Multiscaling analysis of high resolution space-time lidar-rainfall

In this study, we report results from scaling analysis of 2.5 m spatial and 1 s temporal resolution lidar-rainfall data. The high resolution spatial and temporal data from the same observing system allows us to investigate the variability of rainfall at very small scales ranging from few meters to ~1 km in space and few seconds to ~30 min in time. The results suggest multiscaling behaviour in the lidar-rainfall with the scaling regime extending down to the resolution of the data. The results also indicate the existence of a space-time transformation of the form <i>t</i>~<i>L<sup>z</sup></i> at very small scales, where <i>t</i> is the time lag, <i>L</i> is the spatial averaging scale and <i>z</i> is the dynamic scaling exponent

Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation : a tale of the unexpected

ObjectiveTo assess the clinical, radiologic, myopathologic, and proteomic findings in a patient manifesting a multisystem proteinopathy due to a homozygous valosin-containing protein gene (VCP) mutation previously reported to be pathogenic in the heterozygous state.MethodsWe studied a 36-year-old male index patient and his father, both presenting with progressive limb-girdle weakness. Muscle involvement was assessed by MRI and muscle biopsies. We performed whole-exome sequencing and Sanger sequencing for segregation analysis of the identified p.Arg159His VCP mutation. To dissect biological disease signatures, we applied state-of-the-art quantitative proteomics on muscle tissue of the index case, his father, 3 additional patients with VCP-related myopathy, and 3 control individuals.ResultsThe index patient, homozygous for the known p.Arg159His mutation in VCP, manifested a typical VCP-related myopathy phenotype, although with a markedly high creatine kinase value and a relatively early disease onset, and Paget disease of bone. The father exhibited a myopathy phenotype and discrete parkinsonism, and multiple deceased family members on the maternal side of the pedigree displayed a dementia, parkinsonism, or myopathy phenotype. Bioinformatic analysis of quantitative proteomic data revealed the degenerative nature of the disease, with evidence suggesting selective failure of muscle regeneration and stress granule dyshomeostasis.ConclusionWe report a patient showing a multisystem proteinopathy due to a homozygous VCP mutation. The patient manifests a severe phenotype, yet fundamental disease characteristics are preserved. Proteomic findings provide further insights into VCP-related pathomechanisms

Localizing Defects in Multithreaded Programs by Mining Dynamic Call Graphs

Writing multithreaded software for multicore computers confronts many developers with the difficulty of finding parallel programming errors. In the past, most parallel debugging techniques have concentrated on finding race conditions due to wrong usage of synchronization constructs. A widely unexplored issue, however, is that a wrong usage of non-parallel programming constructs may also cause wrong parallel application behavior. This paper presents a novel defect-localization technique for multithreaded shared-memory programs that is based on analyzing execution anomalies. Compared to race detectors that report just on wrong synchronization, this method can detect a wider range of defects affecting parallel execution. It works on a condensed representation of the call graphs of multithreaded applications and employs data-mining techniques to locate a method containing a defect. Our results from controlled application experiments show that we found race conditions, but also other programming errors leading to incorrect parallel program behavior. On average, our approach reduced in our benchmark the amount of code to be inspected to just 7.1% of all methods

Clinical trial readiness to solve barriers to drug development in FSHD (ReSolve): protocol of a large, international, multi-center prospective study

Background Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly-inherited progressive muscular dystrophy caused by de-repression of the DUX4 gene, which causes disease by a toxic-gain-of-function. As molecularly targeted drugs move from preclinical testing into human trials, it is essential that we validate clinical trial tools and methodology to facilitate the drug development process. Methods/design The primary goal of this study is to hasten drug development for FSHD by validating two novel clinical outcome assessments (COAs) and refining clinical trial strategies. We will perform an 18-month longitudinal study in 220 genetically confirmed and clinically affected participants using our FSHD Clinical Trial Research Network, comprised of 8 sites in the United States, and 3 collaborating sites in Europe. Visits occur at baseline and months 3, 12, and 18. At each visit we will collect: 1) a novel FSHD functional composite COA made up of 18 evaluator-administered motor tasks in the domains of shoulder/arm, hand, core/abdominal, leg, and balance function; and 2) electrical impedance myography as a novel muscle quality biomarker (US sites). Other COAs include 1) Domain 1 of the Motor Function Measure; 2) Reachable workspace; 3) orofacial strength using the Iowa Oral Performance Instrument; 4) lean muscle mass using dual-energy X-ray absorptiometry (DEXA); 5) strength as measured by quantitative myometry and manual muscle testing; and 6) the FSHD Health Index and other patient-reported outcomes. Plasma, DNA, RNA, and serum will be collected for future biomarker studies. We will use an industry standard multi-site training plan. We will evaluate the test-retest reliability, validity, and sensitivity to disease progression, and minimal clinically important changes of our new COAs. We will assess associations between demographic and genetic factors and the rate of disease progression to inform refinement of eligibility criteria for future clinical trials. Discussion To the best of our knowledge, this is the largest collaborative study of patients with FSHD performed in the US and Europe. The results of this study will enable more efficient clinical trial design. During the conduct of the study, relevant data will be made available for investigators or companies pursuing novel FSHD therapeutics

Concomitant homozygosity for the prothrombin gene variant with mild deficiency of antithrombin III in a patient with multiple hepatic infarctions: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hereditary causes of visceral thrombosis or thrombosis should be sought among young patients. We present a case of a young man presenting with multiple hepatic infarctions resulting in portal hypertension due to homozygosity of the prothrombin gene mutation not previously described in literature.</p> <p>Case presentation</p> <p>A 42-year-old Caucasian man with a previous history of idiopathic deep vein thrombosis 11 years earlier presented with vague abdominal pains and mildly abnormal liver function tests. An ultrasound and computed tomography scan showed evidence of hepatic infarction and portal hypertension (splenic varices). A thrombophilia screen confirmed a homozygous mutation for the prothrombin gene mutation, with mildly reduced levels of anti-thrombin III (AT III). Subsequent testing of his father and brother revealed heterozygosity for the same gene mutation.</p> <p>Conclusion</p> <p>Hepatic infarction is unusual due to the rich dual arterial and venous blood supply to the liver. In the absence of an arterial or haemodynamic insult causing hepatic infarction, a thrombophilia should be considered. To our knowledge, this is the first reported case of a hepatic infarction due to homozygosity of the prothrombin gene mutation. It is unclear whether homozygotes have a higher risk of thrombosis than heterozygotes. In someone presenting with a first thrombosis with this mutation, the case for life-long anticoagulation is unclear, but it may be necessary to prevent a second and more severe second thrombotic event, as occurred in this case.</p

Effects of Lumacaftor/Ivacaftor on Cystic Fibrosis Disease Progression in Children 2 through 5 Years of Age Homozygous for F508del-CFTR: A Phase 2 Placebo-controlled Clinical Trial.

RATIONALE Lumacaftor/ivacaftor (LUM/IVA) was shown to be safe and well tolerated in children 2 through 5 years of age with cystic fibrosis (CF) homozygous for F508del-CFTR in a phase 3 open-label study. Improvements in sweat chloride concentration, markers of pancreatic function, and lung clearance index2.5 (LCI2.5), along with increases in growth parameters, suggested the potential for early disease modification with LUM/IVA treatment. OBJECTIVE To further assess the effects of LUM/IVA on CF disease progression in children 2 through 5 years of age using chest magnetic resonance imaging (MRI). METHODS This phase 2 study had two parts: a 48-week, randomized, double-blind, placebo-controlled treatment period in which children 2 through 5 years of age with CF homozygous for F508del-CFTR received either LUM/IVA or placebo (Part 1) followed by an open-label period in which all children received LUM/IVA for an additional 48 weeks (Part 2). We report results from Part 1. The primary endpoint was absolute change from baseline in chest MRI global score at Week 48. Secondary endpoints included absolute change in LCI2.5 through Week 48 and absolute changes in weight-for-age, stature-for-age, and body mass index-for-age z-scores at Week 48. Additional endpoints included absolute changes in sweat chloride concentration, fecal elastase-1 levels, serum immunoreactive trypsinogen, and fecal calprotectin through Week 48. The primary endpoint was analyzed using Bayesian methods, where the actual Bayesian posterior probability of LUM/IVA being superior to placebo in the MRI global chest score at Week 48 was calculated using a vague normal prior distribution; secondary and additional endpoints were analyzed using descriptive summary statistics. RESULTS Fifty-one children were enrolled and received LUM/IVA (n=35) or placebo (n=16). For the change in MRI global chest score at Week 48, the Bayesian posterior probability of LUM/IVA being better than placebo (treatment difference <0; higher score indicating greater abnormality) was 76%; the mean treatment difference was -1.5 (95% credible interval, -5.5 to 2.6). Treatment with LUM/IVA also led to within-group numerical improvements in LCI2.5, growth parameters, and biomarkers of pancreatic function as well as greater decreases in sweat chloride concentration compared with placebo from baseline through Week 48. Safety data were consistent with the established safety profile of LUM/IVA. CONCLUSIONS This placebo-controlled study suggests the potential for early disease modification with LUM/IVA treatment, including that assessed by chest MRI, in children as young as 2 years. Clinical trial registered with ClinicalTrials.gov (NCT03625466)

An Integrated Approach to Measuring Emissions from Confined Animal Feeding Operations at the Whole Facility Scale

Agricultural operations produce a variety of particulates and gases that influence air quality. Agriculture, through wind erosion, tillage and harvest operations, burning, diesel-powered machinery and animal production operations, is a source of particulate matter that can enter human lungs and cause pulmonary problems. Animal production operations can be a source of gaseous emissions such as ammonia, odor-causing volatile organic compounds, hydrogen sulfide, greenhouse gases (methane, nitrous oxides) and airborne pathogens. These emissions can negatively impact human health, property values, and the environment. The presence of buildings and other structures often make whole facility measurement capability a requirement for understanding the source strength and characteristics. The ability to use standoff methods to determine the movement and concentrations of emissions on a whole facility basis opens new capabilities for model development and verification. An integrated system to measure whole facility emission was designed to characterize the complex structures and temporally dependent emission rates often associated with production operations. This approach combines state of the art standoff measurement techniques with standard point source monitoring equipment to provide the calibrated, high spatial and temporal frequency data required to develop and validate the models required for emission reduction and regulation. This effort includes the design, construction and operation of a new multi-wavelength lidar developed to map and track particle emissions. The lidar incorporates a laser emitting simultaneous, pulsed NdYAG laser radiation at 355, 532 and 1064 nm at a pulse frequency of 10 kHz. The system also includes open path FTS measurements for integrated chemical concentrations, and state-of-the-art point measurements of turbulence, particulate and gas concentrations. This approach was evaluated in a multidisciplinary atmospheric study at a swine production farm in Iowa. Aerosol plumes emitted from the facility were prominent phenomena, and their variations with temperature, turbulence, stability and feed cycle were studied, using arrays of particle samplers and turbulence detectors. Other lidar measurements focused on air motion as seen by long duration scans of the farm region. Successful operation of this system confirms the value of the multidimensional approach for the determination of agricultural emissions in the complex terrain often accompanying production facilities

Integrating Lidar and Atmospheric Boundary Layer Measurements to Determine Fluxes and Dynamics of Particulate Emissions from an Agriculture Facility

Lidar technology offers the ability to quantify concentrations of small particulates in the atmosphere in certain ranges of time and space. While this is a valuable tool to visualize the behavior of plumes emitted from the surface, the actual flux of particles cannot be estimated from such data alone. To determine the mass flux of particles, the concentrations must be properly integrated with wind and turbulence properties. The goal of this study is to utilize a model that uses wind and particle density information to calculate the flux of particles from an animal facility near Ames, Iowa. The model is a simplified conservation equation for particle density in the atmosphere. This approach essentially quantifies fluxes in and out of a box centered over the facility and estimates the surface source by assuming conservation of mass. In addition, we hypothesize that distinct turbulence structures will sometimes interact with the intermittency of the surface emission from the buildings, resulting in episodic changes in emission fluxes from the site. A second objective involves documenting how intermittent the emission plumes are and how they are connected to periodic large scale turbulence events. Lidar data of particle size and density in the vicinity of the site were collected during an intensive field campaign lasting nearly 2 weeks. In addition to the lidar data, turbulence data were measured at several levels on each of three towers, located upwind, inside and downwind of the source area. The model requires measurements of the vertical profiles of both concentrations of particulates and the mean horizontal wind. The concentrations were measured using the lidar, while winds were measured using a combination of cup anemometers and sonic anemometers. This allows the emission fluxes to be calculated during 15 to 30 minute periods when winds are consistent. Flux calculations await the final calibration of the lidar returns using measured particle densities. Flux estimates will be made when distinct plumes are observed under steady-state wind conditions. Current results are presented showing evidence of episodic plumes of CO2 in response to intermittent vertical motions of turbulences

MRI of the lung (3/3)-current applications and future perspectives

BACKGROUND: MRI of the lung is recommended in a number of clinical indications. Having a non-radiation alternative is particularly attractive in children and young subjects, or pregnant women. METHODS: Provided there is sufficient expertise, magnetic resonance imaging (MRI) may be considered as the preferential modality in specific clinical conditions such as cystic fibrosis and acute pulmonary embolism, since additional functional information on respiratory mechanics and regional lung perfusion is provided. In other cases, such as tumours and pneumonia in children, lung MRI may be considered an alternative or adjunct to other modalities with at least similar diagnostic value. RESULTS: In interstitial lung disease, the clinical utility of MRI remains to be proven, but it could provide additional information that will be beneficial in research, or at some stage in clinical practice. Customised protocols for chest imaging combine fast breath-hold acquisitions from a "buffet" of sequences. Having introduced details of imaging protocols in previous articles, the aim of this manuscript is to discuss the advantages and limitations of lung MRI in current clinical practice. CONCLUSION: New developments and future perspectives such as motion-compensated imaging with self-navigated sequences or fast Fourier decomposition MRI for non-contrast enhanced ventilation- and perfusion-weighted imaging of the lung are discussed. Main Messages • MRI evolves as a third lung imaging modality, combining morphological and functional information. • It may be considered first choice in cystic fibrosis and pulmonary embolism of young and pregnant patients. • In other cases (tumours, pneumonia in children), it is an alternative or adjunct to X-ray and CT. • In interstitial lung disease, it serves for research, but the clinical value remains to be proven. • New users are advised to make themselves familiar with the particular advantages and limitations