`Third' Quantization of Vacuum Einstein Gravity and Free Yang-Mills Theories

Based on the algebraico-categorical (:sheaf-theoretic and sheaf cohomological) conceptual and technical machinery of Abstract Differential Geometry, a new, genuinely background spacetime manifold independent, field quantization scenario for vacuum Einstein gravity and free Yang-Mills theories is introduced. The scheme is coined `third quantization' and, although it formally appears to follow a canonical route, it is fully covariant, because it is an expressly functorial `procedure'. Various current and future Quantum Gravity research issues are discussed under the light of 3rd-quantization. A postscript gives a brief account of this author's personal encounters with Rafael Sorkin and his work.Comment: 43 pages; latest version contributed to a fest-volume celebrating Rafael Sorkin's 60th birthday (Erratum: in earlier versions I had wrongly written that the Editor for this volume is Daniele Oriti, with CUP as publisher. I apologize for the mistake.

Brain MRI and ophthalmic biomarkers of intracranial pressure

Objective: To evaluate the utility of brain MRI and ophthalmic biomarkers for the prediction of intracranial hypertension, we have studied the association between 6 biomarkers and 24-hour intracranial pressure (ICP) monitoring results in 45 patients. Methods: This single-center observational study includes patients who underwent 24-hour ICP monitoring, brain MRI (within 3 months), and ophthalmic assessment (during ICP monitoring). Six biomarkers were investigated: pituitary gland shape, vertical tortuosity of the optic nerve, distension of the optic nerve sheath, optic disc protrusion (MRI), papilledema (slit lamp biomicroscopy), and spontaneous venous pulsations (SVP, infrared video recordings). Results: Forty-five patients (mean age 39 ± 14 years, 38 women) met the inclusion criteria. All 6 biomarkers had a significant association with 24-hour ICP. Concave pituitary gland was observed with moderately elevated median ICP. Protrusion of the optic disc (MRI), papilledema, and absence of SVP were associated with the highest median ICP values. Twenty patients had raised ICP (median 24-hour ICP >5.96 mm Hg, cutoff obtained through Youden index calculation). Patients with all normal biomarkers had normal median ICP in 94% (standard error 6%) of the cases. All patients with ≥3 abnormal biomarkers had intracranial hypertension. The combination of at least 1 abnormal biomarker in MRI and ophthalmic assessments was highly suggestive of intracranial hypertension (area under the curve 0.94, 95% confidence interval 0.93–0.94) Conclusions: Brain MRI and ophthalmic biomarkers can noninvasively guide the management of patients with suspected CSF dynamics abnormalities. Patients with multiple abnormal biomarkers (≥3) or a combination of abnormal MRI and ophthalmic biomarkers are likely to have intracranial hypertension and should be managed promptly

Dynamic variation of CD5 surface expression levels within individual chronic lymphocytic leukemia clones.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonally derived mature CD5high B cells; however, the cellular origin of CLL is still unknown. Patients with CLL also harbor variable numbers of CD5low B cells, but the clonal relationship of these cells to the bulk disease is unknown and can have important implications for monitoring, treating, and understanding the biology of CLL. Here, we use B-cell receptors (BCRs) as molecular barcodes to first show by single-cell BCR sequencing that the great majority of CD5low B cells in the blood of CLL patients are clonally related to CD5high CLL B cells. We investigate whether CD5 state switching was likely to occur continuously as a common event or as a rare event in CLL by tracking somatic BCR mutations in bulk CLL B cells and using them to reconstruct the phylogenetic relationships and evolutionary history of the CLL in four patients. Using statistical methods, we show that there is no parsimonious route from a single or low number of CD5low switch events to the CD5high population, but rather, large-scale and/or dynamic switching between these CD5 states is the most likely explanation. The overlapping BCR repertoires between CD5high and CD5low cells from CLL patient peripheral blood reveal that CLL exists in a continuum of CD5 expression. The major proportion of CD5low B cells in patients are leukemic, thus identifying CD5low B cells as an important component of CLL, with implications for CLL pathogenesis, clinical monitoring, and the development of anti-CD5-directed therapies

Solar flares with and without SOHO/LASCO coronal mass ejections and type II shocks

We analyse of a set of radio rich (accompanied by type IV or II bursts) solar flares and their association with SOHO/LASCO Coronal Mass Ejections in the period 1998 2000. The intensity, impulsiveness and energetics of these events are investigated. We find that, on the average, flares associated both with type IIs and CMEs are more impulsive and more energetic than flares associated with type IIs only (without CME reported), as well as flares accompanied by type IV continua but not type II shocks. From the last two classes, flares with type II bursts (without CMEs reported) are the shortest in duration and the most impulsive.Comment: Advances in Space Research, Volume 38, Issue 5, p. 1007-101

High-dimensional wave atoms and compression of seismic datasets

Wave atoms are a low-redundancy alternative to curvelets, suitable for high-dimensional seismic data processing. This abstract extends the wave atom orthobasis construction to 3D, 4D, and 5D Cartesian arrays, and parallelizes it in a shared-memory environment. An implementation of the algorithm for NVIDIA CUDA capable graphics processing units (GPU) is also developed to accelerate computation for 2D and 3D data. The new transforms are benchmarked against the Fourier transform for compression of data generated from synthetic 2D and 3D acoustic models.National Science Foundation (U.S.); Alfred P. Sloan Foundatio

Combined influence of B-cell receptor rearrangement and somatic hypermutation on B-cell class-switch fate in health and in chronic lymphocytic leukaemia

A diverse B-cell receptor (BCR) repertoire is required to bind a wide range of antigens. BCRs are generated through genetic recombination and can be diversified through somatic hypermutation (SHM) or class-switch recombination (CSR). Patterns of repertoire diversity can vary substantially between different health conditions. We use isotyperesolved BCR sequencing to compare B-cell evolution and class-switch fate in healthy individuals and in patients with chronic lymphocytic leukemia (CLL). We show that the patterns of SHM and CSR in B-cells from healthy individuals are distinct from CLL. We identify distinct properties of clonal expansion that lead to the generation of antibodies of different classes in healthy, malignant, and non-malignant CLL BCR repertoires. We further demonstrate that BCR diversity is affected by relationships between antibody variable and constant regions leading to isotype-specific signatures of variable gene usage. This study provides powerful insights into the mechanisms underlying the evolution of the adaptive immune responses in health and their aberration during disease

Atrial fibrillation in embolic stroke of undetermined source: role of advanced imaging of left atrial function

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. AIMS: Atrial fibrillation (AF) is detected in over 30% of patients following an embolic stroke of undetermined source (ESUS) when monitored with an implantable loop recorder (ILR). Identifying AF in ESUS survivors has significant therapeutic implications, and AF risk is essential to guide screening with long-term monitoring. The present study aimed to establish the role of left atrial (LA) function in subsequent AF identification and develop a risk model for AF in ESUS. METHODS AND RESULTS: We conducted a single-centre retrospective case-control study including all patients with ESUS referred to our institution for ILR implantation from December 2009 to September 2019. We recorded clinical variables at baseline and analysed transthoracic echocardiograms in sinus rhythm. Univariate and multivariable analyses were performed to inform variables associated with AF. Lasso regression analysis was used to develop a risk prediction model for AF. The risk model was internally validated using bootstrapping. Three hundred and twenty-three patients with ESUS underwent ILR implantation. In the ESUS population, 293 had a stroke, whereas 30 had suffered a transient ischaemic attack as adjudicated by a senior stroke physician. Atrial fibrillation of any duration was detected in 47.1%. The mean follow-up was 710 days. Following lasso regression with backwards elimination, we combined increasing lateral PA (the time interval from the beginning of the P wave on the surface electrocardiogram to the beginning of the A\u27 wave on pulsed wave tissue Doppler of the lateral mitral annulus) [odds ratio (OR) 1.011], increasing Age (OR 1.035), higher Diastolic blood pressure (OR 1.027), and abnormal LA reservoir Strain (OR 0.973) into a new PADS score. The probability of identifying AF can be estimated using the formula. Model discrimination was good [area under the curve (AUC) 0.72]. The PADS score was internally validated using bootstrapping with 1000 samples of 150 patients showing consistent results with an AUC of 0.73. CONCLUSION: The novel PADS score can identify the risk of AF on prolonged monitoring with ILR following ESUS and should be considered a dedicated risk stratification tool for decision-making regarding the screening strategy for AF in stroke.One-third of patients with a type of stroke called embolic stroke of undetermined source (ESUS) also have a heart condition called atrial fibrillation (AF), which increases their risk of having another stroke. However, we do not know why some patients with ESUS develop AF. To figure this out, we studied 323 patients with ESUS and used a special device to monitor their heart rhythm continuously for up to 3 years, an implantable loop recorder. We also looked at their medical history, performed a heart ultrasound, and identified some factors that increase the risk of identifying AF in the future. Factors associated with future AF include older age, higher diastolic blood pressure, and problems with the co-ordination and function of the upper left chamber of the heart called the left atrium.Based on these factors, we created a new scoring system that can identify patients who are at higher risk of developing AF better than the current scoring systems, the PADS score. This can potentially help doctors provide more targeted and effective treatment to these patients, ultimately aiming to reduce their risk of having another stroke

Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents

Bone metastases in advanced cancer frequently cause painful complications that impair patient physical activity and negatively affect quality of life. Pain is often underreported and poorly managed in these patients. The most commonly used pain assessment instruments are visual analogue scales, a single-item measure, and the Brief Pain Inventory Questionnaire-Short Form. The World Health Organization analgesic ladder and the Analgesic Quantification Algorithm are used to evaluate analgesic use. Bone-targeting agents, such as denosumab or bisphosphonates, prevent skeletal complications (i.e., radiation to bone, pathologic fractures, surgery to bone, and spinal cord compression) and can also improve pain outcomes in patients with metastatic bone disease. We have reviewed pain outcomes and analgesic use and reported pain data from an integrated analysis of randomized controlled studies of denosumab versus the bisphosphonate zoledronic acid (ZA) in patients with bone metastases from advanced solid tumors. Intravenous bisphosphonates improved pain outcomes in patients with bone metastases from solid tumors. Compared with ZA, denosumab further prevented pain worsening and delayed the need for treatment with strong opioids. In patients with no or mild pain at baseline, denosumab reduced the risk of increasing pain severity and delayed pain worsening along with the time to increased pain interference compared with ZA, suggesting that use of denosumab (with appropriate calcium and vitamin D supplementation) before patients develop bone pain may improve outcomes. These data also support the use of validated pain assessments to optimize treatment and reduce the burden of pain associated with metastatic bone disease

Identification Of A Germline F692L Drug Resistance Variant In Cis With Flt3-ITD In Knock-In Mice

Letter to the Editor.-- Dovey, Oliver M. et al.Internal tandem duplication (ITD) mutations in the juxtamembrane domain of the fms-like tyrosine kinase 3 (FLT3) gene occur in approximately one quarter of cases of acute myeloid leukemia (AML), are associated with constitutive activation of the kinase and confer a poor prognosis.BC is funded by the >China Scholarship Council> for his visiting studies in UK. AM is funded by the Kay Kendall Leukaemia Fund project grant. CG was funded by a Bloodwise Clinical Research Training Fellowship. IV is funded by Spanish Ministerio de Economía y Competitividad subprograma Ramón y Cajal. We thank Servicio Santander Supercomputación for their support. OMD, JLC and GSV are funded by a Wellcome Trust Senior Fellowship in Clinical Science (WT095663MA) and this work was also funded by the Wellcome Trust Sanger InstitutePeer Reviewe

Identification Of A Germline F692L Drug Resistance Variant In Cis With Flt3-ITD In Knock-In Mice

Letter to the Editor.-- Dovey, Oliver M. et al.Internal tandem duplication (ITD) mutations in the juxtamembrane domain of the fms-like tyrosine kinase 3 (FLT3) gene occur in approximately one quarter of cases of acute myeloid leukemia (AML), are associated with constitutive activation of the kinase and confer a poor prognosis.BC is funded by the >China Scholarship Council> for his visiting studies in UK. AM is funded by the Kay Kendall Leukaemia Fund project grant. CG was funded by a Bloodwise Clinical Research Training Fellowship. IV is funded by Spanish Ministerio de Economía y Competitividad subprograma Ramón y Cajal. We thank Servicio Santander Supercomputación for their support. OMD, JLC and GSV are funded by a Wellcome Trust Senior Fellowship in Clinical Science (WT095663MA) and this work was also funded by the Wellcome Trust Sanger InstitutePeer Reviewe