bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer risk algorithms in primary care: can they improve risk estimates and referral decisions?
Authors: Kostopoulou Olga , Arora Kavleen , Pálfi Bence 
Published: June 2021

ABSTRACTBackgroundCancer risk calculators were introduced to clinical practice in the last decade, but they remain underused. We aimed to test their potential to improve risk assessment and 2-week-wait referral decisions.Methods157 GPs were presented with 23 vignettes describing patients with possible colorectal cancer symptoms. GPs gave their intuitive risk estimate and inclination to refer. They then saw the risk score of an algorithm (QCancer was not named) and could update their responses. Half of the sample was given information about the algorithm’s derivation, validation, and accuracy. At the end, we measured their algorithm disposition.ResultsGPs changed their inclination to refer 26% of the time and switched decisions entirely 3% of the time. Post-algorithm decisions improved significantly vis-à-vis the 3% NICE threshold (OR 1.45 [1.27, 1.65], p<.001). The algorithm’s impact was greater where GPs had underestimated risk. GPs who received information about the algorithm had more positive disposition towards it. A learning effect was observed: GPs’ intuitive risk estimates became better calibrated over time, i.e., moved closer to QCancer.ConclusionsCancer risk calculators have the potential to improve 2-week-wait referral decisions. Their use as learning tools to improve intuitive risk estimates is promising and should be further investigated.
CYP2D6 Genotyping for Personalized Therapy of Tamoxifen in Indonesian Women with ER+ Breast Cancer
Authors: Maggadani Baitha Palanggatan , Junusmin Kathleen Irena , Sani Levana L. , Mahendra Caroline , Amelia Margareta , Gabriella  , Irwanto Astrid , Harmita  , Harahap Yahdiana , Haryono Samuel J. 
Published: June 2021

AbstractTamoxifen is a Selective Estrogen-Receptor Modulator (SERM) commonly prescribed for standard of care in estrogen receptor positive (ER+) breast cancer as an adjuvant therapy. Tamoxifen is metabolized by CYP2D6 into its active metabolite, endoxifen, which has been known to play an important role in reducing risk of ER+ breast cancer recurrence. CYP2D6 is a highly polymorphic gene with more than 100 alleles. The phenotype of this gene is categorized into ultrarapid metabolizer (UM), normal metabolizer (NM), intermediate metabolizer (IM), and poor metabolizer (PM). Certain CYP2D6 polymorphisms may cause reduced activity of this enzyme. Studies have found that reduced CYP2D6 activity in IM and PM patients causes low efficacy of standard tamoxifen therapy. This study aims to observe the distribution of CYP2D6 alleles and its correlation with endoxifen levels in Indonesian ER+ breast cancer patients. 151 patients who have received tamoxifen therapy for at least eight weeks were recruited prospectively. DNA and blood samples were collected with buccal swab and finger-prick methods, respectively. Genotyping was performed using the qPCR method while metabolite level measurement was performed using high performance liquid chromatography tandem mass spectrometry. We found that 40.67% of ER+ breast cancer patients recruited were IM. CYP2D6*10 was the most abundant allele (0.288) in this population, and *10/*36 was the most frequently observed diplotype (0.236). Endoxifen levels between the NM-PM, NM-IM, and IM-PM were statistically significant (p-value = 6.26 × 10−5, 9.12 × 10−5, and 4.714 × 10−3, respectively), and dose increase of tamoxifen to 40 mg daily successfully increased endoxifen levels in IMs to a similar level with NMs at baseline. Given these findings, implementing pharmacogenomic testing of CYP2D6 on ER+ breast cancer women who are about to undergo tamoxifen therapy may be beneficial to increase the likelihood of achieving expected endoxifen levels, thus better treatment efficacy.
A Systematic Review: The Dimensions utilized in the Performance Evaluation of Healthcare- An Implication during the COVID-19 Pandemic
Authors: Amer Faten , Hammoud Sahar , Khatatbeh Haitham , Lohner Szimonetta , Boncz Imre , Endrei Dóra 
Published: June 2021

AbstractBackgroundThe balanced scorecard (BSC) has been implemented to evaluate the performance of health care organizations (HCOs). BSC proved to be effective in improving financial performance and patient satisfaction.AimThis systematic review aims to identify key performance indicators (KPIs) and dimensions that are vital and most frequently used by health care managers in BSC implementations. Additionally, it attempts to analyze the resulting dimensions during the COVID-19 era.MethodsThis systematic review adheres to PRISMA guidelines. The PubMed, Embase, Cochrane, and Google Scholar databases and Google search engine were inspected to find all implementations of BSC at HCO. The risk of bias was assessed using the nonrandomized intervention studies (ROBINS-I) tool to evaluate the quality of observational and quasi- experimental studies and the Cochrane (RoB 2) tool for randomized controlled trials (RCTs).ResultsThere were 33 eligible studies, of which we identified 36 BSC implementations. The categorization and regrouping of the 797 KPIs resulted in 46 subdimensions. The reassembly of these subdimensions resulted in 13 major dimensions: financial, efficiency and effectiveness, availability and quality of supplies and services, managerial tasks, health care workers (HCW) scientific development error-free and safety, time, HCW-centeredness, patient-centeredness, technology, and information systems, community care and reputation, HCO building, and communication. On the other hand, this review detected that BSC design modification to include external and managerial perspectives was necessary for many BSC implementations.ConclusionThis review solves the KPI categorization dilemma. It also guides researchers and health care managers in choosing dimensions for future BSC implementations and performance evaluations in general. Consequently, dimension uniformity will improve the data sharing and comparability among studies. Additionally, despite the pandemic negatively influencing many dimensions, the researchers observed a lack of comprehensive HCO performance evaluations. In the same vein, although some resulting dimensions were assessed separately during the pandemic, other dimensions still lack investigation. Lastly, BSC dimensions may play an essential role in tackling the COVID-19 pandemic. However, further research is required to investigate the BSC implementation effect in mitigating the pandemic consequences on HCO.
Discharge prediction of critical patients with spinal cord injury: a machine learning study with 1485 cases
Authors: Fan Guoxin , Liu Huaqing , Yang Sheng , Luo Libo , Wang Lunji , Pang Mao , Liu Bin , Zhang Liangming , Han Lanqing , Rong Limin 
Published: June 2021

AbstractObjectivesPrognostication of spinal cord injury (SCI) is vital, especially for critical patients who need intensive care. The study aims to develop machine-learning (ML) classifiers for discharge prediction of SCI patients in the intensive care unit (ICU).MethodsClinical data of patients diagnosed with SCI were extracted from the publicly available ICU database. A total of 105 ML classifiers were initially developed to predict the discharge destination (dead, further medical care, home), and then the top 3 classifiers with the best performance were stacked into an ensemble classifier (Esb-Clf). To balance the accuracy and the feasibility, the complete Esb-Clf was finally simplified with top 10 features (simplified Esb-Clf). The micro-average area under the curve (AUC) was used to compare the prediction performance of difference ML classifiers and 6 doctors’ artificial prediction.ResultsA total of 1485 SCI patients were used for the early and the recent prediction of discharge destination. In the early prediction, the micro-average AUC of the Esb-Clf and the simplified Esb-Clf was 0.846 and 0.835 during the independent testing, respectively. While in the recent prediction, the micro-average AUC of the Esb-Clf and the simplified Esb-Clf was 0.898 and 0.892. Performance of both the Esb-Clf and the simplified Esb-Clf were superior to the doctors’ in the early and the recent prediction.ConclusionsML classifiers can discriminate the discharge destination of SCI patients with high accuracy, feasibility and interpretability. Whether the simplified Esb-Clf as an online predictive tool is applicable to guiding clinical management needs further verification.
The COVID-19 Yorkshire Rehabilitation Scale (C19-YRS): application and psychometric analysis in a post-COVID-19 syndrome cohort
Authors: Preston Nick , Parkin Amy , Makower Sophie , Ross Denise H , Gee Jeremy , Halpin Stephen J , Horton Mike C , O’Connor Rory J , Sivan Manoj 
Published: June 2021

AbstractBackgroundAs our understanding of the nature and prevalence of Post-COVID-19 syndrome (PCS) is increasing, a measure of the impact of COVID-19 could provide valuable insights into patients’ perceptions in clinical trials and epidemiological studies, as well as routine clinical practice.ObjectiveTo evaluate the clinical usefulness and psychometric properties of the COVID-19 Yorkshire Rehabilitation Scale (C19-YRS) in patients with PCS.DesignA prospective, observational study of 187 consecutive patients attending a post-COVID-19 rehabilitation clinic. The C19-YRS was used to record patients’ symptoms, functioning and disability. A global health question was used to measure the overall impact of PCS on health. Classical psychometric methods (data quality, scaling assumptions, targeting, reliability and validity) were used to assess the C19-YRS.ResultsFor the overall scale, missing data were low, scaling and targeting assumptions were satisfied, and internal consistency was high (Cronbach’s alpha = 0.891). Relationships between perception of health and patients’ reports of symptoms, functioning and disability demonstrated good concordance.ConclusionsThis is the first study to examine the psychometric properties of an outcome measure in patients with PCS. In this sample of patients, the C19-YRS was clinically useful and satisfied standard psychometric criteria, providing preliminary evidence of its suitability as a measure of PCS.
Diverse soil RNA viral communities have the potential to influence grassland ecosystems across multiple trophic levels
Authors: Hillary Luke S. , Adriaenssens Evelien M. , Jones David L. , McDonald James E. 
Published: June 2021

AbstractGrassland ecosystems form 30-40%1 of total land cover and provide essential ecosystem services, including food production, flood mitigation and carbon storage2. Their productivity is closely related to soil microbial communities3, yet the role of viruses within these critical ecosystems is currently undercharacterised4 and in particular, our knowledge of soil RNA viruses is significantly limited5. Here, we applied viromics6 to characterise soil RNA viral communities along an altitudinal productivity gradient of peat, managed grassland and coastal soils. We identified 3,462 viral operational taxonomic units (vOTUs) and assessed their spatial distribution, phylogenetic diversity and potential host ranges. Soil types exhibited showed minimal similarity in viral community composition, but with >10-fold more vOTUs shared between managed grassland soils when compared with peat or coastal soils. Phylogenetic analyses of viral sequences predicted broad host ranges including bacteria, plants, fungi, vertebrates and invertebrates, contrasting with soil DNA viromes which are typically dominated by bacteriophages7. RNA viral communities therefore likely have the ability to influence soil ecosystems across multiple trophic levels. Our study represents an important step towards the characterisation of terrestrial RNA viral communities and the intricate interactions with their hosts, which will provide a more holistic view of the biology of economically and ecologically important terrestrial ecosystems.
Brain histone beta-hydroxy-butyrylation couples metabolism with gene expression
Authors: Cornuti Sara , Chen Siwei , Lupori Leonardo , Finamore Francesco , Samad Muntaha , Raimondi Francesco , Mazziotti Raffaele , Magnan Christophe , Rocchiccioli Silvia , Baldi Pierre , Tognini Paola 
Published: June 2021

ABSTRACTLittle is known about the impact of metabolic stimuli on brain tissue at a molecular level. The ketone body beta-hydroxybutyrate (BHB) can be a signaling molecule regulating gene transcription. Thus, we assessed lysine beta-hydroxybutyrylation (K-bhb) levels in proteins extracted from the cerebral cortex of mice undergoing a ketogenic metabolic challenge (48 hrs fasting). We found that fasting enhanced K-bhb in a variety of proteins including histone H3. ChIP-seq experiments showed that K9 beta-hydroxybutyrylation of H3 (H3K9-bhb) was significantly enriched by fasting on more than 8000 DNA loci. Transcriptomic analysis showed that H3K9-bhb on enhancers and promoters correlated with active gene expression. One of the most enriched functional annotations both at the epigenetic and transcriptional level was “circadian rhythms’’. Indeed, we found that the diurnal oscillation of specific transcripts was modulated by fasting at distinct zeitgebers both in the cortex and suprachiasmatic nucleus. Moreover, specific changes in locomotor activity daily features were observed during re-feeding after 48-hour fasting.Thus, our results suggest that fasting dramatically impinges on the cerebral cortex transcriptional and epigenetic landscape, and BHB acts as a powerful epigenetic molecule in the brain through direct and specific histone marks remodeling in neural tissue cells.
Brain signaling dynamics after vagus nerve stimulation
Authors: Teckentrup Vanessa , Krylova Marina , Jamalabadi Hamidreza , Neubert Sandra , Neuser Monja P. , Hartig Renée , Fallgatter Andreas J. , Walter Martin , Kroemer Nils B. 
Published: June 2021

AbstractThe vagus nerve projects to a well-defined neural circuit via the nucleus tractus solitarii (NTS) and its stimulation elicits a wide range of metabolic, neuromodulatory, and behavioral effects. Transcutaneous vagus nerve stimulation (tVNS) has been established as a promising technique to non-invasively alter brain function. However, the precise dynamics elicited by tVNS in humans are still largely unknown. Here, we performed fMRI with concurrent right-sided tVNS (vs. sham) following a randomized cross-over design (N=40). First, to unravel the temporal profile of tVNS-induced changes in the NTS, we compared fMRI time series to canonical profiles for stimulation ON and OFF cycles. Model comparisons indicated that NTS time series were best fit by block-wise shifts in signal amplitude with stimulation ON and OFF estimates being highly correlated. Therefore, we compared stimulation (ON + OFF) versus baseline phases and found that tVNS increased fMRI BOLD activation in the NTS, but this effect was dependent on sufficient temporal signal-to-noise ratio (tSNR) in the mask. Second, to identify the spatiotemporal evolution of tVNS-induced changes in the brain, we examined lagged co-activation patterns and phase coherence. In contrast to our hypothesis, tVNS did not alter dynamic functional connectivity after correction for multiple comparisons. Third, to establish a positive control for future research, we measured changes in gastric myoelectrical frequency via an electrogastrogram. Again, in contrast to our hypothesis, tVNS induced no changes in gastric frequency. Collectively, our study provides evidence that tVNS can perturb brain signaling in the NTS, but these effects are dependent on tSNR and require precise localization. In light of an absence of acute tVNS-induced effects on dynamic functional connectivity and gastric motility, we discuss which steps are necessary to advance future research on afferent and efferent effects of tVNS.
Human engineered heart tissue transplantation in a guinea pig chronic injury model
Authors: von Bibra Constantin , Shibamiya Aya , Geertz Birgit , Querdel Eva , Köhne Maria , Stuedemann Tim , Starbatty Jutta , Hansen Arne , Hiebl Bernhard , Eschenhagen Thomas , Weinberger Florian 
Published: June 2021

AbstractMyocardial injury leads to an irreversible loss of cardiomyocytes (CM). The implantation of human engineered heart tissue (EHT) has become a promising regenerative approach. Previous studies exhibited beneficial, dose-dependent effects of human induced pluripotent stem cell (hiPSC)–derived EHT patch transplantation in a guinea pig model in the subacute phase of myocardial injury. Yet, advanced heart failure often results from a chronic remodeling process. Therefore, from a clinical standpoint it is worthwhile to explore the ability to repair the chronically injured heart. In this study human EHT patches were generated from hiPSC–derived CMs (15×106 cells) and implanted epicardially four weeks after injury in a guinea-pig cryo-injury model. Cardiac function was evaluated by echocardiography after a follow-up period of four weeks. Hearts revealed large transmural myocardial injuries amounting to 27% of the left ventricle. EHT recipient hearts demonstrated compact muscle islands of human origin in the scar region, as indicated by a positive staining for human Ku80 and dystrophin, remuscularizing 5% of the scar area. Echocardiographic analysis demonstrated no significant difference between animals that received EHT patches and animals in the control group (fractional area change 36% vs. 34%). Thus, EHT patches engrafted in the chronically injured heart but in contrast to the subacute model, grafts were smaller and EHT patch transplantation did not improve left ventricular function, highlighting the difficulties for a regenerative approach.
Delayed effects of climate on vital rates lead to demographic divergence in Amazonian forest fragments
Authors: Scott Eric R. , Uriarte María , Bruna Emilio M. 
Published: June 2021

AbstractDeforestation often results in landscapes where remaining forest habitat is highly fragmented, with remnants of different sizes embedded in an often highly contrasting matrix. Local extinction of species from individual fragments is common, but the demographic mechanisms underlying these extinctions are poorly understood. It is often hypothesized that altered environmental conditions in fragments drive declines in reproduction, recruitment, or survivorship. The Amazon basin, in addition to experiencing continuing fragmentation, is experiencing climate change related increases in the frequency and intensity of droughts and unusually wet periods. Whether plant populations in tropical forest fragments are particularly susceptible to extremes in precipitation remains unclear. Most studies of plants in fragments are relatively short (1–6 years), focus on a single life-history stage, and often do not compare to populations in continuous forest. Even fewer studies consider delayed effects of climate on demographic vital rates despite the importance of delayed effects in studies that consider them. Using a decade of demographic and climate data from an experimentally fragmented landscape in the Central Amazon, we assess the effects of climate on populations of an understory herb (Heliconia acuminata, Heliconiaceae). We used distributed lag non-linear models to understand the delayed effects of climate (measured as standardized precipitation evapotranspiration index, SPEI) on survival, growth, and flowering. We detected delayed effects of climate up to 36 months. Extremes in SPEI in the previous year reduced survival, drought in the wet season 8–11 months prior to the February census increased growth, and drought two dry seasons prior increased flowering probability. Effects of extremes in precipitation on survival and growth were more pronounced in forest fragments compared to continuous forest. The complex delayed effects of climate and habitat fragmentation in our study point to the importance of long-term demography experiments in understanding the effects of anthropogenic change on plant populations.
Laminin-binding Integrins Regulate Angiogenesis by Distinct and Overlapping Mechanisms in Organotypic Cell Culture Models
Authors: Xu Hao , LaFlamme Susan E. 
Published: June 2021

AbstractEndothelial cells engage extracellular matrix and basement membrane components through integrin-mediated adhesion to promote angiogenesis. Our previous studies demonstrated that endothelial expression of laminin-411 and laminin-511 as well as α6 integrins is required for endothelial sprouting and tube formation in organotypic angiogenesis assays. These studies demonstrated that α6 integrins promote migration and regulate the expression of ANGPT2 and CXCR4 and that α6-dependent regulation of CXCR4 contributes to endothelial morphogenesis in our assays. However, these studies did not identify specific roles for the α6β1, α6β4, or α3β1 laminin-binding integrins. Here, we employ RNAi technology to parse the contributions of these integrins. We demonstrate that α6β4 promotes migration, sprouting, and tube formation, and also positively regulates the expression of ANGPT2, but does not promote CXCR4 expression, suggesting that α6β1 functions in this regulation. Additionally, we show that α3β1 regulates endothelial sprouting and tube formation, but is not required for migration in our assays or for the expression of ANGPT2 or CXCR4. Integrin α3β1 promotes the expression of NRP1 and ID1 RNAs, both of which are known to promote angiogenesis. Taken together, our results indicate that laminin-binding integrins play distinct roles during endothelial morphogenesis and do not compensate for one another in organotypic culture.Summary StatementThe laminin-binding integrins α3β1, α6β1, and α6β4 contribute to endothelial sprouting and tube formation in organotypic angiogenesis assays.
Actin force generation in vesicle formation: mechanistic insights from cryo-electron tomography
Authors: Serwas Daniel , Akamatsu Matthew , Moayed Amir , Vegesna Karthik , Vasan Ritvik , Hill Jennifer M , Schöneberg Johannes , Davies Karen M , Rangamani Padmini , Drubin David G 
Published: June 2021

SummaryActin assembly provides force for a multitude of cellular processes. Compared to actin assembly- based force production during cell migration, relatively little is understood about how actin assembly generates pulling forces for vesicle formation. Here, cryo-electron tomography revealed actin filament number, organization, and orientation during clathrin-mediated endocytosis in human cells, showing that force generation is robust despite variance in network organization. Actin dynamics simulations incorporating a measured branch angle indicate that sufficient force to drive membrane internalization is generated through polymerization, and that assembly is triggered from ∼4 founding “mother” filaments, consistent with tomography data. Hip1R actin filament anchoring points are present along the entire endocytic invagination, where simulations show that it is key to pulling force generation, and along the neck, where it targets filament growth and makes internalization more robust. Actin cytoskeleton organization described here allowed direct translation of structure to mechanism with broad implications for other actin-driven processes.Highlights-Filament anchorage points are key to pulling force generation and efficiency.-Native state description of CME-associated actin force-producing networks.-Branched actin filament assembly is triggered from multiple mother filaments.-Actin force production is robust despite considerable network variability.