish the main cost differences between the surgical approaches.Pilot parallel three-arm randomised controlled trial nested within feasibility work.Two UK NHS departments of upper gastrointestinal surgery.Patients aged ≥ 18 years with histopathological evidence of oesophageal or oesophagogastric junctional adenocarcinoma, squamous cell cancer or high-grade dysplasia, referred for oesophagectomy or oesophagectomy following neoadjuvant chemo(radio)therapy.Oesophagectomy, with patients randomised to open surgery, a hybrid open chest and minimally invasive abdomen or totally minimally invasive access.The primary outcome measure for the pilot trial was the number of patients recruited per month, with the main trial considered feasible if at least 2.5 patients per month were recruited.During 21 months of recruitment, 263 patients were assessed for eligibility; of these, 135 (51%) were found to be eligible and 104 (77%) agreed to participate, an average of five patients per month. In total, 41 patients were allocated to open surgery, 43 to the hybrid procedure and 20 to totally minimally invasive surgery. Recruitment is continuing, allowing a seamless transition into the definitive trial. Consequently, the database is unlocked at the time of writing and data presented here are for patients recruited by 31 August 2014. Random allocation achieved a good balance between the arms of the study, which, as a high proportion of patients underwent their allocated surgery (69/79, 87%), ensured a fair comparison between the interventions. Dressing patients with large bandages, covering all possible incisions, was successful in keeping patients blind while pain was assessed during the first week post surgery. Postsurgical length of stay and risk of adverse events were within the typical range for this group of patients, with one death occurring within 30 days among 76 patients. There were good completion rates for the assessment of pain at 6 days post surgery (88%) and of the patient-reported outcomes at 6 weeks post randomisation (74%).Rapid recruitment to the pilot trial and the successful refinement of methodology indicated the feasibility of a definitive trial comparing different approaches to oesophagectomy. Although we have shown a full trial of open compared with minimally invasive oesophagectomy to be feasible, this is necessarily based on our findings from the two clinical centres that we could include in this small preliminary study.Current Controlled Trials ISRCTN59036820.This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 48. See the NIHR Journals Library website for further project information

Transit Photometry as an Exoplanet Discovery Method

Photometry with the transit method has arguably been the most successful exoplanet discovery method to date. A short overview about the rise of that method to its present status is given. The method's strength is the rich set of parameters that can be obtained from transiting planets, in particular in combination with radial velocity observations; the basic principles of these parameters are given. The method has however also drawbacks, which are the low probability that transits appear in randomly oriented planet systems, and the presence of astrophysical phenomena that may mimic transits and give rise to false detection positives. In the second part we outline the main factors that determine the design of transit surveys, such as the size of the survey sample, the temporal coverage, the detection precision, the sample brightness and the methods to extract transit events from observed light curves. Lastly, an overview over past, current and future transit surveys is given. For these surveys we indicate their basic instrument configuration and their planet catch, including the ranges of planet sizes and stellar magnitudes that were encountered. Current and future transit detection experiments concentrate primarily on bright or special targets, and we expect that the transit method remains a principal driver of exoplanet science, through new discoveries to be made and through the development of new generations of instruments.Comment: Review chapte

Regulatory T cell frequency in patients with melanoma with different disease stage and course, and modulating effects of high-dose interferon-α 2b treatment

<p>Abstract</p> <p>Background</p> <p>High-dose interferon-alpha 2b (IFN-α 2b) is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN-α 2b by measuring serum regulatory T cell (Treg), serum transforming growth factor-β (TGF-β), interleukin (IL)-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-α 2b regimen.</p> <p>Methods</p> <p>Patients with melanoma received IFN-α 2b administered intravenously (20 MU/m²each day from day 1 to day 5 for 4 consecutive weeks). Serum Treg levels were measured as whole lymphocytes in CD4⁺cells using flow cytometry while TGF-β, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays.</p> <p>Results</p> <p>Twenty-two patients with melanoma received IFN-α 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (<it>P </it>= 0.001; Mann-Whitney test). Although a trend for reduction of Treg levels following IFN-α 2b treatment was observed (average decrease 0.29% per week), statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (<it>P </it>= 0.082), early recurrence versus no recurrence (<it>P </it>= 0.017), deceased versus surviving patients (<it>P = </it>0.021), and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant). No significant effects were observed on the levels of TGF-β, IL-10, and autoantibodies in patients with melanoma treated with IFN-α 2b.</p> <p>Conclusions</p> <p>Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-α 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response or outcome can be made at present.</p

Pharmacokinetic/pharmacodynamic analysis of adjuvant pegylated interferon α-2b in patients with resected high-risk melanoma

PurposeHigh-dose pegylated interferon α-2b (peginterferon α-2b) significantly decreased disease recurrence in patients with resected stage III melanoma in a clinical study. We investigated the pharmacokinetics (PK) and safety of high-dose peginterferon α-2b in patients with high-risk melanoma.MethodsFor PK analysis, 32 patients received peginterferon α-2b 6 μg/(kg week) subcutaneously for 8 weeks (induction) then 3 μg/(kg week) for 4 weeks (maintenance). PK profiles were determined at weeks 1, 8, and 12. Exposure-response relationships between peginterferon α-2b and absolute neutrophil count (ANC) and alanine aminotransferase (ALT) level were also studied.ResultsPeginterferon α-2b was well-absorbed following SC administration, with a median T (max) of 24 h. Mean half-life estimates ranged from 43 to 51 h. The accumulation factor was 1.69 after induction therapy. PK parameters showed moderate interpatient variability. PK profiles were described by a one-compartmental model with first-order absorption and first-order elimination. Toxicity was profiled and was acceptable; observed side effects were similar to those previously described. Dose reduction produced proportional decreases in exposure and predictable effects on ANC in an Imax model; however, a PK/pharmacodynamic (PK/PD) relationship between peginterferon α-2b and ALT could not be established with high precision.ConclusionsPeginterferon α-2b was well-absorbed and sustained exposure to peginterferon α-2b was achieved with the doses tested. These data confirm and extend previous PK observations of peginterferon α-2b in melanoma and solid tumors. Our PK/PD model of exposure and ANC effect provides useful information for prediction of peginterferon α-2b-related hematologic toxicity

Abundance measurements of H₂O and carbon-bearing species in the atmosphere of WASP-127b confirm its super-solar metallicity

The chemical abundances of exoplanet atmospheres may provide valuable information about the bulk compositions, formation pathways, and evolutionary histories of planets. Exoplanets with large, relatively cloud-free atmospheres, and which orbit bright stars provide the best opportunities for accurate abundance measurements. For this reason, we measured the transmission spectrum of the bright (V∼10.2), large (1.37 RJ), sub-Saturn mass (0.19 MJ) exoplanet WASP-127b across the near-UV to near-infrared wavelength range (0.3–5 μm), using the Hubble and Spitzer Space Telescopes. Our results show a feature-rich transmission spectrum, with absorption from Na, H2O, and CO2, and wavelength-dependent scattering from small-particle condensates. We ran two types of atmospheric retrieval models: one enforcing chemical equilibrium, and the other which fit the abundances freely. Our retrieved abundances at chemical equilibrium for Na, O and C are all super-solar, with abundances relative to solar values of 9+15−6⁠, 16+7−5⁠, and 26+12−9 respectively. Despite giving conflicting C/O ratios, both retrievals gave super-solar CO2 volume mixing ratios, which adds to the likelihood that WASP-127b’s bulk metallicity is super-solar, since CO2 abundance is highly sensitive to atmospheric metallicity. We detect water at a significance of 13.7 σ. Our detection of Na is in agreement with previous ground-based detections, though we find a much lower abundance, and we also do not find evidence for Li or K despite increased sensitivity. In the future, spectroscopy with JWST will be able to constrain WASP-127b’s C/O ratio, and may reveal the formation history of this metal-enriched, highly observable exoplanet

A giant comet-like cloud of hydrogen escaping the warm Neptune-mass exoplanet GJ 436b

Exoplanets orbiting close to their parent stars could lose some fraction of their atmospheres because of the extreme irradiation. Atmospheric mass loss primarily affects low-mass exoplanets, leading to suggest that hot rocky planets might have begun as Neptune-like, but subsequently lost all of their atmospheres; however, no confident measurements have hitherto been available. The signature of this loss could be observed in the ultraviolet spectrum, when the planet and its escaping atmosphere transit the star, giving rise to deeper and longer transit signatures than in the optical spectrum. Here we report that in the ultraviolet the Neptune-mass exoplanet GJ 436b (also known as Gliese 436b) has transit depths of 56.3 +/- 3.5% (1 sigma), far beyond the 0.69% optical transit depth. The ultraviolet transits repeatedly start ~2 h before, and end >3 h after the ~1 h optical transit, which is substantially different from one previous claim (based on an inaccurate ephemeris). We infer from this that the planet is surrounded and trailed by a large exospheric cloud composed mainly of hydrogen atoms. We estimate a mass-loss rate in the range of ~10^8-10^9 g/s, which today is far too small to deplete the atmosphere of a Neptune-like planet in the lifetime of the parent star, but would have been much greater in the past.Comment: Published in Nature on 25 June 2015. Preprint is 28 pages, 12 figures, 2 table

On the (anisotropic) uniform metallic ground states of fermions interacting through arbitrary two-body potentials in d dimensions

We demonstrate that the skeleton of the Fermi surface S_{F;s} pertaining to a uniform metallic ground state (corresponding to fermions with spin index s) is determined by the Hartree-Fock contribution to the dynamic self-energy. The Fermi surface S_{F;s} consists of all points which in addition to satisfying the quasi-particle equation in terms of the Hartree-Fock self-energy, fulfill the equation S_{s}(k) = 0, where S_{s}(k) is defined in the main text; the set of k points which satisfy the Hartree-Fock quasi-particle equation but fail to satisfy S_{s}(k) = 0, constitute the pseudo-gap region of the putative Fermi surface of the interacting system. We consider the behaviour of the ground-state momentum-distribution function n_{s}(k) for k in the vicinity of S_{F;s} and show that whereas for the uniform metallic ground states of the conventional Hubbard Hamiltonian n_{s}(k) is greater/less than 0.5 for k approaching S_{F;s} from inside/outside the Fermi sea, for interactions of non-zero range these inequalities can be violated (without thereby contravening the condition of the non-negativity of the possible jump in n_{s}(k) on k crossing S_{F;s} from directly inside to directly outside the Fermi sea). We discuss, in the light of the findings of the present work, the growing experimental evidence with regard to the `frustration' of the kinetic energy of the charge carriers in the normal states of the copper-oxide-based high-temperature superconducting compounds. [Short abstract]Comment: 30 pages, 3 postscript figures. Brought into conformity with the published versio

Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate and high-risk early stage triple negative breast cancer.

BACKGROUND: Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK-TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected (ctDNA+). PATIENTS AND METHODS: c-TRAK-TN, a multi-centre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or, stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three monthly blood sampling to 12 months (18 months if samples were missed due to COVID), and ctDNA+ patients were randomised 2:1; intervention:observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16/09/2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were i) ctDNA detection rate ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961). RESULTS: 208 patients registered between 30/01/18 - 06/12/19, 185 had tumour sequenced, 171 (92·4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27·3% (44/161,95%CI:20·6-34·9). Seven patients relapsed without prior ctDNA detection. 45 patients entered the therapeutic component (intervention n=31; observation n=14; 1 observation patient was re-allocated to intervention following protocol amendment). Of patients allocated intervention, 72% (23/32) had metastases on staging at time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance. CONCLUSION: c-TRAK-TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes