bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune‐related adverse events in cancer patients being treated with immune checkpoint inhibitors
Authors: Byrne Margaret M. , Lucas Mathew , Pai Lori , Breeze Janis , Parsons Susan K. 
Published: August 2021

AbstractIntroductionWith the increased use of immune checkpoint inhibitors (ICI), it is essential to improve our understanding of immune‐related adverse events (irAE). To date, most studies describing irAE have been performed in clinical trial populations, which may not be an accurate description of irAE in real‐world populations. Also, identification of patients at increased risk of irAE is needed as early recognition may improve irAE outcomes.MethodsWe performed a retrospective analysis of patients who received an ICI between January 2014 and October 2018 at a single institution (Tufts Medical Center). Each patient was followed for up to 12 months for the outcome of a physician‐reported irAE. Kaplan‐Meier curves were created for the time to development and resolution of initial irAE. A Cox proportional hazards model was created to evaluate whether the following variables were independent predictors of an initial irAE: age ≥65 years, female sex, non‐Caucasian race, radiation in previous 6 months, current smoking status, melanoma, and combination ICI (ipilimumab and nivolumab).ResultsOf 131 patients followed, 57 patients (43.5%) developed at least one irAE at a median of 250 days (95% confidence interval (CI) 132 days‐not estimable). The most common irAE included dermatitis, thyroid dysfunction, and pneumonitis. Nearly two‐thirds of patients with an irAE had ICI therapy withdrawn, and nearly 60% had immunosuppression initiated. In multivariable analysis, we found a significant association between irAE development and age ≥65 years hazard ratio (HR) 1.80, 95% CI (1.03‐3.14) and current smoking status (HR 2.26, 95% CI 1.06‐4.82).DiscussionWe detected a high rate of irAE and that irAE and subsequent management can be clinically burdensome in this patient population. While further studies are needed to validate these findings, this study provides insights into the magnitude, time course, management of, and possible predictors of irAE in a real‐world setting.
Aberrant hippocampal mossy fibers in temporal lobe epilepsy target excitatory and inhibitory neurons
Authors: Puhahn‐Schmeiser Barbara , Leicht Kathrin , Gessler Florian , Freiman Thomas M. 
Published: August 2021

SummaryObjectiveThe pathoanatomical correlate of temporal lobe epilepsy is hippocampal sclerosis, characterized by selective neuronal death of mossy cells in the hilus and of pyramidal cells in cornu ammonis 1. Although granule cells survive, they lose mossy cells as a target and redirect their axons (mossy fibers) backward into the molecular cell layer. It has been assumed that this process results in excitatory circuits. We therefore examined whether sprouted mossy fibers form synaptic connection not only with excitatory granule cells but also with inhibitory interneurons, such as basket cells.MethodsResected hippocampal specimens of patients with hippocampal sclerosis were compared to controls of patients with extrahippocampal lesions with only mild sclerosis. Mossy fibers were traced with Neurobiotin or labeled against synaptoporin; inhibitory interneurons were labeled against parvalbumin. Synapses were examined with electron microscopy, labeled with γ‐aminobutyric acid immunogold.ResultsSprouted mossy fibers of epileptic hippocampi innervate not only excitatory granule cells but also inhibitory parvalbuminergic interneurons. Despite neuronal death in hippocampal sclerosis, the axonal plexus of inhibitory parvalbuminergic interneurons surrounding the granule cells is preserved. Connections of sprouted mossy fibers and inhibitory axon terminals were quantified, showing that the number of inhibitory axon terminals significantly exceeds the number of sprouted excitatory mossy fiber terminals (.03 boutons/µm vs. .11 boutons/µm; p < .001).SignificanceAlthough no definite conclusions regarding the function of our findings may be derived from this anatomical study, the observed aberrant connectivity might lead to an increased inhibition and synchronization of granule cells, because the preserved inhibitory interneurons show an additional innervation through sprouted mossy fibers. This might result in the instability of a previously balanced network.
Vitamin D3 potentiates the nephroprotective effects of vildagliptin–metformin combination in a rat model of metabolic syndrome
Authors: Wahba Nehal S. , Abdel‐Ghany Rasha H. , Ghareib Salah A. , Abdel‐Aal Mohamed , Alsemeh Amira E. , Sabry Dina 
Published: August 2021

AbstractThe current study was conducted to investigate the nephroprotective effects of vildagliptin–metformin combination in an experimental model of fructose/salt‐induced metabolic syndrome (MetS). A major aim was to evaluate the potential capacity of vitamin D3 to potentiate the pleiotropic nephroprotective effects of vildagliptin–metformin combination. MetS was induced in adult male Wistar rats by adding fructose (10%) to everyday drinking water and salt (3%) to the diet for 6 weeks. Along with the same concentrations of fructose/salt feeding, MetS rats were then treated orally with either vildagliptin (10 mg/kg/day)–metformin (200 mg/kg/day) combination, vitamin D3 (10 μg/kg/day), or the triple therapy for a further 6 weeks. The incidence of MetS was confirmed 6 weeks after fructose/salt consumption, when the rats exhibited significant weight gain, dyslipidemia, hyperuricemia, insulin resistance, hyperinsulinemia, and impaired glucose tolerance. At the end of the 12‐week experimental period, MetS rats displayed significantly deteriorated renal function, enhanced intrarenal oxidative stress and inflammation together with exaggerated renal histopathological damages and interstitial fibrosis. The study has corroborated antioxidant, anti‐inflammatory, and antifibrotic effects of vildagliptin–metformin combination, vitamin D3, and the triple collaborative therapy, conferring renoprotection in the setting of MetS. Due attention has been paid to the crucial role of dipeptidyl peptidase‐4 inhibition and sirtuin‐1/5′ adenosine monophosphate‐activated protein kinase activation as novel therapeutic targets to optimize renoprotection. The apparent potentiating effect, evoked upon coadministration of vitamin D3 with vildagliptin–metformin combination, may provide a cornerstone for further clinical investigations.
Temperature and spatial connectivity drive patterns in freshwater macroinvertebrate diversity across the Arctic
Authors: Lento Jennifer , Culp Joseph M. , Levenstein Brianna , Aroviita Jukka , Baturina Maria A. , Bogan Daniel , Brittain John E. , Chin Krista , Christoffersen Kirsten S. , Docherty Catherine , Friberg Nikolai , Ingimarsson Finnur , Jacobsen Dean , Lau Danny Chun Pong , Loskutova Olga A. , Milner Alexander , Mykrä Heikki , Novichkova Anna A. , Ólafsson Jón S. , Schartau Ann Kristin , Shaftel Rebecca , Goedkoop Willem 
Published: August 2021

AbstractWarming in the Arctic is predicted to change freshwater biodiversity through loss of unique taxa and northward range expansion of lower latitude taxa. Detecting such changes requires establishing circumpolar baselines for diversity, and understanding the primary drivers of diversity.We examined benthic macroinvertebrate diversity using a circumpolar dataset of >1,500 Arctic lake and river sites. Rarefied α diversity within catchments was assessed along latitude and temperature gradients. Community composition was assessed through region‐scale analysis of β diversity and its components (nestedness and turnover), and analysis of biotic–abiotic relationships.Rarefied α diversity of lakes and rivers declined with increasing latitude, although more strongly across mainland regions than islands. Diversity was strongly related to air temperature, with the lowest diversity in the coldest catchments. Regional dissimilarity was highest when mainland regions were compared with islands, suggesting that connectivity limitations led to the strongest dissimilarity. High contributions of nestedness indicated that island regions contained a subset of the taxa found in mainland regions.High Arctic rivers and lakes were predominately occupied by Chironomidae and Oligochaeta, whereas Ephemeroptera, Plecoptera, and Trichoptera taxa were more abundant at lower latitudes. Community composition was strongly associated with temperature, although geology and precipitation were also important correlates.The strong association with temperature supports the prediction that warming will increase Arctic macroinvertebrate diversity, although low diversity on islands suggests that this increase will be limited by biogeographical constraints. Long‐term harmonised monitoring across the circumpolar region is necessary to detect such changes to diversity and inform science‐based management.
Stimulation of N2O emission via bacterial denitrification driven by acidification in estuarine sediments
Authors: Su Xiaoxuan , Wen Teng , Wang Yingmu , Xu Junshi , Cui Li , Zhang Jinbo , Xue Ximei , Ding Kai , Tang Yijia , Zhu Yong‐guan 
Published: August 2021

AbstractOcean acidification in nitrogen‐enriched estuaries has raised global concerns. For decades, biotic and abiotic denitrification in estuarine sediments has been regarded as the major ways to remove reactive nitrogen, but they occur at the expense of releasing greenhouse gas nitrous oxide (N2O). However, how these pathways respond to acidification remains poorly understood. Here we performed a N2O isotopocules analysis coupled with respiration inhibition and molecular approaches to investigate the impacts of acidification on bacterial, fungal, and chemo‐denitrification, as well as N2O emission, in estuarine sediments through a series of anoxic incubations. Results showed that acidification stimulated N2O release from sediments, which was mainly mediated by the activity of bacterial denitrifiers, whereas in neutral environments, N2O production was dominated by fungi. We also found that the contribution of chemo‐denitrification to N2O production cannot be ignored, but was not significantly affected by acidification. The mechanistic investigation further demonstrated that acidification changed the keystone taxa of sedimentary denitrifiers from N2O‐reducing to N2O‐producing ones and reduced microbial electron‐transfer efficiency during denitrification. These findings provide novel insights into how acidification stimulates N2O emission and modulates its pathways in estuarine sediments, and how it may contribute to the acceleration of global climate change in the Anthropocene.
The Economic Network Resilience of the Guanzhong Plain City Cluster, China: A network analysis from the evolutionary perspective
Authors: Ye Shanshan , Qian Zhu 
Published: August 2021

AbstractThis article applies the network analysis to evaluate the resilience of economic network in Guanzhong Plain City Cluster (GPCC) and examine the impact of network structural properties on economic resilience, thus providing an innovative research perspective and a theoretical framework for evaluating the economic resilience of the city cluster. A modified gravity model is introduced to construct the economic network. Three structural properties of the network, hierarchy, assortativity, and cohesion, are used to evaluate the resilience of the GPCC from 2008 to 2018 and illustrate the characteristics of the resilience. The results show that the economic network of the GPCC is strongly hierarchical with a growing trend, a declining disassortativity, and a weak cohesion. Although the network has formed a core‐peripheral structure, its hierarchy and disassortativity would result in low resilience and high vulnerability, at the risk of external shocks to the GPCC. The impact of the network structure on economic resilience is analyzed by using a regression model, which verifies the validity of applying the network theory to resilience analysis. The results suggest that improving the interactions and economic connections between core and peripheral cities will strengthen the resilience of the GPCC.
Diagnosis of von Willebrand disease: An assessment of the quality of testing in North American laboratories
Authors: Abdulrehman Jameel , Ziemba Yonah C. , Hsu Peihong , Van Cott Elizabeth M. , Plumhoff Elizabeth A. , Meijer Piet , Hollestelle Martine J. , Selby Rita 
Published: August 2021

AbstractBackgroundLaboratory diagnosis of von Willebrand Disease (VWD) is complex. Reliance on laboratory testing can be problematic as different VWD screening panels, assays and methodologies can produce analytic variability in test results.ObjectivesTo compare the degree of imprecision among the VWD assays and within the platelet binding activity (PBA) assays, to determine the consensus among the VWD assays for correct classification of sample results, and to determine consensus among laboratories’ von Willebrand factor (VWF) multimer interpretations and final interpretations of the VWD panels.Patients/MethodsProficiency testing results from the North American Specialized Coagulation Laboratory Association (NASCOLA) submitted by laboratories from 2010 to 2019 for all normal, type (T) 1 VWD and T2 VWD samples were analysed.Results and ConclusionsImprecision was lowest for VWF antigen and highest for collagen binding activity (CBA) with median coefficient of variation (CV) of 12% (interquartile range (IQR) 7%) and 23% (IQR 21%) respectively. Within the VWF PBA assays, the gain‐of‐function mutant GP1b binding (VWF: GP1bM) methods had the least imprecision (CV 9%, IQR 10%). All assays, including the various PBA methods had excellent consensus. The majority of laboratories agreed that normal (median consensus‐82%, IQR 16%) and T1 VWD (median consensus‐100%, IQR 9%) samples had normal multimer distribution. Consensus among laboratories for final interpretations was excellent for normal samples (median 81%, IQR 8%), good for T1 VWD samples (median 59%, IQR 9%), and fair for T2 VWD samples (median 44%, IQR 21%). Consensus on final interpretation decreased as sample complexity increased.
Assessment of proliferation in breast cancer: cell cycle or mitosis? An observational study
Authors: Lashen Ayat G , Toss Michael S , Katayama Ayaka , Gogna Rajan , Mongan Nigel P , Rakha Emad A 
Published: August 2021

Background and aimsProliferation is an important indicator of breast cancer (BC) prognosis, but is assessed using different approaches. Not all cells in the cell cycle are committed to division. This study aimed to characterise quantitative differences between BC cells in the cell cycle and those in mitosis and assess their relationship with other pathological parameters.Methods and resultsA cohort of BC sections (n = 621) was stained with haematoxylin and eosin and immunohistochemistry for Ki‐67. The proportion of mitotic cells and Ki‐67‐positive cells was assessed in the same areas. The Cancer Genome Atlas (TCGA) BC cohort was used to assess MKI‐67 transcriptome level and its association with the mitotic counts. The mean proportion of BC cells in the cell cycle was 24% (range = 1–90%), while the mean proportion of BC cells in mitosis was 5% (range = 0–73%). A low proportion of mitoses to whole cycling cells was associated with low histological grade tumours and the luminal A molecular subtype, while tumours with a high proportion of mitoses to the overall cycling cells were associated with triple‐negative subtype, larger tumour size, grade 3 tumours and lymph node metastasis. The high mitosis/low Ki‐67‐positive cells tumours showed a significant association with variables of poor prognosis, including high‐grade and triple‐negative subtypes.ConclusionThe proportion of BC cells in the cell cycle and mitosis is variable. We show that not only the number of cells in the cell cycle or mitosis, but also the difference between them, provides valuable information on tumour aggressiveness.
Visual assessment of mitotic figures in breast cancer: a comparative study between light microscopy and whole slide images
Authors: Lashen Ayat , Ibrahim Asmaa , Katayama Ayaka , Ball Graham , Mihai Raluca , Toss Michael , Rakha Emad 
Published: August 2021

Background and aimsVisual assessment of mitotic figures in breast cancer (BC) remains a challenge. This is expected to be more pronounced in the digital pathology era. This study aims to refine the criteria of mitotic figure recognition, particularly in whole slide images (WSI).Method and resultsHaematoxylin and eosin (H&E)‐stained BC sections (n = 506) were examined using light microscopy (LM) and WSI. A set of features for identifying mitosis in WSI and to distinguish true figures from mimickers was developed. Changes in the mitotic count between the two platforms was explored. Morphological features of mitoses were recorded separately, including absence of nuclear membrane, chromatin hairy‐like projections, shape, cytoplasmic features, mitotic cell size and relationship to surrounding cells. Each mitotic phase has its own mimickers. Fifty‐eight per cent of mitoses showed absent hairy‐like projection in WSI; however, 89% retained their ragged nuclear border, which distinguished them from mimickers including apoptotic cells, lymphocytes and dark elongated hyperchromatic structures. Mitosis in WSI showed loss of fine details, and there was a 20% average reduction rate of mitotic counts when compared to the same area on LM. Using refined mitosis recognition criteria in WSI resulted in a twofold improvement of interobserver concordance. However, when compared to LM, 19% of cases were underscored in WSIs.ConclusionsAll morphological features of mitosis should be considered to enable recognition and differentiation from their mimickers, particularly in WSI, to ensure reliable BC grading. Refining mitotic cut‐offs per specific area when using WSI, based on the degree of reduction and association with outcome, is warranted.
Rapid triage performed by nurses: Signs and symptoms associated with identifying critically ill patients in the emergency department
Authors: Moura Bruna Roberta Siqueira , Oliveira Gabriella Novelli , Medeiros Giuliana , Vieira Alexandre de Souza , Nogueira Lilia de Souza 
Published: August 2021

AbstractAimAim of this study is to identify signs and symptoms associated with identifying critically ill patients by rapid triage assessment performed by nurses in an emergency department.BackgroundIn some emergency services, the immediate assessment of critically ill patients occurs before opening the hospital formal registration and it is based on the nurse's experience. Studies on the topic are essential to improve this process.DesignThis is a cross‐sectional, quantitative study.MethodsThis study was conducted in a Brazilian emergency department in 2017. Adult patients who presented potentially life‐threatening symptoms underwent rapid triage to determine the medical urgency. Those identified as being critically ill were classified as high priority and streamed to the emergency room.ResultsA total of 154 (84.6%) patients were classified as high priority from the total of 182 evaluations. Altered state of consciousness (35.2%) and altered skin perfusion (25.3%) were frequently identified. Signs and symptoms associated with identifying critically ill patients by rapid triage were alterations in ventilation (OR 6.09; p = 0.028), neurological dysfunction (OR 44.96; p < 0.001) and pain (OR 5.80; p = 0.004).ConclusionNurses should value neurological and ventilation alterations and pain in patients during rapid triage, since these signs and symptoms are associated with high care priority.
Inverse responses of species richness and niche specialization to human development
Authors: Ficken Cari D. , Jeanmougin Martin , Ciborowski Jan J. H. , Rooney Rebecca C. 
Published: August 2021

AbstractAimHumans impact biodiversity by altering land use and introducing nonnative species. Yet the extent to which coexistence processes, such as competition and niche shifts, mediate these relationships is not clear. This study compares how human development influences wetland plant diversity by examining patterns of species richness, niche specialization and nonnative species occurrences along a human development gradient.LocationAlberta, Canada.TaxonPlants.MethodsWe computed species richness and niche specialization (a measure of the range of human development extents over which a species occurs) from species occurrence data across 1582 wetlands. We tested associations between human development extent and species richness, niche specialization and nonnative species using linear mixed models. We used nonmetric multidimensional scaling ordination to examine whether community composition differed among wetlands surrounded by different human development extents.ResultsSpecies richness and niche specialization show contrasting relationships with human development: richness was highest and niche specialization was lowest at intermediate human development extents, suggesting that competitive ability and environmental filtering may contribute to low richness at low and high development extents, respectively. Wetlands surrounded by the highest and lowest human development extents had similar levels of richness and niche specialization, but differed in community composition. The proportion of nonnative species increased with increasing human development, alternatively suggesting that the substitution of native species by nonnatives in developed areas may contribute to reduced richness and influence community assembly.Main conclusionsThese findings demonstrate that human land development plays a major role in shaping species richness by influencing the number of nonnative species and the niche specialization of species inhabiting a wetland. Furthermore, these findings suggest that the proportion of nonnative species is an overlooked factor potentially influencing plant richness; including this variable may help clarify the inconsistent responses of diversity to human development over large spatiotemporal scales.
Novel approach to diagnosis of His bundle capture using individualized left ventricular lateral wall activation time as reference
Authors: Jastrzębski Marek , Moskal Paweł , Kukla Piotr , Bednarek Agnieszka , Kiełbasa Grzegorz , Rajzer Marek , Curila Karol , Vijayaraman Pugazhendhi 
Published: August 2021

AbstractBackgroundDuring nonselective His bundle (HB) pacing, it is clinically important to confirm His bundle capture versus right ventricular septal (RVS) capture. The present study aimed to validate the hypothesis that during HB capture, left ventricular lateral wall activation time, approximated by the V6 R‐wave peak time (V6RWPT), will not be longer than the corresponding activation time during native conduction.MethodsConsecutive patients with permanent HB pacing were recruited; cases with abnormal His‐ventricle interval or left bundle branch block were excluded. Two corresponding intervals were compared: stimulus‐V6RWPT and native HB potential‐V6RWPT. The difference between these two intervals (delta V6RWPT), which was diagnostic of lack of HB capture, was identified using receiver operating characteristic (ROC) curve analysis.ResultsA total of 723 electrocardiograms (ECGs) (219 with native rhythm, 172 with selective HB, 215 with nonselective HB, and 117 with RVS capture) were obtained from 219 patients. The native HB‐V6RWPT, nonselective‐, and selective‐HB paced V6RWPT were nearly equal, while RVS V6RWPT was 32.0 (±9.5) ms longer. The ROC curve analysis indicated delta V6RWPT > 12 ms as diagnostic of lack of HB capture (specificity of 99.1% and sensitivity of 100%). A blinded observer correctly diagnosed 96.7% (321/332) of ECGs using this criterion.ConclusionsWe validated a novel criterion for HB capture that is based on the physiological left ventricular activation time as an individualized reference. HB capture can be diagnosed when paced V6RWPT does not exceed the value obtained during native conduction by more than 12 ms, while longer paced V6RWPT indicates RVS capture.