Treatment of Aspergillus fumigatus in Patients with Cystic Fibrosis: A Randomized, Placebo-Controlled Pilot Study

Many patients with cystic fibrosis develop persistent airway infection/colonization with Aspergillus fumigatus, however the impact of A. fumigatus on clinical outcomes remains unclear. The objective of this study was to determine whether treatment directed against Aspergillus fumigatus improves pulmonary function and clinical outcomes in patients with cystic fibrosis (CF).We performed a double-blind randomized placebo-controlled pilot clinical trial involving 35 patients with CF whose sputum cultures were chronically positive for A. fumigatus. Participants were centrally randomized to receive either oral itraconazole 5 mg/kg/d (N = 18) or placebo (N = 17) for 24 weeks. The primary outcome was the proportion of patients who experienced a respiratory exacerbation requiring intravenous antibiotics over the 24 week treatment period. Secondary outcomes included changes in FEV(1) and quality of life.Over the 24 week treatment period, 4 of 18 (22%) patients randomized to itraconazole experienced a respiratory exacerbation requiring intravenous antibiotics, compared to 5 of 16 (31%) placebo treated patients, P = 0.70. FEV(1) declined by 4.62% over 24 weeks in the patients randomized to itraconazole, compared to a 0.32% improvement in the placebo group (between group difference = -4.94%, 95% CI: -15.33 to 5.45, P = 0.34). Quality of life did not differ between the 2 treatment groups throughout the study. Therapeutic itraconazole blood levels were not achieved in 43% of patients randomized to itraconazole.We did not identify clinical benefit from itraconazole treatment for CF patients whose sputum was chronically colonized with A. fumigatus. Limitations of this pilot study were its small sample size, and failure to achieve therapeutic levels of itraconazole in many patients.ClinicalTrials.gov NCT00528190

The Simons Observatory: Magnetic Sensitivity Measurements of Microwave SQUID Multiplexers

The Simons Observatory (SO) will be a cosmic microwave background (CMB) survey experiment with three small-aperture telescopes and one large-aperture telescope, which will observe from the Atacama Desert in Chile. In total, SO will field $\sim$70,000 transition-edge sensor (TES) bolometers in six spectral bands centered between 27 and 280 GHz in order to achieve the sensitivity necessary to measure or constrain numerous cosmological quantities. The SO Universal Focal Plane Modules (UFMs) each contain a 150 mm diameter TES detector array, horn or lenslet optical coupling, cold readout components, and magnetic shielding. SO will use a microwave SQUID multiplexing ($\mu$MUX) readout at an initial multiplexing factor of $\sim$1000; the cold (100 mK) readout components are packaged in a $\mu$MUX readout module, which is part of the UFM, and can also be characterized independently. The 100 mK stage TES bolometer arrays and microwave SQUIDs are sensitive to magnetic fields, and their measured response will vary with the degree to which they are magnetically shielded. We present measurements of the magnetic pickup of test microwave SQUID multiplexers as a study of various shielding configurations for the Simons Observatory. We discuss how these measurements motivated the material choice and design of the UFM magnetic shielding.Comment: 5 pages, 6 figures, conference proceedings submitted to IEEE Transactions on Applied Superconductivit

Vulnerabilities and fisheries impacts:The uncertain future of manta and devil rays

Manta and devil rays of the subfamily Mobulinae (mobulids) are rarely studied, large, pelagic elasmobranchs, with all eight of well-evaluated species listed on the IUCN Red List as threatened or near threatened. Mobulids have life history characteristics (matrotrophic reproduction, extremely low fecundity, and delayed age of first reproduction) that make them exceptionally susceptible to overexploitation. Targeted and bycatch mortality from fisheries is a globally important and increasing threat, and targeted fisheries are incentivized by the high value of the global trade in mobulid gill plates. Fisheries bycatch of mobulids is substantial in tuna purse seine fisheries. Thirteen fisheries in 12 countries specifically targeting mobulids, and 30 fisheries in 23 countries with mobulid bycatch were identified. Aside from a few recently enacted national restrictions on capture, there is no comprehensive monitoring, assessment or control of mobulid fisheries or bycatch. Recent listing through the Convention on the International Trade in Endangered Species (CITES) may benefit mobulids of the genus Manta (manta rays), but none of the mobulids in the genus Mobula (devil rays) are protected. The relative economic costs of catch mitigation are minimal, particularly compared with a broad range of other, more complicated, marine conservation issues

Age-Related Changes of Myelin Basic Protein in Mouse and Human Auditory Nerve

Age-related hearing loss (presbyacusis) is the most common type of hearing impairment. One of the most consistent pathological changes seen in presbyacusis is the loss of spiral ganglion neurons (SGNs). Defining the cellular and molecular basis of SGN degeneration in the human inner ear is critical to gaining a better understanding of the pathophysiology of presbyacusis. However, information on age-related cellular and molecular alterations in the human spiral ganglion remains scant, owing to the very limited availably of human specimens suitable for high resolution morphological and molecular analysis. This study aimed at defining age-related alterations in the auditory nerve in human temporal bones and determining if immunostaining for myelin basic protein (MBP) can be used as an alternative approach to electron microscopy for evaluating myelin degeneration. For comparative purposes, we evaluated ultrastructural alternations and changes in MBP immunostaining in aging CBA/CaJ mice. We then examined 13 temporal bones from 10 human donors, including 4 adults aged 38–46 years (middle-aged group) and 6 adults aged 63–91 years (older group). Similar to the mouse, intense immunostaining of MBP was present throughout the auditory nerve of the middle-aged human donors. Significant declines in MBP immunoreactivity and losses of MBP+ auditory nerve fibers were observed in the spiral ganglia of both the older human and aged mouse ears. This study demonstrates that immunostaining for MBP in combination with confocal microscopy provides a sensitive, reliable, and efficient method for assessing alterations of myelin sheaths in the auditory nerve. The results also suggest that myelin degeneration may play a critical role in the SGN loss and the subsequent decline of the auditory nerve function in presbyacusis

Patterns and rates of exonic de novo mutations in autism spectrum disorders

Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1,2. To identify further genetic risk factors, we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n= 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant and the overall rate of mutation is only modestly higher than the expected rate. In contrast, there is significantly enriched connectivity among the proteins encoded by genes harboring de novo missense or nonsense mutations, and excess connectivity to prior ASD genes of major effect, suggesting a subset of observed events are relevant to ASD risk. The small increase in rate of de novo events, when taken together with the connections among the proteins themselves and to ASD, are consistent with an important but limited role for de novo point mutations, similar to that documented for de novo copy number variants. Genetic models incorporating these data suggest that the majority of observed de novo events are unconnected to ASD, those that do confer risk are distributed across many genes and are incompletely penetrant (i.e., not necessarily causal). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5 to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favor of CHD8 and KATNAL2 as genuine autism risk factors

The FLUXNET2015 dataset and the ONEFlux processing pipeline for eddy covariance data

The FLUXNET2015 dataset provides ecosystem-scale data on CO2, water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible.Peer reviewe