The International Prognostic Score (IPS) has been used in classic Hodgkin lymphoma (cHL) for 25 years. However, analyses have documented suboptimal performance of the IPS among contemporarily treated ...patients. Harnessing multisource individual patient data from the Hodgkin Lymphoma International Study for Individual Care consortium, we developed and validated a modern clinical prediction model.
Model development via Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines was performed on 4,022 patients with newly diagnosed advanced-stage adult cHL from eight international phase III clinical trials, conducted from 1996 to 2014. External validation was performed on 1,431 contemporaneously treated patients from four real-world cHL registries. To consider association over a full range of continuous variables, we evaluated piecewise linear splines for potential nonlinear relationships. Five-year progression-free survival (PFS) and overall survival (OS) were estimated using Cox proportional hazard models.
The median age in the development cohort was 33 (18-65) years; nodular sclerosis was the most common histology. Kaplan-Meier estimators were 0.77 for 5-year PFS and 0.92 for 5-year OS. Significant predictor variables included age, sex, stage, bulk, absolute lymphocyte count, hemoglobin, and albumin, with slight variation for PFS versus OS. Moreover, age and absolute lymphocyte count yielded nonlinear relationships with outcomes. Optimism-corrected c-statistics in the development model for 5-year PFS and OS were 0.590 and 0.720, respectively. There was good discrimination and calibration in external validation and consistent performance in internal-external validation. Compared with the IPS, there was superior discrimination for OS and enhanced calibration for PFS and OS.
We rigorously developed and externally validated a clinical prediction model in > 5,000 patients with advanced-stage cHL. Furthermore, we identified several novel nonlinear relationships and improved the prediction of patient outcomes. An online calculator was created for individualized point-of-care use.
The replacement of bleomycin with the immune drug conjugate brentuximab vedotin in the first-line chemotherapy regimen for advanced Hodgkin’s lymphoma prolonged both progression-free and overall ...survival.
Antibody responses during infection and vaccination typically undergo affinity maturation to achieve high-affinity binding for efficient neutralization of pathogens
. Similarly, high affinity is ...routinely the goal for therapeutic antibody generation. However, in contrast to naturally occurring or direct-targeting therapeutic antibodies, immunomodulatory antibodies, which are designed to modulate receptor signalling, have not been widely examined for their affinity-function relationship. Here we examine three separate immunologically important receptors spanning two receptor superfamilies: CD40, 4-1BB and PD-1. We show that low rather than high affinity delivers greater activity through increased clustering. This approach delivered higher immune cell activation, in vivo T cell expansion and antitumour activity in the case of CD40. Moreover, an inert anti-4-1BB monoclonal antibody was transformed into an agonist. Low-affinity variants of the clinically important antagonistic anti-PD-1 monoclonal antibody nivolumab also mediated more potent signalling and affected T cell activation. These findings reveal a new paradigm for augmenting agonism across diverse receptor families and shed light on the mechanism of antibody-mediated receptor signalling. Such affinity engineering offers a rational, efficient and highly tuneable solution to deliver antibody-mediated receptor activity across a range of potencies suitable for translation to the treatment of human disease.
To evaluate safety and efficacy outcomes for subjects on the ECHELON-1 study treated in North America (NA).
ECHELON-1 is a global, open-label, randomized phase III study comparing doxorubicin, ...vinblastine, and dacarbazine in combination with brentuximab vedotin (A+AVD) versus ABVD (AVD + bleomycin) as first-line therapy in subjects with stage III or IV classical Hodgkin lymphoma (cHL; NCT01712490). Subjects were randomized 1:1 to receive A+AVD or ABVD intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles.
The NA subgroup consisted of 497 subjects in the A+AVD (
= 250) and ABVD (
= 247) arms. Similar to the primary analysis based on the intent-to-treat population, the primary endpoint modified progression-free survival (PFS) per independent review demonstrated an improvement among subjects who received A+AVD compared with ABVD (HR = 0.60;
= 0.012). For PFS, the risk of progression or death was also reduced (HR = 0.50;
= 0.002). Subsequent anticancer therapies were lower in the A+AVD arm. Grade 3 or 4 adverse events (AEs) were more common, but there were fewer study discontinuations due to AEs in the A+AVD arm as compared with ABVD. Noted differences between arms included higher rates of febrile neutropenia (20% vs. 9%) and peripheral neuropathy (80% vs. 56%), but lower rates of pulmonary toxicity (3% vs. 10%) in subjects treated with A+AVD versus ABVD.
The efficacy benefit and manageable toxicity profile observed in the NA subgroup of ECHELON-1 support A+AVD as a frontline treatment option for patients with stage III or IV cHL.
American robins and dark-eyed juncos migrate across North America and have been found to be competent hosts for some bacterial and viral pathogens, but their contributions to arthropod-borne diseases ...more broadly remain poorly characterized. Here, we sampled robins and juncos in multiple sites across North America for arthropod-borne bacterial pathogens of public health significance. We identified two novel Rickettsia spp. in one wintering migrant per bird species related to bellii, transitional, and spotted rickettsiae fever groups. Stable isotope analyses of feathers suggested spring migration of these common songbirds could disperse these novel rickettsiae hundreds-to-thousands of kilometers to host breeding grounds. Further work is needed to characterize zoonotic potential of these rickettsiae and host reservoir competence.
Muscle force production and power output in active males, regardless of the site of measurement (hand, leg, or back), are higher in the evening than in the morning. This diurnal variation is ...attributed to motivational, peripheral and central factors, and higher core and, possibly, muscle temperatures in the evening. This study investigated whether increasing morning rectal temperatures to evening resting values, by active or passive warm-ups, leads to muscle force production and power output becoming equal to evening values in motivated subjects. Ten healthy active males (mean ± SD: age, 21.2 ± 1.9 yrs; body mass, 75.4 ± 8 kg; height, 1.76 ± .06 m) completed the study, which was approved by the University Ethics Committee. The subjects were familiarized with the techniques and protocol and then completed four sessions (separated by at least 48 h): control morning (07:30 h) and evening (17:30 h) sessions (with an active 5-min warm-up) and then two further sessions at 07:30 h but proceeded by an extended active or passive warm-up to raise rectal temperature to evening values. These last two sessions were counterbalanced in order of administration. During each trial, three measures of handgrip strength, isokinetic leg strength measurements (of knee flexion and extension at 1.05 and 4.19 rad.s−1 through a 90° range of motion), and four measures of maximal voluntary contraction (MVC) on an isometric ergometer (utilizing the twitch-interpolation technique) were performed. Rectal and intra-aural temperatures, ratings of perceived exertion (RPE) and thermal comfort (TC) were measured. Measurements were made after the subjects had reclined for 30 min and after the warm-ups and prior to the measurement of handgrip and isokinetic and isometric ergometry. Muscle temperature was taken after the warm-up and immediately before the isokinetic and MVC measurements. Warm-ups were either active (cycle ergometer at 150 W) or passive (resting in a room at 35°C, relative humidity 45%). Data were analyzed using analysis of variance models with repeated measures. Rectal and intra-aural temperatures were higher at rest in the evening (.56°C and .74°C; p < .05) than in the morning, but there were no differences after the active or passive warm-ups, the subjects' ratings of thermal comfort reflecting this. Muscle temperatures also displayed significant diurnal variation, with higher values in the evening (∼.31°C; p < .05). Grip strength, isokinetic knee flexion for peak torque and peak power at 1.05 rad.s−1, and knee extension for peak torque at 4.19 rad.s−1 all showed higher values in the evening. All other measures of strength or power showed a trend to be higher in the evening ( .10 > p > .05). There was no significant effect of active or passive warm-ups on any strength or power variable, and subjects reported maximal values for effort for each strength measure. In summary, effects of time of day were seen in some measures of muscle performance but, in this population of motivated subjects, there was no evidence that increasing morning rectal temperature to evening values by active or passive warm-up increased muscle strength to evening values. (Author correspondence: B.J.Edwards@ljmu.ac.uk)
The air-breathing Alaska blackfish (Dallia pectoralis) experiences aquatic hypoxia, but restricted air-access in winter due to ice-cover. To lend insight into its overwintering strategy, we examined ...the effects of thermal acclimation (15 °C vs. 5 °C), acute temperature change (to 10 °C), increased pacing frequency, inhibition of sarcoplasmic reticulum (SR) Ca2+ release and uptake and adrenaline (1000 nmol l−1) on the contractile performance of isometrically-contracting, electrically-paced ventricular strips. At routine pacing frequencies, maximal developed force (Fmax) was equivalent at 5 °C (2.1 ± 0.2 mN mm−2) and 15 °C (2.2 ± 0.3 mN mm−2), whereas contraction durations were 2.2- to 2.4-times longer and contraction rates 2.4- to 3.5-times slower at 5 °C. Maximum contraction frequency was reduced by decreased temperature, being 0.91 ± 0.04 Hz at 15 °C, 0.35 ± 0.02 Hz at 5 °C and equivalent between acclimation groups at 10 °C (~0.8 Hz). 15 °C and 5 °C strips were insensitive to SR inhibition at routine stimulation frequencies, but SR function supported high contraction rates at 10 °C and 15 °C. Adrenaline shortened T0.5R and increased relaxation rate by 18–40% at 15 °C, whereas at 5 °C, adrenaline augmented Fmax by 15–25%, in addition to increasing contraction kinetics by 22–82% and decreasing contraction duration by 20%. Overall, the results reveal that ventricular contractility is suppressed in cold-acclimated Alaska blackfish largely by acute and perhaps direct effects of decreased temperature, which effectively preconditions the tissue for low energy supply during winter hypoxia. Additionally, the level of cardiac performance associated with maintained activity in winter is supported by enhanced inotropic responsiveness to adrenaline at 5 °C.
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•The air-breathing Alaska blackfish experiences hypoxia, but restricted air-access in winter.•Temperature, frequency, SR inhibition and adrenaline effects on ventricular contractility were examined.•Contractility was suppressed in cold-acclimated Alaska blackfish largely by direct temperature effects.•Cardiac performance in winter is supported by enhanced responsiveness to adrenaline.
Muscle force production and power output in active males, regardless of the site of measurement (hand, leg, or back), are higher in the evening than the morning. This diurnal variation is attributed ...to motivational, peripheral, and central factors and higher core and, possibly, muscle temperatures in the evening. This study investigated whether decreasing evening resting rectal temperatures to morning values, by immersion in a water tank, leads to muscle force production and power output becoming equal to morning values in motivated subjects. Ten healthy active males (mean ± SD: age, 22.5 ± 1.3 yrs; body mass, 80.1 ± 7.8 kg; height, 1.72 ± 0.05 m) completed the study, which was approved by the local ethics committee of the university. The subjects were familiarized with the techniques and protocol and then completed three sessions (separated by at least 48 h): control morning (07:30 h) and evening (17:30 h) sessions (with an active 5-min warm-up on a cycle ergometer at 150 W) and then a further session at 17:30 h but preceded by an immersion in cold water (∼16.5 °C) to lower rectal temperature (Trec) to morning values. During each trial, three measures of grip strength, isokinetic leg strength measurements (of knee flexion and extension at 1.05 and 4.19 rad s−1 through a 90° range of motion), and three measures of maximal voluntary contraction (MVC) on an isometric dynamometer (utilizing the twitch-interpolation technique) were performed. Trec, rating of perceived exertion (RPE), and thermal comfort (TC) were also measured after the subjects had reclined for 30 min at the start of the protocol and prior to the measures for grip, isokinetic, and isometric dynamometry. Muscle temperature was taken after the warm-up or water immersion and immediately before the isokinetic and MVC measurements. Data were analyzed using general linear models with repeated measures. Trec values were higher at rest in the evening (by 0.37 °C; p < 0.05) than the morning, but values were no different from morning values immediately after the passive pre-cooling. However, Trec progressively decreased throughout the experiments, this being reflected in the subjects' ratings of thermal comfort. Muscle temperatures also displayed significant diurnal variation, with higher values in the evening (by 0.39 °C; p < 0.05). Right grip strength, isometric peak power, isokinetic knee flexion and extension for peak torque and peak power at 1.05 rad s−1, and knee extension for peak torque at 4.19 rad s−1 all showed higher values in the evening (a range of 3-14%), and all other measures of strength or power showed a statistical trend to be higher in the evening (0.10 > p > 0.05). Pre-cooling in the evening significantly reduced force or power variables towards morning values. In summary, effects of time of day were seen in some measures of muscle performance, in agreement with past research. However, in this population of motivated subjects, there was evidence that decreasing evening Trec to morning values by coldwater immersion decreased muscle strength to values similar to those found in the morning. It is concluded that diurnal changes in muscle performance are linked to diurnal changes in Trec. (Author correspondence: B.J.Edwards@ljmu.ac.uk)
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