Symptomatic benefit of momelotinib in patients with myelofibrosis: results from the SIMPLIFY phase III studies

Background: Myelofibrosis (MF)-associated constitutional symptoms can severely impact health-related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24-week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy. Methods: Longitudinal symptom change was evaluated using mixed-effect model repeated measure (MMRM) methodology with individual item-level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item-level odds ratios using multiple predictive imputations for missing data. Results: Momelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of <1.5 points between groups for each post-baseline visit in SIMPLIFY-1. In SIMPLIFY-2, the improvement in TSS observed in momelotinib-treated patients was consistent with that observed in SIMPLIFY-1, whereas progressive TSS deterioration was observed with control. Item-level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib-treated patients were categorized as “improved” or “stable” compared with control in SIMPLIFY-1 and SIMPLIFY-2, respectively. Odds ratios for between-group comparison ranged from 0.75 to 1.21 in SIMPLIFY-1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY-2, the likelihood of symptom improvement in each item was higher in the momelotinib arm. Conclusions: These findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor-naïve and JAK inhibitor-exposed settings

Serum lipids, apoproteins and nutrient intake in rural Cretan boys consuming high-olive-oil diets

A high intake of olive oil has produced high levels of high-density and low levels of low-density lipoprotein cholesterol in short-term dietary trials. To investigate long-term effects of olive oil we have studied the diet and serum lipids of boys in Crete, where a high olive oil consumption is the norm. Seventy-six healthy rural Cretan boys aged 7–9 years were studied. The diet was assessed by a 2-day dietary recall. Blood was collected according to a standardized protocol and sera were analyzed in a rigidly standardized laboratory. The mean daily intake of energy was 11.0 MJ (2629 kcal). The intake of fat (45.0% of energy) and oleic acid (27.2% of energy) was high, and that of saturated fat low (10.0% of energy), reflecting a high consumption of olive oil. The high consumption of olive oil was confirmed by a high proportion of oleic-acid (27.1 %) in serum cholesteryl fatty acids. Mean concentration of serum total cholesterol was 4.42 mmol 1−1 (171 mg dl−1 ), of HDL-cholesterol 1.40 mmol 1−1 (54 mg dl−1), of serum triglycerides 0.59 mmol I−1 (52 mg dl−1 ), of apo-A1 1210 mg 1−1 and of LDL apo-B 798 mg 1−1. The body mass index of the Cretan boys (18.2 kg m−2) was on average 2 kg m−2 higher than that of boys from other countries. Contrary to our expectation, the Cretan boys did not show a more favourable serum lipoprotein pattern than boys from more westernized countries studied previously using the same protocol. Our hypothesis that a typical, olive-oil-rich Cretan diet causes a relatively high HDL- to total cholesterol ratio is not supported by the present findings

Proteoglycan Breakdown of Meniscal Explants Following Dynamic Compression Using a Novel Bioreactor

Motivated by our interest in examining meniscal mechanotransduction processes, we report on the validation of a new tissue engineering bioreactor. This paper describes the design and performance capabilities of a tissue engineering bioreactor for cyclic compression of meniscal explants. We showed that the system maintains a tissue culture environment equivalent to that provided by conventional incubators and that its strain output was uniform and reproducible. The system incorporates a linear actuator and load cell aligned together in a frame that is contained within an incubator and allows for large loads and small displacements. A plunger with six Teflon-filled Delrin compression rods is attached to the actuator compressing up to six tissue explants simultaneously and with even pressure. The bioreactor system was used to study proteoglycan (PG) breakdown in porcine meniscal explants following various input loading tests (0–20% strain, 0–0.1 MPa). The greatest PG breakdown was measured following 20% compressive strain. These strain and stress levels have been shown to correspond to partial meniscectomy. Thus, these data suggest that removing 30–60% of meniscal tissue will result in the breakdown of meniscal tissue proteoglycans

Signal Transmission in the Auditory System

Contains table of contents for Section 3, an introduction and reports on nine research projects.National Institutes of Health Grant 5 T32 NS07047National Institutes of Health Grant 5 P01 NS13126National Institutes of Health Grant 8 R01 DC00194National Institutes of Health Grant 5 R01 NS25995National Institutes of Health Grant 8 R01 DC00238National Institutes of Health Grant 5 R01 NS20322National Institutes of Health Grant 5 R01 DC00235National Institutes of Health Grant 5 R01 NS20269National Institutes of Health Grant 1 P01 NS23734Johnson and Johnson FoundationUnisys Corporation Doctoral Fellowshi

High-Yield Hydrogen Production from Starch and Water by a Synthetic Enzymatic Pathway

BACKGROUND: The future hydrogen economy offers a compelling energy vision, but there are four main obstacles: hydrogen production, storage, and distribution, as well as fuel cells. Hydrogen production from inexpensive abundant renewable biomass can produce cheaper hydrogen, decrease reliance on fossil fuels, and achieve zero net greenhouse gas emissions, but current chemical and biological means suffer from low hydrogen yields and/or severe reaction conditions. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate a synthetic enzymatic pathway consisting of 13 enzymes for producing hydrogen from starch and water. The stoichiometric reaction is C(6)H(10)O(5) (l)+7 H(2)O (l)→12 H(2) (g)+6 CO(2) (g). The overall process is spontaneous and unidirectional because of a negative Gibbs free energy and separation of the gaseous products with the aqueous reactants. CONCLUSIONS: Enzymatic hydrogen production from starch and water mediated by 13 enzymes occurred at 30°C as expected, and the hydrogen yields were much higher than the theoretical limit (4 H(2)/glucose) of anaerobic fermentations. SIGNIFICANCE: The unique features, such as mild reaction conditions (30°C and atmospheric pressure), high hydrogen yields, likely low production costs ($∼2/kg H(2)), and a high energy-density carrier starch (14.8 H(2)-based mass%), provide great potential for mobile applications. With technology improvements and integration with fuel cells, this technology also solves the challenges associated with hydrogen storage, distribution, and infrastructure in the hydrogen economy

Statistical practices of educational researchers: An analysis of their ANOVA, MANOVA, and ANCOVA analyses

Articles published in several prominent educational journals were examined to investigate the use of data-analysis tools by researchers in four research paradigms: between-subjects univariate designs, between-subjects multivariate designs, repeated measures designs, and covariance designs. In addition to examining specific details pertaining to the research design (e.g., sample size, group size equality/inequality) and methods employed for data analysis, we also catalogued whether: (a) validity assumptions were examined, (b) effect size indices were reported, (c) sample sizes were selected based on power considerations, and (d) appropriate textbooks and/or articles were cited to communicate the nature of the analyses that were performed. Our analyses imply that researchers rarely verify that validity assumptions are satisfied and accordingly typically use analyses that are nonrobust to assumption violations. In addition, researchers rarely report effect size statistics, nor do they routinely perform power analyses to determine sample size requirements. We offer many recommendations to rectify these shortcomings.Social Sciences and Humanities Research Counci

Survival of newly formed particles in haze conditions

Intense new particle formation events are regularly observed under highly polluted conditions, despite the high loss rates of nucleated clusters. Higher than expected cluster survival probability implies either ineffective scavenging by pre-existing particles or missing growth mechanisms. Here we present experiments performed in the CLOUD chamber at CERN showing particle formation from a mixture of anthropogenic vapours, under condensation sinks typical of haze conditions, up to 0.1 s(-1). We find that new particle formation rates substantially decrease at higher concentrations of pre-existing particles, demonstrating experimentally for the first time that molecular clusters are efficiently scavenged by larger sized particles. Additionally, we demonstrate that in the presence of supersaturated gas-phase nitric acid (HNO3) and ammonia (NH3), freshly nucleated particles can grow extremely rapidly, maintaining a high particle number concentration, even in the presence of a high condensation sink. Such high growth rates may explain the high survival probability of freshly formed particles under haze conditions. We identify under what typical urban conditions HNO3 and NH3 can be expected to contribute to particle survival during haze.Peer reviewe