Holographic Uniformization

We derive and study supergravity BPS flow equations for M5 or D3 branes wrapping a Riemann surface. They take the form of novel geometric flows intrinsically defined on the surface. Their dual field-theoretic interpretation suggests the existence of solutions interpolating between an arbitrary metric in the UV and the constant-curvature metric in the IR. We confirm this conjecture with a rigorous global existence proof.Comment: 52 pages, 3 figure

Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial

PURPOSE Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: ). RESULTS Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted. (C) 2022 by American Society of Clinical Oncolog

Markers of physiological stress during exercise under conditions of normoxia, normobaric hypoxia, hypobaric hypoxia and genuine high altitude.

Purpose To investigate whether there is a differential response at rest and following exercise to conditions of genuine high altitude (GHA), normobaric hypoxia (NH), hypobaric hypoxia (HH) and normobaric normoxia (NN). Method Markers of sympathoadrenal and adrenocortical function (plasma normetanephrine [PNORMET], metanephrine [PMET], cortisol), myocardial injury (highly sensitive cardiac troponin T [hscTnT]) and function (N-terminal brain natriuretic peptide [NT-proBNP]) were evaluated at rest and with exercise under NN, at 3375 m in the Alps (GHA) and at equivalent simulated altitude under NH and HH. Participants cycled for 2 hours {15 minute warm-up, 105 minutes at 55% Wmax (maximal workload)} with venous blood samples taken prior (T0), immediately following (T120) and 2 hours post-exercise (T240). Results Exercise in the three hypoxic environments produced a similar pattern of response with the only difference between environments being in relation to PNORMET. Exercise in NN only induced a rise in PNORMET and PMET. Conclusion Biochemical markers that reflect sympathoadrenal, adrenocortical and myocardial responses to physiological stress demonstrate significant differences in the response to exercise under conditions of normoxia versus hypoxia while NH and HH appear to induce broadly similar responses to GHA and may therefore be reasonable surrogates

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

Drosophila Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

New techniques for jet calibration with the ATLAS detector

A determination of the jet energy scale is presented using proton–proton collision data with a centre-of-mass energy of √s = 13 TeV, corresponding to an integrated luminosity of 140 fb−1 collected using the ATLAS detector at the LHC. Jets are reconstructed using the ATLAS particle-flow method that combines charged-particle tracks and topo-clusters formed from energy deposits in the calorimeter cells. The anti-kt jet algorithm with radius parameter R=0.4 is used to define the jet. Novel jet energy scale calibration strategies developed for the LHC Run 2 are reported that lay the foundation for the jet calibration in Run 3. Jets are calibrated with a series of simulation-based corrections, including state-of-the-art techniques in jet calibration such as machine learning methods and novel in situ calibrations to achieve better performance than the baseline calibration derived using up to 81 fb−1 of Run 2 data. The performance of these new techniques is then examined in the in situ measurements by exploiting the transverse momentum balance between a jet and a reference object. The b-quark jet energy scale using particle flow jets is measured for the first time with around 1% precision using γ+jet events

Search for top-philic heavy resonances in pp collisions at √s = 13 TeV with the ATLAS detector

A search for the associated production of a heavy resonance with a top-quark or a top-antitop-quark pair, and decaying into a tt¯ pair is presented. The search uses the data recorded by the ATLAS detector in pp collisions at √s = 13 TeV at the Large Hadron Collider during the years 2015–2018, corresponding to an integrated luminosity of 139 fb-1. Events containing exactly one electron or muon are selected. The two hadronically decaying top quarks from the resonance decay are reconstructed using jets clustered with a large radius parameter of R = 1. The invariant mass spectrum of the two top quark candidates is used to search for a resonance signal in the range of 1.0 TeV to 3.2 TeV. The presence of a signal is examined using an approach with minimal model dependence followed by a model-dependent interpretation. No significant excess is observed over the background expectation. Upper limits on the production cross section times branching ratio at 95% confidence level are provided for a heavy Z′ boson based on a simplified model, for Z′ mass between 1.0 TeV and 3.0 TeV. The observed (expected) limits range from 21 (14) fb to 119 (86) fb depending on the choice of model parameters

Search for excited τ-leptons and leptoquarks in the final state with τ-leptons and jets in pp collisions at s√ = 13 TeV with the ATLAS detector

A search is reported for excited τ-leptons and leptoquarks in events with two hadronically decaying τ-leptons and two or more jets. The search uses proton-proton (pp) collision data at s√ = 13 TeV recorded by the ATLAS experiment during the Run 2 of the Large Hadron Collider in 2015–2018. The total integrated luminosity is 139 fb−1. The excited τ-lepton is assumed to be produced and to decay via a four-fermion contact interaction into an ordinary τ-lepton and a quark-antiquark pair. The leptoquarks are assumed to be produced in pairs via the strong interaction, and each leptoquark is assumed to couple to a charm or lighter quark and a τ-lepton. No excess over the background prediction is observed. Excited τ-leptons with masses below 2.8 TeV are excluded at 95% CL in scenarios with the contact interaction scale Λ set to 10 TeV. At the extreme limit of model validity where Λ is set equal to the excited τ-lepton mass, excited τ-leptons with masses below 4.6 TeV are excluded. Leptoquarks with masses below 1.3 TeV are excluded at 95% CL if their branching ratio to a charm quark and a τ-lepton equals 1. The analysis does not exploit flavour-tagging in the signal region

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival