ECLIPSE Study Research Articles

Contrasting the clinical and biological characteristics of young and old COPD patients

Background.The ECLIPSE study was a large, international, prospective, controlled, observational study that included COPD patients (GOLD grades 2–4), as well as smoking and non-smoking participants with normal spirometry, aged 40–75 yrs., who were followed-up regularly for 3 years. Here we sought to contrast the clinical and biological characteristics of young COPDversuscontrols of similar age and older COPD patients included in ECLIPSE.Methods.We compared 106 young (<50 years) and 488 old (>70 years) COPD patients, as well as 119 young smokers and 92 non-smoker controls (<50 years) with normal spirometry.Results.Young COPD patients:(1)were more symptomatic than young controls, often reported a family history of chronic bronchitis, emphysema and asthma, as well as a personal history of asthma and bronchitis, and suffer from a similar disease burden than older patients;(2)were at higher risk of substantial FEV1decline over time; and(3)had reduced serum levels of CC16 (a lung-derived anti-inflammatory protein that relates to lung damage) and, at the same time, reduced pro-inflammatory markers than older COPD patients.Conclusions.Young COPD patients suffer from significant disease burden, display an altered biomarker and disease progression profile reflected by an accelerated risk of lung function decline highlighting the need for early life diagnosis, prevention approaches and treatment.

Study of consecutive eclipses of pulsar J0024-7204O

ABSTRACT The eclipses seen in the radio emission of some pulsars can be invaluable to study the properties of the material from the companion stripped away by the pulsar. We present a study of six consecutive eclipses of PSR J0024–7204O in the globular cluster 47 Tucanae as seen by the MeerKAT radio telescope in the UHF (544–1088 MHz) band. A high scintillation state boosted the signal during one of the orbits and allowed a detailed study of the eclipse properties. We measure significant dispersion measure (DM) variations and detect strong scattering that seems to be the dominating mechanism of the eclipses at these frequencies. A complete drop in the linear polarization together with a small increase in the rotation measure suggests the presence of a magnetic field of $\sim 2$ mG. The study of multiple eclipses allowed us to measure difference in the lengths of the eclipses and DM differences of $\sim 0.01$ pc cm$^{-3}$ in consecutive orbits. One orbit, in particular, shows a delay in recovery of the linear polarization and a visible delay in the arrival of the pulses caused by a stronger scattering event. We suggest that these are caused by a higher variance of density fluctuations during the event.

Comparative Study of Eclipse and RayStation Multi-Criteria Optimization-Based Prostate Radiotherapy Treatment Planning Quality.

Multi-criteria optimization (MCO) function has been available on commercial radiotherapy (RT) treatment planning systems to improve plan quality; however, no study has compared Eclipse and RayStation MCO functions for prostate RT planning. The purpose of this study was to compare prostate RT MCO plan qualities in terms of discrepancies between Pareto optimal and final deliverable plans, and dosimetric impact of final deliverable plans. In total, 25 computed tomography datasets of prostate cancer patients were used for Eclipse (version 16.1) and RayStation (version 12A) MCO-based plannings with doses received by 98% of planning target volume having 76 Gy prescription (PTV76D98%) and 50% of rectum (rectum D50%) selected as trade-off criteria. Pareto optimal and final deliverable plan discrepancies were determined based on PTV76D98% and rectum D50% percentage differences. Their final deliverable plans were compared in terms of doses received by PTV76 and other structures including rectum, and PTV76 homogeneity index (HI) and conformity index (CI), using a t-test. Both systems showed discrepancies between Pareto optimal and final deliverable plans (Eclipse: -0.89% (PTV76D98%) and -2.49% (Rectum D50%); RayStation: 3.56% (PTV76D98%) and -1.96% (Rectum D50%)). Statistically significantly different average values of PTV76D98%,HI and CI, and mean dose received by rectum (Eclipse: 76.07 Gy, 0.06, 1.05 and 39.36 Gy; RayStation: 70.43 Gy, 0.11, 0.87 and 51.65 Gy) are noted, respectively (p < 0.001). Eclipse MCO-based prostate RT plan quality appears better than that of RayStation.

Blood-based Transcriptomic and Proteomic Biomarkers of Emphysema.

Rationale: Emphysema is a chronic obstructive pulmonary disease phenotype with important prognostic implications. Identifying blood-based biomarkers of emphysema will facilitate early diagnosis and development of targeted therapies. Objectives: To discover blood omics biomarkers for chest computed tomography-quantified emphysema and develop predictive biomarker panels. Methods: Emphysema blood biomarker discovery was performed using differential gene expression, alternative splicing, and protein association analyses in a training sample of 2,370 COPDGene participants with available blood RNA sequencing, plasma proteomics, and clinical data. Internal validation was conducted in a COPDGene testing sample (n = 1,016), and external validation was done in the ECLIPSE study (n = 526). Because low body mass index (BMI) and emphysema often co-occur, we performed a mediation analysis to quantify the effect of BMI on gene and protein associations with emphysema. Elastic net models with bootstrapping were also developed in the training sample sequentially using clinical, blood cell proportions, RNA-sequencing, and proteomic biomarkers to predict quantitative emphysema. Model accuracy was assessed by the area under the receiver operating characteristic curves for subjects stratified into tertiles of emphysema severity. Measurements and Main Results: Totals of 3,829 genes, 942 isoforms, 260 exons, and 714 proteins were significantly associated with emphysema (false discovery rate, 5%) and yielded 11 biological pathways. Seventy-four percent of these genes and 62% of these proteins showed mediation by BMI. Our prediction models demonstrated reasonable predictive performance in both COPDGene and ECLIPSE. The highest-performing model used clinical, blood cell, and protein data (area under the receiver operating characteristic curve in COPDGene testing, 0.90; 95% confidence interval, 0.85-0.90). Conclusions: Blood transcriptome and proteome-wide analyses revealed key biological pathways of emphysema and enhanced the prediction of emphysema.

Estimated value-based pricing for blood-based colorectal cancer screening test versus multi-target stool DNA test.

e18911 Background: Stool-based colorectal cancer (CRC) screening with the multi-target stool DNA (mt-sDNA) test is a guideline endorsed strategy for average-risk individuals age ≥45 years and provides a reference for value-based pricing (VBP); maximum price at which a willingness-to-pay threshold is reached. Blood-based tests (BT) are an emerging screening option. Using recent reported BT performance data from the ECLIPSE study (Guardant Health, Inc.)1, the potential VBP of BT compared with multi-target stool DNA (mt-sDNA) was analyzed. Methods: Using the validated CRC-AIM model, we simulated a cohort of 2 million average-risk individuals who received screening with BT at 1, 2, or 3-year intervals or triennial mt-sDNA between the ages of 45-75 years. For BT, CRC sensitivity, advanced adenoma sensitivity, and specificity were based on reported clinical trial data (83%, 13%, and 90%, respectively). Adherence assumptions for BT and mt-sDNA screening were modeled at perfect (100%) or real-world mt-sDNA adherence (RWE). Key outcomes were life-years gained (LYG) per 1000 individuals vs no screening, and VBP of BT vs mt-sDNA ($895 vs $508) was assessed at a willingness-to-pay (WTP) threshold of $50,000 per quality-adjusted life-year. Results: The triennial mt-sDNA was more effective and less costly vs BT at all intervals with both perfect and RWE adherence at the current price. Compared with mt-sDNA screening, LYG of screening with BT was lower (320 vs. 241-314) and the VBP should be at most $49 and $11 and no-cost at the 1-, 2-, and 3-year intervals, respectively (Table), when perfect adherence is assumed. With RWE adherence, the LYG with mt-sDNA was 306 compared to 229-284 with BT across all intervals. To be comparable to RWE triennial mt-sDNA screening, the maximum VBP for BT would need to be $13 at the 1-year interval and no cost for 2- and 3-year interval. Conclusions: Compared to annual, biannual, and triennial BT, triennial mt-sDNA was more effective at all intervals and 44% to 102% less costly. The maximum price of BT should not exceed $49 to be considered a cost-effective option compared to mt-sDNA when WTP is 50,000. [Table: see text]

Colorectal cancer screening with blood-based tests: Estimated impact of a 1-, 2-, or 3-year screening interval compared with annual FIT and triennial mt-sDNA strategies.

10580 Background: Blood-based tests are an emerging option for non-invasive colorectal cancer (CRC) screening for which the Centers for Medicare &amp; Medicaid Services (CMS) has proposed coverage every 3 years for average-risk individuals. Analyses with the CRC-AIM microsimulation model demonstrated that triennial screening with blood-based tests with CMS minimum performance often yields inferior outcomes to stool-based CRC screening (fecal immunochemical test [FIT] and multi-target stool DNA [mt-sDNA]). CRC-AIM was used to explore the impact of blood-based screening intervals, using reported performance characteristics from the ECLIPSE study (Guardant Health, Inc.)1, on estimated clinical outcomes vs FIT and mt-sDNA screening. Methods: Outcomes were simulated for average-risk individuals screened between ages 45-75 years. Intervals were set at 1, 2, or 3 years for blood-based, 3 years for mt-sDNA and annually for FIT screening. The blood-based test was modeled at 83% CRC sensitivity, 13% advanced adenoma sensitivity, and 90% specificity. Perfect adherence (100%) was modeled for blood-based tests and real-world adherence rates used for CRC initial screening tests (mt-sDNA=65.6%; FIT=42.6%) and follow-up colonoscopy (mt-sDNA=72.1%; FIT=46.0%). Primary outcomes were life-years gained (LYG) and colonoscopies (COL) per 1000 individuals for blood-based screening compared to mt-sDNA and FIT. As a secondary analysis, estimates were generated with perfect (100%) adherence assumed for initial screening and follow-up colonoscopy for mt-sDNA and FIT as well. Results: Blood-based testing at a 3-year interval with 100% adherence led to 11% fewer LYG than mt-sDNA at RWE adherence (240 vs 270, respectively), and 9% more COL (1402/1000 vs 1288/1000). Meanwhile, blood-based testing at a 1-year interval and perfect adherence (best case scenario) resulted in the lowest LYG per COL ratio across all scenarios (16% more LYG and 87% more COL compared to mt-sDNA at RWE adherence). Blood-based test results showed similar trends when compared to FIT. Conclusions: Outcomes for blood-based screening every 3 years based on reported test performance characteristics and unrealistic perfect adherence demonstrate fewer LYG as compared to either mt-sDNA or FIT. When compared to real-world adherence for mt-sDNA and FIT, blood-based tests with 1- and 2-year intervals and perfect adherence had higher LYG with the tradeoff of a greater number of diagnostic colonoscopies. [Table: see text]

Serum IL-8 as a Determinant of Response to Phosphodiesterase-4 Inhibition in Chronic Obstructive Pulmonary Disease.

Rationale: Phosphodiesterase-4 (PDE4) inhibitors have demonstrated increased efficacy in patients with chronic obstructive pulmonary disease who had chronic bronchitis or higher blood eosinophil counts. Further characterization of patients who are most likely to benefit is warranted. Objective: To identify determinants of response to the PDE4 inhibitor tanimilast. Methods: A PDE4 gene expression signature in blood was developed by unsupervised clustering of the ECLIPSE study dataset (ClinicalTrials.gov ID: NCT00292552; Gene Expression Omnibus Series ID: GSE76705). The signature was further evaluated using blood and sputum transcriptome data from the BIOMARKER study (NCT03004417; GSE133513), enabling validation of the association between PDE4 signaling and target biomarkers. Predictivity of the associated biomarkers against clinical response was then tested in the phase-2b PIONEER tanimilast study (NCT02986321). Measurements and Main Results: The PDE4 gene expression signature developed in the ECLIPSE dataset classified subgroups of patients associated with different PDE4 signaling in the BIOMARKER cohort with an area under the receiver operator curve of 98%. In the BIOMARKER study, serum IL-8 was the only variable that was consistently associated with PDE4 signaling, with lower levels associated with higher PDE4 activity. In the PIONEER study, the exacerbation rate reduction mediated by tanimilast treatment increased up to twofold in patients with lower IL-8 levels; 36% versus 18%, reaching statistical significance at ⩽20 pg/ml (P = 0.035). The combination with blood eosinophils ⩾150 μl-1 or chronic bronchitis provided further additive exacerbation rate reduction: 45% (P = 0.013) and 47% (P = 0.027), respectively. Conclusions: Using selected heterogeneous datasets, this analysis identifies IL-8 as an independent predictor of PDE4 inhibition, as tanimilast had a greater effect on exacerbation prevention in patients with chronic obstructive pulmonary disease who had lower baseline serum IL-8 levels. Testing of this biomarker in other datasets is warranted. Clinical trial registered with www.clinicaltrials.gov (NCT00292552 [Gene Expression Omnibus Series ID: GSE76705], NCT03004417 [GSE133513], and NCT02986321).

The 2021 Antarctic Total Eclipse: Ground Magnetometer and GNSS Wave Observations From the 40 Degree Magnetic Meridian

AbstractOn 04 December 2021, a total solar eclipse occurred over west Antarctica. Nearly an hour beforehand, a geomagnetic substorm onset was observed in the northern hemisphere. Eclipses are suggested to influence magnetosphere‐ionosphere (MI) coupling dynamics by altering the conductivity structure of the ionosphere by reducing photoionization. This sudden and dramatic change in conductivity is not only likely to alter global MI coupling, but it may also introduce a variety of localized instabilities that appear in both hemispheres. Global navigation satellite system (GNSS) based observations of the total electron content (TEC) in the southern high latitude ionosphere during the December 2021 eclipse show signs of wave activity coincident with the eclipse peak totality. Ground magnetic observations in the same region show similar activity, and our analysis suggest that these observations are due to an “eclipse effect” rather than the prior substorm. We present the first multi‐point interhemispheric study of a total south polar eclipse with local TEC observational context in support of this conclusion.

Analisis Historisitas Gerhana Di Desa Bissoloro Kec. Bungaya Kab. Gowa Perspektif Sains dan Ilmu Falak

Irfan, Nur Aisyah, Nila Sastrawati, Muh. Rasywan Syarif. Myths that develop in Indonesia society, especially in Bissoloro Village, Bungaya District, Gowa Regency, some people have their own beliefs in responding to the occurrence of the eclipse phenomenon by not doing activities outside the home, forbidding children to play outside the house, fearing they will get sick, and not being allowed to see the incident, the eclipse that occurs at night, it is believed that when the eclipse takes place, it is very suitable to uproot the lolo rupa plant to be used as a beauty potion for everyday use. This research is classified as a descriptive qualitative research field. The views of the people of Bissoloro Village in responding to the eclipse phenomenon still follow the beliefs of their ancestors. The development of science changes people’s assumptions, people who take education no longer think that eclipses are something to be afraid of, in fact the eclipse phenomenon is considered a beautiful and extraordinary phenomenon and interesting to observe using astronomical tools. From a scientific perspective, eclipses occur because the positions of the sun, moon, and earth are in a straigh line natural phenomenon occur naturally and can be scientifically From the perspective of astronomy, in the historical study of solar eclipses, it occurred at the time of the Prophet Muhammad. through the hadith clearly states that eclipses do not result in the death or birth of a person.Keywords: Eclipses, Science Perspective, and Astrology.

Thefalse widowlink between neutron star X-ray binaries and spider pulsars

ABSTRACTThe discovery of transitional millisecond pulsars (tMSPs) provided conclusive proof that neutron star (NS) low-mass X-ray binaries (LMXBs) comprise part of the evolutionary pathway towards binary millisecond pulsars (MSPs). Redback and black widow ‘spider’ pulsars are a subcategory of binary MSPs that ‘devour’ their companions through ablation – the process through which material is lifted from the stellar surface by a pulsar wind. In addition to reducing the companion star’s mass, ablation introduces observable characteristics like extended, energy-dependent, and asymmetric eclipse profiles in systems observed at a sufficiently high inclination. Here, we present a detailed study and comparison of the X-ray eclipses of two NS LMXBs: Swift J1858.6 − 0814 and EXO 0748 − 676. Some of the X-ray eclipse characteristics observed in these two LMXBs are similar to the radio eclipse characteristics of eclipsing redback and black widow pulsars, suggesting that they may also host ablated companion stars. X-ray irradiation or a pulsar wind could drive the ablation. We conduct orbital phase-resolved spectroscopy for both LMXBs to map the column density, ionization, and covering fraction of the material outflow. From this, we infer the presence of highly ionized and clumpy ablated material around the companion star in both systems. We term LMXBs undergoing ablation, false widows, and speculate that they may be the progenitors of redback pulsars under the assumption that ablation begins in the LMXB stage. Therefore, the false widows could provide a link between LMXBs and spider pulsars. The detection of radio pulsations during non-accreting states can support this hypothesis.

Dione’s Thermal Inertia and Bolometric Bond Albedo Derived from Cassini/CIRS Observations of Solar Eclipse Ingress

On 2010 May 18 Cassini’s Composite Infrared Spectrometer (CIRS) observed Dione’s leading hemisphere as its surface went into solar eclipse. Surface temperatures derived from each of CIRS’ focal plane 3 (FP3, 600−1100 cm−1) show a rapid decrease in Dione’s surface temperature upon eclipse ingress. This change was compared to the model surface emission to constrain bolometric Bond albedo and thermal inertia. Seven FP3 detectors were able to constrain the observed surface’s thermophysical properties. The bolometric Bond albedo derived from these detectors are consistent with one another (0.54 ± 0.05 to 0.62 ± 0.03) and that of diurnal studies (e.g., 0.49 ± 0.11, Howett et al. 2014). This indicates that Dione’s albedo is uniform to within the uncertainties across the observed region of its leading hemisphere. The derived thermal inertias are consistent across detectors, 9 ± 4 J m−2 K−1 s−1/2 (MKS) to 16 ± 8 MKS, and with previous diurnal studies (e.g., 8 to 12 MKS, Howett et al. 2014). The skin depth probed by the eclipse thermal wave is ∼0.6–1 mm, which is much shallower than that probed by diurnal cycles (∼50 mm). Thus, the agreement in thermal inertia between the eclipse and diurnal studies indicates that Dione’s subsurface structure is uniform from submillimeter to subcentimeter depths. This is different from the Jovian system, where eclipse-derived thermal inertias are much lower than those derived from diurnal studies. The cause of this difference is not known, but one possibility is that the E-ring grains that bombard Dione’s leading hemisphere overturn it, causing uniformity to centimeter depths.

Blood gene expression risk profiles and interstitial lung abnormalities: COPDGene and ECLIPSE cohort studies

BackgroundInterstitial lung abnormalities (ILA) are radiologic findings that may progress to idiopathic pulmonary fibrosis (IPF). Blood gene expression profiles can predict IPF mortality, but whether these same genes associate with ILA and ILA outcomes is unknown. This study evaluated if a previously described blood gene expression profile associated with IPF mortality is associated with ILA and all-cause mortality.MethodsIn COPDGene and ECLIPSE study participants with visual scoring of ILA and gene expression data, we evaluated the association of a previously described IPF mortality score with ILA and mortality. We also trained a new ILA score, derived using genes from the IPF score, in a subset of COPDGene. We tested the association with ILA and mortality on the remainder of COPDGene and ECLIPSE.ResultsIn 1469 COPDGene (training n = 734; testing n = 735) and 571 ECLIPSE participants, the IPF score was not associated with ILA or mortality. However, an ILA score derived from IPF score genes was associated with ILA (meta-analysis of test datasets OR 1.4 [95% CI: 1.2–1.6]) and mortality (HR 1.25 [95% CI: 1.12–1.41]). Six of the 11 genes in the ILA score had discordant directions of effects compared to the IPF score. The ILA score partially mediated the effects of age on mortality (11.8% proportion mediated).ConclusionsAn ILA gene expression score, derived from IPF mortality-associated genes, identified genes with concordant and discordant effects on IPF mortality and ILA. These results suggest shared, and unique biologic processes, amongst those with ILA, IPF, aging, and death.

Longitudinal Association Between Muscle Loss and Mortality in Ever Smokers

Body composition measures, specifically low weight or reduced muscle mass, are associated with mortality in COPD, but the effect of longitudinal body composition changes is undefined. Is the longitudinal loss of fat-free mass (FFM) associated with increased mortality, including in those with initially normal or elevated body composition metrics? Participants with complete data for at least one visit in the COPDGene study (n= 9,268) and the ECLIPSE study (n= 1,760) were included and monitored for 12 and 8 years, respectively. Pectoralis muscle area (PMA) was derived from thoracic CT scans and used as a proxy for FFM. A longitudinal mixed submodel for PMA and a Cox proportional hazards submodel for survival were fitted on a joint distribution, using a shared random intercept parameter and Markov chain Monte Carlo parameter estimation. Both cohorts demonstrated a left-shifted distribution of baseline FFM, not reflected in BMI, and an increase in all-cause mortality risk associated with longitudinal loss of PMA. For each 1-cm2 PMA loss, mortality increased 3.1%(95%CI, 2.4%-3.7%; P< .001) in COPDGene, and 2.4%(95%CI, 0.9%-4.0%; P< .001) in ECLIPSE. Increased mortality risk was independent of enrollment values for BMI and disease severity [BODE (body mass, airflow obstruction, dyspnea, and exercise capacity) index quartiles] and was significant even in participants with initially greater than average PMA. Longitudinal loss of PMA is associated with increased all-cause mortality, regardless of BMI or initial muscle mass. Consideration of novel screening tests and further research into mechanisms contributing to muscle decline may improve risk stratification and identify novel therapeutic targets in ever smokers.

The ECLIPSE Study: Efficacy of Cryoablation on Metastatic Lung Tumors With a 5-Year Follow-Up

IntroductionThe ECLIPSE study aimed to evaluate the feasibility and efficacy of cryoablation (CA) for local tumor control in patients with pulmonary metastatic disease in 5 years of follow-up. MethodsECLIPSE was a prospective, multicenter, single-arm study that included patients treated with CA if they had one to five metastatic lung tumors, each with a diameter of less than or equal to 3.5 cm. Patients were followed up in the course of 5 years. The primary end point was local tumor control, both per tumor and per patient; secondary end points included cancer-specific survival, overall survival, and quality of life (QoL). QoL was evaluated using the Karnofsky Performance Score, the Eastern Cooperative Oncology Group performance score, and the Short Form-12 health survey. ResultsThe study included 40 patients across four sites (three in United States and one in Europe). A total of 60 metastatic pulmonary tumors were treated with 48 CA procedures. Overall local tumor control rates were 87.9% (29 of 33) and 79.2% (19 of 24) per tumor, 83.3% (20 of 24) and 75.0% (15 of 20) per patient, at 3 and 5 years, respectively. A total of five treated patients had local progression throughout the duration of the study. Disease-specific survival rate was 74.8% at 3 years and 55.3% at 5 years, whereas overall survival at 3 and 5 years was 63.2% and 46.7%, respectively. Patient QoL scores did not reach statistical significance. ConclusionsCA is an effective means of long-term local tumor control in patients with metastatic pulmonary tumors.

26592 Characterization of response clusters identified by unsupervised machine learning: A post hoc analysis of the head-to-head ECLIPSE trial of guselkumab and secukinumab in patients with moderate-to-severe psoriasis

Introduction and Objectives: This post hoc analysis of ECLIPSE study data aimed to identify novel PASI response patterns in the guselkumab (GUS) and secukinumab (SEC) treatment arms, through unsupervised machine learning (ML).

Efficacy of guselkumab versus secukinumab in subpopulations of patients with moderate-to-severe plaque psoriasis: results from the ECLIPSE study

Purpose Guselkumab, an interleukin (IL)-23 inhibitor, effectively treats moderate-to-severe plaque psoriasis. Materials and methods ECLIPSE, was a Phase 3, multicenter, 56-week, double-blinded, active-comparator study of guselkumab vs. secukinumab (IL-17A inhibitor) in patients with moderate-to-severe psoriasis. Patients were treated with guselkumab 100 mg (n = 534) or secukinumab 300 mg (n = 514) through week 44. Efficacy (at least a 90% and 100% improvement from baseline in Psoriasis Area and Severity Index [PASI 90 and PASI 100], Investigator’s Global Assessment [IGA] 0/1, and IGA 0) was analyzed across subpopulations defined by baseline: age (<45, 45 to <65, and ≥65 years old), body weight, body mass index (BMI), psoriasis disease severity (body surface area, disease duration, PASI, and IGA), psoriasis by body regions (head, trunk, upper and lower extremities), and prior psoriasis medication history at week 48. Results Overall, 1048 patients were randomized. At week 48, numerically greater proportions of patients achieved PASI 90, PASI 100, IGA 0/1, and IGA 0 with guselkumab vs. secukinumab regardless of baseline age, body weight, BMI, disease severity, body region, and prior medication. The largest differences were in patients ≥65 years old and patients weighing >100 kg. Conclusions Guselkumab treatment provided greater efficacy vs. secukinumab at week 48 in most subpopulations of patients with psoriasis.

Predicting Serum Ferritin Levels in Patients with Iron Overload Treated with the Film-Coated Tablet of Deferasirox during the Eclipse Study

Background: The ECLIPSE trial demonstrated that the new film-coated tablet (FCT) deferasirox (DFX) formulation and the dispersible tablet (DT) had similar safety profiles during 6 months of treatment, although fewer patients experienced severe gastrointestinal-related adverse events, and more patients experienced favorable patient-reported outcomes with FCT than with DT (Taher et al. Am J Hematol 2017). Additionally, FCT patients had a greater reduction in serum ferritin (SF) levels from baseline to end of treatment (geometric mean change −431 vs −153 ng/mL in DT patients) despite both groups experiencing similar DFX exposure, which suggests greater efficacy with FCT. In the absence of FCT efficacy data beyond 6 months, we developed a model to predict SF levels in patients from the ECLIPSE trial if they had continued DFX DT or FCT treatment for 6-12 months.Methods: ECLIPSE was a Phase II, randomized, open-label study in which patients with transfusion-dependent thalassemia (TDT) or International Prognostic Scoring System lower-risk myelodysplastic syndromes (MDS) were randomized to receive DFX DT or FCT. Planned doses in iron chelation therapy (ICT)-naïve patients were DT 20 mg/kg/day or FCT 14 mg/kg/day based on equivalent FCT doses being 30% lower than DT due to improved bioavailability. ICT pre-treated patients received either a DT dose equivalent to their pre-washout dose or a planned 30% reduction for FCT. Dose was adjusted based on SF levels and investigator's judgment every 4 weeks for ICT-naïve patients and every 3 months for ICT pre-treated patients (DT ±5-10 mg/kg/day, max 40 mg/kg/day; FCT ±3.5-7 mg/kg/day, max 28 mg/kg/day); dose adjustments for safety reasons were permitted at any time.Models for predicting ICT effect were built and tested based on 12-month data from the controlled registration study ICL670A108 (Porter et al. Eur J Haematol 2008). Most patients from ECLIPSE had received prior ICT; therefore, for the development of the model, this situation was mimicked using ICL670A108 month 3-9 data for fitting, and month 10-12 data for evaluating model prediction quality. The selected model accounted for baseline SF levels, assigned daily DFX dose per arm and patients' body weight, and predicted the ICT effect for up to 12 months if patients had continued with their therapy (DT or FCT). The model was applied to both DT and FCT arms of the ECLIPSE trial and predictions were obtained from individual estimates of each patient.Results:Trial results: 173 patients were randomized 1:1 to DT (n=86) or FCT (n=87); 70 patients in each arm had TDT and 16 patients had MDS (underlying disease missing in 1 FCT patient). Mean±SD age was 34.9±19.3 years, 51% were female and 90% had previously received ICT. Mean±SD actual daily DFX dose over 24 weeks was 27.5±7.7 mg/kg/day (DT) and 20.8±5.4 mg/kg/day (FCT). At baseline, SF geometric mean was 2381 ng/mL (DT) and 2721 ng/mL (FCT).Model prediction: Model diagnostics suggested a close approximation of the ECLIPSE data, as the predicted SF geometric mean during the first 6 months of treatment was similar to the actual SF values observed during the trial (Figure). The model predicted that SF geometric mean values would continue to decrease over the subsequent 6 months with both DT and FCT, reaching 2162 ng/mL (90% confidence interval [CI] 2029-2304) with DT and 2180 ng/mL (90% CI 2054-2311) with FCT after 12 months of treatment. This corresponds to a predicted, relative decrease of 10% with DT and 19% with FCT.Conclusions: The 6-month results of the model were similar to the actual SF values observed during the ECLIPSE trial, and reliably predicted continued ICT effect for months 7-12 if patients had continued with their assigned treatment (DT or FCT). Previous analyses have indicated that improved patient-reported outcomes, especially increased adherence, are significant mediators of the association between treatment with DT vs FCT and SF reduction from baseline over 6 months of treatment (Taher et al. Haematologica 2017;102[s2]:abst P286). According to the predicted results from this model, and at the doses given in this study, patients treated with FCT would have had a greater reduction in SF at 12 months compared with patients treated with DT; although it should be noted that FCT patients had higher baseline SF. This analysis suggests the FCT offers patients an improved DFX formulation, which could be attributed to improved treatment adherence. [Display omitted] DisclosuresTaher:Novartis Pharmaceuticals: Honoraria, Research Funding; Celgene: Research Funding. Weber:Novartis: Employment. Han:Novartis: Employment. Bruederle:Novartis: Employment. Porter:Celegene: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Bluebird Bio: Consultancy; Novartis: Consultancy, Honoraria, Research Funding.

RAGOONATHA CHARRY AND OBSERVATIONS OF THE TOTAL SOLAR ECLIPSE OF 1868 FROM VANPURTHY (WANPARTHY), INDIA

The eclipse of 18 August 1868, often called as the 'The Great Indian Eclipse', and described as a 'watershed event', took place at a time when what can be called as 'old eclipse studies' was fading and the era of solar physics, using spectroscopy, photography, polarimeter and so on, was starting to bloom. It was also a notable event in the history of the emergence of modern astronomy and astrophysics in India. Although observations of eclipses were conducted earlier, it was in 1868 that the Madras Observatory organised an eclipse expedition, and for the first time an Indian astronomer led a modern astronomical eclipse expedition. Ragoonatha Charry, the First (head) Assistant at the Observatory led a team of astronomy enthusiasts to observe the eclipse from Vanpurthy (Wanparthy) situated near the central line of the path of totality. While the significant scientific breakthroughs, such as the discovery of helium and the spectral characteristics of prominences and the corona, were made during the 1868 eclipse mainly by the British and French expeditions at Guntur and Masulipatnam, this expedition led by an Indian astronomer, had an impact on the public imagination and subsequently on calendar reform in southern India. In this paper, we focus mainly on Ragoonatha Charry's expedition to Vanpurthy, a principality under the dominion of the Nizam of Hyderabad state. We examine the preparatory scientific work done by Ragoonatha Charry, associated personnel on the expedition, the selection and establishment of their observing station, the scientific instruments that they used, the observations that they made, and the impact that this particular eclipse had on the public imagination.

Advances in the management of generalized convulsive status epilepticus: what have we learned?

Convulsive status epilepticus is the most serious manifestation of an epileptic diathesis. In the early stages (5-30 min), there exists class A evidence to support the efficacy of benzodiazepines as first-line treatment. As status epilepticus progresses into the later stages, the evidence for treatment becomes less robust until we are depending upon short case series and case reports for the treatment of refractory status epilepticus. However, the past year saw the publication of three randomized controlled trials in the setting of benzodiazepine-resistant established convulsive status epilepticus: the EcLiPSE and ConSEPT studies, compared levetiracetam to phenytoin in children; and the ESETT study compared fosphenytoin, levetiracetam and sodium valproate in adults and children. In addition, the emergence of data from the SENSE study, a multicentre multinational prospective cohort study and the publication of a systematic review and meta-analysis of the mortality of status epilepticus over the past 30 years, has brought the treatment of status epilepticus into sharp focus. In this update we provide a detailed analysis of these studies and their impact on clinical practice. We review contentious areas of management in status epilepticus where a consensus is lacking and advance the case for more research on existing and alternative treatment strategies.

On the impact of release policies on bug handling activity: A case study of Eclipse

Large software projects follow a continuous development process with regular releases during which bugs are handled. In recent years, many software projects shifted to rapid releases that reduce time-to-market and claim a faster delivery of fixed issues, but also have a shorter period to address bugs. To better understand the impact of rapid releases on bug handling activity, we empirically analyze successive releases of the Eclipse Core projects, focusing on the bug handling rates and durations as well as the feature freeze period. We study the impact of Eclipse’s transition from a yearly to quarterly release cycle. We confirm our findings through feedback received from five Eclipse Core maintainers. Among others, our results reveal that Eclipse’s bug handling process is becoming more stable over time, with a decreasing number of reported bugs before releases, an increasing bug fixing rate and an increasingly balanced bug handling workload before and after releases. The transition to a quarterly release cycle continued to improve bug handling. In addition, more effort is spent on bug fixing during the feature freeze period, while the bug handling rates do not differ between both periods.