Cotadutide is a dual glucagon-like peptide 1 and glucagon receptor agonist under development for the treatment of non-alcoholic steatohepatitis and type 2 diabetes mellitus (T2DM) and chronic kidney ...disease. Non-alcoholic steatohepatitis is a complex disease with no approved pharmacotherapies, arising from an underlying state of systemic metabolic dysfunction in association with T2DM and obesity. Cotadutide has been shown to improve glycaemic control, body weight, lipids, liver fat, inflammation and fibrosis. We conducted a two-part, randomized phase 2a trial in men and women with overweight or obesity diagnosed with T2DM to evaluate the efficacy and safety of cotadutide compared with placebo and liraglutide. The primary endpoints were change from baseline to day 28 of treatment in postprandial hepatic glycogen (part A) and to day 35 of treatment in fasting hepatic glycogen (part B) with cotadutide versus placebo. Secondary endpoints in part B were changes in fasting hepatic glycogen with cotadutide versus the mono glucagon-like peptide 1 receptor agonist, liraglutide, and change in hepatic fat fraction. The trial met its primary endpoint. We showed that cotadutide promotes greater reductions in liver glycogen and fat compared with placebo and liraglutide. Safety and tolerability findings with cotadutide were comparable to those of previous reports. Thus, this work provides evidence of additional benefits of cotadutide that could be attributed to glucagon receptor engagement. Our results suggest that cotadutide acts on the glucagon receptor in the human liver to promote glycogenolysis and improve the metabolic health of the liver. ClinicalTrials.gov registration: NCT03555994 .
Objectives. Currently, there are no prospective studies exploring the prognosis of patients with juvenile primary FM syndrome (JPFS) or their physical, emotional and social outcomes as they enter the ...early adult years. The primary objective of this study was to assess long-term outcomes of a paediatric sample of clinically referred JPFS patients and their matched healthy controls. Methods. Participants were 48 youths (current mean age = 19 years) diagnosed with JPFS in childhood or adolescence and 43 healthy controls matched in age, gender and race. The average length of follow-up was 3.67 years (range 2–6 years). Participants completed online (web-based) self-report questionnaires about current pain and physical symptoms, health status, anxiety, depressive symptoms and current and past treatments. Results. Results showed that 62.5% of participants in the JPFS group continued to experience widespread pain and 60.4% reported having all the cardinal features of FM syndrome (including widespread pain, poor sleep and fatigue) at follow-up. The JPFS group reported significantly lower scores on all measures of health status and physical functioning compared with healthy controls and significantly greater symptoms of anxiety and depression. Conclusion. The results of this controlled follow-up study demonstrate that symptoms of FM appear to be chronic in a majority of clinically referred JPFS patients and the associated physical and emotional impairment can also be persistent. Implications for treatment and the need for further prospective longitudinal studies are discussed.
Background The Alberta Stroke Program Early CT Score (ASPECTS) on baseline imaging is an established predictor of functional outcome in anterior circulation acute ischemic stroke (AIS). We studied ...ASPECTS before intravenous thrombolysis (IVT) and at 24 hours to assess its prognostic value. Methods Data for consecutive anterior circulation AIS patients treated with IVT from 2006 to 2013 were extracted from a prospectively managed registry at our tertiary center. Pre-thrombolysis and 24-hour ASPECTS were evaluated by 2 independent neuroradiologists. Outcome measures included symptomatic intracranial hemorrhage (SICH), modified Rankin Scale (mRS) at 90 days, and mortality. Unfavorable functional outcome was defined by mRS >1. Dramatic ASPECTS progression (DAP) was defined as deterioration in ASPECTS by 6 points or more. Results Of 554 AIS patients thrombolyzed during the study period, 400 suffered from anterior circulation infarction. The median age was 65 years (interquartile range (IQR): 59-70) and the median National Institutes of Health Stroke Scale score was 18 points (IQR: 12-22). Compared with the pre-IVT ASPECTS (area under the curve AUC = .64, 95% confidence interval CI: .54-.65, P = .001), ASPECTS on the 24-hour CT scan (AUC = .78, 95% CI: .73-.82, P < .001), and change in ASPECTS (AUC = .69, 95% CI: .64-.74, P < .001) were better predictors of unfavorable functional outcome at 3 months. DAP, noted in 34 (14.4%) patients with good baseline ASPECTS (8-10 points), was significantly associated with unfavorable functional outcome (odds ratio OR: 9.91, 95% CI: 3.37-29.19, P ≤ .001), mortality (OR: 21.99, 95% CI: 7.98-60.58, P < .001), and SICH (OR: 8.57, 95% CI: 2.87-25.59, P < .001). Conclusion Compared with the pre-thrombolysis score, ASPECTS measured at 24 hours as well as serial change in ASPECTS is a better predictor of 3-month functional outcome.
The Drosophila ovary is an attractive system to study how niches control stem cell self-renewal and differentiation. The niche for germline stem cells (GSCs) provides a Dpp/Bmp signal, which is ...essential for GSC maintenance. bam is both necessary and sufficient for the differentiation of immediate GSC daughters, cystoblasts. Here we show that Bmp signals directly repress bam transcription in GSCs in the Drosophila ovary. Similar to dpp, gbb encodes another Bmp niche signal that is essential for maintaining GSCs. The expression of phosphorylated Mad (pMad), a Bmp signaling indicator, is restricted to GSCs and some cystoblasts, which have repressed bam expression. Both Dpp and Gbb signals contribute to pMad production. bam transcription is upregulated in GSCs mutant for dpp and gbb. In marked GSCs mutant for Med and punt, two essential Bmp signal transducers, bam transcription is also elevated. Finally, we show that Med and Mad directly bind to the bam silencer in vitro. This study demonstrates that Bmp signals maintain the undifferentiated or self-renewal state of GSCs, and directly repress bam expression in GSCs by functioning as short-range signals. Thus, niche signals directly repress differentiation-promoting genes in stem cells in order to maintain stem cell self-renewal.
To establish Down syndrome (DS)-specific growth charts for Hong Kong Chinese children.
Growth data were collected from (1) members of the Hong Kong Down Syndrome Association (cross-sectional); (2) DS ...children attending special schools or living in residential homes (cross-sectional); and (3) the paediatric departments of seven public hospitals (retrospective).
425 DS children (57% males and 43% females) born in 1977-2000, yielding 4987 observations.
The LMS method was used to construct reference centile curves of weight, height, body mass index (BMI) from birth until 14 years and head circumference for the first 4 years.
The median birth length was 49.8 cm and height at age 14 was 146.7 cm for DS boys. Corresponding figures for DS girls were 49.5 and 142.1 cm. The median birth weight was 3.0 kg for DS boys and 2.9 kg for DS girls. At age 14, 26% DS boys (BMI >22.6 kg/m(2)) and 12% DS girls (BMI >23.3 kg/m(2)) were overweight. The median head circumference at birth was 32.8 cm for boys and 32.0 cm for girls.
Chinese DS children had a shorter stature, lower weight and tendency to be overweight than local non-DS children. Their growth patterns differed from those of Chinese DS children in Taiwan, and DS children in the USA and Sweden. Growth retardation was most salient during the first year of life.
Brainhack is an innovative meeting format that promotes scientific collaboration and education in an open, inclusive environment. This NeuroView describes the myriad benefits for participants and the ...research community and how Brainhacks complement conventional formats to augment scientific progress.
Brainhack is an innovative meeting format that promotes scientific collaboration and education in an open, inclusive environment. This NeuroView describes the myriad benefits for participants and the research community and how Brainhacks complement conventional formats to augment scientific progress.
Atmospheric pollution by fine particulates and mercury (Hg) in emerging economies is a serious environmental concern. Here, we present Hg concentrations and isotope compositions of 24-hour integrated ...fine particulate matter (PM2.5) samples collected during January 2014 at four large Chinese cities (three inland cities: Beijing, Changchun and Chengdu; one coastal city: Hong Kong), with an aim of identifying the potential Hg sources and transformation processes. Mean concentrations of PM2.5 (171 ± 62 μg m−3) and PM2.5-bound Hg (1.3 ± 1.1 ng m−3) in Chengdu were the highest. Overall, PM2.5 samples in Chinese inland cities were characterized by moderately negative δ202Hg (−1.08 ± 0.64‰, 1σ), slightly negative Δ199Hg (−0.13 ± 0.28‰, 1σ) and insignificant Δ200Hg (0.03 ± 0.05‰, 1σ). On average, δ202Hg of PM2.5 was the highest in Chengdu (−0.74 ± 0.67‰, 1σ), followed by Beijing (−1.11 ± 0.26‰, 1σ) and Changchun (−1.60 ± 0.45‰, 1σ). PM2.5 from Beijing showed the most negative Δ199Hg (−0.31 ± 0.40‰, 1σ) that was significantly lower than Changchun (−0.12 ± 0.21‰, 1σ) and Chengdu (−0.02 ± 0.15‰, 1σ). Coal combustion and cement production were identified to be the dominant sources of PM2.5-bound Hg in these cities, with additional Hg sources from non-ferrous metal smelting in Chengdu. Besides, Hg emissions from biomass burning were evident in specific days for each city. We found that source materials and isotope fractionation during emission processes could not fully explain the observed Hg isotope compositions in PM2.5, especially the large negative Δ199Hg values (<−0.3‰) in Beijing. The near-unity slope of Δ199Hg vs. Δ201Hg in PM2.5 samples from each studied city indicates that HgII in the fine aerosols was likely photo-reduced to different degrees in the atmosphere following emission from sources.
•Urban fine particulates have moderately negative δ202Hg, slightly negative Δ199Hg and insignificant Δ200Hg.•Coal combustion and cement production were the dominant Hg sources of urban fine particulates.•Hg in urban fine particulates was photo-reduced to different extents after emission from sources.
Promoter hypermethylation is a prevalent phenomenon, found in virtually all cancer types studied thus far, and accounts for tumor suppressor gene silencing in the absence of genetic mutations. The ...mechanism behind the establishment and maintenance of such aberrant hypermethylation has been under intense study. Here, we have uncovered a link between aberrant gene silencing associated with promoter CpG island DNA methylation and the siRNA/miRNA processing enzyme, DICER, in human cancer cells. By comparing demethylated HCT116 colon cancer cells with HCT116 cells genetically rendered hypomorphic for DICER, we identified a group of epigenetically silenced genes that became reactivated in the absence of functional DICER. This reactivation is associated with a dramatic loss of localized promoter DNA hypermethylation. Thus, intact DICER is required to maintain full promoter DNA hypermethylation of select epigenetically silenced loci in human cancer cells.
Background
Given their mostly rural/suburban locations, level II trauma centers (TCs) may offer greater exposure to and experience in managing geriatric trauma patients. We hypothesized that ...geriatric patients would have improved outcomes at level II TCs compared to level I TCs.
Methods
The Pennsylvania Trauma Outcome Study (PTOS) database was retrospectively queried from 2003 to 2017 for geriatric (age ≥65 years) trauma patients admitted to level I and II TCs in Pennsylvania. Patient demographics, injury severity, and clinical outcomes were compared to assess differences in care between level I and II TCs. A multivariate logistic regression model assessed the adjusted impact of care at level I vs II TCs on mortality, complications, and functional status at discharge (FSD). The National Trauma Data Bank (NTDB) was retrospectively queried for geriatric (age ≥65 years) trauma admissions to state-accredited level I or level II TCs in 2013.
Results
112 648 patients met inclusion criteria. The proportion of geriatric trauma patients across level I and level II TCs were determined to be 29.1% and 36.2% (P <.001), respectively. In adjusted analysis, there was no difference in mortality (adjusted odds ratio AOR: 1.13; P = .375), complications (AOR: 1.25; P = .080) or FSD (AOR: 1.09; P = .493) when comparing level I to level II TCs. Adjusted analysis from the NTDB (n = 144 622) also found that mortality was not associated with TC level (AOR: 1.04; P = .182).
Discussion
Level I and level II TCs had similar rates of mortality, complications, and functional outcomes despite a higher proportion (but lower absolute number) of geriatric patients being admitted to level II TCs. Future consideration for location of centers of excellence in geriatric trauma should include both level I and II TCs.
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