bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation of a Neonatal Hyperbilirubinemia Clinical Pathway in a Pediatric Emergency Department
Authors: Miller Collin R. , Haut Catherine , Zomorrodi Arezoo , Chara Karina , Wilson Janice
Published: November 2024

Background:

High volumes and competing priorities delay care initiation for neonatal hyperbilirubinemia within the pediatric emergency department (ED). Our freestanding children’s hospital developed a quality improvement project to implement a nurse-initiated neonatal hyperbilirubinemia clinical pathway (CP) intended to decrease treatment initiation and intravenous fluid (IVF) rates.

Methods:

A multidisciplinary team used the model for improvement to delineate and address key drivers of treatment delays. The team established a nurse-driven CP and enhanced the electronic health record to support and enforce new workflows, which included capillary specimen collection and phototherapy initiation before the first provider assessment. IVF criteria and laboratory evaluation were standardized. The primary aim was to decrease the time to initiation of phototherapy from a mean of 136 to 60 minutes after ED arrival for 6 months. The secondary aim was to decrease the proportion of patients obtaining IVF from 31% to 15% for the same time frame.

Results:

ED arrival to phototherapy initiation decreased from 136 to 49 minutes. The IVF rate decreased from 31% to 12%. ED length of stay decreased from 185 to 122 minutes. Hospital length of stay remained unchanged.

Conclusions:

A nurse-initiated CP for neonates with hyperbilirubinemia improved time-to-care initiation and ED throughput while decreasing unnecessary IVF administration.
Using Quality Improvement to Design and Evaluate an Outpatient Day Treatment Pathway for Pediatric Patients with Diabetes Mellitus Requiring Insulin Initiation
Authors: Azova Svetlana , Baskaran Charumathi , Einis Sara , Fortin Jennifer , Silva Marisa , Gorman Miriam , Ethier Benjamin , Nanavati Sonal , Sterns Olivia , Garvey Katharine , Rhodes Erinn T.
Published: November 2024

Introduction:

Education and management of children with new-onset or established diabetes mellitus (DM) requiring insulin initiation do not always require hospitalization. We developed a pathway for outpatient day treatment of select patients after initial evaluation in the emergency department (ED) at a pediatric, tertiary care academic medical center.

Methods:

A multidisciplinary team identified key initial eligibility criteria for outpatient day treatment for insulin initiation, including absence of diabetic ketoacidosis, age ≥3 years, and plasma beta-hydroxybutyrate (BOHB) <1 mmol/L. Electronic medical record reviews and surveys administered to endocrine providers determined exclusions or reasons for nonparticipation. Refinement of the pathway occurred through iterative plan-do-study-act cycles. Statistical process control evaluated the uptake among eligible patients.

Results:

We launched the pathway in September 2020. Of 534 patients presenting to the ED with new-onset or established DM requiring insulin initiation in the first 2.5 years, 198 were potentially eligible for day treatment. Of these, 65 children (33%) completed the pathway. One additional patient was hospitalized following Day 1 of education due to newly identified psychosocial stressors. The increase of BOHB cutoff to 1.5 mmol/L and the option of rapid-acting insulin bolus for borderline BOHB resulted in a significant shift in utilization from a mean of 24.4% to 41.1%. Persistent barriers to participation include limited appointment availability, weekend presentation, and patient/family concerns.

Conclusions:

Outpatient day treatment was successful for select pediatric patients with new-onset or established DM requiring insulin initiation. However, this approach necessitates flexible resources and supportive patient messaging.
Parrots live in smaller groups on islands
Authors: Beauchamp Guy
Published: November 2024

Species living on islands are predictably different from their mainland counterparts in morphology and behaviour, but the source of these differences is still debated. Islands, in particular, are characterized by depauperate predator communities. Relaxed predation pressure might explain why living in groups, a common anti-predator adaptation in animals, is considered less likely on islands. However, the empirical evidence for this effect is scant and alternative explanations have been overlooked. For instance, smaller groups might be more common because island species are less studied, because a more stable food supply associated with benign climate on islands favours territoriality, or because the population density is too low to allow the formation of larger groups. I examined the determinants of foraging group size in parrots, a large worldwide avian order with many island populations. Using a multivariable phylogenetic framework, I found that foraging group size was smaller on islands than on the continents controlling for ecological variables known to influence group size such as diet and body size. In addition, the island effect persisted after controlling for research effort, climate variables and population density, suggesting that impoverished predator communities are an important driver of group size on islands.
Modelling the age pattern of fertility: an individual-level approach
Authors: Ciganda Daniel , Todd Nicolas
Published: November 2024

Fitting statistical models to aggregate data is still the dominant approach in many demographic and biodemographic applications. Although these macro-level models have proven useful for a variety of tasks, they often have no demographic interpretation. Individual-level modelling, on the other hand, offers a deeper understanding of the mechanisms underlying observed patterns. Their parameters represent quantities in the real world, instead of pure mathematical abstractions. However, estimating these parameters using real-world data has remained a challenge. The approach we introduce in this article attempts to overcome this limitation. Using a likelihood-free inference technique, we show that it is possible to estimate the parameters of a simple but demographically interpretable individual-level model of the reproductive process by exclusively relying on the information contained in a set of age-specific fertility rates. By estimating individual-level models from widely available aggregate data, this approach can contribute to a better understanding of reproductive behaviour and its driving mechanisms, bridging the gap between individual-level and population-level processes. We illustrate our approach using data from three natural fertility populations.
Starmerella fangiana f.a. sp. nov., a new ascomycetous yeast species from Daqu-making environment and other sources
Authors: Wei Yu-Hua , Zhu Hai-Yan , Wen Zhang , Guo Liang-Chen , Bai Mei , Wang Di-Qiang , Huang Wei , Jiang Li-Li , Kajadpai Napapohn , Srisuk Nantana , Han Pei-Jie , Bai Feng-Yan
Published: November 2024

In the survey of yeast diversity in high-temperature Daqu, which is a fermentation starter for Chinese sauce-flavoured Baijiu, six yeast strains representing one novel species of the genus Starmerella were isolated from samples of Daqu and surrounding environments collected in Zunyi city, Guizhou Province, China. Phylogenetic analyses of the internal transcribed spacer (ITS) region and the D1/D2 domains of the large subunit rRNA gene indicate that these six strains are conspecific with three other strains isolated from flowers and duckweed collected in Samoa, India and Thailand. The representative strain QFC-8 of the new species differs from the closet species Starmerella caucasica resolved by the D1/D2 sequence analysis by 13 (3.1 %, 12 substitutions and 1 gap) and 40 (10.3 %, 9 substitutions and 31 gaps) mismatches in the D1/D2 domain and ITS region, respectively. The results suggest that the novel group represents an undescribed species in the genus Starmerella, for which the name Starmerella fangiana sp. nov. is proposed. The holotype strain is CGMCC 2.7773.
Diverse microviruses circulating in invertebrates within a lake ecosystem
Authors: Lund Michael C. , Hopkins Andrew , Dayaram Anisha , Galatowitsch Mark L. , Stainton Daisy , Harding Jon S. , Lefeuvre Pierre , Zhu Qiyun , Kraberger Simona , Varsani Arvind
Published: November 2024

Microviruses are single-stranded DNA bacteriophages and members of the highly diverse viral family Microviridae. Microviruses have a seemingly ubiquitous presence across animal gut microbiomes and other global environmental ecosystems. Most of the studies on microvirus diversity so far have been associated with vertebrate gut viromes. In this study, we investigate the less explored invertebrate microviruses in a freshwater ecosystem. We analysed microviruses from invertebrates in the Chironomidae, Gastropoda, Odonata, Sphaeriidae, Unionidae clades, as well as from water and benthic sediment sampled from a lake ecosystem in New Zealand. Using gene-sharing networks and an expanded framework of informal and proposed microvirus subfamilies, the 463 distinct microvirus genomes identified in this study were grouped as follows: 382 genomes in the Gokushovirinae subfamily and 47 in the Pichovirinae subfamily clade, 18 belonging to Group D, 3 belonging to the proposed Alpavirinae subfamily clade, 1 belonging to the proposed Occultatumvirinae/Tainavirinae subfamilies clade and 12 belonging to an undefined viral cluster VC 1. Inverse associations of microviruses were noted between environmental benthic sediment samples and the Odonata group, while ‘defended’ invertebrates in the Gastropoda, Sphaeriidae and Unionidae groups showed correlative associations in the principal coordinate analysis of unique microvirus genomes (each genome sharing <98% genome-wide pairwise identity with each other) across sample types. This study expands the known diversity of microviruses and highlights the diversity of these relatively poorly classified bacteriophages.
Uncovering the transcriptome-wide RNA modifications in Acinetobacter baumannii
Authors: Ten Kah Ern , Rahman Sadequr , Tan Hock Siew
Published: November 2024

Despite being a major human pathogen, limited studies have reported RNA modifications in Acinetobacter baumannii. These post-transcriptional modifications play crucial regulatory roles in bacteria and have also been shown to modulate bacterial virulence. Using nanopore sequencing, we characterized RNA modifications in a virulent A. baumannii strain (Ab-C98) under free-living (mid-exponential phase in vitro culture) and during an early stage of infection (3 h post-infection) in Galleria mellonella larvae. Analysis revealed that m5C methylations are essential for ribosome synthesis, while m6A and Ψ are involved in metabolic pathways and translation processes. Iron-chelating genes exbD (m5C and m6A) and feoB (m6A and Ψ) and RNA polymerase subunit rpoC (m6A and Ψ) were selectively modified during infection. This first transcriptome-wide study highlights the potential regulatory roles of m5C, m6A and Ψ modifications in A. baumannii during infection.
Increased CRTH2 Expression in Postural Orthostatic Tachycardia Syndrome
Authors: Achemdey Julian , Martin Jose Manuel , Abdallah Hala , Li Mian , Nava Victor E. , Abdallah Hasan
Published: November 2024

Purpose

The exact etiology of Postural Orthostatic Tachycardia Syndrome (POTS) is still unknown but is likely heterogeneous and multifaceted, involving autoimmune, neuropathic, hypovolemic, and hyperadrenergic pathways. Recently, more research has been devoted to understanding POTS’s underlying immune etiology. We investigated the potential association between elevated levels of prostaglandin chemoattractant receptors (CRTH2) expressed on T-cells and the clinical manifestations observed in patients with POTS.

Methods

We performed immunophenotyping using flow cytometry on 20 consecutive patients with POTS confirmed by tilt table testing and compared our findings with healthy controls.

Results

POTS patients demonstrated an increase in CRTH2 levels on (CD8+) T cells and CD8+/CD45RO+ T cells compared to controls.

Conclusions

CRTH2 is expressed significantly on TH2 and CD8+ cells in POTS patients compared with controls. Since CRTH2 mediates the action of mast cell degranulation mediators such as PGD2 on TH2 cells it results in the release of inflammatory cytokines and interleukins that cause vasodilation and cellular inflammation with capillary leak, leading to reduced effective intravascular volume and reduced venous return, which are known as potential mechanisms in the pathophysiology of POTS, we conclude that CRTH2 plays an important role in the pathophysiology of POTS.
Divergent effects of pathological α-synuclein truncations and mutations on phase separation
Authors: Ray Soumik , Chiodaroli Cecilia , Farzadfard Azad , Kunka Antonin , Schott Katharina Helga , Hertel Sophie , Mojtic Kristina , Klausen Louise Kjær , Galvagnion Céline , Buell Alexander K.
Published: November 2024

Phase separated condensates can accelerate α-synuclein (α-Syn) amyloid fibril formation implicated in Parkinson’s disease pathogenesis. The effects of pathological modifications, i.e., truncations and familial mutations on the thermodynamics, material properties, and the extent of amyloid aggregation within α-Syn condensates remain elusive. Here, we quantitatively demonstrate that terminal truncations significantly alter α-Syn phase separation, while familial mutations impart minimal effects. Spontaneous sol-gel phase transitions of the truncated α-Syn variants could give rise to amyloid fibrils almost instantly within condensates, suggesting similarities between molecular interactions driving both processes. Extending our study to model coacervate and condensate systems where α-Syn acts as a client, we find α-Syn can dissolve coacervates and form Pickering clusters on condensate surfaces—regulating their size. Additionally, the C-terminal region of α-Syn modulates nucleic acid sequestration within condensates. Together, our findings reveal diverse effects of α-Syn modifications on phase separation, both in pathological and physiological contexts.

GRAPHICAL ABSTRACT
Minimal protein list for chromatin replication-coupled symmetric histone recycling revealed throughin vitroreconstitution
Authors: Nagae Fritz , Endo Shizuko , Murayama Yasuto , Terakawa Tsuyoshi
Published: November 2024

Upon eukaryotic DNA replication, symmetric histone recycling from parental to daughter strands is vital for transmitting epigenetic information to the next generations. Recent genome-wide sequencing studies have identified several protein regions contributing to symmetric histone recycling in a cell. However, a minimal list of proteins for symmetric histone recycling remains unknown. Here, we successfully reconstituted histone recycling with ∼30 purified proteins and analyzed the products digested by Micrococcal nuclease with the newly developed pipeline called a Repli-pore-seq in which nanopore sequencing and deep-learning-based classification were combined. As a result, we confirmed that the histones were recycled symmetrically to the lagging and leading strands. The recycled histones form tetrasomes or hexasomes and are deposited on the DNA sequences energetically favorable for forming nucleosomes. We also observed the discordance of the recycled position between lagging and leading strands on the GC-rich DNA sequences. Among proteins dispensable for chromatin replication, the lagging-strand maturation factors, Fen1/Cdc9, were also dispensable for symmetric recycling. The removal of Pol δ disrupted the recycling symmetry, and that of Ctf4 or Csm3/Tof1 altered the recycling position. These findings provide critical insights into the molecular players and mechanisms underlying symmetric histone recycling.
A histomorphological atlas of resected mesothelioma discovered by self-supervised learning from 3446 whole-slide images
Authors: Seyedshahi Farzaneh , Rakovic Kai , Poulain Nicolas , Quiros Adalberto Claudio , Powley Ian R. , Richards Cathy , Uraiby Hussein , Klebe Sonja , Nakas Apostolos , Wilson Claire , Sereno Marco , Officer-Jones Leah , Ficken Catherine , Teodosio Ana , Ballantyne Fiona , Murphy Daniel , Yuan Ke , Le Quesne John
Published: November 2024

1

Mesothelioma is a highly lethal and poorly biologically understood disease which presents diagnostic challenges due to its morphological complexity. This study uses self-supervised AI (Artificial Intelligence) to map the histomorphological landscape of the disease. The resulting atlas consists of recurrent patterns identified from 3446 Hematoxylin and Eosin (H&E) stained images scanned from resected tumour slides. These patterns generate highly interpretable predictions, achieving state-of-the-art performance with 0.65 concordance index (c-index) for outcomes and 85% AUC in subtyping. Their clinical relevance is endorsed by comprehensive human pathological assessment. Furthermore, we characterise the molecular underpinnings of these diverse, meaningful, predictive patterns. Our approach both improves diagnosis and deepens our understanding of mesothelioma biology, highlighting the power of this self-learning method in clinical applications and scientific discovery.
MRI R2* captures inflammation in disconnected brain structures after stroke: a translational study
Authors: Koubiyr Ismail , Yamamoto Takayuki , Petit Laurent , Dubourdieu Nadège , Avignone Elena , Cozensa Elise , Galmiche Chloé , Fukutomi Hikaru , Sibon Igor , Dousset Vincent , de Schotten Michel Thiebaut , Panatier Aude , Tible Marion , Tourdias Thomas
Published: November 2024

Ischemic strokes disrupt brain networks, leading to remote effects in key regions like the thalamus, a critical hub for brain functions. However, non-invasive methods to quantify these remote consequences still need to be explored. This study aimed to demonstrate that MRI-derived R2* changes can capture iron accumulation linked with inflammation secondary to stroke-induced disconnection.

In order to link remote R2* changes to stroke-induced disconnection, we first conducted a secondary analysis of 156 prospectively included stroke patients who underwent MRI at baseline and 1-year follow-up. We mapped fibers disconnected by baseline infarcts to compare the R2* changes over 1 year according to the disconnectivity status in specific thalamic nuclei groups. We also identified the predictors of elevated R2* at 1 year in a multivariate context through linear regressions. In parallel, to understand the biological underpinning of the remote R2* changes, we set up a translational mouse model through photothrombotic induction of focal cortical infarcts or sham procedures in 110 C57BL/6J mice. We explored the mice through combinations ofin vivoMRI at 72h, 2-, 4-, and 8-weeks, histology, qPCR for gene expression, mass spectrometry for iron concentration quantification, and additionalex vivohigh-resolution diffusion tensor imaging.

In stroke patients, we found a significant increase of R2* within severely disconnected medial and lateral thalamic nuclei groups from baseline to 1 year. At the same time, no change occurred if these structures were not disconnected. We also showed that the disconnectivity status at baseline was a significant predictor of R2* at follow-up, independently from confounders, establishing a direct and independent relationship between baseline disconnection and the subsequent R2* increase within the associated locations. In mice, we recapitulated the patients’ conditions by observing increased R2* in the stroke groups, specifically within the disconnected thalamic nuclei. Such remote and focal R2* changes peaked at 2 weeks, preceding and correlating with longer-term atrophy at 8 weeks. We established that the remote R2* increase was spatially and temporally correlated with a significant increase of chemically determined iron load bound to ferritin within activated microglial cells.

This study provides critical evidence that R2* is a sensitive marker of inflammation secondary to network disconnection, potentially informing future neuroprotective strategies targeting remote brain regions after stroke.
Detecting interspecific positive selection using convolutional neural networks
Authors: West Charlotte , Walker Conor R. , Arasti Shayesteh , Vasilev Viacheslav , Xu Xingze , De Maio Nicola , Goldman Nick
Published: November 2024

Traditional statistical methods using maximum likelihood and Bayesian inference can detect positive selection from an interspecific phylogeny and a codon sequence alignment based on model assumptions, but they are prone to false positives due to alignment errors and can lack power. These problems are particularly pronounced when faced with high levels of indels and divergence. Leveraging the feature-detection capabilities of convolutional neural networks (CNNs), we achieve higher accuracy in detecting selection across a specific range of phylogenetic scenarios and evolutionary modes. This advantage is particularly evident with noisy data prone to misalignments. Our method shows some ability to account for these errors, where most statistical frameworks fail to do so in a tractable manner. We explore generalisability and identify future avenues to achieve broader utility. Once trained, our CNN model is faster at test time, making it a scalable alternative to traditional statistical methods for large-scale, multi-gene analyses. In addition to binary classification (inference of the presence or absence of positive selection during the evolution of the sequences), we use saliency maps to understand what the model learns and observe how this could be leveraged for sitewise inference of positive selection.
Detritus identification in FlowCAM using a simple binary classifier
Authors: García-Oliva O.
Published: November 2024

Phytoplankton and detritus particles may be co-captured in Flow-CAM systems, leading to misrepresentation of phytoplankton abundance. In this study, I use logistic regression as a binary classifier to identify detritus particles in FlowCAM data from the Southern North Sea. Standard particle features from the manufacturer’s software were used as inputs, with surface texture (intensity variance) and compactness (derived from particle perimeter and area) proving most relevant to detritus classification. This classifier achieved 81% accuracy using a training dataset of approximately 7300 observations, reducing the workload compared to other classification methods. The reconstructed particle size spectra closely matched the observed spectra for detritus and phytoplankton. Binary classifiers like this offer a fast, effective alternative for detritus screening, aiding the pre-processing and re-analysis of FlowCAM datasets.
Ice gliding diatoms establish record-low temperature limit for motility in a eukaryotic cell
Authors: Zhang Qing , Leng Hope T. , Li Hongquan , Arrigo Kevin R. , Prakash Manu
Published: November 2024

Despite periods of permanent darkness and extensive ice coverage in polar environments, photosynthetic ice diatoms display a remarkable capability of living inside the ice matrix. How these organisms navigate such hostile conditions with limited light and extreme cold remains unknown. Using a custom sub-zero temperature microscope during an Arctic expedition, we present the discovery of motility at record-low temperatures in a Eukaryotic cell. By characterizing the gliding motility of several ice diatom species, collected from ice cores in the Chukchi Sea, we record that they retain motility at temperatures as low as –15 °C. Remarkably, ice diatoms can glide on ice substrates, a capability absent in temperate diatoms of the same genus. This unique ability arises from adaptations in extracellular mucilage that allow ice diatoms to adhere to ice, essential for gliding. Even on glass substrates where both cell types retain motility at freezing temperatures, ice diatoms move an order of magnitude faster, with their optimal motility shifting toward colder temperatures. Combining field and laboratory experiments with thermo-hydrodynamic modeling, we reveal adaptive strategies that enable gliding motility at extreme cold temperatures. These strategies involve increasing internal energy efficiency with minimal changes in heat capacity and activation enthalpy, and reducing external dissipation by minimizing the temperature sensitivity of mucilage viscosity. The discovery of diatoms’ ice gliding motility opens new routes for understanding their survival within a harsh ecological niche and their migratory responses to rapid environmental changes. Our work highlights the robust adaptability of ice diatoms in one of Earth’s most extreme settings.
The impact of vaccination on preventing long COVID in the Omicron era: a systematic review and meta-analysis
Authors: Green Rhiannon , Marjenberg Zoe , Lip Gregory Y. H. , Banerjee Amitava , Wisnivesky Juan , Delaney Brendan C. , Peluso Michael J. , Wynberg Elke , Abduljawad Sultan
Published: November 2024

Millions worldwide are living with long COVID. Since therapeutic research is ongoing, long COVID prevention is a pragmatic public health strategy. While prior analyses have shown the benefit of primary vaccination, the effect of booster vaccination on preventing long COVID caused by an Omicron infection has not been fully investigated. This systematic review identified 31 observational studies, among which 11 were deemed suitable for pairwise meta-analyses. Herein, the pooled risk of long COVID was 22–29% (P<0.0001 andP<0.0001, respectively) lower for vaccinated (any vaccination) populations versus unvaccinated (10 studies); 19% (P<0.0001) lower for primary course vaccination versus no vaccination (3 studies); 26% (P<0.0001) lower for booster vaccination versus no vaccination (4 studies) and 23% (P=0.0044) lower for booster vaccination versus primary course vaccination (3 studies). These findings indicate that booster vaccination can provide additional protection against long COVID; thereby, highlighting the importance of seasonal vaccination against new SARS-CoV-2 variants.
ANTIMICROBIAL SUSCEPTIBILITY PATTERNS OF BACTERIAL PATHOGENS IN ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN PATIENTS AT A TERTIARY CARE FACILITY
Authors: Dahal Susma , Thapa Renuka , Gurung Puja , Chaudhary Abinas , Dhakal Dinesh , Shrestha Upendra Thapa , Chaudhary Raina , Acharya Amrit
Published: November 2024

Objectives

The study was aimed to determine the predominant bacteria causing Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) infection in patients and their antibiotics sensitivity pattern in tertiary care setup.

Methods

This descriptive Cross-sectional study was conducted from September 27th2023 to December 26th2023 at Shree Birendra Hospital, chhauni, Kathmandu. Sputum samples that were received in the Microbiology laboratory from in patients for routine diagnosis were included in the study. The samples that were received was subjected to gram staining to assess the quality of the sputum sample, and those samples with good quality (mucoid and muco-purulent) was inoculated onto Blood agar, Chocolate agar and Mac Conkey agar for the isolation of the pathogens, and the media was incubated at 37 degrees Celsius overnight. Culture isolates were identified by standard technique(Cowan and Steel’s Manual for the Identification of Medical Bacteria, 1993) and Kirby-Bauer method was used to test antibiotic sensitivity of the pathogenic organisms following protocol of (Clinical and Laboratory Standards Institute, 2018) guidelines.

Results

Out of 273 sputum samples, 42/273 (15.4%) showed growth. Five different bacterial species were identified. Among the isolates,Acinetobacterspp. was the most common pathogen 21(44.7%) followed byPseudomonas aeruginosa11(23.4%),Klebsiella pneumoniae10(21.3%),Escherichia coli4(8.5%) andCitrobacter freundii 1(2.1%). Highest number of AECOPD cases were observed in female 157(57.9%) with 25(15.9%) positivity and highest number of organisms were isolated in age group 56-70(17) and least in age group 40-55(3).

All theAcinetobacterspp. (n=21) isolates were resistant to all tested medicine. Almost 90.90%Pseudomonas aeruginosa(n=11) were sensitive to Gentamycin and 81.82% to Meropenem, 70%Klebsiella pneumoniae(n=10) were sensitive to Gentamycin, 75%Escherichia coli(n=4) and 100 %Citrobacter freundii(n=1) to Amikacin. 100% (n=47) isolates were resistant to antibiotic penicillin and 100%Escherichia coli and Citrobacter freundii were resistance toCeftriazone and Cefepime while 100% (n=47) were found to be multi-drug resistant.

Conclusion

AcinetobactersppP. aeruginosa, Klebsiella pneumoniae, andEscherichia coliwere the most common bacterial isolates in the current investigation, which revealed a 15.4 % of culture positive. There is a high rate of MDR pattern in all isolated isolates. To further enhance treatment quality and prevent antibiotic resistance, regular surveillance of the etiologies of AECOPD and their pattern of antimicrobial susceptibility is crucial.
Detection of hypertrophic cardiomyopathy on electrocardiogram using artificial intelligence
Authors: Hillis James M , Bizzo Bernardo C , Mercaldo Sarah F , Ghatak Ankita , MacDonald Ashley L , Halle Madeleine A , Schultz Alexander S , L’Italien Eric , Tam Victor , Bart Nicole K , Moura Filipe A , Awad Amine M , Bargiela David , Dagen Sarajune , Toland Danielle , Blood Alexander J , Gross David A , Jering Karola S , Lopes Mathew S , Marston Nicholas A , Nauffal Victor D , Dreyer Keith J , Scirica Benjamin M , Ho Carolyn Y
Published: November 2024

Background

Hypertrophic cardiomyopathy (HCM) is associated with significant morbidity and mortality including sudden cardiac death in the young. Its prevalence is estimated to be 1 in 500, although many people are undiagnosed. The ability to screen electrocardiograms (ECGs) for its presence could improve detection and enable earlier diagnosis.

Objectives

This study evaluated the accuracy of an artificial intelligence device (Viz HCM) in detecting HCM based on 12-lead ECG.

Methods

The device was previously trained using deep learning and provides a binary outcome (HCM suspected or not suspected). This study included 293 HCM-Positive and 2912 HCM-Negative cases, which were selected from three hospitals based on chart review incorporating billing diagnostic codes, cardiac imaging, and ECG features. The device produced an output for 291 (99.3%) HCM-Positive and 2905 (99.8%) HCM-Negative cases.

Results

The device identified HCM with sensitivity 68.4% (95% CI: 62.8-73.5%), specificity 99.1% (95% CI: 98.7-99.4%) and area under the curve 0.975 (95% CI: 0.965-0.982). With assumed population prevalence of 0.002 (1 in 500), the positive predictive value was 13.7% (95% CI: 10.1-19.9%) and the negative predictive value was 99.9% (95% CI: 99.9-99.9%). The device demonstrated consistent performance across demographic and technical subgroups.

Conclusions

The device identified HCM based on 12-lead ECG with good performance. Coupled with clinical expertise, it has the potential to augment HCM detection and diagnosis.
Multi-ancestry GWAS of severe pregnancy nausea and vomiting identifies risk loci associated with appetite, insulin signaling, and brain plasticity
Authors: Fejzo Marlena , Wang Xinran , Zöllner Julia , Pujol-Gualdo Natàlia , Laisk Triin ,   Estonian Biobank Research Team, Finer Sarah , van Heel David A. ,   Genes & Health Research Team, Brumpton Ben , Bhatta Laxmi , Hveem Kristian , Jasper Elizabeth A. , Velez Edwards Digna R. , Hellwege Jacklyn N. , Edwards Todd , Jarvik Gail P. , Luo Yuan , Khan Atlas , MacGibbon Kimber , Gao Yuan , Ge Gaoxiang , Averbukh Inna , Soon Erin , Angelo Michael , Magnus Per , Johansson Stefan , Njølstad Pål R. , Vaudel Marc , Shu Chang , Mancuso Nicholas
Published: November 2024

While most pregnancies are affected by nausea and vomiting, hyperemesis gravidarum (HG) is at the severe end of the clinical spectrum and is associated with dehydration, undernutrition, and adverse maternal, fetal, and child outcomes. Herein we performed a multi-ancestry genome-wide association study (GWAS) of severe nausea and vomiting of pregnancy of 10,974 cases and 461,461 controls across European, Asian, African, and Latino ancestries. We identified ten significantly associated loci, of which six were novel (SLITRK1,SYN3,IGSF11,FSHB,TCF7L2, andCDH9),and confirmed previous genome-wide significant associations with risk genesGDF15,IGFBP7,PGR, andGFRAL. In a spatiotemporal analysis of placental development,GDF15andTCF7L2were expressed primarily in extra villous trophoblast, and using a weighted linear model of maternal, paternal, and fetal effects, we confirmed opposing effects forGDF15between maternal and fetal genotype. Conversely,IGFBP7andPGRwere primarily expressed in developing maternal spiral arteries during placentation, with effects limited to the maternal genome. Risk loci were found to be under significant evolutionary selection, with the strongest effects on nausea and vomiting mid-pregnancy. Selected loci were associated with abnormal pregnancy weight gain, pregnancy duration, birth weight, head circumference, and pre-eclampsia. Potential roles for candidate genes in appetite, insulin signaling, and brain plasticity provide new pathways to explore etiological mechanisms and novel therapeutic avenues.
First Detection of Xylazine in Texas Wastewater and Its Association with Fentanyl Use
Authors: Joseph Katherine M. , Parikh Dhvani , Xuan Qin , Li Feng , Balliew John , Mena Kristina D. , Wu Fuqing
Published: November 2024

The United States is dealing with the drug overdose crisis that has intensified over the past decade and compounded by the emergence of new threats particularly xylazine, a veterinary sedative increasingly found in illicit drug supplies. This study investigates the prevalence of xylazine in El Paso, Texas, a U.S.-Mexico border city where its impact remains poorly understood. We employed wastewater analysis to detect xylazine and examine its potential correlation with fentanyl use over a 14-month period (June 2023 to July 2024). Our results show that xylazine was detected in wastewater samples from three of the four treatment plants serving the city. The prevalence of xylazine was heterogeneous, with the highest detection rate of 29% observed in one sewershed. All samples on xylazine-positive days also tested positive for norfentanyl, a fentanyl metabolite, demonstrating the widespread fentanyl consumption. Notably, sewersheds with higher xylazine detection exhibited significantly higher fentanyl loads, suggesting a community-level association between the two substances use. This study provides the first evidence of xylazine in Texas wastewater and highlights the urgent need for enhanced monitoring and targeted public health interventions to mitigate the growing threat of xylazine, particularly in border communities affected by the opioid crisis.
The osteoarthritis associated sphingolipid sphingomyelin 34:1 causes inflammatory pain in mice
Authors: Rickman Rebecca H. , Pattison Luke A. , Qiu Lanhui , Dannawi Maya , Welsh Fraser , Smith Ewan St. John
Published: November 2024

Osteoarthritis (OA) is a condition affecting synovial joints that has a multifactorial pathogenesis and where pain is the main symptom driving clinical decision making. During OA, a plethora of mediators are released by infiltrating immune cells and resident cells, such fibroblast-like synoviocytes. Although the roles of certain OA-associated disease mediators are well-understood, there are a number of molecules that are dysregulated in OA for which no role has been identified. For example, in dogs and humans with OA, dysregulation of the synovial fluid lipidome occurs and some findings have been replicated by studying the plasma lipidome in a mouse model of osteoarthritis. One upregulated lipid is the sphingomyelin N-palmitoyl-D-erythro-sphingosylphosphorylcholine (d18:1/16:0), also known as SM(d34:1), referred to here as SM. This study investigated the ability of SM to cause joint pain and neuronal hyperexcitability in mice. Overnight incubation of sensory neurons with either SM or a structurally related ceramide produced a decrease in rheobase, i.e. hyperexcitability. By contrast, when injected into the knee joint of mice, SM, but not the related ceramide, evoked joint swelling, mechanical hyperalgesia and decreased digging behaviour. Moreover, when studying the excitability of retrograde traced, knee-innervating sensory neurons, only those isolated from SM-injected mice exhibited hyperexcitability. The results generated demonstrate that a dysregulated lipidome can contribute to inflammatory OA pain, further work being necessary to determine the mechanism by which SM exerts its activity.
Evaluation of gene expression-based predictors of lymph node metastasis in bladder cancer
Authors: Johansson Hafdís Birta , Liedberg Fredrik , Bernardo Carina , Zadoroznyj Aymeric , Höglund Mattias , Eriksson Pontus , Sjödahl Gottfrid
Published: November 2024

The presence of cancer in pelvic lymph nodes removed during radical surgery for muscle-invasive bladder cancer (MIBC) is a key determinant of patient outcome. It would be beneficial to predict node status preoperatively to individually tailor the use of neoadjuvant chemotherapy and extent of lymph node dissection. Several studies have published node status predictors based on RNA expression signatures in the primary tumor, but none have been successfully validated in subsequent reports.

We use gene expression data and node status from the two largest available MIBC cohorts to evaluate 12 published node-predictive signatures. Additionally, we examine the extent of overlap between differentially expressed genes and signatures across the two datasets, and we train new prediction models which we evaluate in cross-validation and by application to the independent cohort.

All published node status predictors performed either no better than chance or only slightly better than chance in two independent validation datasets (maximal AUC 0.59 and 0.65 and maximum balanced accuracy 0.54 and 0.57 in the two cohorts). Most differentially expressed genes and signatures were only identified in one dataset and only a few, such as upregulation of interferon-response in node negative cases, were enriched in the same direction in both datasets. Transcriptomic predictors trained in one dataset performed poorly when applied to the other independent dataset (AUC 0.60 and 0.62).

In this systematic evaluation, neither the 12 published signatures nor our own models reached an adequate performance for clinical node status prediction in independent data. This indicates that the biological determinants of nodal spread are poorly captured by bulk tumor RNA expression profiles.
Progressive chromosome shape changes quantified during cell divisions
Authors: Kakui Yasutaka , Kusano Yoshiharu , Clarence Tereza , Lopez Maya , Hirota Toru , Khatri Bhavin S. , Uhlmann Frank
Published: November 2024

Mitotic chromosomes give genome portions the required compaction and mechanical stability for faithful inheritance during cell divisions. Here, we record human chromosome dimensions from their appearance in prophase over successive times in a mitotic arrest. Chromosomes first appear long and uniformly thin. Then, individual chromosome arms become discernible, which continuously shorten and thicken - the longer a chromosome arm, the thicker it becomes. The observed chromosome arm length to width relationship can be described by a power law with progressively increasing exponent. In the search for a molecular explanation of this behavior, the popularloop extrusionmodel provides no obvious means by which longer arms become thicker. Instead, we find that simulations of an alternativeloop capturemodel recapitulate key features of our observations, including the gradually developing arm length to width relationship. Our analyses portray chromosomes as out-of-equilibrium structures in the process of transitioning towards, but on biologically relevant time scales not typically reaching, steady state.
Temporal expectations modulate coupling between frontal and sensory brain areas
Authors: Nagy Péter , Kovács Petra , Boncz Ádám , Szalárdy Orsolya , Baumgartner Robert , Ignatiadis Karolina , Winkler István , Tóth Brigitta
Published: November 2024

Temporal prediction is a crucial mechanism that allows the brain to optimize sensory processing by anticipating event timing. This predictive ability enhances processing efficiency by modulating brain activity through cortical oscillations that periodically influence neuronal excitability. For example, stimuli with predictable timing are processed more accurately. Although it is well-established that predictions are generated across large-scale brain networks, the roles of different cortical regions, particularly the frontal cortices and sensory areas, remain debated. In this study, we investigated the role of frontal cortices in temporal prediction during auditory perception. Cue tones predicted the timing of auditory targets with different levels of certainty (50%, 80%). We recorded electroencephalographic data (EEG) while participants detected the targets. Functional connectivity analyses revealed that the level of predictability modulates the relative contributions of frontal and auditory cortices during both the anticipation and detection of targets: as the certainty of predictions grows, the involvement of frontal brain regions increases. Our findings suggest that the auditory temporal prediction network relies on an integrated system of frontal and sensory regions, which are sensitive to the level of predictability.
Compulsion derived from incentive cocaine-seeking habits is associated with a downregulation of the dopamine transporter in striatal astrocytes
Authors: Fouyssac Maxime , Hynes Tristan , Belin-Rauscent Aude , Joshi Dhaval D. , Belin David
Published: November 2024

The development of compulsive cue-controlled -incentive- drug-seeking habits, a hallmark of substance use disorder, is predicated on an intrastriatal shift in the locus of control over behaviour from a nucleus accumbens (Nac) core - dorsomedial striatum network to a Nac core - anterior dorsolateral striatum (aDLS) network. Such shift parallels striatal adaptations to chronic drug, including cocaine self-administration, marked by dopamine transporter (DAT) alterations originating in the ventral striatum that spread eventually to encompass the aDLS. Having recently shown that heroin self-administration results in a pan-striatal reduction in astrocytic DAT that precedes the development of aDLS dopamine-dependent incentive heroin-seeking habits we tested the hypothesis that similar adaptations occurr following cocaine exposure. We compared DAT protein levels in whole tissue homogenates, and astrocytes cultured from ventral and dorsal striatal territories of drug naïve male Sprague Dawley rats to those of rats with a history of cocaine-taking or an aDLS dopamine-dependent incentive cocaine-seeking habit. Cocaine exposure resulted in a decrease in whole tissue and astrocytic DAT across all territories of the striatum. We further demonstrated that compulsive, i.e., punishment-resistant, incentive cocaine-seeking habits were associated with a reduction in DAT mRNA levels in the Nac shell, but not the Nac core-aDLS incentive habit system. Together with the recent evidence of heroin-induced downregulation of striatal astrocytic DAT, these findings suggest that alterations in astrocytic DAT may represent a common mechanism underlying the development of compulsive incentive drug-seeking habits across drug classes.
In vivo CRISPR screens identify key modifiers of CAR T cell function in myeloma
Authors: Korell Felix , Knudsen Nelson H. , Kienka Tamina , Escobar Giulia , Nobrega Celeste , Anderson Seth , Cheng Andrew Y. , Zschummel Maria , Bouffard Amanda , Kann Michael C. , Goncalves Sadie , Pope Hans W. , Pezeshki Mitra , Rojas Alexander , Suermondt Juliette S. M. T. , Phillips Merle , Berger Trisha R. , Park Sangwoo , Salas-Benito Diego , Darnell Elijah P. , Birocchi Filippo , Leick Mark B. , Larson Rebecca C. , Doench John G. , Sen Debattama , Yates Kathleen B. , Manguso Robert T. , Maus Marcela V.
Published: November 2024

Chimeric antigen receptor (CAR) T cells are highly effective in hematologic malignancies. However, loss of CAR T cells can contribute to relapse in a significant number of patients. These limitations could potentially be overcome by targeted gene editing to increase CAR T cell persistence. Here, we performedin vivoloss-of-function CRISPR screens in BCMA-targeting CAR T cells to investigate genes that influence CAR T cell persistence, function and efficacy in a human multiple myeloma model. We tracked the expansion and persistence of CRISPR-library edited T cellsin vitroand then at early and late timepointsin vivoto track the performance of gene modified CAR T cells from manufacturing to survival in tumors. The screens revealed several context-specific regulators of CAR T cell expansion and persistence. Ablation ofRASA2andSOCS1enhanced T cell expansionin vitro, while loss ofPTPN2,ZC3H12A, andRC3H1conferred early selective growth advantages to CAR T cellsin vivo. Strikingly, we identified cyclin-dependent kinase inhibitor 1B (CDKN1B), a cell cycle regulator, as the most important factor limiting CAR T cell fitness at late timepointsin vivo.CDKN1Bablation increased BCMA CAR T cell proliferation and effector function in response to antigen, significantly enhancing tumor clearance and overall survival. Thus, our findings reveal differing effects of gene-perturbation on CAR T cells over time and in different selective environments, highlightCDKN1Bas a promising target to generate highly effective CAR T cells for multiple myeloma, and underscore the importance ofin vivoscreening as a tool for identifying genes to enhance CAR T cell function and efficacy.
The White Sea littoral oligochaeteLumbricillussp. as a model for annelid development studies
Authors: Matveicheva E.P. , Neretina T.V. , Ekimova I.A. , Konduktorova V.V. , Semenova M.L. , Nikishin D.A.
Published: November 2024

Oligochaetes play a significant role in aquatic ecosystems, and studying their development can contribute to a deeper understanding of the evolutionary features of embryonic development in the phylum Annelida. In this paper, we initially explored a littoral oligochaete species from the White Sea, which is abundant in the vicinity of the White Sea Biological Station MSU and reproduces in the early summer. A molecular phylogenetic analysis utilizing COI and 18S markers confirmed that the species under investigation belongs to the genusLumbricillus, family Enchytridae. The early stages of embryonic development were described in detail, and the timing of the onset of key stages was established. The specifics of the cellular patterns observed in the early embryo were elucidated using the fluorescence staining and confocal microscopy. The embryonic development ofLumbricillussp. exhibits characteristics that are consistent with the typical development of oligochaetes. Additionally, it displays specific characteristics that are typical of representatives of the Enchytriidae family, including equal size of the 2nd and 2D blastomeres and a small size of the 4D blastomere in comparison to the large 4D blastomere. The combination of synchrony and low developmental variability, coupled with the accessibility of the object, ease of maintenance and manipulation, makesLumbricillussp. a highly promising object for the study of embryonic development in Annelides.