This prospective, randomized, double-blind, placebo-controlled, phase III trial assessed the efficacy, safety, and tolerability of mycophenolate mofetil (MMF) as a steroid-sparing agent in patients ...with myasthenia gravis (MG).
Patients with acetylcholine receptor antibody-positive class II-IVa MG (MG Foundation of America MGFA criteria) taking corticosteroids for at least 4 weeks were randomized to MMF (2 g/day) or placebo for 36 weeks. The primary endpoint was a composite measure defined as achievement of minimal manifestations or pharmacologic remission (MGFA post-intervention status), with reduction of corticosteroid dose on a set schedule. Secondary endpoints included disease severity, quality-of-life scores, and safety.
A total of 44% of MMF-treated (n = 88) and 39% of placebo-receiving (n = 88) patients achieved the primary endpoint (p = 0.541). Improvements in mean quantitative MG, MG activities of daily living, and 36-item Short-Form health survey scores were similar in both groups. Numbers of adverse events were similar in both groups. The most commonly reported adverse events in the MMF-treated group were headache (12.5%) and worsening of MG (11.4%), and in the placebo group, worsening of MG (20.5%) and diarrhea (10.2%).
Initiation of mycophenolate mofetil (MMF) treatment was not superior to placebo in maintaining myasthenia gravis (MG) control during a 36-week schedule of prednisone tapering. There were no significant differences in the primary or secondary endpoints between the study groups. MMF was well tolerated and adverse events were consistent with previous studies. Experience from this large, international, multicenter, phase III study employing full MG Foundation of America guidelines will aid the design of future MG studies.
Ultrahigh energy neutrinos are interesting messenger particles since, if detected, they can transmit exclusive information about ultrahigh energy processes in the Universe. These particles, with ...energies above 10 super(16)eV , interact very rarely. Therefore, detectors that instrument several gigatons of matter are needed to discover them. The ARA detector is currently being constructed at the South Pole. It is designed to use the Askaryan effect, the emission of radio waves from neutrino-induced cascades in the South Pole ice, to detect neutrino interactions at very high energies. With antennas distributed among 37 widely separated stations in the ice, such interactions can be observed in a volume of several hundred cubic kilometers. Currently three deep ARA stations are deployed in the ice, of which two have been taking data since the beginning of 2013. In this article, the ARA detector "as built" and calibrations are described. Data reduction methods used to distinguish the rare radio signals from overwhelming backgrounds of thermal and anthropogenic origin are presented. Using data from only two stations over a short exposure time of 10 months, a neutrino flux limit of 1.5x10 super(-6)GeV/cm super(2)/s/sr is calculated for a particle energy of 10 super(18)eV , which offers promise for the full ARA detector.
Governments have committed to conserving ≥17% of terrestrial and ≥10% of marine environments globally, especially “areas of particular importance for biodiversity” through “ecologically ...representative” Protected Area (PA) systems or other “area‐based conservation measures”, while individual countries have committed to conserve 3–50% of their land area. We estimate that PAs currently cover 14.6% of terrestrial and 2.8% of marine extent, but 59–68% of ecoregions, 77–78% of important sites for biodiversity, and 57% of 25,380 species have inadequate coverage. The existing 19.7 million km² terrestrial PA network needs only 3.3 million km² to be added to achieve 17% terrestrial coverage. However, it would require nearly doubling to achieve, cost‐efficiently, coverage targets for all countries, ecoregions, important sites, and species. Poorer countries have the largest relative shortfalls. Such extensive and rapid expansion of formal PAs is unlikely to be achievable. Greater focus is therefore needed on alternative approaches, including community‐ and privately managed sites and other effective area‐based conservation measures.
The recognition and translation of mammalian mitochondrial mRNAs are poorly understood. To gain further insights into these processes in vivo, we characterized mice with a missense mutation that ...causes loss of the translational activator of cytochrome oxidase subunit I (TACO1). We report that TACO1 is not required for embryonic survival, although the mutant mice have substantially reduced COXI protein, causing an isolated complex IV deficiency. We show that TACO1 specifically binds the mt-Co1 mRNA and is required for translation of COXI through its association with the mitochondrial ribosome. We determined the atomic structure of TACO1, revealing three domains in the shape of a hook with a tunnel between domains 1 and 3. Mutations in the positively charged domain 1 reduce RNA binding by TACO1. The Taco1 mutant mice develop a late-onset visual impairment, motor dysfunction and cardiac hypertrophy and thus provide a useful model for future treatment trials for mitochondrial disease.
We report on studies of the viability and sensitivity of the Askaryan Radio Array (ARA), a new initiative to develop a Teraton-scale ultra-high energy neutrino detector in deep, radio-transparent ice ...near Amundsen-Scott station at the South Pole. An initial prototype ARA detector system was installed in January 2011, and has been operating continuously since then. We describe measurements of the background radio noise levels, the radio clarity of the ice, and the estimated sensitivity of the planned ARA array given these results, based on the first five months of operation. Anthropogenic radio interference in the vicinity of the South Pole currently leads to a few-percent loss of data, but no overall effect on the background noise levels, which are dominated by the thermal noise floor of the cold polar ice, and galactic noise at lower frequencies. We have also successfully detected signals originating from a 2.5km deep impulse generator at a distance of over 3 km from our prototype detector, confirming prior estimates of kilometer-scale attenuation lengths for cold polar ice. These are also the first such measurements for propagation over such large slant distances in ice. Based on these data, ARA-37, the ∼200km2 array now in its initial construction phase, will achieve the highest sensitivity of any planned or existing neutrino detector in the 1016–1019eV energy range.
Parasites of the genus Plasmodium are transmitted to mammalian hosts by anopheline mosquitoes. Within the insect vector, parasite growth and development are potentially limited by antimicrobial ...defence molecules. Here, we describe the isolation of cDNA and genomic clones encoding a cecropin antibacterial peptide from the malaria vector mosquito Anopheles gambiae. The locus was mapped to polytene division 1C of the X chromosome. Cecropin RNA was induced by infection with bacteria and Plasmodium. RNA levels varied in different body parts of the adult mosquito. During development, cecropin expression was limited to the early pupal stage. The peptide was purified from both adult mosquitoes and cell culture supernatants. Anopheles gambiae synthetic cecropins displayed activity against Gram‐negative and Gram‐positive bacteria, filamentous fungi and yeasts.
Global maps of the mesoscale eddy available potential energy (EAPE) field at a depth of 500 m are created using potential density anomalies in a high‐resolution 1/12.5° global ocean model. Maps made ...from both a free‐running simulation and a data‐assimilative reanalysis of the HYbrid Coordinate Ocean Model (HYCOM) are compared with maps made by other researchers from density anomalies in Argo profiles. The HYCOM and Argo maps display similar features, especially in the dominance of western boundary currents. The reanalysis maps match the Argo maps more closely, demonstrating the added value of data assimilation. Global averages of the simulation, reanalysis, and Argo EAPE all agree to within about 10%. The model and Argo EAPE fields are compared to EAPE computed from temperature anomalies in a data set of “moored historical observations” (MHO) in conjunction with buoyancy frequencies computed from a global climatology. The MHO data set allows for an estimate of the EAPE in high‐frequency motions that is aliased into the Argo EAPE values. At MHO locations, 15–32% of the EAPE in the Argo estimates is due to aliased motions having periods of 10 days or less. Spatial averages of EAPE in HYCOM, Argo, and MHO data agree to within 50% at MHO locations, with both model estimates lying within error bars observations. Analysis of the EAPE field in an idealized model, in conjunction with published theory, suggests that much of the scatter seen in comparisons of different EAPE estimates is to be expected given the chaotic, unpredictable nature of mesoscale eddies.
Key Points
Global maps of the mesoscale eddy available potential energy are made from a HYCOM simulation and reanalysis
Modeled eddy available potential energy compares well to Argo observations globally, and to moored instruments locally
Model‐data comparisons of eddy available potential energy exhibit intrinsic scatter
Immune responses of the malaria vector mosquito Anopheles gambiae were monitored systematically by the induced expression of five RNA markers after infection challenge. One newly isolated marker ...encodes a homologue of the moth Gram-negative bacteria-binding protein (GNBP), and another corresponds to a serine protease-like molecule. Additional previously described markers that respond to immune challenge encode the antimicrobial peptide defensin, a putative galactose lectin, and a putative serine protease. Specificity of the immune responses was indicated by differing temporal patterns of induction of specific markers in bacteria-challenged larvae and adults, and by variations in the effectiveness of different microorganisms and their components for marker induction in an immune-responsive cell line. The markers exhibit spatially distinct patterns of expression in the adult female mosquito. Two of them are highly expressed in different regions of the midgut, one in the anterior and the other in the posterior midgut. Marker induction indicates a significant role of the midgut in insect innate immunity. Immune responses to the penetration of the midgut epithelium by a malaria parasite occur both within the midgut itself and elsewhere in the body, suggesting an immune-related signaling process.
Purpose
Literature on outcomes after SSRF, stratified for rib fracture pattern is scarce in patients with moderate to severe traumatic brain injury (TBI; Glasgow Coma Scale ≤ 12). We hypothesized ...that SSRF is associated with improved outcomes as compared to nonoperative management without hampering neurological recovery in these patients.
Methods
A post hoc subgroup analysis of the multicenter, retrospective CWIS-TBI study was performed in patients with TBI and stratified by having sustained a non-flail fracture pattern or flail chest between January 1, 2012 and July 31, 2019. The primary outcome was mechanical ventilation-free days and secondary outcomes were in-hospital outcomes. In multivariable analysis, outcomes were assessed, stratified for rib fracture pattern.
Results
In total, 449 patients were analyzed. In patients with a non-flail fracture pattern, 25 of 228 (11.0%) underwent SSRF and in patients with a flail chest, 86 of 221 (38.9%). In multivariable analysis, ventilator-free days were similar in both treatment groups. For patients with a non-flail fracture pattern, the odds of pneumonia were significantly lower after SSRF (odds ratio 0.29; 95% CI 0.11–0.77;
p
= 0.013). In patients with a flail chest, the ICU LOS was significantly shorter in the SSRF group (beta, − 2.96 days; 95% CI − 5.70 to − 0.23;
p
= 0.034).
Conclusion
In patients with TBI and a non-flail fracture pattern, SSRF was associated with a reduced pneumonia risk. In patients with TBI and a flail chest, a shorter ICU LOS was observed in the SSRF group. In both groups, SSRF was safe and did not hamper neurological recovery.
Diversity in colorectal cancer biology is associated with variable responses to standard chemotherapy. We aimed to identify and validate DNA hypermethylated genes as predictive biomarkers for ...irinotecan treatment of metastatic CRC patients. Candidate genes were selected from 389 genes involved in DNA Damage Repair by correlation analyses between gene methylation status and drug response in 32 cell lines. A large series of samples (n=818) from two phase III clinical trials was used to evaluate these candidate genes by correlating methylation status to progression-free survival after treatment with first-line single-agent fluorouracil (Capecitabine or 5-fluorouracil) or combination chemotherapy (Capecitabine or 5-fluorouracil plus irinotecan (CAPIRI/FOLFIRI)). In the discovery (n=185) and initial validation set (n=166), patients with methylated
(
did not benefit from CAPIRI over Capecitabine treatment (discovery set: HR=1.2 (95%CI 0.7-1.9,
=0.6), validation set: HR=0.9 (95%CI 0.6-1.4,
=0.5)), whereas patients with unmethylated
did (discovery set: HR=0.4 (95%CI 0.3-0.6,
=0.00001), validation set: HR=0.5 (95%CI 0.3-0.7,
=0.0008)). These results could not be replicated in the external data set (n=467), where a similar effect size was found in patients with methylated and unmethylated
for FOLFIRI over 5FU treatment (methylated
: HR=0.7 (95%CI 0.5-0.9,
=0.01), unmethylated
: HR=0.8 (95%CI 0.6-1.2,
=0.4)). In conclusion,
promoter hypermethylation status is a potential predictive biomarker for response to treatment with irinotecan, when combined with capecitabine. This finding could not be replicated in an external validation set, in which irinotecan was combined with 5FU. These results underline the challenge and importance of extensive clinical evaluation of candidate biomarkers in multiple trials.
PDF
