Calibration of parent and fragment ion detection rates in Rosettas ROSINA/DFMS mass spectrometer

The Double Focusing Mass Spectrometer DFMS embarked on the European Space Agency’s Rosetta mission as part of the ROSINA instrument suite. It boasts a high mass resolution and a high sensitivity, which have guaranteed spectacular discoveries during Rosetta’s rendez-vous with comet 67P/Churyumov-Gerasimenko. This paper describes the DFMS data calibration procedure for determining the parent and fragment ion count rates in the neutral mode, which serve as the basis for retrieving the neutral gas densities. A new approach to computing secondary electron yields is presented. Attention is given to an analysis of the mass peak shapes, which change with magnet temperature. Discrete counting statistical effects also affect the peak shape at low counts. If not accounted for, changes of mass peak shape can induce errors of up to 20% on the determination of the ion fluxes. An assessment of the different sources of uncertainty on the obtained count rates and ratios of count rates is presented

The pharmaceutical death-ride of dihydroartemisinin

In the 2010 second edition of WHO's guidelines for the treatment of malaria, the relatively new fixed dose combination dihydroartemisinin-piperaquine is included as one of the recommended artemisinin combination therapies. However, experimental testing demonstrates that, due to its intrinsic chemical instability, dihydroartemisinin is not suitable to be used in pharmaceutical formulations. In addition, data show that the currently available dihydroartemisinin preparations fail to meet the internationally accepted stability requirements. At a time when many efforts aim to ban counterfeit and substandard drugs from the malaria market, the obvious question rises how WHO and public-private partnerships, such as Medicine for Malaria venture (MMV), can support the production and marketing of anti-malarial drugs that do not even meet the International Pharmacopoeia requirements

Dysregulated Proinflammatory and Fibrogenic Phenotype of Fibroblasts in Cystic Fibrosis

Morbi-mortality in cystic fibrosis (CF) is mainly related to chronic lung infection and inflammation, uncontrolled tissue rearrangements and fibrosis, and yet the underlying mechanisms remain largely unknown. We evaluated inflammatory and fibrosis responses to bleomycin in F508del homozygous and wild-type mice, and phenotype of fibroblasts explanted from mouse lungs and skin. The effect of vardenafil, a cGMP-specific phosphodiesterase type 5 inhibitor, was tested in vivo and in culture. Responses of proinflammatory and fibrotic markers to bleomycin were enhanced in lungs and skin of CF mice and were prevented by treatment with vardenafil. Purified lung and skin fibroblasts from CF mice proliferated and differentiated into myofibroblasts more prominently and displayed higher sensitivity to growth factors than those recovered from wild-type littermates. Under inflammatory stimulation, mRNA and protein expression of proinflammatory mediators were higher in CF than in wild-type fibroblasts, in which CFTR expression reached similar levels to those observed in other non-epithelial cells, such as macrophages. Increased proinflammatory responses in CF fibroblasts were reduced by half with submicromolar concentrations of vardenafil. Proinflammatory and fibrogenic functions of fibroblasts are upregulated in CF and are reduced by vardenafil. This study provides compelling new support for targeting cGMP signaling pathway in CF pharmacotherapy

Sulphur-bearing species in the coma of comet 67P/Churyumov–Gerasimenko

Several sulphur-bearing species have already been observed in different families of comets. However, the knowledge on the minor sulphur species is still limited. The comet’s sulphur inventory is closely linked to the pre-solar cloud and holds important clues to the degree of reprocessing of the material in the solar nebula and during comet accretion. Sulphur in pre-solar clouds is highly depleted, which is quite puzzling as the S/O ratio in the diffuse interstellar medium is cosmic. This work focuses on the abundance of the previously known species H2S, OCS, SO, S2, SO2 and CS2 in the coma of comet 67P/Churyumov–Gerasimenko measured by Rosetta Orbiter Spectrometer for Ion and Neutral Analysis/Double Focusing Mass Spectrometer between equinox and perihelion 2015. Furthermore, we present the first detection of S3, S4, CH3SH and C2H6S in a comet, and we determine the elemental abundance of S/O in the bulk ice of (1.47 ± 0.05) × 10−2. We show that SO is present in the coma originating from the nucleus, but not CS in the case of 67P, and for the first time establish that S2 is present in a volatile and a refractory phase. The derived total elemental sulphur abundance of 67P is in agreement with solar photospheric elemental abundances and shows no sulphur depletion as reported for dense interstellar clouds. Also the presence of S2 at heliocentric distances larger than 3 au indicates that sulphur-bearing species have been processed by radiolysis in the pre-solar cloud and that at least some of the ice from this cloud has survived in comets up the present

Precision muon reconstruction in Double Chooz

We describe a muon track reconstruction algorithm for the reactor anti-neutrino experiment Double Chooz. The Double Chooz detector consists of two optically isolated volumes of the liquid scintillator viewed by PMTs, and an Outer Veto above these made of crossed scintillator strips. Muons are reconstructed by their Outer Veto hit positions along with timing information from the other two detector volumes. All muons are fit under the hypothesis that they are through-going and ultrarelativistic. If the energy depositions suggest that the muon may have stopped, the reconstruction fits also for this hypothesis and chooses between the two via the relative goodness-of-fit. In the ideal case of a through-going muon intersecting the center of the detector, the resolution is ~40mm in each transverse dimension. High quality muon reconstruction is an important tool for reducing the impact of the cosmogenic isotope background in Double Chooz. © 2014 Elsevier B.V

Burden of Illness and Quality of Life in Tuberous Sclerosis Complex: Findings From the TOSCA Study

Research on tuberous sclerosis complex (TSC) to date has focused mainly on the physical manifestations of the disease. In contrast, the psychosocial impact of TSC has received far less attention. The aim of this study was therefore to examine the impact of TSC on health, quality of life (QoL), and psychosocial well-being of individuals with TSC and their families. Questionnaires with disease-specific questions on burden of illness (BOI) and validated QoL questionnaires were used. After completion of additional informed consent, we included 143 individuals who participated in the TOSCA (TuberOus SClerosis registry to increase disease Awareness) study. Our results highlighted the substantial burden of TSC on the personal lives of individuals with TSC and their families. Nearly half of the patients experienced negative progress in their education or career due to TSC (42.1%), as well as many of their caregivers (17.6% employed; 58.8% unemployed). Most caregivers (76.5%) indicated that TSC affected family life, and social and working relationships. Further, well-coordinated care was lacking: a smooth transition from pediatric to adult care was mentioned by only 36.8% of adult patients, and financial, social, and psychological support in 21.1, 0, and 7.9%, respectively. In addition, the moderate rates of pain/discomfort (35%) and anxiety/depression (43.4%) reported across all ages and levels of disease demonstrate the high BOI and low QoL in this vulnerable population

Treatment Patterns and Use of Resources in Patients With Tuberous Sclerosis Complex: Insights From the TOSCA Registry

Tuberous Sclerosis Complex (TSC) is a rare autosomal-dominant disorder caused by mutations in the TSC1 or TSC2 genes. Patients with TSC may suffer from a wide range of clinical manifestations; however, the burden of TSC and its impact on healthcare resources needed for its management remain unknown. Besides, the use of resources might vary across countries depending on the country-specific clinical practice. The aim of this paper is to describe the use of TSC-related resources and treatment patterns within the TOSCA registry. A total of 2,214 patients with TSC from 31 countries were enrolled and had a follow-up of up to 5 years. A search was conducted to identify the variables containing both medical and non-medical resource use information within TOSCA. This search was performed both at the level of the core project as well as at the level of the research projects on epilepsy, subependymal giant cell astrocytoma (SEGA), lymphangioleiomyomatosis (LAM), and renal angiomyolipoma (rAML) taking into account the timepoints of the study, age groups, and countries. Data from the quality of life (QoL) research project were analyzed by type of visit and age at enrollment. Treatments varied greatly depending on the clinical manifestation, timepoint in the study, and age groups. GAB Aergics were the most prescribed drugs for epilepsy, and mTOR inhibitors are dramatically replacing surgery in patients with SEGA, despite current recommendations proposing both treatment options. mTOR inhibitors are also becoming common treatments in rAML and LAM patients. Forty-two out of the 143 patients (29.4%) who participated in the QoL research project reported inpatient stays over the last year. Data from non-medical resource use showed the critical impact of TSC on job status and capacity. Disability allowances were more common in children than adults (51.1% vs 38.2%). Psychological counseling, social services and social worker services were needed by <15% of the patients, regardless of age. The long-term nature, together with the variability in its clinical manifestations, makes TSC a complex and resource-demanding disease. The present study shows a comprehensive picture of the resource use implications of TSC

Natural clusters of tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND): new findings from the TOSCA TAND research project.

BACKGROUND: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have unique, individual patterns that pose significant challenges for diagnosis, psycho-education, and intervention planning. A recent study suggested that it may be feasible to use TAND Checklist data and data-driven methods to generate natural TAND clusters. However, the study had a small sample size and data from only two countries. Here, we investigated the replicability of identifying natural TAND clusters from a larger and more diverse sample from the TOSCA study. METHODS: As part of the TOSCA international TSC registry study, this embedded research project collected TAND Checklist data from individuals with TSC. Correlation coefficients were calculated for TAND variables to generate a correlation matrix. Hierarchical cluster and factor analysis methods were used for data reduction and identification of natural TAND clusters. RESULTS: A total of 85 individuals with TSC (female:male, 40:45) from 7 countries were enrolled. Cluster analysis grouped the TAND variables into 6 clusters: a scholastic cluster (reading, writing, spelling, mathematics, visuo-spatial difficulties, disorientation), a hyperactive/impulsive cluster (hyperactivity, impulsivity, self-injurious behavior), a mood/anxiety cluster (anxiety, depressed mood, sleep difficulties, shyness), a neuropsychological cluster (attention/concentration difficulties, memory, attention, dual/multi-tasking, executive skills deficits), a dysregulated behavior cluster (mood swings, aggressive outbursts, temper tantrums), and an autism spectrum disorder (ASD)-like cluster (delayed language, poor eye contact, repetitive behaviors, unusual use of language, inflexibility, difficulties associated with eating). The natural clusters mapped reasonably well onto the six-factor solution generated. Comparison between cluster and factor solutions from this study and the earlier feasibility study showed significant similarity, particularly in cluster solutions. CONCLUSIONS: Results from this TOSCA research project in an independent international data set showed that the combination of cluster analysis and factor analysis may be able to identify clinically meaningful natural TAND clusters. Findings were remarkably similar to those identified in the earlier feasibility study, supporting the potential robustness of these natural TAND clusters. Further steps should include examination of larger samples, investigation of internal consistency, and evaluation of the robustness of the proposed natural clusters