The Dynamics of Germinal Centre Selection as Measured by Graph-Theoretical Analysis of Mutational Lineage Trees

We have developed a rigorous graph-theoretical algorithm for quantifying the shape properties of mutational lineage trees. We show that information about the dynamics of hypermutation and antigen-driven clonal selection during the humoral immune response is contained in the shape of mutational lineage trees deduced from the responding clones. Age and tissue related differences in the selection process can be studied using this method. Thus, tree shape analysis can be used as a means of elucidating humoral immune response dynamics in various situations

Immunoglobulin variable-region gene mutational lineage tree analysis: application to autoimmune diseases

Lineage trees have frequently been drawn to illustrate diversification, via somatic hypermutation (SHM), of immunoglobulin variable-region (IGV) genes. In order to extract more information from IGV sequences, we developed a novel mathematical method for analyzing the graphical properties of IgV gene lineage trees, allowing quantification of the differences between the dynamics of SHM and antigen-driven selection in different lymphoid tissues, species, and disease situations. Here, we investigated trees generated from published IGV sequence data from B cell clones participating in autoimmune responses in patients with Myasthenia Gravis (MG), Rheumatoid Arthritis (RA), and Sjögren's Syndrome (SS). At present, as no standards exist for cell sampling and sequence extraction methods, data obtained by different research groups from two studies of the same disease often vary considerably. Nevertheless, based on comparisons of data groups within individual studies, we show here that lineage trees from different individual patients are often similar and can be grouped together, as can trees from two different tissues in the same patient, and even from IgG- and IgA-expressing B cell clones. Additionally, lineage trees from most studies reflect the chronic character of autoimmune diseases

Pemetrexed plus Cetuximab in Patients with Recurrent Non-small Cell Lung Cancer (NSCLC): A Phase I/II Study from the Hoosier Oncology Group

PurposePemetrexed is a standard treatment against recurrent non-small cell lung cancer (NSCLC), and cetuximab has single-agent activity against NSCLC. This study evaluates the safety and efficacy of the combination of these agents in patients with advanced NSCLC.Patients and MethodsPatients with recurrent NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1 were entered. Patients on the phase I portion of the study received cetuximab 400 mg/m2 intravenously (IV) on day −7 followed by weekly doses of cetuximab at 250 mg/m2 IV with escalating doses of pemetrexed every 3 weeks (dose levels: 500, 600, 750, 900 mg/m2) in a standard 3 + 3 design. Once the maximum tolerated dose (MTD) of the combination was determined, patients were enrolled on the phase II portion. The primary end point was to determine the median time to disease progression (TTP) (null hypothesis 12 weeks, alternative hypothesis 24 weeks).ResultsThirty-six patients were enrolled (phase I: n = 13, phase II: n = 23). Patient characteristics included 60.6% men, median age 64 years (range, 37–80 years), 57.6% had performance status 0 and 54.6% had adenocarcinoma histology. The median number of previous regimens was 2 (range, 1–6). The maximum tolerated dose of pemetrexed in combination with cetuximab was determined to be 750 mg/m2. The median TTP was 14.6 weeks. The median survival time was 42 weeks and 1-year survival was 38.5%.ConclusionThe combination of pemetrexed at 750 mg/m2 every 21 days with weekly cetuximab at 250 mg/m2 was feasible; however, in this unselected patient population, the combination regimen does not seem to improve TTP compared with historical controls of either single agent

Methods and application areas of endoscopic optical coherence tomography

We review the current state of research in endoscopic optical coherence tomography (OCT). We first survey the range of available endoscopic optical imaging techniques. We then discuss the various OCT-based endoscopic methods that have thus far been developed. We compare the different endoscopic OCT methods in terms of their scan performance. Next, we examine the application range of endoscopic OCT methods. In particular, we look at the reported utility of the methods in digestive, intravascular, respiratory, urinary and reproductive systems. We highlight two additional applications—biopsy procedures and neurosurgery—where sufficiently compact OCT-based endoscopes can have significant clinical impacts

The pharmacokinetics of the interstitial space in humans

BACKGROUND: The pharmacokinetics of extracellular solutes is determined by the blood-tissue exchange kinetics and the volume of distribution in the interstitial space in the different organs. This information can be used to develop a general physiologically based pharmacokinetic (PBPK) model applicable to most extracellular solutes. METHODS: The human pharmacokinetic literature was surveyed to tabulate the steady state and equilibrium volume of distribution of the solutes mannitol, EDTA, morphine-6-glucuronide, morphine-3-glucuronide, inulin and β-lactam antibiotics with a range of protein binding (amoxicillin, piperacillin, cefatrizine, ceforanide, flucloxacillin, dicloxacillin). A PBPK data set was developed for extracellular solutes based on the literature for interstitial organ volumes. The program PKQuest was used to generate the PBPK model predictions. The pharmacokinetics of the protein (albumin) bound β-lactam antibiotics were characterized by two parameters: 1) the free fraction of the solute in plasma; 2) the interstitial albumin concentration. A new approach to estimating the capillary permeability is described, based on the pharmacokinetics of the highly protein bound antibiotics. RESULTS: About 42% of the total body water is extracellular. There is a large variation in the organ distribution of this water – varying from about 13% of total tissue water for skeletal muscle, up to 70% for skin and connective tissue. The weakly bound antibiotics have flow limited capillary-tissue exchange kinetics. The highly protein bound antibiotics have a significant capillary permeability limitation. The experimental pharmacokinetics of the 11 solutes is well described using the new PBPK data set and PKQuest. CONCLUSIONS: Only one adjustable parameter (systemic clearance) is required to completely characterize the PBPK for these extracellular solutes. Knowledge of just this systemic clearance allows one to predict the complete time course of the absolute drug concentrations in the major organs. PKQuest is freely available

A Glycemia Risk Index (GRI) of Hypoglycemia and Hyperglycemia for Continuous Glucose Monitoring Validated by Clinician Ratings

BackgroundA composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data.MethodsWe assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low-glucose and low-glucose hypoglycemia; very high-glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation.ResultsThe analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals.ConclusionThe GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments

GW190412: Observation of a Binary-Black-Hole Coalescence with Asymmetric Masses

We report the observation of gravitational waves from a binary-black-hole coalescence during the first two weeks of LIGO’s and Virgo’s third observing run. The signal was recorded on April 12, 2019 at 05∶30∶44 UTC with a network signal-to-noise ratio of 19. The binary is different from observations during the first two observing runs most notably due to its asymmetric masses: a ∼30 M_⊙ black hole merged with a ∼8 M_⊙ black hole companion. The more massive black hole rotated with a dimensionless spin magnitude between 0.22 and 0.60 (90% probability). Asymmetric systems are predicted to emit gravitational waves with stronger contributions from higher multipoles, and indeed we find strong evidence for gravitational radiation beyond the leading quadrupolar order in the observed signal. A suite of tests performed on GW190412 indicates consistency with Einstein’s general theory of relativity. While the mass ratio of this system differs from all previous detections, we show that it is consistent with the population model of stellar binary black holes inferred from the first two observing runs

Properties and Astrophysical Implications of the 150 M_⊙ Binary Black Hole Merger GW190521

The gravitational-wave signal GW190521 is consistent with a binary black hole (BBH) merger source at redshift 0.8 with unusually high component masses, 85⁺²¹₋₁₄ M_⊙ and 66⁺¹⁷₋₁₈ M_⊙, compared to previously reported events, and shows mild evidence for spin-induced orbital precession. The primary falls in the mass gap predicted by (pulsational) pair-instability supernova theory, in the approximate range 65–120 M_⊙. The probability that at least one of the black holes in GW190521 is in that range is 99.0%. The final mass of the merger 142⁺²⁸₋₁₆ M_⊙) classifies it as an intermediate-mass black hole. Under the assumption of a quasi-circular BBH coalescence, we detail the physical properties of GW190521's source binary and its post-merger remnant, including component masses and spin vectors. Three different waveform models, as well as direct comparison to numerical solutions of general relativity, yield consistent estimates of these properties. Tests of strong-field general relativity targeting the merger-ringdown stages of the coalescence indicate consistency of the observed signal with theoretical predictions. We estimate the merger rate of similar systems to be 0.13_(-0.11)^(+0.30) Gpc⁻³ yr⁻¹. We discuss the astrophysical implications of GW190521 for stellar collapse and for the possible formation of black holes in the pair-instability mass gap through various channels: via (multiple) stellar coalescences, or via hierarchical mergers of lower-mass black holes in star clusters or in active galactic nuclei. We find it to be unlikely that GW190521 is a strongly lensed signal of a lower-mass black hole binary merger. We also discuss more exotic possible sources for GW190521, including a highly eccentric black hole binary, or a primordial black hole binary