ACCERT: Auckland's cancer cachexia evaluating resistance training study

Background: Cancer Cachexia (CC) is a common problem seen in many advanced malignancies including Non- Small-Cell Lung Cancer (NSCLC). In CC there is a significant loss of adipose tissue and skeletal muscle mass. Muscle wasting is the main cause of impaired function, leading to respiratory complications and fatigue. The optimal treatment for CC is the complete removal of the tumour; unfortunately with advanced NSCLC this is unachievable. The next best options are to increase nutritional intake to counteract weight loss, address the anorexia, inflammation, and metabolic alterations i.e. loss of body fat and the skeletal muscle wasting. This requires the need to utilise a multi-targeted approach to decrease the inflammation and to stimulate the skeletal anabolic pathways with the use of progressive resistance training (PRT). PRT has shown acceptability and benefits in other cancer populations. This study aims to identify a novel multi-targeted treatment regimen that will alleviate and/or stabilise CC weight loss. Methods: This is a randomised, open-label study to investigate whether 2 sessions each week of PRT followed by essential amino acids (EAA's) high in leucine, when administered in addition to Eicosapentaenoic Acid (EPA) and a Cox-2 inhibitor is acceptable to NSCLC cachectic patients for a period of 20 weeks (primary endpoint). Secondary endpoints include Lean Body Mass, MRI thigh skeletal muscle values, QoL and Fatigue questionnaires, serum pro-inflammatory cytokine profiles, and hand and leg strength. Safety data will also be collected. Outcome measures to power a future study will be determined from the trend in difference between the two groups. 21 patients are planned to be randomised in a 1:2 ratio Arm A EPA and Cox-2 inhibitor vs. Arm B EPA, Cox-2 inhibitor, PRT followed by EAA's. All patients are offered to continue with the study medications and/or PRT sessions on compassionate use. Main inclusion criteria include: histological proven NSCLC patients who have at least 5% weight loss and fulfil the following cachectic definition (Evans Clin Nut 2008 27). A guest patient was enrolled in May 2012, followed by study participants in June 201

A Novel Visualization Tool for Evaluating Medication Side-Effects in Multi-drug Regimens

The evaluation and management of medication side-effects is a common and complex task for physicians. Information visualization has the potential to increase the efficiency and reduce the cognitive load involved in this process. We describe the design and development of Rxplore, a novel tool for assessing medication side-effects. Rxplore supports simultaneous lookup of multiple medications and an intuitive visual representation of query results. In a pilot study of Rxplore’s usability and utility, physicians rated the system highly for efficiency, intuitiveness, and clinical value

New Orleans and Hurricane Katrina. III: The 17th Street Drainage Canal

The failure of the levee and floodwall section on the east bank of the 17th Street drainage canal was one of the most catastrophic breaches that occurred during Hurricane Katrina. It produced a breach that rapidly scoured a flow pathway below sea level, so that after the storm surge had largely subsided, floodwaters still continued to stream in through this breach for the next two and a half days. This particular failure contributed massively to the overall flooding of the Metropolitan Orleans East Bank protected basin. Slightly more than half of the loss of life, and a similar fraction of the overall damages, occurred in this heavily populated basin. There are a number of important geotechnical and geoforensic lessons associated with this failure. Accordingly, this paper is dedicated solely to investigating this single failure. Geological and geotechnical details, such as a thin layer of sensitive clay that was laid down by a previous hurricane, proper strength characterization of soils at and beyond the toe of the levee, and recognition of a water-filled gap on the inboard side of the sheet pile cutoff wall are judged to be among the most critical factors in understanding this failure. The lessons learned from this study are of importance for similar flood protection systems throughout other regions of the United States and the world

Azimuthal asymmetries in lepton-pair production at a fixed-target experiment using the LHC beams (AFTER)

A multi-purpose fixed-target experiment using the proton and lead-ion beams of the LHC was recently proposed by Brodsky, Fleuret, Hadjidakis and Lansberg, and here we concentrate our study on some issues related to the spin physics part of this project (referred to as AFTER). We study the nucleon spin structure through $pp$ and $pd$ processes with a fixed-target experiment using the LHC proton beams, for the kinematical region with 7 TeV proton beams at the energy in center-of-mass frame of two nucleons $\sqrt{s}=115$ GeV. We calculate and estimate the $\cos2\phi$ azimuthal asymmetries of unpolarized $pp$ and $pd$ dilepton production processes in the Drell--Yan continuum region and at the $Z$-pole. We also calculate the $\sin(2\phi-\phi_S)$, $\sin(2\phi+\phi_S)$ and $\sin2\phi$ azimuthal asymmetries of $pp$ and $pd$ dilepton production processes with the target proton and deuteron longitudinally or transversally polarized in the Drell--Yan continuum region and around $Z$ resonances region. We conclude that it is feasible to measure these azimuthal asymmetries, consequently the three-dimensional or transverse momentum dependent parton distribution functions (3dPDFs or TMDs), at this new AFTER facility.Comment: 15 pages, 40 figures. Version accepted for publication in EPJ

Chronic e-cigarette exposure alters the human bronchial epithelial proteome

Rationale: E-cigarettes vaporize propylene glycol/vegetable glycerin (PG/VG), nicotine, and flavorings. However, the long-term health effects of exposing lungs to vaped e-liquids are unknown. Objectives: To determine the effects of chronic vaping on pulmonary epithelia. Methods: We performed research bronchoscopies on healthy nonsmokers, cigarette smokers, and e-cigarette users (vapers) and obtained bronchial brush biopsies and lavage samples from these subjects for proteomic investigation. We further employed in vitro and murine exposure models to support our human findings. Measurements and Main Results: Visual inspection by bronchoscopy revealed that vaper airways appeared friable and erythematous. Epithelial cells from biopsy samples revealed approximately 300 proteins that were differentially expressed in smoker and vaper airways, with only 78 proteins being commonly altered in both groups and 113 uniquely altered in vapers. For example, CYP1B1 (cytochrome P450 family 1 subfamily B member 1), MUC5AC (mucin 5 AC), and MUC4 levels were increased in vapers. Aerosolized PG/VG alone significantly increasedMUC5AC protein in human airway epithelial cultures and in murine nasal epithelia in vivo.We also found that e-liquids rapidly entered cells and that PG/VG reduced membrane fluidity and impaired protein diffusion. Conclusions: We conclude that chronic vaping exerts marked biological effects on the lung and that these effects may in part be mediated by the PG/VG base. These changes are likely not harmless and may have clinical implications for the development of chronic lung disease. Further studies will be required to determine the full extent of vaping on the lung

Rapid solubility and mineral storage of CO2 in basalt

The long-term security of geologic carbon storage is critical to its success and public acceptance. Much of the security risk associated with geological carbon storage stems from its buoyancy. Gaseous and supercritical CO2 are less dense than formation waters, providing a driving force for it to escape back to the surface. This buoyancy can be eliminated by the dissolution of CO2 into water prior to, or during its injection into the subsurface. The dissolution makes it possible to inject into fractured rocks and further enhance mineral storage of CO2 especially if injected into silicate rocks rich in divalent metal cations such as basalts and ultra-mafic rocks. We have demonstrated the dissolution of CO2 into water during its injection into basalt leading to its geologic solubility storage in less than five minutes and potential geologic mineral storage within few years after injection [1–3]. The storage potential of CO2 within basaltic rocks is enormous. All the carbon released from burning of all fossil fuel on Earth, 5000 GtC, can theoretically be stored in basaltic rocks [4]

Investigation of the Performance of the New Orleans Flood Protection System in Hurricane Katrina on August 29, 2005: Volume 1

This report presents the results of an investigation of the performance of the New Orleans regional flood protection system during and after Hurricane Katrina, which struck the New Orleans region on August 29, 2005. This event resulted in the single most costly catastrophic failure of an engineered system in history. Current damage estimates at the time of this writing are on the order of $100 to$200 billion in the greater New Orleans area, and the official death count in New Orleans and southern Louisiana at the time of this writing stands at 1,293, with an additional 306 deaths in nearby southern Mississippi. An additional approximately 300 people are currently still listed as “missing”; it is expected that some of these missing were temporarily lost in the shuffle of the regional evacuation, but some of these are expected to have been carried out into the swamps and the Gulf of Mexico by the storm’s floodwaters, and some are expected to be recovered in the ongoing sifting through the debris of wrecked homes and businesses, so the current overall regional death count of 1,599 is expected to continue to rise a bit further. More than 450,000 people were initially displaced by this catastrophe, and at the time of this writing more than 200,000 residents of the greater New Orleans metropolitan area continue to be displaced from their homes by the floodwater damages from this storm event. This investigation has targeted three main questions as follow: (1) What happened?, (2) Why?, and (3) What types of changes are necessary to prevent recurrence of a disaster of this scale again in the future? To address these questions, this investigation has involved: (1) an initial field reconnaissance, forensic study and data gathering effort performed quickly after the arrival of Hurricanes Katrina (August 29, 2005) and Rita (September 24, 2005), (2) a review of the history of the regional flood protection system and its development, (3) a review of the challenging regional geology, (4) detailed studies of the events during Hurricanes Katrina and Rita, as well as the causes and mechanisms of the principal failures, (4) studies of the organizational and institutional issues affecting the performance of the flood protection system, (5) observations regarding the emergency repair and ongoing interim levee reconstruction efforts, and (6) development of findings and preliminary recommendations regarding changes that appear warranted in order to prevent recurrence of this type of catastrophe in the future. In the end, it is concluded that many things went wrong with the New Orleans flood protection system during Hurricane Katrina, and that the resulting catastrophe had it roots in three main causes: (1) a major natural disaster (the Hurricane itself), (2) the poor performance of the flood protection system, due to localized engineering failures, questionable judgments, errors, etc. involved in the detailed design, construction, operation and maintenance of the system, and (3) more global “organizational” and institutional problems associated with the governmental and local organizations responsible for the design, construction, operation, maintenance and funding of the overall flood protection system

Report from the fifth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative)

This is the report from the fifth meeting of the Harmonising Outcome Measures for Eczema initiative (HOME V). The meeting was held on 12–14 June 2017 in Nantes, France, with 81 participants. The main aims of the meeting were (i) to achieve consensus over the definition of the core domain of long-term control and how to measure it and (ii) to prioritize future areas of research for the measurement of the core domain of quality of life (QoL) in children. Moderated whole-group and small-group consensus discussions were informed by presentations of qualitative studies, systematic reviews and validation studies. Small-group allocations were performed a priori to ensure that each group included different stakeholders from a variety of geographical regions. Anonymous whole-group voting was carried out using handheld electronic voting pads according to predefined consensus rules. It was agreed by consensus that the long-term control domain should include signs, symptoms, quality of life and a patient global instrument. The group agreed that itch intensity should be measured when assessing long-term control of eczema in addition to the frequency of itch captured by the symptoms domain. There was no recommendation of an instrument for the core outcome domain of quality of life in children, but existing instruments were assessed for face validity and feasibility, and future work that will facilitate the recommendation of an instrument was agreed upon. The Harmonising Outcome Measures for Eczema (HOME) initiative is an international group working together to develop a core outcome set (COS) for clinical trials in eczema (synonymous with atopic eczema and atopic dermatitis). HOME is coordinated from the Centre of Evidence Based Dermatology, University of Nottingham, U.K. Participation in HOME is open to anyone with an interest in outcomes for eczema. A COS is the agreed upon minimum set of instruments that should be included in all clinical trials for a particular condition. Use of a COS does not preclude using other instruments; other domains and instruments can also be included to meet the specific requirements of individual trials. COS initiatives are active across many fields of medicine and should enable better synthesis of trial data and reduce selective outcome reporting bias. The HOME initiative follows the best current guidance on developing a COS. Four core domains have been identified: clinician-reported signs; patient-reported symptoms; quality of life; and long-term control. The core outcome measurement instruments for clinician-reported signs and patient-reported symptoms have been established: the Eczema Area and Severity Index (EASI) for measuring clinician reported signs was agreed on at the HOME III meeting, and the Patient-Oriented Eczema Measure (POEM) was chosen to measure patient-reported symptoms at the HOME IV meeting. This is a report from the fifth consensus meeting of the HOME initiative (HOME V), which was held on 12–14 June 2017 in Nantes, France. The local organizers were Sebastien Barbarot and Jean-Francois Stalder of Nantes University Hospital, France

Paleobiology of titanosaurs: reproduction, development, histology, pneumaticity, locomotion and neuroanatomy from the South American fossil record

Fil: García, Rodolfo A.. Instituto de Investigación en Paleobiología y Geología. Museo Provincial Carlos Ameghino. Cipolletti; ArgentinaFil: Salgado, Leonardo. Instituto de Investigación en Paleobiología y Geología. General Roca. Río Negro; ArgentinaFil: Fernández, Mariela. Inibioma-Centro Regional Universitario Bariloche. Bariloche. Río Negro; ArgentinaFil: Cerda, Ignacio A.. Instituto de Investigación en Paleobiología y Geología. Museo Provincial Carlos Ameghino. Cipolletti; ArgentinaFil: Carabajal, Ariana Paulina. Museo Carmen Funes. Plaza Huincul. Neuquén; ArgentinaFil: Otero, Alejandro. Museo de La Plata. Universidad Nacional de La Plata; ArgentinaFil: Coria, Rodolfo A.. Instituto de Paleobiología y Geología. Universidad Nacional de Río Negro. Neuquén; ArgentinaFil: Fiorelli, Lucas E.. Centro Regional de Investigaciones Científicas y Transferencia Tecnológica. Anillaco. La Rioja; Argentin

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy