Randomized Phase 2 Clinical Trial of Olaratumab in Combination with Gemcitabine and Docetaxel in Advanced Soft Tissue Sarcomas.

Gemcitabine plus docetaxel is an effective treatment regimen for advanced soft tissue sarcomas (STSs). However, the prognosis for patients remains poor, and thus there is an urgent medical need for novel and effective therapies to improve long-term outcomes. The aim of the ANNOUNCE 2 trial was to explore the addition of olaratumab (O) to gemcitabine (G) and docetaxel (D) for advanced STS. Adults with unresectable locally advanced/metastatic STS, ≤2 prior lines of systemic therapy, and ECOG PS 0-1 were eligible. In Phase 2, patients were randomized 1:1 from two cohorts (O-naïve and O-pretreated) to 21-day cycles of olaratumab (20 mg/kg Cycle 1 and 15 mg/kg other cycles, Days 1 and 8), gemcitabine (900 mg/m2, Days 1 and 8), and docetaxel (75 mg/m2, Day 8). The primary objective was overall survival (OS) in the O-naïve population (α level = 0.20). Secondary endpoints included OS (O-pretreated), other efficacy parameters, patient-reported outcomes, safety, pharmacokinetics, and immunogenicity. A total of 167 and 89 patients were enrolled in the O-naïve and O-pretreated cohorts, respectively. Baseline patient characteristics were well balanced. No statistically significant difference in OS was observed between the investigational vs. control arm for either cohort (O-naïve cohort: HR = 0.95 (95% CI: 0.64-1.40), p = 0.78, median OS, 16.8 vs. 18.0 months; O-pretreated cohort: HR = 0.67 (95% CI: 0.39-1.16), p = 0.15, median OS 19.8 vs. 17.3 months). Safety was manageable across treatment arms. There was no statistically significant difference in the primary endpoint of OS between the two arms in the O-naïve population, and therefore based on hierarchical evaluation no other outcomes in this study can be considered statistically significant. No new safety signals were observed

Toward a theory-led metaframework for considering socioeconomic health inequalities within systematic reviews

Objectives To develop a theory-led framework to inform reviewers’ understanding of what, how, and why health care interventions may lead to differential effects across socioeconomic groups. Study Design and Setting A metaframework approach combined two theoretical perspectives (socioeconomic health inequalities and complex interventions) into a single framework to inform socioeconomic health inequality considerations in systematic reviews. Results Four theories relating to complexity within systematic reviews and 16 health inequalities intervention theories informed the development of a metaframework. Factors relating to the type of intervention, implementation, context, participant response, and mechanisms associated with differential effects across socioeconomic groups were identified. The metaframework can inform; reviewer discussions around how socioeconomic status (SES) can moderate intervention effectiveness during question formulation, approaches to data extraction and help identify a priori analysis considerations. Conclusion The metaframework offers a transparent, practical, theory-led approach to inform a program theory for what, how, and why interventions work for different SES groups in systematic reviews. It can enhance existing guidance on conducting systematic reviews that consider health inequalities, increase awareness of how SES can moderate intervention effectiveness, and encourage a greater engagement with theory throughout the review process

Massive Ellipticals at High Redshift: NICMOS Imaging of Z~1 Radio Galaxies

We present deep, continuum images of eleven high-redshift (0.811 < z < 1.875) 3CR radio galaxies observed with NICMOS. Our images probe the rest-frame optical light where stars are expected to dominate the galaxy luminosity. The rest-frame UV light of eight of these galaxies demonstrates the well-known ``alignment effect''. Most of the radio galaxies have rounder, more symmetric morphologies at rest-frame optical wavelengths. Here we show the most direct evidence that in most cases the stellar hosts are normal elliptical galaxies with de Vaucouleurs law light profiles. For a few galaxies very faint traces of the UV-bright aligned component are also visible in the infrared images. We derive both the effective radius and surface-brightness for nine of eleven sample galaxies by fitting surface-brightness models to them. We find their sizes are similar to those of local FRII radio source hosts and are in general larger than other local galaxies. The derived host galaxy luminosities are very high and lie at the bright end of luminosity functions constructed at similar redshifts. The galaxies in our sample are also brighter than the rest-frame size--surface-brightness locus defined by the low-redshift sources. Passive evolution roughly aligns the z ~ 1 galaxies with the low-redshift samples. The optical host is sometimes centered on a local minimum in the rest-frame UV emission, suggesting the presence of substantial dust obscuration. We also see good evidence of nuclear point sources in three galaxies. Overall, our results are consistent with the hypothesis that these galaxies have already formed the bulk of their stars at redshifts greater than z >~ 2, and that the AGN phenomenon takes place within otherwise normal, perhaps passively evolving, galaxies. (abridged)Comment: 28 pages, 14 figures, accepted to ApJ. Uses AASTEX and emulateapj

Criteria for the diagnosis of corticobasal degeneration

Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed

Elevated carbon dioxide and ozone alter productivity and ecosystem carbon content in northern temperate forests

Three young northern temperate forest communities in the north‐central United States were exposed to factorial combinations of elevated carbon dioxide ( CO 2 ) and tropospheric ozone (O 3 ) for 11 years. Here, we report results from an extensive sampling of plant biomass and soil conducted at the conclusion of the experiment that enabled us to estimate ecosystem carbon (C) content and cumulative net primary productivity ( NPP ). Elevated CO 2 enhanced ecosystem C content by 11%, whereas elevated O 3 decreased ecosystem C content by 9%. There was little variation in treatment effects on C content across communities and no meaningful interactions between CO 2 and O 3 . Treatment effects on ecosystem C content resulted primarily from changes in the near‐surface mineral soil and tree C, particularly differences in woody tissues. Excluding the mineral soil, cumulative NPP was a strong predictor of ecosystem C content ( r 2  = 0.96). Elevated CO 2 enhanced cumulative NPP by 39%, a consequence of a 28% increase in canopy nitrogen (N) content (g N m −2 ) and a 28% increase in N productivity ( NPP /canopy N). In contrast, elevated O 3 lowered NPP by 10% because of a 21% decrease in canopy N, but did not impact N productivity. Consequently, as the marginal impact of canopy N on NPP (∆ NPP /∆N) decreased through time with further canopy development, the O 3 effect on NPP dissipated. Within the mineral soil, there was less C in the top 0.1 m of soil under elevated O 3 and less soil C from 0.1 to 0.2 m in depth under elevated CO 2 . Overall, these results suggest that elevated CO 2 may create a sustained increase in NPP , whereas the long‐term effect of elevated O 3 on NPP will be smaller than expected. However, changes in soil C are not well‐understood and limit our ability to predict changes in ecosystem C content.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108065/1/gcb12564.pd

Elevated carbon dioxide and ozone alter productivity and ecosystem carbon content in northern temperate forests

Three young northern temperate forest communities in the north-central United States were exposed to factorial combinations of elevated carbon dioxide (CO2) and tropospheric ozone (O3) for 11 years. Here, we report results from an extensive sampling of plant biomass and soil conducted at the conclusion of the experiment that enabled us to estimate ecosystem carbon (C) content and cumulative net primary productivity (NPP). Elevated CO2 enhanced ecosystem C content by 11%, whereas elevated O3 decreased ecosystem C content by 9%. There was little variation in treatment effects on C content across communities and no meaningful interactions between CO2 and O3. Treatment effects on ecosystem C content resulted primarily from changes in the near-surface mineral soil and tree C, particularly differences in woody tissues. Excluding the mineral soil, cumulative NPP was a strong predictor of ecosystem C content (r2 = 0.96). Elevated CO2 enhanced cumulative NPP by 39%, a consequence of a 28% increase in canopy nitrogen (N) content (g N m−2) and a 28% increase in N productivity (NPP/canopy N). In contrast, elevated O3 lowered NPP by 10% because of a 21% decrease in canopy N, but did not impact N productivity. Consequently, as the marginal impact of canopy N on NPP (ΔNPP/ΔN) decreased through time with further canopy development, the O3 effect on NPP dissipated. Within the mineral soil, there was less C in the top 0.1 m of soil under elevated O3 and less soil C from 0.1 to 0.2 m in depth under elevated CO2. Overall, these results suggest that elevated CO2 may create a sustained increase in NPP, whereas the long-term effect of elevated O3 on NPP will be smaller than expected. However, changes in soil C are not well-understood and limit our ability to predict changes in ecosystem C content

Introductory programming: a systematic literature review

As computing becomes a mainstream discipline embedded in the school curriculum and acts as an enabler for an increasing range of academic disciplines in higher education, the literature on introductory programming is growing. Although there have been several reviews that focus on specific aspects of introductory programming, there has been no broad overview of the literature exploring recent trends across the breadth of introductory programming. This paper is the report of an ITiCSE working group that conducted a systematic review in order to gain an overview of the introductory programming literature. Partitioning the literature into papers addressing the student, teaching, the curriculum, and assessment, we explore trends, highlight advances in knowledge over the past 15 years, and indicate possible directions for future research

Effect of dolutegravir on folate, vitamin B12 and mean corpuscular volume levels among children and adolescents with HIV: a sub‐study of the ODYSSEY randomized controlled trial

INTRODUCTION: Dolutegravir-based antiretroviral therapy (ART) is the preferred antiretroviral treatment for children and adolescents living with HIV. A large surveillance study in Botswana previously raised concerns about an association between pre-conception dolutegravir and neural tube defects. Before these concerns were subsequently resolved, we set up a sub-study to look at the effect of dolutegravir on levels of folate and vitamin B12 in children and adolescents within the randomized ODYSSEY trial, as folate and vitamin B12 are known to play a crucial role in neural tube development. METHODS: We conducted the sub-study among Ugandan ODYSSEY participants and compared folate and vitamin B12 between children randomized to dolutegravir-based ART (DTG) and non-dolutegravir-based standard-of-care treatment (SOC). Plasma folate was measured at enrolment and week 4 on stored samples; in addition, plasma and red blood cell (RBC) folate and vitamin B12 were assayed at week ≥96 in prospectively collected samples. RBC mean corpuscular volume (MCV) was measured 24-weekly in all ODYSSEY participants. Samples analysed in the sub-study were collected between September 2016 and October 2020. RESULTS: A total of 229 children aged ≥6 years were included in the sub-study with median age at trial enrolment of 12.3 (interquartile range [IQR] 9.0, 14.7) years, and CD4 count of 501 (IQR 228, 695); 112 (49%) children were male. Most participants (225/229, 98%) had plasma folate results at enrolment and 214 (93%) children had results available for RBC folate, vitamin B12 and plasma folate at week ≥96. MCV results were analysed on 679 children aged ≥6 years enrolled in ODYSSEY. At week 4, mean plasma folate was significantly higher in the dolutegravir arm than in SOC (difference [DTG-SOC] 1.6 ng/ml, 95% CI 0.8, 2.3; p<0.001), and this difference persisted to week ≥96 (2.7 ng/ml, 95% CI 1.7, 3.7; p<0.001). Mean RBC folate at ≥96 weeks was also higher in the DTG arm (difference 73 ng/ml, 95% CI 3, 143; p = 0.041). There was no difference in the treatment arms for vitamin B12 levels at ≥96 weeks or change in MCV through trial follow-up. CONCLUSIONS: Plasma and RBC folate levels were higher in children and adolescents receiving dolutegravir-based ART than on other ART regimens. Further studies are needed to clarify the mechanisms of these interactions and the clinical implications of increased blood folate levels