MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only ...hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17∼92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17∼92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17∼92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17∼92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.
MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only ...hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-1792 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-1792 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-1792 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-1792 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.
Strategic alliances are the most common type of collaboration agreement used by shipping lines to provide worldwide maritime container transport services. Since their first appearance just before the ...mid-1990s, they have progressed to account for 90% of global container shipping capacity with the top eight container operators organizing today their East/West route services through one of the main three strategic alliances. This paper reviews comprehensively and critically the literature on the subject, over 25 years of research on this topic. This includes 85 articles published in peer-reviewed journals between 1994 and 2019, and analyzed and grouped into three main research areas: formation, management, and optimization of strategic alliances. The output of the analysis is then used to provide a future research agenda
.
Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on ...the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy.
In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2–25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing ≥20 kg) or 0·25 mg/kg (for individuals weighing <20 kg), or daily oral placebo (matched to risdiplam in colour and taste). Randomisation was conducted by permutated block randomisation with a computerised system run by an external party. Patients, investigators, and all individuals in direct contact with patients were masked to treatment assignment. The primary endpoint was the change from baseline in the 32-item Motor Function Measure total score at month 12. All individuals who were randomly assigned to risdiplam or placebo, and who did not meet the prespecified missing item criteria for exclusion, were included in the primary efficacy analysis. Individuals who received at least one dose of risdiplam or placebo were included in the safety analysis. SUNFISH is registered with ClinicalTrials.gov, NCT02908685. Recruitment is closed; the study is ongoing.
Between Oct 9, 2017, and Sept 4, 2018, 180 patients were randomly assigned to receive risdiplam (n=120) or placebo (n=60). For analysis of the primary endpoint, 115 patients from the risdiplam group and 59 patients from the placebo group were included. At month 12, the least squares mean change from baseline in 32-item Motor Function Measure was 1·36 (95% CI 0·61 to 2·11) in the risdiplam group and –0·19 (–1·22 to 0·84) in the placebo group, with a treatment difference of 1·55 (0·30 to 2·81, p=0·016) in favour of risdiplam. 120 patients who received risdiplam and 60 who received placebo were included in safety analyses. Adverse events that were reported in at least 5% more patients who received risdiplam than those who received placebo were pyrexia (25 21% of 120 patients who received risdiplam vs ten 17% of 60 patients who received placebo), diarrhoea (20 17% vs five 8%), rash (20 17% vs one 2%), mouth and aphthous ulcers (eight 7% vs 0), urinary tract infection (eight 7% vs 0), and arthralgias (six 5% vs 0). The incidence of serious adverse events was similar between treatment groups (24 20% of 120 patients in the risdiplam group; 11 18% of 60 patients in the placebo group), with the exception of pneumonia (nine 8% in the risdiplam group; one 2% in the placebo group).
Risdiplam resulted in a significant improvement in motor function compared with placebo in patients aged 2–25 years with type 2 or non-ambulant type 3 spinal muscular atrophy. Our exploratory subgroup analyses showed that motor function was generally improved in younger individuals and stabilised in older individuals, which requires confirmation in further studies. SUNFISH part 2 is ongoing and will provide additional evidence regarding the long-term safety and efficacy of risdiplam.
F Hoffmann-La Roche.
Purpose Prostate biopsy side effects have a role in the controversy over screening for prostate cancer. We measured the precise incidence of infection after prostate biopsy and determined risk ...factors. Materials and Methods We performed a prospective, multicenter study in France from April to June 2013. All prostate biopsies done during this period were included in study. A web based questionnaire was used to identify patient characteristics, biopsy methods and postoperative infectious episodes. External audit helped ensure data completeness. The primary outcome was the post-biopsy infection rate. We determined risk factors for infectious complications using univariate and multivariate analysis. Results The study included 2,718 patients, of whom 6% reported receiving antibiotics in the previous 6 months and 7.4% had a history of prostatitis. Recommended antibiotic prophylaxis consisting of 2 fluoroquinolone tablets 2 hours before examination for prostate biopsy was noted in 78.3% of cases. Post-biopsy sepsis was found in 76 subjects (2.8%). On multivariate analysis predictors of post-biopsy sepsis were noncompliance with antibiotic prophylaxis guidelines (OR 2.3, 95% CI 1.4–3.9, p = 0.001), antibiotic treatment in the previous 6 months (OR 2.1, 95% CI 1.1–3.9, p = 0.015) and a history of prostatitis (OR 1.7, 95% CI 1.2–2.4, p = 0.002). Conclusions In this study the incidence of post-prostate biopsy sepsis was 2.8% and no deaths were reported. Risk factors identified on multivariate analysis were noncompliance with antibiotic prophylaxis according to guidelines, antibiotic treatment in the previous 6 months and a history of prostatitis.
Fine-scale physical structures and ocean dynamics strongly influence and
regulate biogeochemical and ecological processes. These
processes are particularly challenging to describe and understand ...because of their ephemeral nature. The OSCAHR (Observing
Submesoscale Coupling At High Resolution) campaign was conducted in fall 2015
in which a fine-scale structure (1–10 km∕1–10 days) in the
northwestern Mediterranean Ligurian subbasin was pre-identified using both
satellite
and numerical modeling data. Along the ship track, various variables were measured at the surface (temperature, salinity,
chlorophyll a and nutrient concentrations) with ADCP current velocity. We
also deployed a new model of the CytoSense automated flow cytometer (AFCM)
optimized for small and dim cells, for near real-time characterization of the
surface phytoplankton community structure of surface waters with a spatial
resolution of a few kilometers and an hourly temporal resolution. For the
first time with this optimized
version of the AFCM, we were able to fully resolve Prochlorococcus picocyanobacteria in addition to the easily
distinguishable Synechococcus. The vertical physical dynamics and biogeochemical properties of the studied area were
investigated by continuous high-resolution CTD profiles thanks to a moving vessel profiler (MVP) during the vessel underway
associated with a high-resolution pumping system deployed during fixed
stations allowing sampling of the water column at a fine resolution
(below 1 m). The observed fine-scale feature presented a cyclonic structure with a relatively cold core surrounded by warmer
waters. Surface waters were totally depleted in nitrate and phosphate. In addition to the doming of the isopycnals by the cyclonic
circulation, an intense wind event induced Ekman pumping. The upwelled subsurface cold nutrient-rich water fertilized surface waters
and was marked by an increase in Chl a concentration.
Prochlorococcus and pico- and nano-eukaryotes were more abundant in
cold core waters, while Synechococcus dominated in warm boundary
waters. Nanoeukaryotes were the main contributors (>50 %)
in terms of pigment content (red fluorescence) and biomass. Biological observations based on the mean cell's red fluorescence
recorded by AFCM combined with physical properties of surface waters suggest a distinct origin for two warm boundary waters.
Finally, the application of a matrix growth population model based on high-frequency AFCM measurements in warm boundary surface
waters provides estimates of in situ growth rate and apparent net primary production for Prochlorococcus (μ=0.21 d−1, NPP =0.11 mgCm-3d-1) and Synechococcus (μ=0.72 d−1, NPP =2.68
mgCm-3d-1), which corroborate their opposite surface distribution pattern. The innovative adaptive strategy applied
during OSCAHR with a combination of several multidisciplinary and complementary approaches involving high-resolution in situ
observations and sampling, remote-sensing and model simulations provided a deeper understanding of the marine biogeochemical dynamics
through the first trophic levels.
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