Psychometric validation of the Pyruvate Kinase Deficiency Diary and Pyruvate Kinase Deficiency Impact Assessment in adults in the phase 3 ACTIVATE trial

© 2023 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Background: Pyruvate kinase (PK) deficiency is a rare hereditary disorder characterized by chronic hemolytic anemia and serious sequalae which negatively affect patient quality of life. This study aimed to psychometrically validate the first disease-specific patient-reported outcome (PRO) instruments: the 7-item PK Deficiency Diary (PKDD) and 12-item PK Deficiency Impact Assessment (PKDIA), designed to assess signs, symptoms, and impacts of PK deficiency in patients enrolled in the ACTIVATE global phase 3 study of mitapivat versus placebo (NCT03548220). Methods: All validation analyses for the PKDD and PKDIA were performed on blinded data, with analyses on item integrity, scoring, reliability, and validity conducted on data from screening and baseline. Completion rates and baseline response distributions were characterized using descriptive statistics. Item response modelling was used to inform a weighted scoring system. Reliability was assessed by internal consistency and test–retest reliability; and validity by convergent and known-groups analyses. Results: Of the 80 adults enrolled, baseline data were available for 77 (96.3%) and 78 (97.5%) patients for the PKDD and PKDIA, respectively. Item responses skewed right, indicating that mean values exceeded median values, especially for items utilizing a 0–10 numeric scale, which were subsequently recoded to a 0–4 scale; 4 items were removed from the PKDIA due to redundancy or low relevance to the trial population. Both the PKDD and PKDIA demonstrated high internal consistency (McDonald’s coefficient ω = 0.86 and 0.90, respectively), test–retest reliability (intra-class coefficients of 0.94 and 0.87, respectively), and convergent validity with other PROs (linear correlation coefficients [|r|] between 0.30–0.73 and 0.50–0.82, respectively). Conclusions: The findings provide evidence of validity and reliability for the PKDD and PKDIA, the first disease-specific PRO measures for PK deficiency, and can therefore increase understanding of, and more accurately capture, the wider impact of PK deficiency on health-related quality of life. Trial registration ClinicalTrials.gov, NCT03548220. Registered June 07, 2018; https://www.clinicaltrials.gov/ct2/show/NCT03548220.Peer reviewe

Radiological-pathological correlation of pleomorphic liposarcoma of the anterior mediastinum in a 17-year-old girl

Liposarcoma is a soft-tissue sarcoma typically seen in adults. It is extremely rare in children. It most often occurs in the extremities or in the retroperitoneum. We present a very rare case of an anterior mediastinal liposarcoma of the pleomorphic subtype in a 17-year-old girl, along with radiological and pathological correlation. The location, patient age and histological subtype are exceedingly uncommon for this tumor

Universal features of correlated bursty behaviour

Inhomogeneous temporal processes, like those appearing in human communications, neuron spike trains, and seismic signals, consist of high-activity bursty intervals alternating with long low-activity periods. In recent studies such bursty behavior has been characterized by a fat-tailed inter-event time distribution, while temporal correlations were measured by the autocorrelation function. However, these characteristic functions are not capable to fully characterize temporally correlated heterogenous behavior. Here we show that the distribution of the number of events in a bursty period serves as a good indicator of the dependencies, leading to the universal observation of power-law distribution in a broad class of phenomena. We find that the correlations in these quite different systems can be commonly interpreted by memory effects and described by a simple phenomenological model, which displays temporal behavior qualitatively similar to that in real systems

Quantitative Changes in Hydrocarbons over Time in Fecal Pellets of Incisitermes minor May Predict Whether Colonies Are Alive or Dead

Hydrocarbon mixtures extracted from fecal pellets of drywood termites are species-specific and can be characterized to identify the termites responsible for damage, even when termites are no longer present or are unable to be recovered easily. In structures infested by drywood termites, it is common to find fecal pellets, but difficult to sample termites from the wood. When fecal pellets appear after remedial treatment of a structure, it is difficult to determine whether this indicates that termites in the structure are still alive and active or not. We examined the hydrocarbon composition of workers, alates, and soldiers of Incisitermes minor (Hagen) (family Kalotermitidae) and of fecal pellets of workers. Hydrocarbons were qualitatively similar among castes and pellets. Fecal pellets that were aged for periods of 0, 30, 90, and 365 days after collection were qualitatively similar across all time periods, however, the relative quantities of certain individual hydrocarbons changed over time, with 19 of the 73 hydrocarbon peaks relatively increasing or decreasing. When the sums of the positive and negative slopes of these 19 hydrocarbons were indexed, they produced a highly significant linear correlation (R2 = 0.89). Consequently, the quantitative differences of these hydrocarbons peaks can be used to determine the age of worker fecal pellets, and thus help determine whether the colony that produced them is alive or dead

Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Zoonotic disease research in East Africa

Abstract Background The East African region is endemic with multiple zoonotic diseases and is one of the hotspots for emerging infectious zoonotic diseases with reported multiple outbreaks of epidemic diseases such as Ebola, Marburg and Rift Valley Fever. Here we present a systematic assessment of published research on zoonotic diseases in the region and thesis research in Kenya to understand the regional research focus and trends in publications, and estimate proportion of theses research transitioning to peer-reviewed journal publications. Methods We searched PubMed, Google Scholar and African Journals Online databases for publications on 36 zoonotic diseases identified to have occurred in the East Africa countries of Burundi, Ethiopia, Kenya, Tanzania, Rwanda and Uganda, for the period between 1920 and 2017. We searched libraries and queried online repositories for masters and PhD theses on these diseases produced between 1970 and 2016 in five universities and two research institutions in Kenya. Results We identified 771 journal articles on 22, and 168 theses on 21 of the 36 zoonotic diseases investigated. Research on zoonotic diseases increased exponentially with the last 10 years of our study period contributing more than half of all publications 460 (60%) and theses 102 (61%) retrieved. Endemic diseases were the most studied accounting for 656 (85%) and 150 (89%) of the publication and theses studies respectively, with publications on epidemic diseases associated with outbreaks reported in the region or elsewhere. Epidemiological studies were the most common study types but limited to cross-sectional studies while socio-economics were the least studied. Only 11% of the theses research transitioned to peer-review publications, taking an average of 2.5 years from theses production to manuscript publication. Conclusion Our findings demonstrate increased attention to zoonotic diseases in East Africa but reveal the need to expand the scope, focus and quality of studies to adequately address the public health, social and economic threats posed by zoonoses

Geo‐Hydromorphological Assessment of Europe’s Southernmost Blanket Bogs

Blanket bogs are a globally rare type of ombrotrophic peatland internationally recognised for long‐term terrestrial carbon storage, the potential to serve as carbon sinks, habitat provision and for their palaeoenvironmental archive. This habitat is protected in the European Union under the Habitats Directive (92/43/EEC), but a number of blanket bogs located in the Cantabrian Mountains (northern Spain), representing the southernmost known edge‐of‐range for this habitat in Europe, are currently not recognised and are at increased threat of loss. Using climatic data, topography, aerial photography and peat depth surveys, this study has identified ten new areas of blanket bog located between the administrative regions of Cantabria and Castilla y León. Peat depth data and topography were used to provide a detailed geomorphological description and hydromorphological classification (mesotope units) of these currently unrecognised areas of blanket bog. Maximum peat depth measured across the ten sites ranged from 1.61 m to 3.78 m covering a total area of 18.6 ha of blanket bog (> 40 cm peat depth). The volume of peat accumulated across the sites was determined to be more than 216,000 m3 and is estimated to hold 19.89 ± 3.51kt C. Twenty‐four individual hydrological mesotope units were described indicating a diverse assemblage of blanket bogs in this region. The peatlands identified in this research extend the known limit of blanket bogs in Europe farther south than previously recorded and combined with four other unprotected blanket bogs recently identified in the Cantabrian Mountains, these peatlands represent 10.5% of blanket bog currently recognised and protected in Spain. The range of anthropogenic pressures currently acting on peatlands in the Cantabrian Mountains indicates that without protection these important landforms and carbon stored may be lost. An urgent update of European peatland inventories is thus required to preserve these valuable carbon stores and potential carbon sinks

Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer

<p>Abstract</p> <p>Background</p> <p>Ovarian cancer (OvCa) most often derives from ovarian surface epithelial (OSE) cells. Several lines of evidence strongly suggest that increased exposure to progesterone (P4) protects women against developing OvCa. However, the underlying mechanisms of this protection are incompletely understood.</p> <p>Methods</p> <p>To determine downstream gene targets of P4, we established short term <it>in vitro </it>cultures of non-neoplastic OSE cells from six subjects, exposed the cells to P4 (10^-6M) for five days and performed transcriptional profiling with oligonucleotide microarrays containing over 22,000 transcripts.</p> <p>Results</p> <p>We identified concordant but modest gene expression changes in cholesterol/lipid homeostasis genes in three of six samples (responders), whereas the other three samples (non-responders) showed no expressional response to P4. The most up-regulated gene was <it>TMEM97 </it>which encodes a transmembrane protein of unknown function (MAC30). Analyses of outlier transcripts, whose expression levels changed most significantly upon P4 exposure, uncovered coordinate up-regulation of 14 cholesterol biosynthesis enzymes, insulin-induced gene 1, low density lipoprotein receptor, <it>ABCG1</it>, endothelial lipase, stearoyl- CoA and fatty acid desaturases, long-chain fatty-acyl elongase, and down-regulation of steroidogenic acute regulatory protein and <it>ABCC6</it>. Highly correlated tissue-specific expression patterns of <it>TMEM97 </it>and the cholesterol biosynthesis genes were confirmed by analysis of the GNF Atlas 2 universal gene expression database. Real-time quantitative RT-PCR analyses revealed 2.4-fold suppression of the <it>TMEM97 </it>gene expression in short-term cultures of OvCa relative to the normal OSE cells.</p> <p>Conclusion</p> <p>These findings suggest that a co-regulated transcript network of cholesterol/lipid homeostasis genes and <it>TMEM97 </it>are downstream targets of P4 in normal OSE cells and that <it>TMEM97 </it>plays a role in cholesterol and lipid metabolism. The P4-induced alterations in cholesterol and lipid metabolism in OSE cells might play a role in conferring protection against OvCa.</p