Whole Blood Profiling of T-cell-Derived microRNA Allows the Development of Prognostic models in Inflammatory Bowel Disease

Background: MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. Methods: In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohn''s disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. Results: In stage 1, each leukocyte subset [CD4+ and CD8+ T-cells and CD14+ monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20-3.27; logrank p = 1.80 × 10-3), in particular CD [HR 2.81; IQR: 1.11-3.53, p = 6.50 × 10-4]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. Interpretation: We have identified and validated unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

CO Signatures in Subtropical Convective Clouds and Anvils during CRYSTAL-FACE: An Analysis of Convective Transport and Entrainment using Observations and a Cloud-Resolving Model

Convective systems are an important mechanism in the transport of boundary layer air into the upper troposphere. The Cirrus Regional Study of Tropical Anvils and Cirrus Layers-Florida Area Cirrus Experiment (CRYSTAL-FACE) campaign, in July 2002, was developed as a comprehensive atmospheric mission to improve knowledge of subtropical cirrus systems and their roles in regional and global climate. In situ measurements of carbon monoxide (CO), water vapor (H2Ov), and total water (H2Ot) aboard NASA's WB-57F aircraft and CO aboard the U.S. Navy's Twin Otter aircraft were obtained to study the role of convective transport. Three flights sampled convective outflow on 11, 16 and 29 July found varying degrees of CO enhancement relative to the free troposphere. A cloud-resolving model used the in situ observations and meteorological fields to study these three systems. Several methods of filtering the observations were devised here using ice water content, relative humidity with respect to ice, and particle number concentration as a means to statistically sample the model results to represent the flight tracks. A weighted histogram based on ice water content observations was then used to sample the simulations for the three flights. In addition, because the observations occurred in the convective outflow cirrus and not in the storm cores, the model was used to estimate the maximum CO within the convective systems. In general, anvil-level air parcels contained an estimated 20-40% boundary layer air in the analyzed storms

CO Signatures in Subtropical Convective Clouds and Anvils During CRYSTAL-FACE: An Analysis of Convective Transport and Entertainment Using Observations and a Cloud-Resolving Model

Convective systems are an important mechanism in the transport of boundary layer air into the upper troposphere. The Cirrus Regional Study of Tropical Anvils and Cirrus Layers-Florida Area Cirrus Experiment (CRYSTAL-FACE) campaign, in July 2002, was developed as a comprehensive atmospheric mission to improve knowledge of subtropical cirrus systems and their roles in regional and global climate. In situ measurements of carbon monoxide (CO), water vapor (H20v), and total water (H20t) aboard NASA's . WB-57F aircraft and CO aboard the U.S. Navy's Twin Otter aircraft were obtained to study the role of convective transport. Three flights sampled convective outflow on 11, 16 and 29 July found varying degrees of CO enhancement relative to the fiee troposphere. A cloud-resolving model used the in situ observations and meteorological fields to study these three systems. Several methods of filtering the observations were devised here using ice water content, relative humidity with respect to ice, and particle number concentration as a means to statistically sample the model results to represent the flight tracks. A weighted histogram based on ice water content observations was then used to sample the simulations for the three flights. In addition, because the observations occurred in the convective outflow cirrus and not in the storm cores, the model was used to estimate the maximum CO within the convective systems. In general, anvil-level air parcels contained an estimated 20-40% boundary layer air in the analyzed storms

Development and Validation of Real-Time RT-LAMP Assays for the Specific Detection of Zika Virus

Two one-step real-time reverse transcription loop-mediated isothermal amplification (RT-LAMP) assays for the detection of Zika virus (ZIKV) were developed, based on two different primer design approaches: (1) open source, based on a combination of sequence diversity clustering (phylogeny and principal component analysis) and LAVA algorithm, using 45 whole genome ZIKV sequences retrieved from the National Center for Biotechnology Information (NCBI) database; (2) standard software for LAMP primer design (Primer Explorer V4), using 59 sequences of the ZIKV 3′ UTR. The assays were firstly evaluated with External Quality Assessment panels from INSTAND e.V. (Germany) and EVD-LabNet (The Netherlands) including 4 and 12 unknown samples, respectively, and secondly, with 9 human, mosquito, and monkey ZIKV isolates from Africa (Senegal, Ivory Coast, and Uganda) and America (Brazil). The limit of detection as determined by probit analysis was 181 molecules for both RT-LAMP assays, and 100% reproducibility in the assays was obtained for 103 molecules (4/8 repetitions were positive for 102 molecules). Both assays were specific, amplifying only ZIKV RNA and not cross-detecting other arboviruses included in this study

Whole Blood Profiling of T-cell-Derived microRNA Allows the Development of Prognostic models in Inflammatory Bowel Disease

Background: MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. Methods: In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohns disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. Results: In stage 1, each leukocyte subset [CD4(+) and CD8(+)T-cells and CD14(+) monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4(+) T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20-3.27; logrank p = 1.80 x 10(-3)), in particular CD [HR 2.81; IQR: 1.11-3.53, p = 6.50 x 10(-4)]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. Interpretation: We have identified and validated unique CD4(+) T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated.Funding Agencies|Crohns and Colitis UK [CCUK] [M2016/2]; LifeArc, EdinburghBiotechnology and Biological Sciences Research Council (BBSRC)</p