Using non-participant observation to uncover mechanisms: insights from a realist evaluation

This article outlines how a realist evaluation of dementia care in hospitals used non-participant observation to support the refinement and testing of mechanisms likely to lead to the use of person-centred care. We found that comments and explanations of their actions from hospital staff during observation periods provided insights into the reasoning that generated their actions for care in real time. This informed subsequent data collection and analysis. Two worked examples of mechanisms first identified during non-participant observation demonstrate (1) how they were uncovered, and (2) how this informed research activities for theory refinement. Early, iterative engagement with the analytic process, primarily involving reflection and debate with the research team, maximised the potential of observation data to support surfacing underlying mechanisms, linking them to specific contexts and outcomes.Peer reviewedFinal Accepted Versio

Efficacy of Omaveloxolone in Friedreich's Ataxia: Delayed-Start Analysis of the MOXIe Extension

BACKGROUND: MOXIe was a two-part study evaluating the safety and efficacy of omaveloxolone in patients with Friedreich's ataxia, a rare, progressive neurological disease with no proven therapy. MOXIe part 2, a randomized double-blind placebo-controlled trial, showed omaveloxolone significantly improved modified Friedreich's Ataxia Rating Scale (mFARS) scores relative to placebo. Patients who completed part 1 or 2 were eligible to receive omaveloxolone in an open-label extension study. OBJECTIVE: The delayed-start study compared mFARS scores at the end of MOXIe part 2 with those at 72 weeks in the open-label extension period (up to 144 weeks) for patients initially randomized to omaveloxolone versus those initially randomized to placebo. METHODS: We performed a noninferiority test to compare the difference between treatment groups (placebo to omaveloxolone versus omaveloxolone to omaveloxolone) using a single mixed model repeated measures (MMRM) model. In addition, slopes of the change in mFARS scores were compared between both groups in the open-label extension. RESULTS: The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (-2.17 ± 1.09 points) was preserved after 72 weeks in the extension (-2.91 ± 1.44 points). In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks. CONCLUSIONS: These results support the positive results of MOXIe part 2 and indicate a persistent benefit of omaveloxolone treatment on disease course in Friedreich's ataxia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Transport of Explosive Residue Surrogates in Saturated Porous Media

Department of Defense operational ranges may become contaminated by particles of explosives residues (ER) as a result of low-order detonations of munitions. The goal of this study was to determine the extent to which particles of ER could migrate through columns of sandy sediment, representing model aquifer materials. Transport experiments were conducted in saturated columns (2 × 20 cm) packed with different grain sizes of clean sand or glass beads. Fine particles (approximately 2 to 50 μm) of 2,6-dinitrotoluene (DNT) were used as a surrogate for ER. DNT particles were applied to the top 1 cm of sand or beads in the columns, and the columns were subsequently leached with artificial groundwater solutions. DNT migration occurred as both dissolved and particulate phases. Concentration differences between unfiltered and filtered samples indicate that particulate DNT accounted for up to 41% of the mass recovered in effluent samples. Proportionally, more particulate than dissolved DNT was recovered in effluent solutions from columns with larger grain sizes, while total concentrations of DNT in effluent were inversely related to grain size. Of the total DNT mass applied to the uppermost layer of the column, <3% was recovered in the effluent with the bulk remaining in the top 2 cm of the column. Our results suggest there is some potential for subsurface migration of ER particles and that most of the particles will be retained over relatively short transport distances

State versus Trait: Validating State Assessment of Child and Parental Catastrophic Thinking about Child Pain

Pain catastrophizing has emerged as one of the most robust predictors of child pain outcomes. Although assessments of state (i.e., situation-specific) pain catastrophizing in children and parents are often used, their psychometric properties are unknown. This study aimed to assess factor structure, reliability and predictive validity of state versions of Pain Catastrophizing Scales for children (PCS-C State) and parents (PCS-P State) relative to corresponding trait versions for child and parental pain-related outcomes. Data were pooled from 8 experimental pain studies wherein child and/or parent state catastrophizing (measured immediately before application of a pain stimulus) and trait catastrophizing were assessed in community-based samples of children aged 8&ndash;18 years (N=689) and their parents (N=888) in Dutch or English. Exploratory factor analyses were conducted to examine the underlying factor structure of the PCS-P/PCS-C State, revealing a single factor solution that explained 55.53% of the variance for children and 49.72% for parents. Hierarchical linear regression analyses were used to examine relative influence of state versus trait catastrophizing on child and parent pain-related outcomes. Child and parent state catastrophizing were significantly associated with child pain intensity, child state anxiety and parental distress. State catastrophizing scores showed stronger associations than trait scores for most outcomes

Patterns of local and nonlocal water resource use across the western U.S. determined via stable isotope intercomparisons

In the western U.S., the mismatch between public water demands and natural water availability necessitates large interbasin transfers of water as well as groundwater mining of fossil aquifers. Here we identify probable situations of nonlocal water use in both space and time based on isotopic comparisons between tap waters and potential water resources within hydrologic basins. Our approach, which considers evaporative enrichment of heavy isotopes during storage and distribution, is used to determine the likelihood of local origin for 612 tap water samples collected from across the western U.S. We find that 64% of samples are isotopically distinct from precipitation falling within the local hydrologic basin, a proxy for groundwater with modern recharge, and 31% of samples are isotopically distinct from estimated surface water found within the local basin. Those samples inconsistent with local water sources, which we suggest are likely derived from water imported from other basins or extracted from fossil aquifers, are primarily clustered in southern California, the San Francisco Bay area, and central Arizona. Our isotope-based estimates of nonlocal water use are correlated with both hydrogeomorphic and socioeconomic properties of basins, suggesting that these factors exert a predictable influence on the likelihood that nonlocal waters are used to supply tap water. We use these basin properties to develop a regional model of nonlocal water resource use that predicts (r2 = 0.64) isotopically inferred patterns and allows assessment of total interbasin transfer and/or fossil aquifer extraction volumes across the western U.S.Fil: Good, Stephen P.. University of Utah; Estados UnidosFil: Kennedy, Casey D.. United States Department Of Agriculture. Agriculture Research Service; Estados UnidosFil: Stalker Jeremy C.. Jacksonville University; Estados UnidosFil: Chesson, Lesley A.. IsoForensics; Estados UnidosFil: Valenzuela, Luciano Oscar. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Sociales. Departamento de Arqueología. Laboratorio de Ecología Evolutiva Humana (Sede Quequén); Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Utah; Estados UnidosFil: Beasley, Melanie M.. University of California at San Diego; Estados UnidosFil: Ehleringer, James R. University of Utah; Estados UnidosFil: Bowen, Gabriel J.. University of Utah; Estados Unido

Serendipitous discovery of a dying Giant Radio Galaxy associated with NGC 1534, using the Murchison Widefield Array

This article has been accepted for publication in Monthly Notices of the Royal Astronomical Society. © 2015 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society.Recent observations with the Murchison Widefield Array at 185~MHz have serendipitously unveiled a heretofore unknown giant and relatively nearby ($z = 0.0178$) radio galaxy associated with NGC\,1534. The diffuse emission presented here is the first indication that NGC\,1534 is one of a rare class of objects (along with NGC\,5128 and NGC\,612) in which a galaxy with a prominent dust lane hosts radio emission on scales of $\sim$700\,kpc. We present details of the radio emission along with a detailed comparison with other radio galaxies with disks. NGC1534 is the lowest surface brightness radio galaxy known with an estimated scaled 1.4-GHz surface brightness of just 0.2\,mJy\,arcmin$^{-2}$. The radio lobes have one of the steepest spectral indices yet observed: $\alpha=-2.1\pm0.1$, and the core to lobe luminosity ratio is $Peer reviewe

Echinocandin Treatment of Pneumocystis Pneumonia in Rodent Models Depletes Cysts Leaving Trophic Burdens That Cannot Transmit the Infection

Fungi in the genus Pneumocystis cause pneumonia (PCP) in hosts with debilitated immune systems and are emerging as co-morbidity factors associated with chronic diseases such as COPD. Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung. Within the alveolar lumen, Pneumocystis spp., appear to have a bi-phasic life cycle consisting of an asexual phase characterized by binary fission of trophic forms and a sexual cycle resulting in formation of cysts, but the life cycle stage that transmits the infection is not known. The cysts, but not the trophic forms, express β -1,3-D-glucan synthetase and contain abundant β -1,3-D-glucan. Here we show that therapeutic and prophylactic treatment of PCP with echinocandins, compounds which inhibit the synthesis of β -1,3-D-glucan, depleted cysts in rodent models of PCP, while sparing the trophic forms which remained in significant numbers. Survival was enhanced in the echincandin treated mice, likely due to the decreased β -1,3-D-glucan content in the lungs of treated mice and rats which coincided with reductions of cyst numbers, and dramatic remodeling of organism morphology. Strong evidence for the cyst as the agent of transmission was provided by the failure of anidulafungin-treated mice to transmit the infection. We show for the first time that withdrawal of anidulafungin treatment with continued immunosuppression permitted the repopulation of cyst forms. Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse. Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens

Study of redshifted H I from the epoch of reionization with drift scan

The detection of the Epoch of Reionization (EoR) in the redshifted 21-cm line is a challenging task. Here we formulate the detection of the EoR signal using the drift scan strategy. This method potentially has better instrumental stability as compared to the case where a single patch of sky is tracked. We demonstrate that the correlation time between measured visibilities could extend up to 1-2 hr for an interferometer array such as the Murchison Widefield Array (MWA), which has a wide primary beam. We estimate the EoR power based on cross-correlation of visibilities across time and show that the drift scan strategy is capable of the detection of the EoR signal with comparable/better signal-to-noise as compared to the tracking case. We also estimate the visibility correlation for a set of bright point sources and argue that the statistical inhomogeneity of bright point sources might allow their separation from the EoR signal

The impact of physical activity on fatigue and quality of life in lung cancer patients: a randomised controlled trial protocol

Background: People with lung cancer have substantial symptom burden and more unmet needs than the general cancer population. Physical activity (PA) has been shown to positively influence quality of life (QOL), fatigue and daily functioning in the curative treatment of people with breast and colorectal cancers and lung diseases, as well as in palliative settings. A randomised controlled trial (RCT) is needed to determine if lung cancer patients benefit from structured PA intervention. The Physical Activity in Lung Cancer (PAL) trial is designed to evaluate the impact of a 2-month PA intervention on fatigue and QOL in patients with non-resectable lung cancer. Biological mechanisms will also be studied.Methods/design: A multi-centre RCT with patients randomised to usual care or a 2-month PA programme, involving supervised PA sessions including a behavioural change component and home-based PA. QOL questionnaires, disease and functional status and body composition will be assessed at baseline, 2, 4 and 6 months follow-up. The primary endpoint is comparative levels of fatigue between the 2 arms. Secondary endpoints include: QOL, functional abilities and physical function. Exploratory endpoints include: anxiety, depression, distress, dyspnoea, PA behaviour, fitness, hospitalisations, survival, cytokines and insulin-like growth factor levels.Discussion: This study will provide high-level evidence of the effect of PA programmes on cancer-related fatigue and QOL in patients with advanced lung cancer. If positive, the study has the potential to change care for people with cancer using a simple, inexpensive intervention to improve their QOL and help them maintain independent function for as long as possible.Trial registration: Australian New Zealand Clinical Trials Registry No. ACTRN12609000971235. © 2012 Dhillon et al.; licensee BioMed Central Ltd

Somatic Mutation Profiles of MSI and MSS Colorectal Cancer Identified by Whole Exome Next Generation Sequencing and Bioinformatics Analysis

BACKGROUND: Colorectal cancer (CRC) is with approximately 1 million cases the third most common cancer worldwide. Extensive research is ongoing to decipher the underlying genetic patterns with the hope to improve early cancer diagnosis and treatment. In this direction, the recent progress in next generation sequencing technologies has revolutionized the field of cancer genomics. However, one caveat of these studies remains the large amount of genetic variations identified and their interpretation. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the first work on whole exome NGS of primary colon cancers. We performed 454 whole exome pyrosequencing of tumor as well as adjacent not affected normal colonic tissue from microsatellite stable (MSS) and microsatellite instable (MSI) colon cancer patients and identified more than 50,000 small nucleotide variations for each tissue. According to predictions based on MSS and MSI pathomechanisms we identified eight times more somatic non-synonymous variations in MSI cancers than in MSS and we were able to reproduce the result in four additional CRCs. Our bioinformatics filtering approach narrowed down the rate of most significant mutations to 359 for MSI and 45 for MSS CRCs with predicted altered protein functions. In both CRCs, MSI and MSS, we found somatic mutations in the intracellular kinase domain of bone morphogenetic protein receptor 1A, BMPR1A, a gene where so far germline mutations are associated with juvenile polyposis syndrome, and show that the mutations functionally impair the protein function. CONCLUSIONS/SIGNIFICANCE: We conclude that with deep sequencing of tumor exomes one may be able to predict the microsatellite status of CRC and in addition identify potentially clinically relevant mutations