bluuebunny/crossref_metadata_2025 huggingface dataset:
Study on the value of isolation and extraction of pathological positive cells to improve the detection rate:control trial
Authors: Luo JianQuan , Yang JiaCheng
Published: December 2024

OBJECTIVE

The density of pathological positive cells was calculated by flow cytometry, and the target cells were isolated and extracted to improve the detection rate.

DESIGN

a case-control study.

SETTING

Hematology Department of Hospital

PARTICIPANTS

Selected from MDS 33 cases, 17 cases of malignant tumors, 29 cases of lupus erythematosus, 4 cases of plasmodium falciparum disease, a total of 76 cases as positive blood specimens.

MAIN OUTCOME MEASURES

Design Research group (group I) : Flow cytometry was used to analyze and calculate the density of various cell types, and then cell separation solution was used to accurately separate and extract target cells of the same density by adjusting the gradient of two different densities, that is, to collect pathologically positive blood cells of the same density. A control group (group II) was established: the whole blood samples of the same patient were compared and analyzed by direct push-film observation.

RESULTS

As shown in Figure 2AB-3AB-4AB-5AB, A large number of positive abnormal cells were extracted from group I, which improved the accuracy and specificity of diagnosis. In the control group (group II), only a few positive abnormal cells were found, which was very easy to misdiagnose and miss diagnosis. Data are analyzed from Table 3. According to the statistical results of group I, the positive detection rates were MDS=76%, malignant tumor cells =53%, lupus erythematosus cells =62%, Plasmodium falciparum =75%. In the control group (group II), the positive detection rate was MDS=27%, malignant tumor cells =11%, lupus erythematosus cells =33%, Plasmodium falciparum =25%. Chi-square test was used to compare the mean value of independent samples between groups, and the difference was statistically significant (P<0.05).

CONCLUSIONS

The density of pathologically positive blood cells can be measured by flow cytometry according to the specimens that need to be reviewed by microscopy as indicated by blood routine, and the target cells extracted can be accurately separated, that is, the same density of pathologically positive blood cells can be collected. Combined with the gold standard method of artificial microscopy, the detection rate was significantly improved, and the occurrence of misdiagnosis and missed diagnosis was reduced. For the difference in cell density of various forms in different types of specimens, it only needs to be distinguished from normal cell density, and abnormal pathological positive cells can be accurately extracted, which can help diagnose the positive detection rate of diseases, which is of great significance and value
Targeted Screening of Unruptured Intracranial Aneurysms in 50- to 60-Year-Old Female Smokers – Inconsiderate Overdiagnosis or a Chance to Improve Women’s Health?
Authors: Huhtakangas Justiina , Vasankari Ville , Numminen Jussi , Niemelä Mika , Korja Miikka
Published: December 2024

Introduction

Aneurysmal subarachnoid hemorrhage (aSAH) causes a substantial proportion of all deaths among middle-aged people, especially women. Since female smokers in particular have a high risk of aSAH and SAH deaths, targeted screening of 50–60-year-old female smokers could be justified as a preventive action to reduce premature deaths and morbidity.

Methods

This prospective screening study has been carried out at Helsinki University Hospital in the Department of Neurosurgery in two phases during 2020 and 2023–2024. In order to minimize recruitment bias, the Helsinki Biobank and THL Biobank were responsible for sending out preliminary invitation letters to self-caring 50- to 60-year-old women who were known to be active smokers. We informed the potential candidates about the study and answered any questions before their decision to participate. Once written consent was provided, participants filled in a detailed questionnaire on lifestyle and health, and underwent computed tomography angiography (CTA) analysis. We studied the prevalence of unruptured intracranial aneurysms (UIAs) among the study participants. Moreover, we assessed morbidity, mortality and costs related to screening.

Results

Of the 458 preliminary invitation letters, 160 potential participants initially replied. Of these, 116 returned questionnaires and written consents. Ultimately, 108 smoking women underwent CTA imaging. Eleven UIAs were found in eleven (10%) female smokers, one of which was intracavernous and extradural. Two women were operated on without complications – one with a middle cerebral artery aneurysm and one with a posterior communicating artery aneurysm. Most (n=8) patients with small (<5mm) intradural aneurysms were treated with non-invasive preventive actions (smoking cessation, blood pressure control) and followed with CTA or MRA thereafter.

Conclusions

Small UIAs, which may be best suited for non-invasive preventive actions, seem to be common in 50- to 60-year-old female smokers. Targeted screening of women in this age group may offer a chance to reduce morbidity or mortality of aSAH. Whether this leads to improved health and reduction in SAH-related deaths in the long run requires a longer follow-up.
Leveraging whole genomes, mitochondrial DNA, and haploblocks to decipher complex demographic histories: an example from a broadly admixed arctic fish
Authors: Dallaire Xavier , Normandeau Eric , Brazier Thomas , Harris Les , Michael Michael M. Hansen , Mérot Claire , Moore Jean-Sébastien
Published: December 2024

The study of phylogeography has transitioned from mitochondrial haplotypes to genome-wide analyses, blurring the line between this field and population genomics. Whole-genome sequencing offers the opportunity to join use both and provides the density of markers necessary to investigate genetic linkage and recombination along the genome. This facilitates the unraveling of complex demographic histories of admixture between divergent lineages, as is often the case in species evolving in recently deglaciated habitats. In this study, we sequenced 1120 Arctic Char genomes from 33 populations across Canada and Western Greenland to characterize patterns of genetic variation and diversity, and how they are shaped by hybridization between the Arctic and Atlantic glacial lineages. Several lines of evidence supported mito-nuclear discordance in lineage distribution, with all Canadian populations under the 66thparallel being characterized by introgression from the Atlantic lineage, leading to higher nuclear genetic diversity. By scanning the genome using local PCAs, we identified putative low-recombining haploblocks as local ancestry tracts from either lineage and described the impacts of recombination on the introgression landscape in admixed populations. Finally, we inferred conflicting origins of recolonization using whole genomes vs. ancestry tracts for the Arctic lineage, suggesting that haplotypes sheltered from introgression by low recombination could enlighten complex post-glacial histories. Overall, we argue that Whole-Genome Sequencing, even at low depths of coverage, provides a versatile approach to the study of phylogeographic dynamics.
Punishing temporal judgement boosts sense of agency and modulates its underlying neural correlates
Authors: Hill Christopher M. , Samnani Numa , Barzi Leo , Wilson Matt
Published: December 2024

Feeling in control of one’s actions is fundamental to the formation of action-outcome relationships. Reinforcement and its valence also change the action-outcome relationship, either through behavior promotion or diminishment. In this study we evaluated how reward and punishment reinforcement modulate sense of agency, as measured by intentional binding. Moreover, using electroencephalography (EEG) we evaluated how reward and punishment reinforcement changes outcome event related potentials associated with the accuracy of participants’ judgement of the time interval between a key press and audio tone. We found that punishment reinforcement increased intentional binding between the action and outcome more than reward and control feedback. This was also reflected in the outcome event related potentials, where punishment elicited greater P300s and Late Positive Potentials compared to reward and control. We also found increased N100s and diminished P300s and Late Positive Potentials when the participants did not actively participate in evoking the tone. Taken together, our findings showcase that punishment reinforcement boosts sense of agency and modulates associated neural activity more than reward and no reinforcement, as a function of increasing attention and arousal. These findings illuminate the greater effect punishment reinforcement has on behavior and brain activity by its modification of sense of agency, which is important for the development of treatments in psychiatric and neurological diseases.
The genetic architecture of gene expression in individuals of African and European ancestry
Authors: Fletez-Brant Kipper , Sauteraud Renan , Liang Yanyu , Micheletti Steven , Nandakumar Priyanka , Sugathan Aarathi , Song Kijoung , Cavazos Taylor B. , Thomas Amal , Tunney Robert J. , Hicks Barry , O’Connell Jared , Shringarpure Suyash , Kukar Katelyn , Moreno Meghan , DelloRusso Emily , Wong Corinna D. , Petrakovitz Aaron , Atla Goutham , Cortes Adrian , Gormley Padhraig , Howe Laurence , Mishra Rajashree , Seaton Daniel ,   the 23andMe Research Team, Gentleman Robert C. , Pitts Steven J. , Vacic Vladimir
Published: December 2024

We conducted two large scale studies of the genetics of gene expression in individuals of African ancestry within a cohort of consented 23andMe research participants and in LCL samples from the 1000 Genomes Project African superpopulation. We discovered nearly four times as many eQTLs, compared to tissue-matched eQTL studies in European cohorts. Additionally, we found that the majority of eQTLs were not detectable across populations; those that were, however, were found to be highly concordant. Performing eQTL studies in African ancestry cohorts resulted in more signals per gene and smaller credible sets of causal variants. We showed that comparisons of heritability of gene expression could be confounded by population substructure, but that variation in local genetic ancestry did not majorly impact eQTL discovery. Finally, we showed improvements in variant-to-gene mapping of African-American GWAS signals when using African compared to European ancestry eQTL studies
Association Between Abdominal Obesity, Cardiovascular Fitness, and Incident Hypertension in Middle-Aged Korean Adults
Authors: Chae Jisuk , Kim Mihee , Jung Soo young , Yoo Seung Don , Kang Si-Hyuck , Lee Kyesan , Kim Jung-Hyun , Lee Junga
Published: December 2024

BACKGROUND

Hypertension is a global health crisis that significantly increases the risk of cardiovascular diseases, stroke, and chronic kidney disease. Despite advances in treatment, the prevalence of hypertension continues to rise. It is important to know the association between abdominal obesity, cardiovascular fitness, and hypertension in middle-aged Koreans to develop effective prevention and management strategies for hypertension. This study aims to investigate the association between body composition, physical fitness, and hypertension in middle-aged Korean population. We examined the impact of abdominal obesity and cardiovascular fitness on the risk of hypertension.

METHODS and RESULTS

A cross-sectional study was conducted among 60 healthy adults (mean aged 54.23±7.34) recruited. Participants underwent assessments of anthropometry, body composition, blood pressure, and physical fitness. The primary outcome was the prevalence of hypertension. Secondary outcomes included body composition measures (body fat mass, body lean mass and waist circumference), and physical fitness assessments (grip strength, sit-ups, sit-and-reach test, and YMCA step test). Participants with hypertension had significantly higher body fat mass and waist circumference compared to those without hypertension. The risk of hypertension was significantly increased by 17.7% with a 1 kg increase in body fat and by 11.9% with a 1 cm increase in waist circumference. The risk of hypertension was significantly increased in the group with hypertension accompanied by abdominal obesity as cardiovascular fitness, measured by the YMCA step test, decreased (Adjusted OR: 0.326, 95% CI: 0.168-0.631).

CONCLUSION

These findings highlight the significant association between abdominal obesity, reduced cardiovascular fitness, and hypertension in middle-aged Korean adults. Abdominal obesity and low cardiovascular fitness were identified as independent risk factors for hypertension in this population. These results suggest that weight management to reduce abdominal obesity and regular physical activity to promote cardiovascular fitness are key to the prevention and management of hypertension.
Acceptability and Feasibility of a Multicomponent Intervention to Improve Acute Myocardial Infarction Care in Northern Tanzania: the MIMIC Pilot Trial
Authors: Hertz Julian T. , Sakita Francis M. , Haukila Kelvin F. , Shayo Pankrasi S. , Shayo Frida M. , Willy Joyce , Lameck Godfrey , Kisanga Emmanuel , Bosworth Hayden B. , Bettger Janet P. , Rahim Faraan O.
Published: December 2024

Background

The Multicomponent Intervention to Improve Acute Myocardial Infarction Care (MIMIC) was developed to increase uptake of evidence-based care for acute myocardial infarction in Tanzania. MIMIC consists of five components: triage cards, pocket cards, an online training module, patient educational pamphlets, and clinical champions. Our aim was to determine the acceptability and feasibility of this intervention among emergency department (ED) providers in Tanzania.

Methods

During a one-year pilot of the MIMIC intervention at the Kilimanjaro Christian Medical Centre in northern Tanzania, ED physicians and nurses were approached and invited to complete a survey eliciting their perspectives on MIMIC. The survey included the four-item Acceptability of Intervention Measurement (AIM) and four-item Feasibility of Intervention Measurement (FIM) tools. Mean AIM and FIM scores were generated by assigning scores of 1-5 for each response (1= strongly disagree, 2 = disagree, 3= neutral, 4= agree, 5= strongly agree), and dividing by four.

Results

Sixty-four participants were enrolled, including 27 (42%) physicians and 37 (58%) nurses. The mean AIM score was 4.82 (sd = 0.31) out of a maximum possible score of 5. The mean FIM score was 4.61 (sd 0.47). Of participants, 63 (98%) reported using the pocket cards and 54 (84%) reported completing the training module, which took a mean of 16.5 (sd 13.3) minutes to complete. Of 36 nurses who worked in triage, all (100%) reported using the MIMIC triage cards.

Conclusions

The MIMIC intervention is highly acceptable and feasible in a northern Tanzanian ED. Use of a co-design approach in the development of the MIMIC intervention likely increased the acceptability and feasibility the intervention to staff. Additional study is needed to determine the effectiveness of this intervention on clinical care processes and patient outcomes.

Trial Registration

ClinicalTrials.govNCT04563546; registered on September 21st, 2020;https://clinicaltrials.gov/study/NCT04563546
A general strategy for generating expert-guided, simplified views of ontologies
Authors: Caron Anita R. , Puig-Barbe Aleix , Quardokus Ellen M. , Balhoff James P. , Belfiore Jasmine , Chipampe Nana-Jane , Hardi Josef , Herr Bruce W. , Kir Huseyin , Roncaglia Paola , Musen Mark A. , McLaughlin James A. , Börner Katy , Osumi-Sutherland David
Published: December 2024

Annotation with widely used, well-structured ontologies, combined with the use of ontology-aware software tools, ensures data and analyses are Findable, Accessible, Interoperable and Reusable (FAIR). Standardized terms with synonyms support lexical search. Ontology structure supports biologically meaningful grouping of annotations (typically by location and type). However, there are significant barriers to the adoption and use of ontologies by researchers and resource developers.

One barrier is complexity. Ontologies serving diverse communities are often more complex than needed for individual applications. It is common for atlases to attempt their own simplifications by manually constructing hierarchies of terms linked to ontologies, but these typically include relationship types that are not suitable for grouping annotations.

Here, we present a suite of tools for validating user hierarchies against ontology structure, using them to generate graphical reports for discussion and ontology views tailored to the needs of the HuBMAP Human Reference Atlas, and the Human Developmental Cell Atlas. In both cases, validation is a source of corrections and content for both ontologies and user hierarchies.
Bovine endometrial organoids: A new tool to study conceptus-maternal interactions in mammals
Authors: Edge Jessica C. , Amelkina Olga , Tinning Haidee , Giovanardi Gianluca , Mancinelli Elena , Gardner Samantha , Vasconcelos Elton JR , Pensabene Virginia , Forbes Karen , O’Connell Mary J , Ruane Peter , Forde Niamh
Published: December 2024

In cattle, communication between endometrium and conceptus during the peri-implantation period is crucial for successful pregnancy. Understanding these interactions is vital as most early pregnancy loss occurs during this time. A major challenge in understanding uterine function and early pregnancy is lack of appropriatein-vitromodels. Two-dimensional models are available, but do not recapitulate the endometrium’s complex multicellular structure. Here, we describe a hormonally responsive organoid model of the bovine endometrium, developed as a tool for studying endometrial function and early pregnancy. Bovine glandular epithelial cells were isolated from reproductive tracts and cultured in an extracellular matrix hydrogel (Cultrex 2) at 38.5°C, 5% CO (n=3). RNA was extracted and qPCR confirmed the presence of gland markers:leukemia inhibitory factor, mucin-1, insulin-like growth factor binding protein-1, kruppel-like factor-5andforkhead box protein-A2. Organoids were imaged at specific time-points to monitor growth and passaged 3 times in 1:2 or 1:3 ratios after growing for a minimum of 10 days per passage. Morphologically, organoids were spherical and fast-growing at passages 0 and 1, but this declines following passage 2. Bovine endometrial organoids (n=3, passage 0) were treated with 1000 ng/ml recombinant ovine Interferon Tau (IFNT) or 10 μg/ml progesterone (P4) for 24 hours and analysed by RNASeq to assess hormone responsiveness. Differential expression analysis by DeSeq2 negative binomial distribution model followed by Wald test and Benjamini-Hochberg correction identified 373 transcripts significantly upregulated (padj<0.05 or log2fold change >0.05) in response to P4 treatment, with downstream analysis showing significant overrepresentation (FDR<0.05) of genes associated with positive regulation of protein localisation to plasma membrane and cell periphery. Of the 240 genes significantly downregulated by P4 these were significantly overrepresented (FDR<0.05) in biological processes of cilium and cytoskeleton organisation. IFNT treatment resulted in significant upregulation of 414 genes and downregulation of 119 genes. The largest cluster associated with differentially expressed genes in response to IFNT is defence to virus and interferon signalling. There were 30 genes altered by both P4 treatment and IFNT treatment. Organoids were also shown to express conserved microRNAs, and it was possible to culture them in a microfluidics device - making them a useful model for a multitude of potential investigations. This model provides a tool to investigate bovine endometrial function and peri-implantation communication, subsequently allowing species comparison to understand diversity in reproductive strategies.
Profiling of yeastSaccharomyces cerevisiaemitochondrial AMPylome reveals a regulation of ATP synthase coupling trough subunit δ
Authors: Panja Chiranjit , Masanta Suchismita , Wiesyk Aneta , Niedzwiecka Katarzyna , Baranowska Emilia , Cysewski Dominik , Sipko Marta , Anielska-Mazur Anna , Malinowska Agata , Kucharczyk Roza
Published: December 2024

The adenylation (AMPylation) of proteins as a posttranslational modification is used by bacteria during infection of host cells. These new virulence factors - AMPylases mainly belonging to the FIC domain containing proteins and constitute a potential drug target. Human FIC protein (HYPE) controls the activity of BiP chaperone under endoplasmic reticulum stress. No FIC family proteins have yet been identified in yeastSaccharomyces cerevisiae. The second family of AMPylases are SelO proteins which control the redox homeostasis in mitochondria and chloroplasts. We describe here the first global screening of AMPylated proteins in yeastS. cerevisiaemitochondrial proteome from wild type and SelO (Fmp40) lacking cells. Through quantitative mass-spectrometry-based proteomics, we identified a total of 169 AMPylated proteins in mitochondria while AMPylated peptides of 115 proteins were identified infmp40Δmitochondria, indicating on the presence of another, besides Fmp40, not yet identified AMPylase in yeast. We confirmed AMPylation of Atp1, Atp2, Atp3 and Atp16 subunits of mitochondrial ATP synthase by western blotting. Interestingly, we found AMPylation and phosphorylation of many residues, what indicates on the complex regulation of the ATP synthase activity. We confirmed the importance of one of such residues in Atp16, showing that its post-translational modification serves to regulate ATP synthase and OXPHOS coupling in both fermentative and respiratory growth conditions. This regulation serves to maintain the proper potential of the inner mitochondrial membrane, particularly under conditions of fermentative growth. This dataset represents the first library of AMPylated mitochondrial yeast proteins reported to date and supplements the AMPylome of human chronic lymphocytic leukemia cell line from human HYPE containing and HYPE lacking cells. The data represents a foundation for substrate specific investigations that can ultimately decipher the biological role of the AMPylation in the mitochondria.
Asymmetric Interactions Shape Survival During Population Range Expansions
Authors: Gray Jason M. , Barker-Clarke Rowan J. , Scott Jacob G. , Hinczewski Michael
Published: December 2024

An organism that is newly introduced into an existing population has a survival probability that is dependent on both the population density of its environment and the competition it experiences with the members of that population. Expanding populations naturally form regions of high and low density, and simultaneously experience ecological interactions both internally and at the boundary of their range. For this reason, systems of expanding populations are ideal for studying the combination of density and ecological effects. Conservation ecologists have been studying the ability of an invasive species to establish for some time, attributing success to both ecological and spatial factors. Similar behaviors have been observed in spatially structured cell populations, such as those found in cancerous tumors and bacterial biofilms. In these scenarios, novel organisms may be the introduction of a new mutation or bacterial species with some form of drug resistance, leading to the possibility of treatment failure. In order to gain insight into the relationship between population density and ecological interactions, we study an expanding population of interacting wild-type cells and mutant cells. We simulate these interactions in time and study the spatially dependent probability for a mutant to survive or to take over the front of the population wave (gene surfing). Additionally, we develop a mathematical model that describes this survival probability and find agreement when the payoff for the mutant is positive (corresponding to cooperation, exploitation, or commensalism). By knowing the types of interactions, our model provides insight into the spatial distribution of survival probability. Conversely, given a spatial distribution of survival probabilities, our model provides insight into the types of interactions that were involved to generate it.
Inflammatory reactivity is unrelated to childhood adversity or provoked modulation of nociception
Authors: Bedwell Gillian J , Mqadi Luyanduthando , Kamerman Peter , Hutchinson Mark R , Parker Romy , Madden Victoria J
Published: December 2024

Adversity in childhood is robustly associated with persistent pain in adulthood. Neuro-immune interactions are a candidate mechanistic link between childhood adversity and persistent pain, given that both childhood adversity and persistent pain are associated with neural and immune upregulation in adulthood. As such, we aimed to clarify whether immune reactivity is associated with provoked differences in nociceptive processing in humans. Pain-free adults (n=96; 61 female; median (range) age: 23 (18-65) years old) with a history of mild to severe childhood adversity underwent psychophysical assessments before and afterin vivoneural provocation (high-frequency electrical stimulation) and then, separately,in vivoimmune provocation (influenza vaccine administration). Psychophysical assessments included the surface area of secondary hyperalgesia after neural provocation and change in conditioned pain modulation (test stimulus: pressure pain threshold; conditioning stimulus: cold water immersion) after immune provocation. Immune reactivity was assessed as IL-6 and TNF-α expression afterin vitrolipopolysaccharide provocation of whole blood. We hypothesised associations between immune reactivity and (1) childhood adversity, (2) induced secondary hyperalgesia, and (3) vaccine-associated change in conditioned pain modulation. We found that provoked expression of pro-inflammatory cytokines was not statistically associated with childhood adversity, induced secondary hyperalgesia, or vaccine-associated change in conditioned pain modulation. The current findings from a heterogenous sample cast doubt on two prominent ideas: that childhood adversity primes the inflammatory system for hyper-responsiveness in adulthood and that nociceptive reactivity is linked to inflammatory reactivity. This calls for the broader inclusion of heterogeneous samples in fundamental research to unpack the psychoneuroimmunological mechanisms underlying vulnerability to persistent pain.
Analyzing the determinants for using health research evidence in health planning in Tanzania: a cross-sectional study
Authors: Kagoma Pius , Mongi Richard , Kalolo Albino
Published: December 2024

Introduction

Achieving Universal Health Coverage (UHC) requires utilizing research evidence to inform the decision-making process. However, little information is available on the determinants for using research evidence in planning in Lower Middle-Income Countries (LMICs), including Tanzania. This paper aims to investigate the determinants of using health research evidence in health planning in Tanzania.

Materials and methods

This study employed a cross-sectional study design. Data on health research evidence and its determinants were collected using a structured questionnaire from 422 respondents from 9 regions of Tanzania from October to December 2023. The data were analyzed using STATA version 18 for descriptive and inferential statistics. The association between variables was determined using a chi-square test at a 95% confidence level.

Results

The study revealed that 66.2% of participants strongly agreed to use health research evidence during planning. However, significant barriers were identified, including lack of dissemination (74.5%), inadequate human and non-human resources (70.0%), and insufficient knowledge and training in research (63.7%). A chi-square test confirmed significant associations between these barriers and the reduced use of research evidence (p<0.05). Conversely, more than 70% of respondents identified opportunities such as the availability of research coordinators, university partnerships, available research budgets, and internet access, all significantly associated with increased health research evidence use. More than 50% of participants reported motivational factors that like continuous quality improvement agenda in the healthcare sector, availability of short and long-term courses, on-the-job training, and provision of incentives like extra duty allowances were positively linked to research utilization.

Conclusion

The study found that 66.2% of participants used health research evidence in planning, but barriers like lack of dissemination, resource shortages, and inadequate training persisted. Interventions should focus on improving dissemination, resources, and training. Future research should explore strategies for enhancing these interventions.
Digitisation and linkage of PDF formatted 12-lead ECGs in Adult Congenital Heart Disease
Authors: Alkan Muhammet , Deligianni Fani , Anagnostopoulos Christos , Zakariyya Idris , Veldtman Gruschen
Published: December 2024

BACKGROUND

12-lead ECG’s form an essential part of the late follow-up of adults with congenital heart disease (ACHD). Such ECGs are most frequently reviewed by clinicians in paper or PDF formats. These visual representations of the original vector data do not easily lend themselves to be directly analysed with the increasingly powerful Machine Learning algorithms that hold promise in risk prediction and early prevention of adverse events.

OBJECTIVES

In this work, we set out to recreate the original digital signals from ECG PDF documents by a series of data processing steps, validate accuracy of the process, and demonstrate its potential utility in research.

METHODS

Using 4153 ECG PDF documents from 436 ACHD patients, we created a “pipeline” to successfully digitise the visually represented ECG vector datasets. We then proceed with the validation of the digitised ECG dataset using several features that are also calculated by the vendor, such as QRS duration, PR interval and ventricular rate, on all the patients.

RESULTS

We confirmed a strong correlation with the vendor measured ECG parameters including PR interval (R= 0.941,P< 0.05), QRS duration (R= 0.949,P< 0.05) and ventricular rate (R= 0.971,P< 0.05). Further, using Support Vector Machine (SVM), a well-established Machine Learning (ML) model we demonstrate the ability of the digitised ECG dataset to accurately predict anatomic diagnosis in ACHD.

CONCLUSIONS

Digitisation of PDF formatted ECG signal data can be accomplished with good accuracy and can be used in clinical research in ACHD.
Proteomic Sensors for Quantitative, Multiplexed and Spatial Monitoring of Kinase Signaling
Authors: Comstock William J , Navarro Marcos VAS , Maybee Deanna V , Rho Yiseo , Wagner Mateusz , Wang Yingzheng , Smolka Marcus B
Published: December 2024

Understanding kinase action requires precise quantitative measurements of their activityin vivo. In addition, the ability to capture spatial information of kinase activity is crucial to deconvolute complex signaling networks, interrogate multifaceted kinase actions, and assess drug effects or genetic perturbations. Here we developed a proteomic kinase activity sensor platform (ProKAS) for the analysis of kinase signaling using mass spectrometry. ProKAS is based on a tandem array of peptide sensors with amino acid barcodes that allow multiplexed analysis for spatial, kinetic, and screening applications. We engineered a ProKAS module to simultaneously monitor the activities of the DNA damage response kinases ATR, ATM, and CHK1 in response to genotoxic drugs, while also uncovering differences between these signaling responses in the nucleus, cytosol, and replication factories. Furthermore, we developed anin silicoapproach for the rational design of specific substrate peptides expandable to other kinases. Overall, ProKAS is a novel versatile system for systematically and spatially probing kinase action in cells.
Statistical Analysis Plan for the Optimal Post rTpa-Iv Monitoring in Ischemic Stroke Trial (OPTIMIST)
Authors: Billot Laurent , Bompoint Severine , Ouyang Menglu , Xu Lizheng , Wang Xia , Malavera Alejandra , Johnson Brenda , Summers Debbie , Khatri Pooja , Muñoz-Venturelli Paula , Day Diana , Sui Yi , Song Lili , Wan Zaidi Wan Asyraf , Huy Thang Nguyen , Delcourt Candice , Robinson Thompson , Jan Stephen , Lindley Richard I , Urrutia Victor C , Anderson Craig S
Published: December 2024

1

The OPTIMIST trial aims to determine whether low-intensity monitoring is at least as effective (“non-inferior”) to standard monitoring, on the functional recovery of patients who have received recombinant tissue plasminogen activator or equivalent lytic reperfusion treatment for acute ischaemic stroke. It is designed as an international, multicenter, stepped-wedge (4 periods/3 steps) cluster randomized trial. This statistical analysis plan pre-specifies the method of analysis for every outcome and key variable collected in the trial.

The primary outcome is an “unfavourable outcome” at Day 90, defined as a score of 2 to 6 on the modified Rankin scale. The primary analysis will consist in a log-binomial regression adjusted for the effect of time and for clustering by site using a random effect. The non-inferiority margin was pre-specified as a relative risk of 1.15 for a bad outcome; thus, non-inferiority will be declared if the upper bound of the 95% confidence interval around the relative risk is lower than 1.15.

The primary analysis will adjust for calendar time (6-month intervals) and will be based on imputed data. The analysis plan also includes planned sensitivity analyses including covariate adjustments and subgroup analyses.

2

Administrative information

2.1

Study identifiers

Protocol Number: GI-AU-NMH-2019-CA Version: 3.0, Date: 3 March 2021

ClinicalTrials.gov register Identifier:NCT03734640

Australian New Zealand Clinical Trial Registry: ACTRN 12619001556134

2.2

Revision history

2.3

Contributors to the statistical analysis plan

LB – Main author; developed the initial draft and prepared subsequent versions. SB - Prepared initial draft and reviewed subsequent versions. MO, CA - Reviewed every draft and approved final version. LX - Prepared economic analysis section and approved final version. SJ - Comments on economic analysis plan; approved final draft. XW, AM, BJ, DS, PK, PM-V, DD, YS, LS, WAWZ, NHT, CD, TR, RIL - Approved final draft.
Machine learning models for predicting medium-term heart failure prognosis: Discrimination and calibration analysis
Authors: Nishino Takuya , Kato Katsuhito , Tara Shuhei , Hayashi Daisuke , Seki Tomohisa , Takiguchi Toru , Kubota Yoshiaki , Yamamoto Takeshi , Maruyama Mitsunori , Kodani Eitaro , Kobayashi Nobuaki , Shirakabe Akihiro , Otsuka Toshiaki , Yokobori Shoji , Kondo Yukihiro , Asai Kuniya
Published: December 2024

Background

The number of patients with heart failure (HF) is increasing with an aging population, shifting care from hospitals to clinics. Predicting medium-term prognosis after discharge can improve clinical care and reduce readmissions; however, no established model has been evaluated with both discrimination and calibration.

Objectives

This study aimed to develop and assess the feasibility of machine learning (ML) models in predicting the medium-term prognosis of patients with HF.

Methods

This study included 4,904 patients with HF admitted to four affiliated hospitals at Nippon Medical School (2018–2023). Four ML models—logistic regression, random forests, extreme gradient boosting, and light gradient boosting—were developed to predict the endpoints of death or emergency hospitalization within 180 days of discharge. The patients were randomly divided into training and validation sets (8:2), and the ML models were trained on the training dataset and evaluated using the validation dataset.

Results

All models demonstrated acceptable performance as assessed by the area under the precision-recall curve. The models showed favorable agreement between the predicted and observed outcomes in the calibration evaluations with the calibration slope and Brier score. Successful risk stratification of medium-term outcomes was achieved for individual patients with HF. The SHapley Additive exPlanations algorithm identified nursing care needs as a significant predictor alongside established laboratory values for HF prognosis.

Conclusions

ML models effectively predict the 180-day prognosis of patients with HF, and the influence of nursing care needs underscores the importance of multidisciplinary collaboration in HF care.

Clinical Trial Registration

URL:https://www.umin.ac.jp/ctr; unique identifier: UMIN000054854
Transposable elements drive regulatory and functional innovation of F-box genes
Authors: Almeida Miguel Vasconcelos , Li Zixin , Rebelo-Guiomar Pedro , Dallaire Alexandra , Fiedler Lukáš , Price Jonathan L. , Sluka Jan , Liu Xiaodan , Butter Falk , Rödelsperger Christian , Miska Eric A.
Published: December 2024

Protein domains of transposable elements (TEs) and viruses increase the protein diversity of host genomes by recombining with other protein domains. By screening 10 million eukaryotic proteins, we identified several domains that define multi-copy gene families and frequently co-occur with TE/viral domains. Among these, a Tc1/Mariner transposase helix-turn-helix (HTH) domain was captured by F-box genes in theCaenorhabditisgenus, creating a new class of F-box genes. For specific members of this class, likefbxa-215, we found that the HTH domain is required for diverse processes including germ granule localisation, fertility, and thermotolerance. Furthermore, we provide evidence that HSF-1 mediates the transcriptional integration offbxa-215into the heat-shock response by binding to Helitron TEs directly upstream of thefbxa-215locus. The interactome of HTH-bearing F-box factors suggests roles in post-translational regulation and proteostasis, consistent with established functions of F-box proteins. Based on AlphaFold2 multimer proteome-wide screens, we propose that the HTH domain may diversify the repertoire of protein substrates that F-box factors regulate post-translationally. We further demonstrate that F-box genes repeatedly and independently captured TE domains throughout eukaryotic evolution, and describe an additional instance in zebrafish. In conclusion, we identify recurrent TE domain captures by F-box genes in eukaryotes and provide insights into how these novel proteins are integrated within host gene regulatory networks.
Synaptic facilitation enhances the reliability and precision of high frequency neurotransmission
Authors: Bernal-Correa Ana Maria , Dagostin Andre , von Gersdorff Henrique , Kushmerick Christopher
Published: December 2024

The small and tortuous volume of synaptic clefts limits the diffusion of Ca2+ions during high frequency spiking. Extracellular Ca2+levels ([Ca2+]o) of 0.8 mM or lower have been measured or calculated for different synapses. Here, we recorded evoked postsynaptic potentials (EPSP) and action potentials (AP) from young adult male and female mouse auditory brainstem principal neurons to investigate the relationship between neurotransmission reliability, stimulation frequency and [Ca2+]o. In 0.8 mM [Ca2+]o, we observed AP failures during afferent fiber stimulation at 100 Hz. Surprisingly, AP failures, EPSP-AP latency and jitter were all greatly reduced when stimulation frequency was increased to 500 Hz. Analysis of the EPSP/AP waveform revealed marked facilitation at 500 Hz that was not present at 100 Hz. Raising [Ca2+]oto 1.2 mM or 2.0 mM reduced or eliminated facilitation and, in these conditions, stimulation at 500 Hz increased the number of AP failures. In 0.8 mM [Ca2+]o, afferent fiber stimulation over a broad range of frequencies from 10-1000 Hz produced three different types of spiking responses: Type I cells exhibited band-pass filtering, with best response at approximately 500 Hz, Type II cells exhibited low-pass filtering above 600 Hz, and Type III cells exhibited shallow band-pass filtering centered at approximately 300 Hz. To predict AP success or failure, we built a model based on three factors: size of the EPSP, membrane potential immediately prior to the synaptic event and the number of preceding failures. We conclude that synaptic facilitation can contribute positively to the maintenance of reliable and precise high frequency neurotransmission in the auditory brainstem.

Significance Statement

Facilitation of evoked postsynaptic currents is a common feature of synapses. The strength of facilitation and its role in reaching spike threshold depends on intrinsic properties of the synapse, stimulation frequency, and extracellular Ca2+concentration ([Ca2+]o). Physiological levels of [Ca2+]ocan vary from 0.8 to 1.2 mM depending on synaptic activity. In the mouse Medial Nucleus of the Trapezoid Body, synaptic facilitation is readily observable in slice experiments using relatively low (0.8 mM) [Ca2+]o, but is partially or completely obscured by short-term synaptic depression when [Ca2+]ois high (1.2 or 2.0 mM). Here we show that facilitation can rescue the reliability of high-frequency (500 Hz) action potential firing in low [Ca2+]o, resulting in band-pass filter transmission.
The physiological impact of an N-terminal Halo-tag on GIPR function in mice
Authors: Davies Iona , Manchanda Yusman , Sloop Kyle W , Bloom Stephen R , Tan Tricia MM , Tomas Alejandra , Jones Ben
Published: December 2024

Aims

G protein-coupled receptors (GPCRs) modified with self-labelling enzymatic tags (e.g. Halo, SNAP, CLIP) have enabled thein vitrostudy of receptor expression and trafficking. We developed aGiprHalo/Halomouse model to gain insights into endogenous glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signalling, an important modulator of glucose and appetite homeostasis.

Methods

GiprHalo/Halomice were generated through ES cell-based gene targeting and physiologically characterised via body weight, oral glucose tolerance test and intraperitoneal glucose tolerance test analysis. Live cell imaging was used to measure cAMP responses in dispersed pancreatic islets fromGiprWt/WtandGiprHalo/Halolittermates in response to GIP. cAMP accumulation and surface receptor expression were assessed in AD293 cells transiently transfected with mouse and human untagged GIPR and Halo-GIPR. Endogenous pancreatic islet expression of Halo-GIPR was determined by immunohistochemistry.

Results

GiprHalo/Halomice displayed comparable body weights and responses to oral glucose administration asGiprHalo/WtandGiprWt/Wtlittermates. However,GiprHalo/Halomice only responded to high dose human GIP during intraperitoneal glucose tolerance testing, and cAMP responses to GIP were impaired inGiprHalo/Haloislets. Despite unimpaired surface expression,in vitrocAMP responses were lessened in AD293 cells expressing Halo-GIPR compared to untagged GIPR. Anti-Halo staining in mouseGiprHalo/Wtpancreatic islets displayed detectable signal.

Conclusions

While theGiprHalo/Halomouse model could be used to study endogenous GIPR expression, due to reduced responses we advise against its use for endogenous GIPR trafficking and signalling. Our study highlights the importance of carefully phenotyping mouse models in which modifications to endogenous proteins have been introduced.
High-resolution imaging of organic and inorganic nanoparticles at nanometre-scale resolution by X-ray ensemble diffraction microscopy
Authors: Chen Ning-Jung , Yeh Chia-Hui , Cao Huai-Yu , Chen Nai-Chi , Chen Chun-Jung , Chen Chun-Yu , Tsai Yi-Wei , Lin Jhih-Min , Huang Yu-Shan , Hsiao Chien-Nan , Chen Chien-Chun
Published: December 2024

Coherent diffraction microscopy (CDM) is a robust direct imaging method due to its unique 2D/3D phase retrieval capacity. Nonetheless, its resolution faces limitations due to a diminished signal-to-noise ratio (SNR) in high-frequency regions. Addressing this challenge, X-ray ensemble diffraction microscopy (XEDM) emerges as a viable solution, ensuring an adequate SNR in high-frequency regions and effectively surmounting resolution constraints. In this article, two experiments were conducted to underscore XEDM's superior spatial resolution capabilities. These experiments employed 55 nm-sized silicon–gold nanoparticles (NPs) and 19 nm-sized nodavirus-like particles (NV-LPs) on the coherent X-ray scattering beamline of the Taiwan Photon Source. The core–shell density distribution of the silicon–gold NPs was successfully obtained with a radial resolution of 3.4 nm per pixel, while NV-LPs in solution were reconstructed at a radial resolution of 1.3 nm per pixel. The structural information was directly retrieved from the diffraction intensities without prior knowledge and was subsequently confirmed through transmission electron microscopy.
When audit confronts blockchain
Authors: Pimentel Erica , Boulianne Emilio , Spence Crawford
Published: December 2024

Purpose

Previous work has explored the ability of auditors to expand successfully into seemingly unrelated fields, referred to as new audit spaces. The present paper focuses on how auditors respond to challenges when entering a new audit field and devising strategies to sensemake and sensegive about those challenges.

Design/methodology/approach

This study builds on findings from 32 interviews with auditors and participant observation of interactions between auditors and blockchainers to understand how auditors approached a new audit space.

Findings

We find that when auditors enter a new audit space, they endeavour to impose a logic of auditability. First, they determine an acceptable knowledge basis for this target audit space by developing a codified set of rules to organize knowledge, then develop a codified set of practices to verify conformity to the auditor’s set of rules. Next, auditors engage in three strategic tactics to influence members of the target audit space: appealing to the financial benefits of adopting a logic of auditability; appealing to their credentials from established audit markets; and appealing to bona fides in the target audit space to establish credibility. We posit that these sensemaking and sensegiving strategies do not take hold in the blockchain space because auditors are approaching these activities from a different mental model than blockchain natives. Because auditors are unable to adopt the mental model of the blockchain space, they are unable to devise strategies to compellingly influence blockchain natives and secure a stronghold in this new audit space. We developed a model for sensemaking and sensegiving when auditors enter new audit spaces.

Originality/value

This paper challenges and contrasts prior accounts of the seemingly unending expansion of audit firms into new spaces. The study demonstrates that there are limitations to auditors’ abilities to transplant their verification skills in the blockchain field.